* 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.
Reference：
[1] Bulletin of the Chemical Society of Japan, 1998, vol. 71, # 6, p. 1401 - 1407
4
[ 7589-27-7 ]
[ 332-42-3 ]
Yield
Reaction Conditions
Operation in experiment
92%
With N-Bromosuccinimide; triphenylphosphine In dichloromethane
Production Example 1 Synthesis of 4-fluorophenethyl bromide Triphenylphosphine (222 g) and N-bromosuccinimide (151 g) were added to a solution of 4-fluorophenethyl alcohol (100 g) in methylene chloride (1 l) under ice cooing, followed by stirring for 1 hr. After concentrating the resultant solution under reduced pressure, the precipitated crystals were filtered off and the filtrate was concentrated to give the title compound (133 g) as a colorless oil (yield: 92percent). 1H-NMR (400 MHz, CDCl3): δ(ppm) 3.14(2H, t, J=8Hz), 3.54(2H, t, J=8Hz), 6.98-7.03(2H, m), 7.15-7.18(2H, m).
78%
With phosphorus tribromide In hexane at 0℃; for 12 h;
Step 1: Preparation of 1-(2-bromoethyl)-4-fluorobenzene [Show Image] Phosphorus tribromide (19.3 g, 71.3 mmol) was added slowly into a solution of 2-(4-fluorophenyl)ethanol (5.0 g, 35.7 mmol) in hexane at 0 °C. After 12 hours under stirring, the reaction mixture was diluted with a 10percent aqueous solution of NaHCO3 and ethyl acetate. The organic layer was washed with water and brine, dried (Na2SO4) and concentrated under vacuum to give the title compound (5.7 g, 78 percent). TLC: ethylacetate/ Hexane (3/7): Rf: 0.85. 1H NMR (CDCl3, 400 MHz): δ 7.20-7.16 (m, 2H), 7.03-6.99 (m, 2H), 3.56 (t, J=7.40 Hz, 2H), 3.15 (t, J=7.44 Hz, 2H).
78%
With phosphorus tribromide In hexane at 0℃; for 12 h;
Step 1: Preparation of 1-(2-bromoethy -4-fluorobenzenePhosphorus tribromide (19.3 g, 71.3 mmol) was added slowly into a solution of 2-(4- fluorophenyl)ethanol (5.0 g, 35.7 mmol) in hexane at 0 'C. After 12 hours under stirring, the reaction mixture was diluted with a 10percent aqueous solution of NaHC03 and ethyl acetate. The organic layer was washed with water and brine, dried (Na2S04) and concentrated under vacuum to give the title compound (5.7 g, 78 percent). TLC: ethylacetate/ Hexane (3/7): R, : 0.85. 1H NMR (CDCI3, 400 MHz): δ 7.20-7.16 (m, 2H), 7.03-6.99 (m, 2H), 3.56 (t, J=7.40 Hz, 2H), 3.15 (t, J=7.44 Hz, 2H).
31%
With phosphorus tribromide In toluene at 0 - 20℃; for 120 h;
To a solution of 2-(4-fluorophenyl)ethyl alcohol (13.4 mL, 107 mmol) in dry toluene (150 mL) at 0°C was added phosphorous tribromide (21.1 mL, 224 mmol). The resulting mixture was stirred at ambient temperature for 5 days and then recooled to 0°C and crushed ice (200 g) added. The aqueous layer was extracted with ether (2 x 120 mL) and the combined organic extracts were then washed with saturated aqueous sodium bicarbonate solution (2 x 30 mL), dried (MgSO4) and concentrated in vacuum. Distillation afforded 2-(4-fluorophenyl)ethyl bromide as a colorless oil (14.08g, 31percent); b.p. 103°C (at) 12 mm Hg.
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 18, p. 7035 - 7044
[2] Tetrahedron Asymmetry, 2001, vol. 12, # 4, p. 585 - 596
[3] Patent: US2002/19531, 2002, A1,
[4] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 8, p. 2989 - 3002
[5] Patent: EP2508526, 2012, A1, . Location in patent: Page/Page column 48
[6] Patent: WO2012/130915, 2012, A1, . Location in patent: Page/Page column 59
[7] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 4, p. 495 - 500
[8] Patent: EP1734037, 2006, A2, . Location in patent: Page/Page column 70-71
[9] Journal of the American Chemical Society, 1941, vol. 63, p. 602,603
[10] Helvetica Chimica Acta, 1973, vol. 56, p. 2460 - 2479
[11] Tetrahedron Asymmetry, 1998, vol. 9, # 15, p. 2725 - 2737
[12] Helvetica Chimica Acta, 2004, vol. 87, # 3, p. 580 - 591
[13] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 18, p. 4752 - 4756
[14] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 4, p. 1515 - 1519
[15] Patent: WO2008/61688, 2008, A1, . Location in patent: Page/Page column 33
[16] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2282 - 2292
5
[ 7589-27-7 ]
[ 497-19-8 ]
[ 332-42-3 ]
Reference：
[1] Patent: US5677324, 1997, A,
6
[ 7589-27-7 ]
[ 7789-60-8 ]
[ 332-42-3 ]
Reference：
[1] Patent: US2002/151717, 2002, A1,
7
[ 405-50-5 ]
[ 332-42-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 18, p. 4752 - 4756
[2] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 4, p. 495 - 500
[3] Tetrahedron Asymmetry, 2001, vol. 12, # 4, p. 585 - 596
[4] Tetrahedron Asymmetry, 1998, vol. 9, # 15, p. 2725 - 2737
[5] Helvetica Chimica Acta, 1973, vol. 56, p. 2460 - 2479
[6] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2282 - 2292
8
[ 70931-33-8 ]
[ 70931-13-4 ]
[ 332-42-3 ]
Reference：
[1] Patent: US4243805, 1981, A,
9
[ 405-99-2 ]
[ 332-42-3 ]
[ 65130-46-3 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 24, p. 5622 - 5626
10
[ 352-13-6 ]
[ 332-42-3 ]
Reference：
[1] Journal of the American Chemical Society, 1941, vol. 63, p. 602,603
11
[ 6529-53-9 ]
[ 90867-08-6 ]
[ 332-42-3 ]
[ 90867-09-7 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1998, vol. 71, # 6, p. 1401 - 1407
12
[ 332-42-3 ]
[ 7116-38-3 ]
Reference：
[1] Green Chemistry, 2018, vol. 20, # 14, p. 3191 - 3196
13
[ 332-42-3 ]
[ 1583-88-6 ]
Reference：
[1] Journal of the American Chemical Society, 1941, vol. 63, p. 602,603
14
[ 332-42-3 ]
[ 74-89-5 ]
[ 459-28-9 ]
Reference：
[1] Journal of the American Chemical Society, 1941, vol. 63, p. 602,603
With N-Bromosuccinimide; triphenylphosphine; In dichloromethane;
Production Example 1 Synthesis of 4-fluorophenethyl bromide Triphenylphosphine (222 g) and N-bromosuccinimide (151 g) were added to a solution of 4-fluorophenethyl alcohol (100 g) in methylene chloride (1 l) under ice cooing, followed by stirring for 1 hr. After concentrating the resultant solution under reduced pressure, the precipitated crystals were filtered off and the filtrate was concentrated to give the title compound (133 g) as a colorless oil (yield: 92%). 1H-NMR (400 MHz, CDCl3): delta(ppm) 3.14(2H, t, J=8Hz), 3.54(2H, t, J=8Hz), 6.98-7.03(2H, m), 7.15-7.18(2H, m).
78%
With phosphorus tribromide; In hexane; at 0℃; for 12h;
Step 1: Preparation of 1-(2-bromoethyl)-4-fluorobenzene [Show Image] Phosphorus tribromide (19.3 g, 71.3 mmol) was added slowly into a solution of 2-(4-fluorophenyl)ethanol (5.0 g, 35.7 mmol) in hexane at 0 C. After 12 hours under stirring, the reaction mixture was diluted with a 10% aqueous solution of NaHCO3 and ethyl acetate. The organic layer was washed with water and brine, dried (Na2SO4) and concentrated under vacuum to give the title compound (5.7 g, 78 %). TLC: ethylacetate/ Hexane (3/7): Rf: 0.85. 1H NMR (CDCl3, 400 MHz): delta 7.20-7.16 (m, 2H), 7.03-6.99 (m, 2H), 3.56 (t, J=7.40 Hz, 2H), 3.15 (t, J=7.44 Hz, 2H).
78%
With phosphorus tribromide; In hexane; at 0℃; for 12h;
Step 1: Preparation of 1-(2-bromoethy -4-fluorobenzenePhosphorus tribromide (19.3 g, 71.3 mmol) was added slowly into a solution of 2-(4- fluorophenyl)ethanol (5.0 g, 35.7 mmol) in hexane at 0 'C. After 12 hours under stirring, the reaction mixture was diluted with a 10% aqueous solution of NaHC03 and ethyl acetate. The organic layer was washed with water and brine, dried (Na2S04) and concentrated under vacuum to give the title compound (5.7 g, 78 %). TLC: ethylacetate/ Hexane (3/7): R, : 0.85. 1H NMR (CDCI3, 400 MHz): delta 7.20-7.16 (m, 2H), 7.03-6.99 (m, 2H), 3.56 (t, J=7.40 Hz, 2H), 3.15 (t, J=7.44 Hz, 2H).
31%
With phosphorus tribromide; In toluene; at 0 - 20℃; for 120h;
To a solution of 2-(4-fluorophenyl)ethyl alcohol (13.4 mL, 107 mmol) in dry toluene (150 mL) at 0C was added phosphorous tribromide (21.1 mL, 224 mmol). The resulting mixture was stirred at ambient temperature for 5 days and then recooled to 0C and crushed ice (200 g) added. The aqueous layer was extracted with ether (2 x 120 mL) and the combined organic extracts were then washed with saturated aqueous sodium bicarbonate solution (2 x 30 mL), dried (MgSO4) and concentrated in vacuum. Distillation afforded 2-(4-fluorophenyl)ethyl bromide as a colorless oil (14.08g, 31%); b.p. 103C (at) 12 mm Hg.
With hydrogen bromide; In sulfuric acid; water; for 3h;Heating / reflux;
7c) 1 -(2-Bromoethyl)-4-fluorobenzene (Compound V: R3 = 4-F, R4 = H, m = 2, Q = Br). 60.8 g of 47% hydrobromic acid (0.353 mol) was added slowly to a solution of 2-(4-fluorophenyl)ethanol (20 g; 0.143 mol) in concentrated sulphuric acid (8.5 ml; 0.16 mol). The mixture was heated under reflux for 3 h, then it was cooled to room temperature and 50 ml of dichloromethane was added.The organic phase was separated and washed successively with 1 N NaOH and water and was then dried over Na2SO4. After filtration and evaporation of the solvent at reduced pressure, approx. 13 g of raw compound was obtained, which was purified by flash chromatography (n-hexane/ethyl acetate = 9/1). 10.6 g of 1 -(2-bromoethyl)-4- fluorobenzene was thus obtained.1H-NMR (delta, CDCI3): 3.13 (t, J = 9 Hz, 2H); 3.54 (t, J = 9 Hz, 2H); 6.9-7.3 (m, 4H)
4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid ethyl ester[ No CAS ]
[ 332-42-3 ]
2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With potassium carbonate; In dimethyl sulfoxide; at 90℃; for 16h;
A solution of 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxyiic acid ethyl ester (2.5 g, 10.54 mmol) in dimethyl sulfoxide (50 mL) was treated with 1 -(2-bromo-ethyl)-4- fluoro-benzene (2.10 g, 10.54 mmol) and potassium carbonate (4.30 g, 31.64 mmol), and the reaction mixture was heated to 90 0C for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with brine (2 x 100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography (hexanes:ethyl acetate,. : 1) to provide 2-{ l-[2-(4-fluoro- phenyl)-ethyl]-lH-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid ethyl ester (1.57 g, 45% yield) as a white solid. MS (M+eta)+ = 360; R1 = 1.65 min.
