* 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] Journal of Organic Chemistry USSR (English Translation), 1988, vol. 24, p. 149 - 154[2] Zhurnal Organicheskoi Khimii, 1988, vol. 24, # 1, p. 168 - 174
2
[ 98-82-8 ]
[ 3575-19-7 ]
[ 7073-94-1 ]
[ 5433-01-2 ]
[ 586-61-8 ]
Reference：
[1] Russian Journal of General Chemistry, 2010, vol. 80, # 2, p. 263 - 267
3
[ 51605-97-1 ]
[ 5433-01-2 ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: With sulfuric acid; sodium nitrite In ethanol; water at -5℃; Inert atmosphere Stage #2: With copper In ethanol; water for 4 h; Reflux; Inert atmosphere
2-Bromo-4-isopropylaniline 12 (2.65 g, 12.4 mmol, 1.0 eq.) was added over 15 min. to a mixture of ethanol 96percent (23 mL) and conc. sulfuric acid (2.5 mL) at -5°C under vigorous stirring. Then, a solution of sodium nitrite (1.42 g, 20.7 mmol, 1.67 eq.) in water (3 mL) was added at -5°C over 1 h and the resulting mixture was stirred for 30 minutes, followed by addition of copper powder (12.0 g). The reaction mixture was refluxed for 4 h and filtered through glass frit. The filtrated was poured into cold water (60 mL) and the organic product was extracted with DCM (4 x 50 mL). The combined organic extracts were dried over potassium carbonate and concentrated. Fractional distillation (11 mmHg, 89-90°C) of the residue gave 13 as yellowish oil (1.91g, 77percent yield).
Reference：
[1] Synthesis (Germany), 2016, vol. 48, # 19, p. 3301 - 3308
[2] Journal of the Chemical Society, 1939, p. 1299,1301
[3] Journal of Organic Chemistry, 1939, vol. 4, p. 20,26
[4] Angewandte Chemie - International Edition, 2012, vol. 51, # 3, p. 794 - 797
Reference：
[1] Journal of the Chemical Society, 1939, p. 1299,1301
[2] Angewandte Chemie - International Edition, 2012, vol. 51, # 3, p. 794 - 797
[3] Synthesis (Germany), 2016, vol. 48, # 19, p. 3301 - 3308
9
[ 5702-74-9 ]
[ 5433-01-2 ]
Reference：
[1] Journal of the Chemical Society, 1939, p. 1299,1301
[2] Journal of Organic Chemistry, 1939, vol. 4, p. 20,26
[3] Synthesis (Germany), 2016, vol. 48, # 19, p. 3301 - 3308
10
[ 68748-07-2 ]
[ 5433-01-2 ]
Reference：
[1] Journal of the Chemical Society, 1939, p. 1299,1301
[2] Journal of Organic Chemistry, 1939, vol. 4, p. 20,26
[3] Synthesis (Germany), 2016, vol. 48, # 19, p. 3301 - 3308
11
[ 30951-66-7 ]
[ 5433-01-2 ]
Reference：
[1] Journal of Organic Chemistry, 1972, vol. 37, # 1, p. 126 - 131
12
[ 98-82-8 ]
[ 7073-94-1 ]
[ 5433-01-2 ]
[ 586-61-8 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1988, vol. 24, p. 149 - 154[2] Zhurnal Organicheskoi Khimii, 1988, vol. 24, # 1, p. 168 - 174
13
[ 98-82-8 ]
[ 3575-19-7 ]
[ 7073-94-1 ]
[ 5433-01-2 ]
[ 586-61-8 ]
Reference：
[1] Russian Journal of General Chemistry, 2010, vol. 80, # 2, p. 263 - 267
14
[ 98-82-8 ]
[ 7073-94-1 ]
[ 5433-01-2 ]
[ 586-61-8 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1988, vol. 24, p. 149 - 154[2] Zhurnal Organicheskoi Khimii, 1988, vol. 24, # 1, p. 168 - 174
15
[ 98-82-8 ]
[ 3575-19-7 ]
[ 7073-94-1 ]
[ 5433-01-2 ]
[ 586-61-8 ]
Reference：
[1] Russian Journal of General Chemistry, 2010, vol. 80, # 2, p. 263 - 267
16
[ 5433-01-2 ]
[ 124-38-9 ]
[ 5651-47-8 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With magnesium In tetrahydrofuran at 50 - 60℃; Stage #2: for 0.666667 h; Stage #3: With hydrogenchloride In tetrahydrofuran; water
Intermediate C. Method A: 3-Isopropylbenzoic acid (C-a). To a solution of l-bromo-3-isopropylbenzene (1.24 g, 6.23 mmol) in THF (18 ml) was added magnesium wire (0.151 g, 1 eq.). The mixture was heated to 50 to 600C until the magnesium was dissolved. To this solution was added an excess of solid CO2 and after 40 min the reaction mixture was acidified with IM aq. HCl. The product was extracted into DCM, the organic layer was dried over MgSO4 and evaporated, yielding the target product (1.07 g <n="127"/>(quantitative)). 1H-NMR (CDCl3) δ (ppm) 8.00 (s, IH), 7.95 (d, IH), 7.49 (d, IH), 7.41 (t, IH), 3.00 (m, IH), 1.30 (d, 6H).