With potassium carbonate; In dimethyl sulfoxide; at 95℃; for 16h;
A solution of 3-iodo-5-methyl-lH-pyrazole (1.45 g, 6.97 mmol) in dimethyl sulfoxide (10 mL) was treated with l-(2-brorno-ethyl)-4-fiuoro-benzene (1.41 g, 6.97 mmol) and potassium carbonate (2.89g, 20.91 mmol), and the reaction mixture was heated to 95 0C for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL). and washed with brine (2 x 100 mL). The organic phase was dried (Na2SO.*) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (hexanes:ethyl acetate, 1 :1) to provide l-[2-(4-fluoro- phenyl)-ethyI]-3-iodo-5-methyl-l//-pyrazole as a yellow oil. MS (M+eta)+ = 331.
With potassium carbonate; sodium iodide; In DMF (N,N-dimethyl-formamide); at 60℃;
To a solution of 1-(2-bromo-ethyl)-4-fluoro-benzene (587 mg, 3.7 mmol) and pyrrolidine-2,5-dione (succinimide, 733.3 mg, 7.4 mmol) in dimethylformamide (15 ml) was added potassium carbonate (2.0 g, 14.8 mmol) and sodium iodide (277 mg, 1.9 mmol). The reaction mixture was warmed to 60 C and kept at 60 C overnight with stirring. The reaction mixture was cooled to room temperature and concentrated in vacuo. The concentrate was diluted with ethyl acetate and washed twice with a saturated sodium bicarbonate aqueous solution, twice with water, once with brine, and concentrated in vacuo. The residue was purified by silica gel chromatography (100% ethylacetate) to afford 1-[2-(4-fluoro-phenyl) -ethyl]-pyrrolidine-2,5-dione 309 (570 mg, 2.6 mmol, 70%) as a solid. 1H NMR (CDCl3) delta 7.14 (m, 2H), 6.94 (t, 2H), 3.68 (t, 2H), 2.84 (t, 2H), 2.63 (s, 4H).
70%
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 60℃;
To a solution of 1-(2-bromo-ethyl)-4-fluoro-benzene (587 mg, 3.7 mmol) and pyrrolidine-2,5-dione (succinimide, 733.3 mg, 7.4 mmol) in dimethylformamide (15 ml) was added potassium carbonate (2.0 g, 14.8 mmol) and sodium iodide (277 mg, 1.9 mmol). The reaction mixture was warmed to 60 C and kept at 60 C overnight with stirring. The reaction mixture was cooled to room temperature and concentrated in vacuo. The concentrate was diluted with ethyl acetate and washed twice with a saturated sodium bicarbonate aqueous solution, twice with water, once with brine, and concentrated in vacuo. The residue was purified by silica gel chromatography (100% ethylacetate) to afford 1-[2-(4-fluoro-phenyl)-ethyl]-pyrrolidine-2,5-dione 309 (570 mg, 2.6 mmol, 70%) as a solid. ¹H NMR (CDCl3) No. 7.14 (m, 2H), 6.94 (t, 2H), 3.68 (t, 2H), 2.84 (t, 2H), 2.63 (s, 4H).
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃;
To a mixture of 5-(1H-pyrazol-3-yl)-thiophene-2-carbonitrile [300mg, 1.72mmol, Reference Example 3 (b) ], potassium carbonate [(500MG,] 3. [6MMOL)] and [N, N-] [DIMETHYLFORMAMIDE] (4ml) was added 1- (2-bromoethyl)-4-fluoro-benzene (566mg, 3.4mmol). The resulting mixture was heated to [80C] and stirred overnight. The reaction mixture was then quenched in water and extracted with diethyl ether. The organic layer was dried (MgSO4), concentrated, and then subjected to flash column chromatography using a mixture of cyclohexane and ethyl acetate [(8] : 2, v/v) as eluent, to provide [5-{1-[2-(4-] [FLUORO-PHENYL !-ETHYL]-1 H-PVRAZOL-3-YL}-THIOPHENE-2-CARBONITRILE.]
2-(4-fluorophenethyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 70℃; for 6h;
A solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (40 mg, 0.11 mmol), prepared as described in Example 1,2-(4-fluorophenyl)ethyl bromide (22 mg), and K2CO3 (35 mg, 0.25 mmol) in DMF (1 ml), was heated at 70 C. for 6 hours. After this time, the reaction mixture was cool to RT and diluted with ethyl acetate. The resultant mixture was washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified using reverse phase preparative HPLC to give the title compound, 2-(4-fluorophenethyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (21.2 mg, 40%) as a yellow foam. MS M+H=479; 1H NMR (CDCl3) delta 8.18 (1H), 7.35 (4H), 7.26 (4H), 7.12 (2H), 6.95 (2H), 4.29(2H), 3.13 (2H).
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4h;
The product from step 2 (10 g, 40 mmol) was dissolved in DMF(100 ml) and 4-fluorophenylethyl bromide (8.9 g, 44 mmol) and potassium carbonate (10 g, 72 mmol) were added. The reaction was heated to 100 C. and stirred at that temperature for 4 hours. Filtration of inorganics and evaporation of DMF to gave the product.
N-(1-acetylpiperidin-4-yl)-N-(2-methyl-2-propen-1-yl)-3-methoxyaniline[ No CAS ]
[ 332-42-3 ]
2,2-dimethyl-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxyindoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide;Zinc chloride; potassium carbonate; In 5,5-dimethyl-1,3-cyclohexadiene; ethanol; ethyl acetate;
396-3) 2,2-Dimethyl-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methoxyindoline Under nitrogen atmosphere, N-(1-acetylpiperidin-4-yl)-N-(2-methyl-2-propen-1-yl)-3-methoxyaniline (1.50 g) was heated under reflux in the presence of zinc chloride (2.0 g) in xylene (30 ml) for 4 hr. After cooling the reaction mixtures, a 5 N aqueous solution (20 ml) of sodium hydroxide and ethyl acetate (100 ml) were added thereto and the resultant mixture was stirred for 30 min. The ethyl acetate layer was separated, washed successively with water and brine and dried over magnesium sulfate. After evaporating the solvent, the residue was dissolved in ethanol (30 ml). Then a 5 N aqueous solution (10 ml) of sodium hydroxide was added thereto and the mixture was heated under reflux for 2.5 hr. After concentrating the mixture, the residue was partitioned between ethyl acetate and water followed by extraction with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system) to give a yellow oily mixture (0.91 g) containing 2,2-dimethyl-1-(piperidin-4-yl)-6-methoxyindoline. This mixture was reacted with <strong>[332-42-3]4-fluorophenethyl bromide</strong> (0.8 g) inN,N-dimethylformamide (20 ml) in the presence of potassium carbonate (1.5 g) at 70 C. for 6 hr. Then the reaction mixtures were concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate followed by extraction with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by high performance liquid chromatography (ODS column, acetonitrile/water/70% perchloric acid system). After concentrating the solvent, the residue was basified, extracted with ethyl acetate, washed with water, dried and concentrated to give the title compound (0.31 g) as a pale yellow oil. Next, this product was converted into an oxalate in a conventional manner to give a pale greenish blue powder. Oxalate: m.p.: 228 C. (decomp.). 1H-NMR(400 MHz,DMSO-d6); delta(ppm) 1.22(6H, s), 1.58-1.69(2H, m), 2.50-2.75(4H, m), 2.94-3.11(4H, m), 3.15-3.25(2H, m), 3.36-3.61(3H, m), 3.66(3H, s), 6.01(1H, d, J=8Hz), 6.22(1H, s), 6.82(1H, d, J=8Hz), 7.14-7.24(2H, m), 7.30-7.38(2H, m). ESI-Mass; 383(MH+).
With hydrogenchloride; Ki; potassium carbonate;SiO2; In tetrahydrofuran; water; ethyl acetate;
EXAMPLE 99 Scheme K, step a: 4-[1-Oxo-1-(2,3-dimethoxyphenyl)methyl]-N-2-(4-fluorophenylethyl)-piperidine (6) Solid K2CO3 (184 g, 1.33 mol) and KI (5.5 g, 0.03 mol) were added to a solution of 4-(2,3-dimethoxybenzoyl)piperidine (16) (190 g, 0.67 mol) and 2-(4-fluorophenyl)ethyl bromide (135 g, 0.67 mol) in tetrahydrofuran (3 L) and water (720 mL). The resulting mixture was stirred under reflux for 18 hours. The mixture was concentrated (40 C./20 torr) to remove the majority of tetrahydrofuran. The resulting aqueous solution was extracted with methylene chloride (3*1.2 L) and the combined organic solutions were washed with brine (1.5 L) and dried (MgSO4). The mixture was filtered through a silica gel pad (SiO2 60, 230-400 mesh, 10 cm*16 cm i.d.) and SiO2 was washed with EtOAc (5 L). The combined filtrates were concentrated (35 C./20 torr) to a residue which was dissolved in EtOAc (2 L). The solution was treated with HCl gas until the solution turned acidic (moist pH paper). The mixture was filtered to afford the title compound (6) as an off-white solid after air-drying (226 g, 84%); m.p. 232-234 C. IR (KBr) 3431, 2935, 2629, 2548, 1676, 1580, 1512, 1476, 1487, 1317, 1267, 1227, 1161, 1076, 1017, 1001, 954, 836, 764 cm-1; 1H NMR (DMSO-d6) 8 11.0 (s, 1H, HCl), 7.0-7.4 (m, 7H, aryl), 3.85 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.6 (m, 1H), 3.4 (m, 2H), 3.2 (m, 2H), 3.0 (m, 4H), 2.0 (m, 4H); 13C NMR (DMSO-d6) 8 203.6, 161.1 (d, JF-C=241.0 Hz), 152.5, 146.6, 133.4, 133.3, 132.7, 130.6. 124.3, 119.8, 116.1, 115.4 (d, JF-C=21.2 Hz), 61.3, 56.5, 56.0, 50.9, 44.9, 28.4, 25.0;
With potassium iodide; potassium carbonate; In tetrahydrofuran; water; ethyl acetate;
A mixture of 4-(2,3-dimethoxybenzoyl)piperidine (16) (18.5 g, 64.7 mmol), 2-(4-fluorophenyl)ethyl bromide (13.2 g, 65.0 mmol), potassium carbonate (17.92 g, 129.7 mmol) and potassium iodide (0.54 g, 3.25 mmol) in tetrahydrofuran (300 mL) and water (70 mL) was heated at reflux overnight. The resulting mixture was allowed to cool and then concentrated in vacuum to remove the tetrahydrofuran. The residual material was extracted with methylene chloride (3*120 mL) and the combined organic extracts were washed with brine (150 mL), dried (MgSO4), filtered through a plug of silica with ethyl acetate (500 mL) and concentrated in vacuum to afford the title compound (6) as a yellow oil. (22.69 g, 94%).
With hydrogenchloride; Ki; potassium carbonate;SiO2; In tetrahydrofuran; water; ethyl acetate;
EXAMPLE 99 Scheme K, step a: 4-[1-Oxo-1-(2,3-dimethoxyphenyl)methyl]-N-2-(4-fluorophenylethyl)-piperidine (6) Solid K2CO3 (184 g, 1.33 mol) and KI (5.5 g, 0.03 mol) were added to a solution of 4-(2,3-dimethoxybenzoyl)piperidine (16) (190 g, 0.67 mol) and 2-(4-fluorophenyl)ethyl bromide (135 g, 0.67 mol) in tetrahydrofuran (3 L) and water (720 mL). The resulting mixture was stirred under reflux for 18 hours. The mixture was concentrated (40 C./20 torr) to remove the majority of tetrahydrofuran. The resulting aqueous solution was extracted with methylene chloride (3*1.2 L) and the combined organic solutions were washed with brine (1.5 L) and dried (MgSO4). The mixture was filtered through a silica gel pad (SiO2 60, 230-400 mesh, 10 cm*16 cm i.d.) and SiO2 was washed with EtOAc (5 L). The combined filtrates were concentrated (35 C./20 torr) to a residue which was dissolved in EtOAc (2 L). The solution was treated with HCl gas until the solution turned acidic (moist pH paper). The mixture was filtered to afford the title compound (6) as an off-white solid after air-drying (226 g, 84%); m.p. 232-234 C. IR (KBr) 3431, 2935, 2629, 2548, 1676, 1580, 1512, 1476, 1487, 1317, 1267, 1227, 1161, 1076, 1017, 1001, 954, 836, 764 cm-1; 1H NMR (DMSO-d6) delta 11.0 (s, 1H, HCl), 7.0-7.4 (m, 7H, aryl), 3.85 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.6 (m, 1H), 3.4 (m, 2H), 3.2 (m, 2H), 3.0 (m, 4H), 2.0 (m, 4H); 13C NMR (DMSO-d6) delta 203.6, 161.1 (d, JF-C=241.0 Hz), 152.5, 146.6, 133.4, 133.3, 132.7, 130.6. 124.3, 119.8, 116.1, 115.4 (d, JF-C=21.2 Hz), 61.3, 56.5, 56.0, 50.9, 44.9, 28.4, 25.0;
PREPARATION 75 2-(4-Fluorophenyl)ethyl Iodide STR187 A mixture containing 2-(4-fluorophenyl)ethyl bromide (see Preparation 76) (10 g), sodium iodide (10 g) and acetone (200 ml) was stirred at room temperature for 20 hours then filtered. The filtrate was concentrated in vacuo to give the title compound as a colourless oil, 12 g. 1 H-NMR (CDCl3): delta=7.20-7.10 (m,2H), 7.05-6.95 (m,2H), 3.35-3.30 (t,2H), 3.20-3.10 (t,2H) ppm.