92%
Stage #1: With tert.-butyl lithium In diethyl ether; pentane at -78℃; for 0.166667 h; Stage #3: With hydrogenchloride In diethyl ether; water; pentane
Method 72; 3-Isopropylbenzoic acid; A solution of l-bromo-3-isopropylbenzene (500 mg, 2.51 mmol) in pentane/ether (1:1; 8 ml) was treated with t-butyllithium (1.7 M in pentane, 3.0 ml) at -78 °C. The mixture was stirred at -78 0C for 10 min and then CO2 (g) was bubbled into the mixture for several minutes. The reaction was quenched with 10percent HCl and extracted with EtOAc. The organic layer was dried with NaCl (sat) then Na2SO4 (s). The solvents were removed under reduced pressure to give a white solid (379 mg, 92percent); m/z 166.
Reference：
[1] Patent: WO2007/75896, 2007, A2, . Location in patent: Page/Page column 125-126
[2] Patent: WO2006/40568, 2006, A1, . Location in patent: Page/Page column 73
[3] Journal of Organic Chemistry, 1972, vol. 37, # 1, p. 126 - 131
[4] Angewandte Chemie - International Edition, 2012, vol. 51, # 3, p. 794 - 797
17
[ 5433-01-2 ]
[ 5651-47-8 ]
Reference：
[1] Journal of the American Chemical Society, 1955, vol. 77, p. 3763,3764
[2] Patent: WO2007/27842, 2007, A1, . Location in patent: Page/Page column 121-122
18
[ 5433-01-2 ]
[ 5369-16-4 ]
Reference：
[1] Yakugaku Zasshi, 1955, vol. 75, p. 289,291[2] Chem.Abstr., 1956, p. 2502
19
[ 5433-01-2 ]
[ 34246-57-6 ]
Reference：
[1] Angewandte Chemie - International Edition, 2012, vol. 51, # 3, p. 794 - 797
20
[ 5433-01-2 ]
[ 78191-00-1 ]
[ 40428-87-3 ]
Yield
Reaction Conditions
Operation in experiment
66%
Stage #1: With n-butyllithium In tetrahydrofuran at -60℃; for 0.5 h; Inert atmosphere Stage #2: at -30℃; for 3 h; Inert atmosphere
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of N2 was placed a solution of 1-bromo-3- (propan-2-yl)benzene (5.0 g, 25.11 mmol, 1.00 equiv) in THF (250 mL). This was followed by the addition of n-BuLi (20 mL, 2.00 equiv) dropwise with stirring at -60 °C. The mixture was stirred at -60°C for 30 mm. To this was added N-methoxy-N-methylacetamide (3.9 g, 37.82 mmol, 1.50 equiv) dropwise with stirring at -30 °C. The resulting solution was stirred for 3 h at -30 °C in a liquid N2 bath. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was diluted with 200 mL of EtOAc, washed with 2x100 mL of brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column with EtOAc/petroleum ether (1:10). This resulted in 2.7 g (66percent) of the title product as colorless oil.