EXAMPLE 8 3-Fluoro-10-(4-[2-(4-fluorophenyl)ethyl]piperazino)-8-isopropyl-10,11-dihydrodibenzo(b,f)thiepin A mixture of 3.0 g 10-chloro-3-fluoro-8-isopropyl-10,11-dihydrodibenzo(b,f)thiepin (Example 1), 4.1 g 1-[2-(4-fluorophenyl)ethyl]-piperazine and 7 ml of chloroform was refluxed for 8 hours and processed as in the foregoing case. Chromatography of the crude product on alumina yielded 2.2 g of a homogeneous oily base, which is transformed to the dimaleate, m.p. 171-174 C. (acetone). The required 1-[2-(4-fluorophenyl)ethyl]piperazone has not heretofore been described in the literature. It may be obtained from the known 2-(4-fluorophenyl)ethyl bromide (M. C. Suter and A. W. Weston, J. Amer. Chem. Soc. 63, 602, 1941) in the following manner:
With methylmagnesium bromide;palladium; In acetic acid; toluene; mineral oil;
EXAMPLE 20 2(3,5-Dimethoxyphenyl)-3-Methyl-5-(p-Fluorophenyl)Pentane 3,5-Dimethoxy propiophenone (52.0 g.) was added to a suspension prepared from 13.9 g. 57% sodium hydride in mineral oil (which had been freed of mineral oil by washing with toluene) and 130 ml. toluene. The resulting mixture was refluxed 30 minutes, 51 g. of 2(p-fluorophenyl)ethyl bromide added and refluxed 21/2 hours. The mixture was worked up with water and HCl and the product distilled to give 66.4 g. 1-(3,5-dimethoxyphenyl)-2-methyl-4(p-fluorophenyl)-1-butanone b.p. 160 - 175/0.3mm. This ketone in 300 ml. ether was treated with 130 ml. of 3 molar methyl magnesium bromide in ether and worked up with ammonium chloride to give 71.0 g. 2(3,5-dimethoxyphenyl)-3-methyl-5(p-fluorophenyl)-2-pentanol. This alcohol was hydrogenated in acetic acid containing 2 ml. H2 SO4 using palladium catalyst to give 55.0 g. of desired compound b.p. 150 - 155/0.3mm. Gas chromatography showed 2 isomers of ratio 63/37. Analysis Calcd. for C20 H25 FO2: C, 75.95; H, 7.96 Found: C, 76.04; H, 8.22
With methylmagnesium bromide;palladium; In acetic acid; toluene; mineral oil;
EXAMPLE 20 2(3,5-Dimethoxyphenyl)-3-Methyl-5-(p-Fluorophenyl)Pentane 3,5-Dimethoxy propiophenone (52.0 g.) was added to a suspension prepared from 13.9 g. 57% sodium hydride in mineral oil (which had been freed of mineral oil by washing with toluene) and 130 ml. toluene. The resulting mixture was refluxed 30 minutes, 51 g. of 2(p-fluorophenyl)ethyl bromide added and refluxed 2-Y2. The mixture was worked up with water and HCl and the product distilled to give 66.4 g. 1-(3,5-dimethoxyphenyl)-2-methyl-4(p-fluorophenyl)-1-butanone b.p. 160 - 175/0.3mm. This ketone in 300 ml. ether was treated with 130 ml. of 3 molar methyl magnesium bromide in ether and worked up with ammonium chloride to give 71.0 g. 2(3,5-dimethoxyphenyl)-3-methyl-5(p-fluorophenyl)-2-pentanol. This alcohol was hydrogenated in acetic acid containing 2 ml. H2 SO4 using palladium catalyst to give 55.0 g. of desired compound b.p. 150 - 155/0.3mm. Gas chromatography showed 2 isomers of ratio 63/37. Analysis Calcd. for C20 H25 FO2: C, 75.95; H, 7.96 Found: C, 76.04; H, 8.22
With potassium carbonate In ethanol for 24h; Heating / reflux;
7d
7d) 1-(2-(4-Fluorophenyl)ethyll-4-pipehdine methanamine (Compound Xl: R3 = 4-F, R4 = H, R6+R7 = -CH2-CH2-, n = 1 , p = 2, m =2). N-hexahydro-4-pyridinylmethyl-N-phenylmethylidenamine (17.9 g; 0.0879 mol) was dissolved in absolute ethanol (100 ml) containing anhydrous potassium carbonate (24.3 g; 0.176 mol) and 1-(2- bromoethyl)-4-fluorobenzene (prepared as described in the previous Example 7c) (18.0 g; 0.088 mol). The reaction mixture was heated under reflux for 24 h. After cooling to room temperature, the suspension was filtered and the solvent was evaporated at reduced pressure. The residue obtained was suspended in 3N HCI (120 ml) and stirred at room temperature for 3 h.The acidic aqueous phase was washed 4 times with ethyl acetate, then it was alkalized to pH approx. 13 with 6N NaOH and, finally, it was extracted 3 times with ethyl acetate. The organic phase thus obtained was dried over anhydrous Na2SO4 and, after filtration, the solvent was removed by evaporation at reduced pressure to give 17.2 g of 1-[2-(4- fluorophenyl)ethyl]-4-piperidine methanamine.1H-NMR (6, CDCI3): 1.2-1.5 (m, 5H); 1.6-1.8 (m, 2H); 1.9-2.1 (m, 2H);2.4-2.6 (m, 4H); 2.7-2.8 (m, 2H); 2.9-3.1 (m, 2H); 6.9-7.2 (m, 4H).MS shows 237 (MH+), 220 (base peak).
With potassium carbonate; In N,N-dimethyl-formamide; at 90 - 95℃;
A solution of isonipectoamide (10.9 g, 85.0 mmol), 2-(4-fluorophenyl)ethyl bromide (15.7 g, 77.3 mmol), and K2CO3 (2.3 g, 167 mmol) was prepared in DMF (280 mL) and stirred under argon at 90-95 C. overnight. The cooled solution was concentrated to a white oily solid. The solid was partitioned between water and CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed 2× with water, dried (MgSO4), filtered, and evaporated to an oily solid. The solid was recrystallized from EtOAc to afford 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxamide as a white powder, m.p. 177-178 C. (decomp.). Anal. Calcd. for C14H19FN2O: C, 67.18; H, 7.65: N, 11.19. Found: C, 67.25; H, 7.67; N, 11.13.
With potassium carbonate; In ethanol; at 100℃; for 18h;
Example 82Preparation of Compound 411Compound 257 was deprotected using the method described in Example 3. The deprotected product (0.041 g, 0.12mmol) was then taken up in ethanol (4mL), and to the resulting solution was added 2-(4-fluorophenyl)ethyl bromide (0.034g, 0.17mmol) and K2CO3 (0.024g, 0.17mmol), and the reaction was heated to 100 0C and stirred at this temperature for 18 hours. Concentration and PLC (3% MeOH/ CH2Cl2) provided compound 411 as a white film.
lambda/-(3,4-Difluoro-phenyl)-lambda/-piperidin-4-yl-propionannide (500 mg, 1.86 mmol) 2-(4- fluorophenyl)ethylbromide (568 mg, 2,80 mmol) and diisopropylamine (0.39 ml_, 2.80 mmol) were dissolved in lambda/,lambda/-dimethylformamid (10 ml_) and heated to 60 0C for 4 hours. Diethylether (20 ml_) was added and the organic phase was washed twice with aqueous sodium hydroxide, dried over sodium sulphate and filtrated. A solution of hydrochloric acid in ethanol was added and lambda/-(3,4-difluoro-phenyl)-/V- {1 -[2-(4-fluoro-phenyl)-ethyl]-piperidin-4-yl}-propionamide precipitated as the hydrochloric acid salt (730 mg, 100%). LC-ESI-HRMS of [M+H]+ shows 391.1978 Da. CaIc. 391.199722 Da, dev. -4.9 ppm
With tetrabutyl-ammonium chloride; sodium hydroxide; In water; at 75 - 80℃; for 3.5h;
The title compound was prepared by General Method 2. 4-chlorophenylhydrazine hydrochloride (2.2 g) was added to a vigorously stirred mixture of tetra-n-butylammonium chloride (200 mg) in 50% aqueous sodium hydroxide (12 mL) followed by <strong>[332-42-3]4-fluorophenethyl bromide</strong> (2.5 g). The mixture was heated at 75-80 0C (oil bath temp.) for 3.5 h. After cooling to room temperature, water was added and the mixture extracted with chloroform and the chloroform layer was washed with brine. The combined extract was dried (sodium sulfate), evaporated in vacuo to give a dark oil which was chromatographed over silica gel, eluting with chloroform followed by recrystallization from cyclohexane to obtain 750 mg of product.
In propyl cyanide; at 60℃; for 8h;Inert atmosphere;
f)(R)-l-(4-Fluorophenethyl)-3-((S)-2-phenyl-2-(piperidin-l-yl)propanoyloxy)-l- azoniabicyclo [2.2.2] octane bromide; (iS)-((i?)-quinuclidin-3-yl) 2-phenyl-2-(piperidin-l-yl)propanoate (prepared in step e) (19.67g as a 140mg/mL solution in butanenitrile :toluene) was charged to a reaction vessel followed by 4-fluorophenethylbromide (13.99g) and butanenitrile (19.7mL). The reaction mixture was heated to 600C (+/-5C) and stirred at this temperature for at least 8hrs. The reaction was monitored by HPLC analyzing the (5)-((i?)-quinuclidin-3-yl) 2-phenyl-2- (piperidin-l-yl)propanoate : product ratio (specification >;96:4). The reaction mixture was cooled to 400C over at least 40mins (0.5C/min) and then cooled to -5C over at least 6hrs (0.125C/min). During the cool no crystallisation had occurred when at 200C. Therefore the reaction was seeded with a sample of (i?)-l-(4-fluorophenethyl)-3-((5)-2-phenyl-2- (piperidin-l-yl)propanoyloxy)-l-azoniabicyclo[2.2.2]octane bromide (25mg - obtainable by methods described in WO 2008/075005 - Form A). After the reaction mixture reached - 5C toluene (39.3mL) was added and the slurry stirred at -5C for at least lhr. (R)-l-(4- Fluorophenethyl)-3-((iS)-2-phenyl-2-(piperidin- 1 -yl)propanoyloxy)- 1 - azoniabicyclo[2.2.2]octane bromide was then collected by filtration, washing the filtercake with butanenitrile (39.3mL). The (i?)-l-(4-Fluorophenethyl)-3-((5)-2-phenyl-2-(piperidin- l-yl)propanoyloxy)-l-azoniabicyclo[2.2.2]octane bromide product was then dried under vacuum at 45C. The product was then analysed by HPLC purity and NMR assay. 3Og, 96% yield, >;99.5% HPLC purity, >;99.5w/w% assay.
In acetonitrile; at 20℃; for 24h;
Preparation of Example 44 Bromide; (3R)-1-[2-(4-Fluorophenyl)ethyl]-3-[(2S)-2-phenyl-2-piperidin-1-ylpropanoyl]oxy}-1-azoniabicyclo[2.2.2]octane Crystalline Form A; (3R)-1-Azabicyclo[2.2.2]oct-3-yl (2S)-2-phenyl-2-piperidin-1-ylpropanoate (Example 2b, Isomer 1, 3 g) in acetonitrile (25 mL) was treated with 1-<strong>[332-42-3](2-bromoethyl)-4-fluorobenzene</strong> (2.384 g) and the mixture stirred at RT for 24 h. The mixture was concentrated to dryness, and the residue purified on silica gel eluting with 10% methanol in dichloromethane. The product containing fractions were combined, concentrated to dryness and the foam residue re-dissolved in acetonitrile (20 mL). To the solution was added diethyl ether (40 mL) and the resulting solid collected by filtration. The solid was dissolved in hot acetone (75 mL) and then allowed to cool overnight. The resulting solid was collected by filtration and dried at 50 C. to afford the titled compound (3.70 g).m/e 465 [M]30 1H NMR (400 MHz, DMSO) delta 7.58-7.54 (2H, m), 7.40-7.32 (4H, m), 7.31-7.26 (1H, m), 7.23-7.16 (2H, m), 5.14-5.09 (1H, m), 3.95-3.85 (1H, m), 3.62-3.51 (1H, m), 3.50-3.36 (4H, m), 3.25-3.16 (2H, m), 2.95 (2H, t), 2.48-2.31 (4H, m), 2.24-2.18 (1H, m), 2.02-1.69 (4H, m), 1.57 (3H, s), 1.56-1.48 (4H, m), 1.47-1.40 (2H, m).
A flask containing tetrahydrofuran (6.0 niL; Aldrich) was charged with sodium amide (0.488 g, 11.89 mmol; Acros) and chilled to 0 0C. (4-Fluorophenyl)hydrazine (1.0 g, 7.9 mmol; Aldrich) was added in portions. After 5 minutes the solid had completely dissolved. The ice bath was removed and stirring was continued for 1 hour. The solution was chilled again in an ice bath and l-<strong>[332-42-3](2-bromoethyl)-4-fluorobenzene</strong> (1.731 ml, 8.72 mmol; Aldrich) was added dropwise. After 10 minutes the ice bath was removed and stirring was continued for 1.5 hours. The mixture was poured into water (5 mL). The tetrahydrofuran was removed under reduce pressure and the residue was diluted with water (20 mL). The aqueous layer was extracted with diisopropyl ether (2x25 mL) and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product which was carried on without further purification: MS (DCI/NH3) m/z 248.9 (M+H)+.
With potassium carbonate; In acetonitrile; at 70℃; for 54h;
K2CO3 (285 mg, 2.06 mmol) and 1-<strong>[332-42-3](2-bromoethyl)-4-fluorobenzene</strong> (0.43 ml, 3.1 mmol) were added to a suspension of Intermediate 4 (320 mg, 1.04 mmol) in acetonitrile (30 ml) and the mixture was stirred at 70 C for 54 h. The solvent was evaporated and the residue was partitioned between water and DCM. The organic phase was dried over Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography on silica gel (eluent: petroleum ether: EtOAc 6:4) to give (E)-3-{1'-[2-(4-fluoro-phenyl)-ethyl]-4-oxo-spiro(chromane-2,3'-azetidine)-6-yl}-acrylic acid methyl ester (120 mg) as a brown oil. Y = 30% LC-MS: (ES+) MH+:396 1H NMR (300 MHz, Chloroform-d) delta (ppm) 8.03 (d, J=2.35 Hz, 1 H), 7.68 (dd, J=8.51, 2.35 Hz, 1 H), 7.65 (d, J=15.26 Hz, 1 H), 7.12-7.24 (m, 2 H), 7.08 (d, J=8.51 Hz, 1 H), 6.94-7.04 (m, 2 H), 6.40 (d, J=16.14 Hz, 1 H), 3.82 (s, 3 H), 3.27-3.71 (m, 4 H) 3.15 (bs, 2 H), 2.49-3.03 (m, 4 H).
30%
With potassium carbonate; In acetonitrile; at 70℃; for 54h;
Example 35: (£)-3-{1 '-[2-(4-Fluoro-phenyl)-ethyl]-4-oxo-spiro(chromane-2,3'- azetidine)-6-yl}-/V-hydroxy-acrylamideSTEP AK2C03 (285 mg, 2.06 mmol) and 1 -<strong>[332-42-3](2-bromoethyl)-4-fluorobenzene</strong> (0.43 ml, 3.1 mmol) were added to a suspension of Intermediate 4 (320 mg, 1 .04 mmol) in acetonitrile (30 ml) and the mixture was stirred at 70 C for 54 h. The solvent was evaporated and the residue was partitioned between water and DCM. The organic phase was dried over Na2S04, filtered and evaporated. The crude residue was purified by column chromatography on silica gel (eluent: petroleum ether: EtOAc 6:4) to give (£)-3-{1 '-[2-(4-fluoro-phenyl)-ethyl]-4-oxo-spiro(chromane-2,3'-azetidine)-6-yl}- acrylic acid methyl ester (120 mg) as a brown oil.Y = 30%LC-MS: (ES+) MH+:3961 H NMR (300 MHz, Chloroform-d) delta (ppm) 8.03 (d, J=2.35 Hz, 1 H), 7.68 (dd, J=8.51 , 2.35 Hz, 1 H), 7.65 (d, J=15.26 Hz, 1 H), 7.12-7.24 (m, 2 H), 7.08 (d, J=8.51 Hz, 1 H), 6.94-7.04 (m, 2 H), 6.40 (d, J=16.14 Hz, 1 H), 3.82 (s, 3 H), 3.27-3.71 (m, 4 H) 3.15 (bs, 2 H), 2.49-3.03 (m, 4 H).
General procedure: Magnesium turnings (13.2 g, 0.55 mol) were placed in dry THF (25 mL) undernitrogen. A small amount (10 mL) of (2-bromoethyl)benzene (92.5 g, 0.50 mol) dissolvedin dry THF (300 mL), added to the magnesium slurry and stirred for a few minutes withwarming until the reaction commenced. The remainder of the (2-bromoethyl)benzenesolution was added dropwise to maintain reflux over an hour, then the reaction mixturewas aged at reflux for an additional an hour. The reaction mixture was cooled to 25 C. In a separate flask, diethyl oxalate (88.2 g, 0.6 mol) was dissolved in dry THF (100mL) and cooled to -10 C. The supernatant solution of (2-phenylethyl)magnesiumbromide was sucked under nitrogen through a sintered-glass filter into a dropping funnel.The reaction temperature was held at -10 C as the solution of Grignard reagent wasadded dropwise over an hour to the diethyl oxalate. The sintered-glass funnel anddropping funnel were then rinsed with dry THF (100 mL), and the rinse was added to thebatch. The reaction mixture was allowed to stand for 30 min and then quenched byaddition of 3 M HCl (145 mL).Hexane (500 mL) was added, and the aqueous layer was discarded. The organicphase was washed with brine (100 mL) and saturated NaHCO3 (100 mL), until theaqueous layer measured to pH 5.0. The organic phase was dried with anhydrous Na2SO4.Filtered and washed with hexane, and the combined layers were concentrated to an oil invacuum. The crude keto ester (103.0 g) was vacuum distilled at 105-110 C (0.2-0.3 mmHg) to afford a colourless oil 90.0 g with 60% yield.
1.01 g
The title compound 16 was prepared according to Scheme 5. Magnesium turnings (0.32 g, 0.013 mmol) were taken in dry THF (40 mL) and L· (catalytic amount) was added under nitrogen atmosphere at ambient temperature. A solution of 4-fluoro-(2-bromoethyl) benzene (2.5 g, 12.312 mmol) in dry THF (20 mL) was added drop wise to the above mixture at 70 C. The resulting reaction mixture was heated at 70 C for lh and then cooled to ambient temperature. Separately, a solution of diethyl oxalate (2.16 g, 14.774 mmol) in dry THF (20 mL) was prepared and cooled to -10 C. The previously prepared Grignard reagent ws added to the solution of diethyl oxalate at -10 C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 30 min. The resulting reaction mixture was poured into water (150 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phase was dried over NaiSOy filtered and concentrated under reduced pressure. The resulting erode material was purified by flash chromatography (15% EtOAc in hexane) yielding ethy l 4-(4-fluorophenyl)-2-oxobutanoate (compound 16.3; 1.01 g, 4.507 mmol). LCMS: Method B, 4.476 min, MS: ES+ 242.5 (M+18).
2e) 2-({1 -r2-(4-fluorophenyl)ethyllpiperidin-3-yl)methyl)-3,4-dihvdro- pyrazinoH ,2-b1indazol-1 (2H)-one; A solution of 1 .25M HCI in ethanol (4.8 ml; 0.006 mol) was added to a solution containing tert-butyl 3-[(1 -oxo-3,4-dihydropyrazino[1 ,2- b]indazol-2(1 H)-yl)methyl]piperidine-1 -carboxylate (0.77 g; 0.002 mol) in ethyl acetate (7 ml), kept stirred at room temperature. The mixture thus obtained was kept under stirring at room temperature for 2h, then the solvent was removed by evaporation at reduced pressure. The residue thus obtained was taken up with ethyl acetate (5 ml) and filtered. The solid product was dissolved with 1 -(2- bromoethyl)-4-fluorobenzene (0.81 g; 0.004 mol) in anhydrous DMF (10 ml). Caesium carbonate (1 .95 g; 0.006 mol) was added to the resultant solution, kept stirred at room temperature. The mixture was then kept under strong stirring at room temperature for 48h and then was processed by adding water (20 ml) and ethyl acetate (25 ml). The aqueous phase was extracted several times with ethyl acetate (3x 20 ml) and the organic phases collected together were dried on Na2SO4. The solvent was then removed by evaporation at reduce pressure and the residue was purified by flash chromatography on silica gel, using a mixture of hexane:ethyl acetate in a ratio of 7:3 as eluent.Thus, 170 mg of 2-({1 -[2-(4-fluorophenyl)ethyl]piperidin-3-yl}methyl)- 3,4-dihydropyrazino[1 ,2-b]indazol-1 (2H)-one were obtained.1 H-NMR (300 MHz, DMSO-d6) delta: 8.00 (d, J = 8,48 Hz; 1 H), 7,75 (d, J = 8,77 Hz; 1 H); 7,31 - 7,41 (m, 1 H); 7,18 - 7,30 (m, 3H); 6,99 - 7,1 1 (m, 2H); 4,70 (t, J = 6,14 Hz; 2H), 3,88 (t, J = 6,14 Hz; 2H), 3,32 - 3,56 (m, 2H); 2,63 - 2,86 (m, 4H); 2,39 - 2,47 (m, 2H); 1 ,79 - 2,1 1 (m, 3H); 1 ,67 (d, J = 10,23 Hz; 2H); 1 ,35 - 1 ,53 (m, 1 H);1 ,03 (d, J = 9,35 Hz; 1 H).
With potassium carbonate; sodium iodide; In acetonitrile; at 55 - 80℃; for 4h;
A mixture of tert-butyl (S)-1-((S)-3,3-dimethyl-1-oxo-1-((S)-piperidin-3-ylamino)butan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (Intermediate 49; 100 mg, 0.25 mmol), 1-(2-bromoethyl)- 4-fluorobenzene (61 mg, 0.30 mmol), potassium carbonate (100 mg, 0.72 mmol) and sodium iodide (25 mg, 0.17 mmol) in acetonitrile (3.0 mL) was heated at 55 C for 2 hours. The mixture was then heated at 80 C for an additional 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and water, and the organic layer was washed with, brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0-10% MeOH: CH2Cl2) to give the product as a colorless solid (105 mg, 80%).