Intermediate C. Method A: 3-Isopropylbenzoic acid (C-a). To a solution of l-bromo-3-isopropylbenzene (1.24 g, 6.23 mmol) in THF (18 ml) was added magnesium wire (0.151 g, 1 eq.). The mixture was heated to 50 to 600C until the magnesium was dissolved. To this solution was added an excess of solid CO2 and after 40 min the reaction mixture was acidified with IM aq. HCl. The product was extracted into DCM, the organic layer was dried over MgSO4 and evaporated, yielding the target product (1.07 g <n="127"/>(quantitative)). 1H-NMR (CDCl3) delta (ppm) 8.00 (s, IH), 7.95 (d, IH), 7.49 (d, IH), 7.41 (t, IH), 3.00 (m, IH), 1.30 (d, 6H).
92%
Method 72; 3-Isopropylbenzoic acid; A solution of l-bromo-3-isopropylbenzene (500 mg, 2.51 mmol) in pentane/ether (1:1; 8 ml) was treated with t-butyllithium (1.7 M in pentane, 3.0 ml) at -78 C. The mixture was stirred at -78 0C for 10 min and then CO2 (g) was bubbled into the mixture for several minutes. The reaction was quenched with 10% HCl and extracted with EtOAc. The organic layer was dried with NaCl (sat) then Na2SO4 (s). The solvents were removed under reduced pressure to give a white solid (379 mg, 92%); m/z 166.
Example 198Preparation of 2-ri-(3,6-dimethylpyrazin-2-yl)-3-(3-isopropylphenyl)-lH-pyrazol-5- yllamino-4-fluorobenzoic acidStep 1: Preparation of 3-isopropylbenzoic acid; 3-isopropylbenzoic acid was prepared following a known literature procedure from 1-bromo 3-isoproylbenzene (Smith, J.G.; Turle, R.A.; /. Org. Chem. 1972, 37, 126-131).
With magnesium; In tetrahydrofuran; for 0.75h;Heating / reflux;
A solution of 3-bromoisopropylbenzene (25 mmol) in 20 ml_ of dry THF was added dropwise over 20 min to 1.22 g (50 mmol) of magnesium turnings in 10 mL of refluxing THF under nitrogen and the mixture was refluxed for an additional 25 min to form the Grignard reagent. The Grignard solution was cooled and added by cannula to a suspension of CuBr-dimethylsulfide complex (0.52 g, 2.5 mmol) in dry THF at -25 C. The suspension was stirred at -25 C for 20 min, and then a solution of 1,4 cyclohexanedione, monoethylene ketal (3.9 g, 25 mmol) in 15 mL of THF was added dropwise over 5 min. The mixture was allowed to gradually warm to ambient temperature. After chromatography over silica gel, eluting with 20% to 30% ethyl acetate in heptane, alcohol 9 (5.6 g, 20 mmol, 80%) was isolated as a colorless oil which crystallized to a white solid on cooling: 1H NMR (CDCI3) 8 7.39 (s, 1 H), 7.33 (m, 1 H), 7.28 (t, J= 7.5 Hz, 1 H), 7.13 (d, J= 7.5 Hz, 1 H), 4.0 (m, 4 H), 2.91 (hept, J=7Hz, 1 H), 2.15(171, 4 H), 1.82 (br d, J= 11.5 Hz, 2 H), 1.70 (br d, J= 11.5 Hz, 2 H), 1.25 (d, J = 7 Hz, 6 H); MS (Cl) m/z 259.2 (M-OH).
With magnesium; In tetrahydrofuran; for 0.75h;Heating / reflux;
A solution of 3-bromoisopropylbenzene (25 mmol) in 20 mL of dry THF is added dropwise over 20 min to 1.22 g (50 mmol) of magnesium turnings in 10 mL of refluxing THF under nitrogen and the mixture is refluxed for an additional 25 min to form the Grignard reagent. The Grignard solution is cooled and added by cannula to a suspension of CuBr-dimethylsulfide complex (0.52 g, 2.5 mmol) in dry THF at-25 C. The suspension is stirred at-25 C for 20 min, and then a solution of 1,4 cyclohexanedione, monoethylene ketal (3.9 g, 25 mmol) in 15 mL of THF is added dropwise over 5 min. The mixture is allowed to gradually warm to ambient temperature. After chromatography over silica gel, eluting with 20% to 30% ethyl acetate in heptane, alcohol 21 (5.6 g, 20 mmol, 80%) as a colorless oil which crystallizes to a white solid on cooling : 1H NMR (CDC13) 8 7.39 (s, 1 H), 7.33 (m, 1 H), 7. 28 (t, J= 7.5 Hz, 1 H), 7.13 (d, J= 7.5 Hz, 1 H), 4.0 (m, 4 H), 2.91 (hept, J= 7 Hz, 1 H), 2.15 (m, 4 H), 1.82 (brd, J= 11. 5 Hz, 2 H), 1.70 (brd, J= 11. 5 Hz, 2 H), 1.25 (d, J= 7 Hz, 6 H); MS (CI) m/z 259.2 (M-OH).