With potassium carbonate; In acetonitrile; at 80℃; for 18h;
General procedure: A test tube equipped with a stir bar was charged with (S)-tert-butyl piperidin-3-ylcarbamate (205 mg, 1.02 mmol) and potassium carbonate (281 mg, 2.03 mmol). 1-(2-Bromoethyl)-2-fluorobenzene (170 muL, 1.22 mmol) and acetonitrile (3.0 mL) were added, and the mixture was heated in an 80 C oil bath. After heating overnight (~18 h), the reaction was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc. The combined organics were concentrated under reduced pressure. The crude material was purified by silica gel chromatography (Rf in 60:40 hexanes:EtOAc = 0.24) to give the product as a colorless, viscous oil that slowly crystallized on standing (238 mg, 72%).
rel-2-amino-N-{8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxy-2-methylpropyl}oxy)-7-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide[ No CAS ]
rel-2-amino-N-{8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxy-2-methylpropyl}oxy)-7-[2-(4-fluorophenyl)ethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 50℃; for 42h;
Step 3: Preparation of rel-2-Amino-N-{8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2- hydroxy-2-methylpropyl}oxy)-7-[2-(4-fluorophenyl)ethoxy]-2,3-dihydroimidazo[1 ,2- c]quinazolin-5-yl}pyrimidine-5-carboxamideTo a suspension of rel-2-amino-N-{8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxy-2- methylpropyl}oxy)-7-hydroxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide (0.55 g) in DMF (7.5 mL) was treated with Cs2C03 (0.68 g, 2.10 mmoi) followed by 2-(4- fluorophenyl)ethyl bromide (0.12 mL, 0.839 mmoi). The resulkting suspension was stirred for 20 h at room temperature, and for 6 h at 50 C. To the resulting mixture was added additional 2-(4-fluorophenyl)ethyl bromide (0.10 mL, 0.700 mmoi), and the resulting mixture was stirred for 16 h at 50 C. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated between water (50 mL) and a 4:1 CH2CI2 / isopropanol solution (50 mL). The organic phase was washed with a saturated NaHC03 solution (50 mL), dried (anh. Na2S04) and concentrated under reduced pressure. The residue was purified using HPLC to afford rel-2-amino-N-{8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4- yl]-2-hydroxy-2-methylpropyl}oxy)-7-[2-(4-fluorophenyl)ethoxy]-2,3-dihydroimidazo[1 ,2- c]quinazolin-5-yl}pyrimidine-5-carboxamide (0.046 g, 1 .5% over 2 steps): HPLC ret. time 1 .21 min.; 1H NMR (DMSO-d6 + 1 drop TFA-d) delta 1.07 (d, J=6.4 Hz, 3H), 1.09 (d, J=6.4 Hz, 3H), 1.35 (s, 3H), 2.63-2.78 (m, 2H), 3.10 (app t, J=6.9 Hz, 2H), 3.22 (br s, 2H), 3.42-3.54 (m, 2H), 3.86- 3.98 (m, 2H), 4.30 (s, 2H), 4.15-4.25 (m, 2H), 4.42 (app t, J=6.8 Hz, 2H), 4.46-4.54 (m, 2H), 7.06 (t, J=8.9 Hz, 2H), 7.33 (dd, J=5.7, 8.7 Hz, 2H), 7.41 (d, J=9.0 Hz, 1 H), 7.99 (d, J=9.0 Hz, 1 H), 9.01 (s, 2H); mass spectrum m/z 645 (( -1 )", 100%), 647 ((M+1 )+, 12%).
rel-N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxy-2-methylpropyl}oxy)-7-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyridine-3-carboxamide[ No CAS ]
rel-N-{8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxy-2-methylpropyl}oxy)-7-[2-(4-fluorophenyl)ethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyridine-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;
Step 2: Preparation of rel-N-{8-({(2R)-3-[(2R,6S)-2,6-Dimethylmorpholin- -yl]-2-hydroxy-2- methylpropyl}oxy)-7-[2-(4-fluorophenyl)ethoxy]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5- yl}pyridine-3-carboxamideTo a suspension of rel-N-[8-({(2 )-3-[(2 ,6S)-2,6-dimethylmorpholin-4-yl]-2-hyclroxy-2- methylpropyl}oxy)-7-hydroxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]pyridine-3-carboxamide (0.200 g) in DMF (7.5 mL) was added Cs2C03 (0.513 g, 1 .57 mmol, 4.0 equiv.) followed by 2-(4- fluorophenyl)ethyl bromide (0.1 1 mL, 0.787 mmol). The resulting suspension was stirred at room temperature for 16 h, then was concentrated under reduced pressure. The resuide was The residue was separated between water (50 mL) and a 4:1 CH2CI2 / isopropanol solution (50 mL). The organic phase was washed with a saturated NaHC03 solution (50 mL), dried (anh. Na2S04) and concentrated under reduced pressure. The residue (0.26 g) was purified using MPLC (Isolute Flash NH2 reverse phase column; 100% CH2CI2 for 10 min., gradient to 90% CH2CI2 : 10% MeOH over 10 minutes; gradient to 80% CH2CI2 : 20% MeOH over 10 min.; and 80% CH2CI2 : 20% MeOH for 10 min.) to give material (0.10 g) which was further purified using preparative HPLC to give rel-N-{8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxy-2- methylpropyl}oxy)-7-[2-(4-fluorophenyl)ethoxy]-2,3-dihydroimidazo[1 ,2-c]quinazolin-5- yl}pyridine-3-carboxamide (0.015 g, 0.5% over 2 steps): HPLC ret. time 1 .34 min.; 1H NMR (DMSO-cfe + 1 drop TFA-d) delta 1.06 (d, J=6.6 Hz, 3H), 1.10 (d, J=6.6 Hz, 3H), 1 .37 (s, 3H), 2.66- 2.79 (m, 2H), 3.1 1 (app t, J=7.1 Hz, 2H), 3.23 (br s, 2H), 3.44-3.54 (m, 2H), 3.89-3.97 (m, 2H), 4.15 (s, 2H), 4.22-4.28 (m, 2H), 4.47 (app t, J=6.8 Hz, 2H), 4.53-4.60 (m, 2H), 7.07 (t, J=8.8 Hz, 2H), 7.33 (dd, J=5.6, 8.6 Hz, 2H), 7.47 (d, J=9.1 Hz, 1 H), 7.90 (dd, J=5.1 ,8.1 Hz, 1 H), 8.04 (d, J=9.1 Hz, 1 H), 8.86 (br d, J=8.1 Hz, 1 H), 8.95 (dd, J=1.5, 5.3 Hz, 1 H), 9.47 (d, J=1 .5 Hz, 1 H): mass spectrum m/z 631 ((M+1 ) 0.8%).
Step 2: Preparation of tert-buty -[2-(4-fluorophenyl)ethyl]piperazine-1-carboxylateTert-butyl piperazine-1-carboxylate (5.5 g, 29.6 mmol) was added portionwise into a solution of 1- <strong>[332-42-3](2-bromoethyl)-4-fluorobenzene</strong> (3.0 g, 14.8 mmol) in dichloromethane at 0 C. The resulting mixture was stirred for 12 hours. The reaction mixture was diluted with dichloromethane, and then washed with water and brine, dried (Na2S04) and concentrated under vacuum. Purification by flash chromatography (neutral alumina, pet ether 96 / EtOAc 4) gave the title compound (1.99 g, 44 %). TLC: ethylacetate/ hexane (3/7): Rf : 0.3. LCMS (Method C): Mass found (M+ 309.2), Rt (min): 2.39, Area (%): 74.9 (Max. chrom.).
In dichloromethane; at 0℃; for 12h;
Step 2: Preparation of tert-butyl 4-[2-(4-fluorophenyl)ethyl]piperazine-1-carboxylate [Show Image] Tert-butyl piperazine-1-carboxylate (5.5 g, 29.6 mmol) was added portionwise into a solution of 1-<strong>[332-42-3](2-bromoethyl)-4-fluorobenzene</strong> (3.0 g, 14.8 mmol) in dichloromethane at 0 C. The resulting mixture was stirred for 12 hours. The reaction mixture was diluted with dichloromethane, and then washed with water and brine, dried (Na2SO4) and concentrated under vacuum. Purification by flash chromatography (neutral alumina, pet ether 96 / EtOAc 4) gave the title compound (1.99 g, 44 %). TLC: ethylacetate/ hexane (3/7): Rf: 0.3. LCMS (Method C): Mass found (M+ 309.2), Rt (min): 2.39, Area (%): 74.9 (Max. chrom.).
3-methyl-4-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)-1-oxa-8-azaspiro[4.5]dec-3-en-2-one, dihydrochloride salt[ No CAS ]
[ 1401993-16-5 ]
Yield
Reaction Conditions
Operation in experiment
54%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 0.75h;Microwave irradiation;
Example 3: Preparation of 8-[2-(4-fluorophenyl)ethyl]-3-methyl-4-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)-1-oxa-8-azaspiro[4.5]dec-3-en-2-one [Show Image] A mixture of 3-methyl-4-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)-1-oxa-8-azaspiro[4.5]dec-3-en-2-one dihydrochloride (Example 1, 300 mg, 0.61 mmol), anhydrous potassium carbonate (180 mg, 1.3 mmol) and 4-fluorophenethylbromide (160 mg, 0.78 mmol) in anhydrous N,N-dimethylformamide (3 mL) was heated at 80C for 45 minutes under microwave irradiation. The reaction mixture was concentrated under vacuum. The residue was taken up in dichloromethane (20 mL), washed with water (20 mL) and brine (20 mL), dried (MgSO4) and concentrated under vacuum. After purification by flash chromatography (silica), the title compound was obtained as a white solid (190 mg, 54%). 1H NMR (DMSO-d6, 400 MHz): delta 7.41 (m, 1 H), 7.15 (m, 5H), 6.99 (m, 2H), 3.94 (m, 1 H), 3.87 (m, 1 H), 3.56 (m, 2H), 3.26 (m, 4H), 2.96 (m, 2H), 2.80 (m, 2H), 2.63 (m, 2H), 2.49 (m, 3H), 2.03 (m, 1 H), 2.03 (s, 3H), 1.74 (m, 2H). LCMS (Method D): Mass found (M+ 546.3), Rt (min): 4.47, Area (%): 95.5 (Max), 96.0 (254 nm). HPLC (Method A): Rt (min): 4.67, Area (%): 96.8 (Max), 96.4 (254 nm).
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 0.75h;microwave irradiation;
Example 3: Preparation of 8-r2-(4-fluorophenyl)ethvn-3-methyl-4-({4-f3- (trifluoromethvHphenvnpiperazin-1-yl>carbonyl)-1-oxa-8-azaspirof4.51dec-3-en-2-one A mixture of 3-methyl-4-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)-1-oxa-8- azaspiro(4.5]dec-3-en-2-one dihydrochloride (Example 1 , 300 mg, 0.61 mmol), anhydrous potassium carbonate (180 mg, 1.3 mmol) and 4-fluorophenethylbromide (160 mg, 0.78 mmol) in anhydrous N,N-dimethylformamide (3 mL) was heated at 80C for 45 minutes under microwave irradiation. The reaction mixture was concentrated under vacuum. The residue was taken up in dichloromethane (20 mL), washed with water (20 mL) and brine (20 mL), dried (MgS04) and concentrated under vacuum. After purification by flash chromatography (silica), the title compound was obtained as a white solid. 1H NMR (DMSO-d6, 400 MHz): delta 7.41 (m, 1 H), 7.15 (m, 5H), 6.99 (m, 2H), 3.94 (m, 1 H), 3.87 (m, 1 H), 3.56 (m, 2H), 3.26 (m, 4H), 2.96 (m, 2H), 2.80 (m, 2H), 2.63 (m, 2H), 2.49 (m, 3H), 2.03 (m, 1 H), 2.03 (s, 3H), 1.74 (m, 2H). LCMS (Method D): Mass found (M+ 546.3), Rt (min): 4.47, Area (%): 95.5 (Max), 96.0 (254 nm). HPLC (Method A): Rt (min): 4.67, Area (%): 96.8 (Max), 96.4 (254 nm).
General procedure: To a solution of the appropriatehalide (7a-c, 9a-f or 11b-h) in 2ml of DMSO NaN3is added and the solution was stirred overnight. Then, 6,CuSO4*5H2O (0.2 eq), sodium ascorbate (0.10 eq), and 2mlof distilled water are added to the solution and the solutionwas stirred overnight. The solution is diluted in water andthe mixture is extracted 3 times with EtOAc. The combinedorganic phase is washed twice with a solution of NH4Cl5Mand then twice with brine. The combined organic phaseis dried with MgSO4, to afford the crude product. Thepurification was performed as stated for each compound.
General procedure: 6-Hydroxyphthalide (9) (0.33 mmol) was dissolved in N,N-dimethylformamide (DMF; 3 mL) and stirred over K2CO3 (1.14 mmol) for 5 min. The appropriately substituted alkyl bromide (0.37 mmol) was added and the reaction mixture was stirred for 12 h at 50-100 ºC. The K2CO3 was removed by filtration and the reaction mixture was dried in a stream of air. The resulting residue was recrystallized from ethanol to yield the C6-substituted phthalide analogues 6a-r.1 Benzylaminophthalide (6s) was synthesized according to the same procedure from 6-aminophthalide (8) and benzyl bromide
Example 2. Preparation of 10-(4-fluorophenethyl)-7-chloro-2,3,5 JO J 1,1 la-hexahydro- 1H- indolizino [7, 6-bl indole [Compound No. 21:[0274] A mixture of 7-chloro-2,3,5, 10,11,1 la-hexahydro- lH-indolizino [7, 6-b] indole and 10-chloro-2,3,5, 6,7,1 lc-hexahydro-lH-indolizino[7,8-b]indole (non- separable regioisomers, 500 mg, 2.03 mmol, 1 equiv) and l-<strong>[332-42-3](2-bromoethyl)-4-fluorobenzene</strong> (577 mg, 2.84 mmol, 1.4 equiv) were heated to 95 C with triethyl amine (0.85 mL, 6.09 mmol, 3 equiv) in 6 mL of EtOH for 18 h. The mixture was brought to RT followed by dilution with EtOAc (40 mL), washed with water (2x10 mL), then with brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography over 230-400-mesh silica gel using a gradient of MeOH in EtOAc (0 to 50%). The product was further purified by reverse phase HPLC.Column: ZORBAX SB C18, 4.6 x 250 mm, 5mu?iota, retention time (min): 9.47, purity: 80.24%; 1HNMR (CD3OD, TFA salt) d (ppm): 7.38 (s,lH), 7.30 (d,lH), 7.10 (m,3H), 6.90 (m,2H), 5.05 (d,lH), 4.40 (m,lH), 4.20 (m,2H), 3.50 (m,lH), 3.20 (m,2H),3.10 (m,2H), 3.0 (m,2H), 2.5-2.3 (m,3H), 2.0 (m,lH).
Example 1. Preparation of 7-(4-fluorophenethyl)-10-chloro-2,3,5,6,7J lc-hexahydro-lH- indolizino[7,8-blindole [Compound No. 11:[0273] A mixture of 7-chloro-2,3,5, 10,11,1 la-hexahydro- lH-indolizino [7, 6-b] indole and lO-chloro-2,3,5, 6,7,1 lc-hexahydro-lH-indolizino[7,8-b]indole (non- separable regioisomers, 500 mg, 2.03 mmol, 1 equiv) and l-<strong>[332-42-3](2-bromoethyl)-4-fluorobenzene</strong> (577 mg, 2.84 mmol, 1.4 equiv) were heated at 95 C with triethyl amine (0.85 mL, 6.09 mmol, 3 equiv) in 6 mL of EtOH for 18h. The mixture was brought to RT followed by dilution with EtOAc (40 mL), washed with water (2x10 mL), and once with brine, then dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by columnchromatography over 230-400-mesh silica gel using a gradient of MeOH in EtOAc (0 to 50%). The product was further purified by reverse phase HPLC.Column: ZORBAX SB C18, 4.6 x 250 mm, 5mu, retention time (min): 9.71, purity: 95.20%; 1HNMR (DMSO, TFA salt) d (ppm): 7.50 (m,lH), 7.40 (m,3H), 7.12 (m,3H), 5.0 (m,lH), 3.80 (m,2H), 3.60 (m,2H), 3.55 (m,2H), 3.45 (m,lH), 3.38-3.20 (m,2H), 3.10 (m,2H), 2.70 (m,lH), 2.25 (m,2H).
4a-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol[ No CAS ]
2-(4-fluorophenethyl)-4a-phenethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 50℃; for 20h;
General procedure: A mixture of the amine 9, alkyl bromide (1.2 equiv) and NaHCO3 (2 equiv) in DMF (20 mL) was heated at 50 C for 20 h. After cooling to room temperature, the reaction mixture was poured into ice-H2O, and the product was extracted with Et2O. The ethereal extracts were washed with saturated NH4Cl solution. After drying over Na2SO4, the solvent was removed in vacuo to afford an oil. The crude oil was subjected to flash chromatography on silica gel using 75% EtOAc in hexanes as the eluent to give the compounds 3a-h as a solid.
General procedure: A solution of 4 in dry THF was stirred under argon at -20 C. A solution of n-butyllithium, 2.5 M in hexane (1.5 equiv), was added to the reaction, producing a deep red color. The mixture was stirred at -20 C for 2 h. Alkyl bromide (1.5 equiv) was added, producing a yellow solution, which was then stirred and brought to 20 C over 1 h. The reaction mixture was then treated with saturated NH4Cl solution. The reaction mixture was partitioned between Et2O and H2O. The organic layer was dried over anhyd Na2SO4 and removal of the solvent gave an orange oil. Column chromatography of the crude material using 20% hexanes in Et2O gave compound 5 as a pure yellow oil.
With caesium carbonate; In N,N-dimethyl-formamide; at 70℃;
A mixture of 90c (50 mg, 0.14 mmol), Cs2C03 (68 mg, 0.21 mmol) and 4- fluorophenylethylbromide (37 mg, 0.17 mmol) in DMF (2 mL) was heated at 70C overnight, TLC (DCM:MeOH=20: l) showed that the starting material was consumed. The mixture was cooled to RT, partitioned between EA (30 mL) and H20 (30 mL) and the organic layer was separated, washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by chromatography (PE:EA =10: 1 to 1 : 2) to give 126a (40 mg, 58%) as a yellow oil. LC-MS (Waters): R, 6.07 min; m/z calculated for C29H3,FN204 [M+H]+ 491.1 , found [M+H]+ 491.1.
1-(4-fluorophenethyl)-4-(2-methoxyphenethyl)piperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 24h;
Compound 29. 1 -(4-fluorophenethyl)-4-(2-methoxyphenethyl)piperidine A 250 mL round bottom flask was equipped with a magnetic stir bar, and then charged with 5 grams (0.0537 mol) of 4-picoline, 8.77 grams (0.0644 mol) of 2- methoxybenzaldehyde, and 50 ml of acetic anhydride. The reaction mass was heated to reflux and maintained at that temperature for 72 hours. The reaction mixture was then cooled to room temperature, and subjected to silica chromatography. Yield of (E)-4-(2- methoxystyryl)pyridine was 7.15 grams (63%). The 7.15 grams of (E)-4-(2- methoxystyryl)pyridine was then charged into a 500 mL hydrogenation flask, to which was added 100 mL of acetic acid as well as 50 mg of Pt02. The reaction mass was subjected to 45 psi of hydrogen gas, and allowed to react at room temperature for 16 hours. The reaction mixture was then filtered through a pad of celite, evaporated, basified with aqueous Na2C03 solution, and the combined extraction solvents were removed under reduced pressure via rotovap. The residue was then subjected to silica chromatography, yielding 6.1 grams (82.1 % yield) of 4-(2-methoxyphenethyl)piperidine. A 100 mL round bottom flask equipped with a magnetic stir bar was then charged with 1.0 grams of 4-(2-methoxyphenethyl)piperidine (0.0046 mol), 1.3 grams of 4-fluorophenethylbromide (0.0064 mol), 1.87 grams of K2C03 (0.0135 mol), and 20 mL of DMF as solvent. The reaction mass was then heated to 70 C for 24 hours. The excess DMF was removed via reduced pressure, partitioned with water and dichloromethane, the organic layer separated; excess solvent removed under reduced pressure and the residue was subjected to silica chromatography. Yield of l-(4-fluorophenethyl)-4-(2- methoxyphenethyl)piperidine was 0.99 grams (63.0% yield). lH NMR (300 MHz, CDC13) delta 1.33-1.55 (m, 7H), 2.33-2.60 (m, 10H), 3.80 (s, 3H), 6.80-7.32 (m, 8H) ppm.
methyl 2-(1H-imidazol-4-yl)pyridine-4-carboxylate[ No CAS ]
2-[1-[2-(4-fluorophenyl)ethyl]imidazol-4-yl]pyridine-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
C. methyl 2-{1-[2-(pyrrolidin-1-yl)ethyl]-1H-imidazol-4-yl}pyridine-4-carboxylate A mixture of methyl 2-(1H-imidazol-4-yl)pyridine-4-carboxylate (20 mg, 0.10 mmol), 1-(2-chloroethyl)pyrrolidine hydrogen chloride (34 mg, 0.2 mmol) and cesium carbonate (130 mg, 0.4 mmol) in 2 mL DMF was heated at 120 C. for 2 hr. The reaction mixture was purified by ISCO flash column chromatography (MeOH/DCM=0-100%). Example 92 2-[1-[2-(4-fluorophenyl)ethyl]imidazol-4-yl]pyridine-4-carboxylic acid The title compound was prepared in 48% yield from methyl 2-(1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 5) and <strong>[332-42-3]4-fluorophenethyl bromide</strong> according to the procedure for the preparation of Example 44, followed by saponification using NaOH in MeOH.?HNMR (400 MHz, DMSO): oe 3.09 (2H, t, J=7.1 Hz), 4.27 (2H, t, J=7.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.24 (2H, t, J=7.1 Hz), 7.57 (1H, d, J=3.8 Hz), 7.63 (1H, s), 7.82 (1H, s), 8.26 (1H, s), 8.63 (1H, d, J=5.0 Hz). [M+H] Calc?d for C17H14FN302, 312.Found, 312.
(1-(4-fluorophenethyl)piperidin-4-yl)diphenylmethanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With triethylamine; In acetonitrile; at 85℃; for 19h;
(1-(4-Fluorophenethyl)piperidin-4-yl)diphenylmethanol To a vial was added the diphenyl(piperidin-4-yl)methanol (0.099 g, 0.370 mmol), 1-<strong>[332-42-3](2-bromoethyl)-4-fluorobenzene</strong> (0.047 mL, 0.337 mmol) and acetonitrile (10 mL). The TEA (0.070 mL, 0.505 mmol) was then added and the reaction stirred at 85 C. at for 19 h and was cooled to rt. The reaction was diluted with water and extracted with EtOAc (3*15 mL). The EtOAc layer was collected and dried with MgSO4, filtered and adsorbed to silica then purified by MPLC (15 min, 0-10% MeOH:DCM) to produce pure (1-(4-fluorophenethyl)piperidin-4-yl)diphenylmethanol (0.123 g, 0.316 mmol, 94% yield). 1H NMR (400 MHz, CDCl3): delta 7.51-7.47 (m, 4H), 7.32-7.27 (m, 4H), 7.21-7.11 (m, 4H), 6.98-6.92 (m, 2H), 3.06-3.00 (m, 2H), 2.78-2.72 (m, 2H), 2.56-2.51 (m, 2H), 2.50-2.42 (m, 1H), 2.21 (br s, 1H), 2.08-1.99 (m, 2H), 1.57-1.48 (m, 4H). 13C NMR (125 MHz, CDCl3): delta 161.2 (d, J=243.6 Hz), 145.9, 136.5 (d, J=3.2 Hz), 129.9 (d, J=7.9 Hz), 128.1, 126.5, 125.8, 115.0 (d, J=21.2 Hz), 79.5, 60.8, 54.1, 44.2, 33.0, 26.4, 21.0. LCMS Retention time: 3.733 min. LCMS purity 96.8%. HRMS (ESI): m/z calcd for C26H28FNO [M+H]+ 390.2155. found 390.2228.
4a-(3-phenylpropyl)-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol[ No CAS ]
2-(4-fluorophenethyl)-4a-(3-phenylpropyl)-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 50℃; for 20h;
General procedure: A mixture of the amine 9, alkyl bromide (1.2 equiv) and NaHCO3 (2 equiv) in DMF (20mL) was heated at 50C for 20h. After cooling to room temperature, the reaction mixture was poured into ice- H2O, and the product was extracted with Et2O. The ethereal extracts were washed with saturated NH4Cl solution, dried over Na2SO4, and the solvent was removed in vacuo to afford an oil. The crude oil was subjected to flash chromatography on silica gel using 75% EtOAc in hexanes as the eluent to give the 10-12 as solids.
4a-(4-phenylbutyl)-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol[ No CAS ]
2-(4-fluorophenethyl)-4a-(4-phenylbutyl)-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 50℃; for 20h;
General procedure: A mixture of the amine 9, alkyl bromide (1.2 equiv) and NaHCO3 (2 equiv) in DMF (20mL) was heated at 50C for 20h. After cooling to room temperature, the reaction mixture was poured into ice- H2O, and the product was extracted with Et2O. The ethereal extracts were washed with saturated NH4Cl solution, dried over Na2SO4, and the solvent was removed in vacuo to afford an oil. The crude oil was subjected to flash chromatography on silica gel using 75% EtOAc in hexanes as the eluent to give the 10-12 as solids.
4a-(5-phenylpentyl)-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol[ No CAS ]
2-(4-fluorophenethyl)-4a-(5-phenylpentyl)-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 50℃; for 20h;
General procedure: A mixture of the amine 9, alkyl bromide (1.2 equiv) and NaHCO3 (2 equiv) in DMF (20mL) was heated at 50C for 20h. After cooling to room temperature, the reaction mixture was poured into ice- H2O, and the product was extracted with Et2O. The ethereal extracts were washed with saturated NH4Cl solution, dried over Na2SO4, and the solvent was removed in vacuo to afford an oil. The crude oil was subjected to flash chromatography on silica gel using 75% EtOAc in hexanes as the eluent to give the 10-12 as solids.
(9H-carbazol-3-yl)(4-(4-fluorophenethyl)piperazin-1-yl)methanone[ No CAS ]
(9-(4-fluorophenethyl)-9H-carbazol-3-yl)(4-(4-fluorophenethyl)piperazin-1-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
NaH (30 mg, 0.74 mmol) was added to a stirred solution of Compound 1037 (0.15 g, 0.37 mmol) in DMF (5 mL) at room temperature. The reaction mixture was cooled to 0 C and stirred for 30 minutes. 1 -<strong>[332-42-3](2-bromoethyl)-4-fluorobenzene</strong> (120 mg, 0.59 mmol) was added at 0 C and this temperature was maintained for two hours. Then, the reaction mixture was slowly warmed to room temperature and stirred for 12 hours. After complete consumption of the starting material, based on TLC, ice water was added very slowly to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water followed by brine solution, dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the crude product. The crude compound was purified by preparative TLC, to afford pure (9-(4-fluorophenethyl)-9 - - carbazol-3-yl)(4-(4-fluorophenethyl)piperazin-1 -yl)methanone (Compound 1039) as an off-white semisolid (40 mg, 61 %). 1 H NMR (400 MHz, DMSO-d6): delta 8.23-8.20 (m, 2H), 7.59 (d, J = 8.4 Hz, 1 H), 7.55 (d, J = 8.8 Hz, 1 H), 7.47-7.39 (m, 2H), 7.30-7.16 (m, 5H), 7.09 (t, J = 8.8 Hz, 2H), 7.01 (t, J = 8.8 Hz, 2H), 4.62 (t, J = 7.2 Hz, 2H), 3.55 (br s, 4H), 3.05 (t, J = 7.6 Hz, 2H), 2.77- 2.73 (m, 2H), 2.58-2.42 (m, 6H). LCMS: m/z 524.46 [M+H]+.
2-((1H-indol-4-yl)oxy)isonicotinonitrile[ No CAS ]
2-((1-(4-fluorophenethyl)-1H-indol-4-yl)oxy)isonicotinonitrile[ No CAS ]
2-((3-bromo-1-(4-fluorophenethyl)-1H-indol-4-yl)oxy)isonicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%; 25%
With tetrabutylammomium bromide; caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 48h;
To a stirred solution of 2-((1H-indol-4-yl) oxy) isonicotinonitrile 1 (150 mg, 0.64 mmol) (from Example 47, Step 1) in DMF (5 mL) at 0 C, were added 1-(2-bromoethyl)-4- fluorobenzene 2 (194 mg, 0.96 mmol), Cs2CO3 (416 mg, 1.28 mmol) and nBu4NBr (10 mg, 0.03 mmol). The mixture was warmed to RT and stirred for 48 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (15 mL), dried (Na2504), filtered, and concentrated under reduced pressure. The residue was purified via preparative HPLC to afford compound 3 (70 mg, 30%) and compound 4 (70 mg, 25%) both as a pale yellow oil.j00384j Analytical data for Compound 3: ?HNMR(400IVIHz, CDC13): 8.34 (dd, J 5.1, 0.7 Hz, 1H), 7.24-7.22 (m, 2H), 7.18 (dd, J= 5.1, 1.3 Hz, 1H), 7.09-7.07 (m, 1H), 7.03-6.88 (m, 5H), 6.84 (d, J= 3.2 Hz, 1H), 6.16 (d, J= 3.1 Hz, 1H), 4.34 (t, J= 7.2 Hz, 2H), 3.10 (t, J 7.2 Hz, 2H); LCMS Mass: 358.0 (M+1).
6-[2-(4-fluorophenyl)ethyl]-3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With tetrabutylammomium bromide; sodium hydroxide; In dichloromethane; at 20℃; for 48h;
General procedure: TBAB (0.443g, 1.38mmol), phenethyl bromide (0.65mL, 2.50mmol) and 5.0mL of 25% m/m NaOH solution were added to a solution of 10a (0.25g, 1.275mmol) in 15mL of dry DCM. The mixture was stirred at rt for 48h, and then diluted with 20mL of DCM and 20mL of water. The collected organic phase was washed twice with 20mL of brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with ethyl acetate, to afford 12b as pale brown solid (0.270g, 70% yield).
With potassium carbonate; In acetonitrile; for 24h;Inert atmosphere; Reflux;
General procedure: To a mixture of the benzyl piperidine intermediate 5 (200 mg,0.770 mmol) and potassium carbonate (266 mg, 1.93 mmol) inMeCN (3.0 mL) was added (2-bromoethyl)benzene (137 muL, 1.00 mmol). After reflux for 24 h, EtOAc (9.0 mL) was added to thereaction mixture and the whole was filtered. The filtrate was evaporatedin vacuo and the residue was purified by silica gel chromatographyusing 0-1% MeOH/CHCl3 as eluent to give 228 mg(90%) of the title compound as a pale yellow solid.
N-(2-trifluoromethyl-4-chlorophenyl)-2-aminocyclohexanesulfonamide[ No CAS ]
N-(2-trifluoromethyl-4-chlorophenyl)-2-(4-fluorophenylethylamino)cyclohexylsulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56.5%
General procedure: According to the method given in the reference27, to a suspension containing activated powdered 4 A molecular sieves (500 mg) in dry anhydrous DMF (10 mL), dry cesium hydroxide monohydrate (336 mg, 2 mmol, 1.3 equiv) was added in a 100 mL flask, and the mixture was stirred for 10 min. After 2-aminocycloalkylsulfonamide (II) (535 mg, 1.5 mmol, 1.0 equiv) was added, the mixture was stirred for an additional 30 min. After alkylating agent (1.5 mmol, 1.0 equiv) was added to the suspension, the reaction was allowed to proceed at room temperature for 10 h. The reaction mixture was filtered to remove undissolved solids and the residues were washed several times with ethyl acetate. The filtrate was taken up in 100 mL water, and extracted with ether (3×80 mL). The organic layer was dried over anhydrous sodium sulfate, then filtered and evaporated. The crude product was purified by column chromatography using petroleum ether and ethyl acetate (5:1 v/v) as the eluting solvent to afford pure title compounds III.
4-chloro-N-(3-hydroxybenzyl)-N-(pyridin-4-ylmethyl)benzamide[ No CAS ]
4-chloro-N-(3-(4-fluorophenethoxy)benzyl)-N-(pyridin-4-ylmethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With potassium carbonate; In acetone; at 56℃; for 18h;
General procedure: Acetone (0.5 mL) was added to phenol (4-6) (50 mg,0.144 mmol). Then K2CO3 (39.7 mg, 0.287 mmol, 2eq.) and bromide(0.144 mmol,1eq.) were added and the reaction mixturewas stirredat 56 C overnight. Thereafter, the reaction mixture was filtered,centrifuged, and the supernatant was evaporated to dryness. Thecrude was purified using prep TLC or Biotage flash column chromatographyto afford the desired final compound.
N-(3-hydroxybenzyl)-2-(4-methoxyphenyl)-N-(pyridin-4-ylmethyl)acetamide[ No CAS ]
N-(3-(4-fluorophenethoxy)benzyl)-2-(4-methoxyphenyl)-N-(pyridin-4-ylmethyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With potassium carbonate; In acetone; at 56℃; for 18h;
General procedure: Acetone (0.5 mL) was added to phenol (4-6) (50 mg,0.144 mmol). Then K2CO3 (39.7 mg, 0.287 mmol, 2eq.) and bromide(0.144 mmol,1eq.) were added and the reaction mixturewas stirredat 56 C overnight. Thereafter, the reaction mixture was filtered,centrifuged, and the supernatant was evaporated to dryness. Thecrude was purified using prep TLC or Biotage flash column chromatographyto afford the desired final compound.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 8h;
Anhydrous K2CO3 (1.27 g, 9.21 mmol, 2.5 eq) and <strong>[332-42-3]4-fluorophenethyl bromide</strong> (1 g, 4.61 mmol, 1.25 eq) was added to a solution of Intermediate 45 (744 mg, 3.68 mmol) in DMF (30 mL) and the resulting mixture was allowed to stir at RT for 8 h. The mixture was then diluted with water (30 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (210 mL), saturated aqueous NaHCO3 (215 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography over silica gel (100-200 mesh) by using a gradient mixture of 0-10% EtOAc-hexane as the eluent to afford Cmpd 51 (700 mg, 58%). 1H NMR: (DMSO-d6) delta 8.61 (d, J=4.3 Hz, 1H), 7.85-7.96 (m, 2H), 7.31-7.38 (m, 2H), 7.07-7.19 (m, 4H), 4.78 (t, J=7.2 Hz, 2H), 4.27 (q, J=7.2 Hz, 2H), 3.12 (t, J=7.2 Hz, 2H), 1.29 (t, J=7.0 Hz, 3H); MS: 340 [M+H]+; MP: 94-95C.; TLC: 30% EtOAc in hexane: Rf: 0.40.
5-bromo-1-(4-fluorophenethyl)-1H-pyrazolo[3,4-c]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To a stirred solution of e-bromo-IH-pyrroloP^-clpyridine (800 mg, 4.06 mmol) in DMF (8 mL), NaH (60%), 243.6 mg, 6.09 mmol) was added at 0C. The reaction mixture was allowed to stir at RT for 45 min, then it was cooled to 0C and methyl iodide (384 mg, 2.706 mmol) was added to the mixture and stirred at RT for 3 h. The reaction mixture was quenched in ice water and extracted with EtOAc (2 x 50 mL), washed with brine (30 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated. The resultant crude compound was triturated with n-pentane to afford the title compound (500 mg, 58.6%) as a brown solid. LC-MS (method 1): Rt = 1.26 min; m/z = 210.95 (M+H+).
With potassium carbonate; In dimethyl sulfoxide; at 50℃; for 39h;Inert atmosphere;
To a 40 mL vial equipped with a stir bar was added 1-(2-bromoethyl)-4-fluorobenzene (2.334 g, 11.49 mmol) and <strong>[55717-45-8]6-bromopyridin-3-ol</strong> (1.00 g, 5.75 mmol), thenDMSO (30 ml) and potassium carbonate (1.589 g, 11.49 mmol). The vial was vented to aN2 stream (bubbler), then placed in a 50 C oil bath with stirring for 18h. (t=0). To thereaction solution was added 1-(2-bromoethyl)-4-fluorobenzene (2.334 g, 11.49 mmol).The mixture was stirred at 50 C for 3h. To the reaction mixture was added potassiumcarbonate (1.589 g, 11.49 mmol). The reaction mixture was stirred for 18h. The reactionmixture was cooled to r.t., then was transfered to a 500 mL separatory funnel and was diluted with water (150 mL). The mixture was extracted with Et20 (100 mL). The organic phase was washed with brine (50 mL), then dried over MgSO4, filtered, then concentrated in vacuo. The resulting residue was dissolved in a mm. of acetone and then wasconcentrated onto Celite in vacuo. The resulting powder was subjected to Si02 purification (80g Si02, hexanes:EtOAc 100:0-80:20) to afford a colorless oil that crystallized upon standing to afford 2-bromo-5-(4-fluorophenethoxy)pyridine (1.5337 g, 90 %) as a colorless, crystalline solid. ?H NMR (500MHz, CDC13) 8.04 (d, J=3.0 Hz, 1H), 7.36 (dd, J=8.7, 0.5 Hz, 1H), 7.26 - 7.21 (m, 2H), 7.08 (dd, J=8.8, 3.2 Hz, 1H), 7.05- 6.99 (m, 2H), 4.18 (t, J=6.8 Hz, 2H), 3.08 (t, J=6.8 Hz, 2H).
90%
With potassium carbonate; In dimethyl sulfoxide; at 50℃; for 39h;Inert atmosphere;
To a 40 mL vial equipped with a stir bar was added l-(2-bromoethyl)-4- fluorobenzene (2.334 g, 11.49 mmol) and 6-bromopyri din-3 -ol (1.00 g, 5.75 mmol), then DMSO (30 ml) and potassium carbonate (1.589 g, 11.49 mmol).The vial was vented to a N2 stream (bubbler), then placed in a 50 C oil bath with stirring for 18h.(t=0).To the reaction solution was added l-(2-bromoethyl)-4-fluorobenzene (2.334 g, 11.49 mmol).The mixture was stirred at 50 C for 3h.To the reaction mixture was added potassium carbonate (1.589 g, 11.49 mmol).The reaction mixture was stirred for 18h.The reaction mixture was cooled to r.t., then was transfered to a 500 mL separatory funnel and was diluted with water (150 mL).The mixture was extracted with Et20 (100 mL).The organic phase was washed with brine (50 mL), then dried over MgSCri, filtered, then concentrated in vacuo.The resulting residue was dissolved in a min.of acetone and then was concentrated onto Celite in vacuo.The resulting powder was subjected to S1O2 purification (80g S1O2, hexanes:EtOAc 100:0^80:20) to afford a colorless oil that crystallized upon standing to afford 2-bromo-5-(4-fluorophenethoxy)pyridine (1.5337 g, 90 %) as a colorless, crystalline solid.NMR (500MHz, CDCh) d 8.04 (d, J=3.0 Hz, 1H), 7.36 (dd, =8.7, 0.5 Hz, 1H), 7.26 - 7.21 (m, 2H), 7.08 (dd, =8.8, 3.2 Hz, 1H), 7.05 - 6.99 (m, 2H), 4.18 (t, =6.8 Hz, 2H), 3.08
1-(4-fluorophenethyl)-5-methyl-6-nitroindoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With potassium carbonate; In dichloromethane; at 20℃; for 3h;
5-methyl-6-nitroindoline (340 mg)With 1-<strong>[332-42-3](2-bromoethyl)-4-fluorobenzene</strong> (275 mg)Dissolved in dichloromethane, added potassium carbonate (2.8 g) and reacted at room temperature for 3 h.At the end of the reaction, diluted with 50 mL of ethyl acetate,It was washed with water and the organic phase was dried over anhydrous magnesium sulfate.Filtration removes solid insolubles,The filtrate was concentrated under reduced pressure to give the product (380 mg, 67%).
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 80℃; for 16h;
6-Hydroxy-1-tetralone (39) (1.0 g, 6.16 mmol) was suspended in DMF (15 mL)containing K2C03 (2.0 g, 14.46 mmol) and KI (0.5 g). The reaction solution was treated with 4-fluorophenethybromide (48) (1.5 g, 7.38 mmol) and heated under 80C for 16 hours. Thereaction progress was monitored using silica gel TLC with ethyl acetate:hexane (1:3). Upon completion, the reaction was filtered through a pad of celite and concentrated in vacuo. The crude thus obtained was purified by column chromatography (ethyl acetate/hexane, 1:4) to give Compound 49 (1.2g. 68 %).
With potassium carbonate; In acetonitrile; at 20℃;
General procedure: To a stirring solution of 8 (0.5 mmol) in CH3CN (10 mL) wasadded 1-(2-Bromoethyl)-4-fluorobenzene or 1-(3-bromopropyl)-4-fluorobenzene (0.5 mmol) and K2CO3 (1.0 mmol) at room temperature.The mixture was stirred overnight at room temperature and filtered. The filtrate was diluted by H2O (25 mL), and extractedby DCM (20 mL x 3). The combined organic layer was washed bybrine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified over silica gel column (DCM: MeOH = 20 : 1)to yield oils 10a-b (yield, 65-89%).
tert-butyl (5S)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate[ No CAS ]
tert-butyl (5S)-2-[2-(4-fluorophenyl)ethyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With caesium carbonate; In acetonitrile;
tert-Butyl (5S)-2-[2-(4-fluorophenyl)ethyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate tert-Butyl (5S)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (250 mg, 1.04 mmol) was initially charged in acetonitrile (10 ml). Caesium carbonate (851 mg, 2.61 mmol) and 1-<strong>[332-42-3](2-bromoethyl)-4-fluorobenzene</strong> (223 mg, 1.10 mmol) were subsequently added. After stirring overnight, the reaction mixture was admixed at room temperature with water and ethyl acetate. The organic phase was removed and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and filtered, and the filtrate was concentrated. 340 mg (83% of theory) of the title compound were obtained. LC-MS (Method 4): Rt=0.98 min; MS (ESIpos): m/z=362 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.364 (0.43), 1.391 (16.00), 1.406 (2.02), 1.414 (0.60), 2.039 (0.72), 2.049 (0.64), 2.638 (0.44), 2.909 (0.64), 2.927 (1.21), 2.946 (0.68), 3.807 (0.87), 3.825 (1.29), 3.843 (0.76), 4.352 (0.47), 4.366 (0.64), 4.376 (0.41), 7.062 (0.61), 7.084 (1.28), 7.106 (0.77), 7.219 (0.78), 7.233 (0.93), 7.240 (0.73), 7.254 (0.57).
(E)-N'-(3-ethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dimethyl formimidamide[ No CAS ]
[ 332-42-3 ]
C17H21FN4O2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 24h;
General procedure: To a solution of 8 (0.3 g, 1.43 mmol) indry DMF was added (2-bromoethyl)benzene (396 mg, 2.14 mmol) and K2CO3 (296 mg, 2.14 mmol),and the mixture was stirred at 100 C for 24 h. The reaction mixture was diluted with ethyl acetate(EA), and the organic layer was washed with water for three times, and dried over anhydrous Na2SO4,and concentrated under reduced pressure to afford the crude product for the next step withoutfurther purification.Crude product in MeOH:H2O (v/v = 9:1) was added LiOH.H2O (180 mg, 4.28 mmol), and thenheated to 55 C for 12 h. The solvent was acidified to pH 7 by using concentrated HCl and evaporatedunder vacuum. The residue was purified by silica gel column (DCM/MeOH, 20/1) to afford 9a
(7aR,12bS)‐9‐hydroxy‐3‐(4‐fluorophenethyl)‐2,3,4,4a,5,6‐hexahydro‐1H‐4,12‐methanobenzofuro[3,2‐e]‐isoquinolin‐7(7aH)‐one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 90℃;
General procedure: To a stirred solution of N-norhydromorphone (S10 in the SupplementaryMaterials, 0.406 g, 1.5 mmol) in DMF (10 mL) were added NaHCO3 (0.504 g, 6 mmol) and 1-(2-bromoethyl)-4-chlorobenzene (0.480 mL, 3.3 mmol). The mixture was heated at 90 C overnight,cooled to room temperature, filtered through Celite, and concentrated in vacuo. Water (10 mL) wasadded and the mixture extracted with CHCl3 (3 × 20 mL). The combined organics were washed withH2O (5 × 20 mL), dried over Na2SO4, filtered through Celite, and concentrated in vacuo to afford 2ifree base as a crude colorless oil. Purification of this oil by SiO2 column chromatography with 10%NH4OH in MeOH/CHCl3 (gradient, 0 ? 4% of 10% NH4OH) afforded 2i (0.420 g, 70%) as a colorlessoil.
Stage #1: 6H-purine-6-thione With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h;
Stage #2: (2-bromoethyl)-4-fluorobenzene In N,N-dimethyl-formamide at 20℃; for 5h;
1 6-((4-Fluorophenethyl)thio)-9H-purine (9)
6-mercaptopurine monohydrate (300.0 mg, 1.76 mmol) and K2CO3 (243.7 mg, 1.76 mmol) are dissolved in DMF (25 ml). The reaction mixture is stirred for 1 h at room temperature. Then 4-fluorophenethyl bromide (358.0 mg, 1.76 mmol) is added and it is stirred for 5 h at room temperature. The solvent is evaporated under reduced pressure and AcOEt (100 ml) is added. The organic phase is washed with distilled water (3 x 100 ml) by adding a little NaCl. It is dried over anhydrous Mg2SO4, filtered and concentrated until it is dry. The crude product is purified by means of a chromatographic column using CH2Cl2/MeOH (10:1) as eluent. In this manner, product 9 is obtained in the form of a white solid (285.0 mg, 59%). 1H-NMR (300 MHz, DMSO-d6): δ 13.51 (s, 1H), 8.70 (s, 1H), 8.42 (s, 1H), 7.45 - 7.26 (m, 2H), 7.22 - 6.94 (m, 2H), 3.59 (t, J= 7.6 Hz, 2H), 3.02 (t, J = 7.5 Hz, 2H). 13C-NMR (75 MHz, DMSO-d6): δ 160.9 (d, J = 241.7 Hz, 1C), 158.6 (1C), 151.5 (1C), 149.2 (1C), 142.9 (1C), 136.3 (d, J = 2.7 Hz, 1C), 130.4 (d, J = 7.9 Hz, 2C), 130.4 (1C), 115.0 (d, J = 21.0 Hz, 2C), 34.3 (1C), 29.2 (1C). HPLC: Purity > 99%, t.r. = 6.99 min. MS (ES): m/z 275 [M+1]. M.p. 184 - 186 °C. Elemental analysis (C13H11FN4S) Calculated: C 56.82%, H 4.04%, N 20.42%, S 11.69%. Found: C 56.38%, H 4.01%, N 20.04%, S 11.43%.
3-[(4-fluorophenethyl)sulfanyl]-5-(pyridin-4-yl)-4H-1,2,4-triazol-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With sodium hydroxide In methanol at 20℃; for 2.5h;
General procedure for the synthesis of 5-(pyridin-4-yl)-3-(alkylsulfanyl)-4H-1,2,4-triazol-4-amine derivatives9, 13-15, and 17-18.
General procedure: The 4-amino-5-(4-pyridinyl)-4H-1,2,4-triazole-3-thiol (5) (200 mg, 1.03 mmol) and NaOH(41 mg, 1.02 mmol) were dissolved in MeOH (8 mL); after complete dissolution, the suitable alkyl halidederivative (1.03 mmol) was added dropwise. We generally employed alkyl bromide derivatives to preparedesigned compounds, except for desired compound 9 for which we used the suitable alkyl chloride derivative.The reaction mixture was stirred for 2.5 hours at room temperature. Upon completion of the reaction, thesolvent was removed under reduced pressure and the solid residue was re-crystalized from diethylether/ethanol, providing the pure final pyridyl-triazole derivatives as a powder. The registered CAS number forcompound 9 has been already assigned and is available at https://www.cas.org; however, its syntheticprocedure, chemical and structural characterization are not available in literature.
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