Reference Example 2 In accordance with Reference Example 1 and using 3-(1-methylethyl)aniline instead of 3-ethylaniline, the following Reference Example compound 2 was synthesised.
With triethylamine;palladium diacetate; tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide;
A. (E)-3-(3-lsopropyl-phenyl)-acrylicacid methyl ester; EPO <DP n="122"/>A solution of <strong>[5433-01-2]1-bromo-3-isopropylbenzene</strong> (5.0 g, 24 mmol), methyl acrylate (4.3 mL, 48 mmol), triethylamine (5.0 mL, 36 mmol), Pd(OAc)2 (0.16 g, 0.7 mmol) and tri-ortho-tolyl- phosphine (0.45 g, 1.4 mmol) in DMF (50 mL) is heated under reflux overnight. The solvent was removed in vacuo, the residue is taken up in AcOEt, washed with water, dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (eluent: hexane/AcOEt 98/2) to give the title compound. TLC, Rf (hexane/AcOEt 19/1) = 0.25. MS(EI+): 222 (M+18).
With potassium chloride; tetrabutylammonium acetate; palladium diacetate; potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 24h;Inert atmosphere;
1-Bromo-3-isopropylbenzene 13 (1.5 g, 7.5 mmol, 1.0 eq.), acrolein-diethylacetal (3.57g, 23.43 mmol, 3.1 eq.), Bu4NOAc (5.0 g, 16.6 mmol, 2.2 eq.), potassium carbonate (1.56 g, 11.3 mmol, 1.5 eq.), potassium chloride (0.75 g, 7.6 mmol, 1.01 eq.) and palladium(II) acetate (50 mg, 0.22 mmol, 0.029 eq.) were suspended in DMF (32 mL) and heated for 24 h at 90C. The reaction mixture was cooled to room temperature, diluted with water (25 mL) and acidified with HCl 2M. After extraction with methyl-tert-butyl ether, the organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel (hexane/EtOAc 19/1) to give 14 (928 mg, 71% yield).
With potassium chloride; tetrabutylammonium acetate; potassium carbonate;palladium diacetate; In N,N-dimethyl-formamide; at 90℃; for 24h;
A. (E)-3-(3-lsorhoropyl-phenyl)-propenal; 1-Btauomo-3-isopropylbenzene (14.5 g, 69 mmol), acrolein-diethylacetal (33.5 mL, 208 mmol), Bu4NOAc (44 g, 138 mmol), K2CO3 (14.5 g, 104 mmol), KCI (5.2 g, 70 mmol) and Pd(OAc)2 (0.5 g, 2 mmol) are suspended in 290 mL DMF and heated for 24 h at 900C. The reaction mixture is cooled to ambient temperature, diluted with water (10OmL) and acidified with 2N HCI. After extraction with TBME, the organic layer is washed with water, dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography on silica gel (eluent: hexane/AcOEt 19/1) to give the titie compound. TLC, Rf (hexane/AcOEt 10/1) = 0.56. MS(EI+): 175 (M+1).
EXAMPLE 50 Preparation of Ethyl beta-Amino-m-Isopropylcinnamate. To the Grignard reagent prepared from 39.5 g (0.198 mol) of <strong>[5433-01-2]m-bromocumene</strong> and 4.9 g (0.20 mol) of magnesium in 150 ml of ether was added 11.2 g (0.099 mol) of ethyl cyanoacetate dropwise with stirring at 10. The mixture was stirred at reflux for 22 hours and was allowed to stand at 23 for four days. Then, 10.6 g (0.20 mol) of NH4 Cl in 60 ml of water was added with stirring at 10-15, followed by 0.20 mol of 2N HCl at 0. The layers were separated, and the water layer was extracted with 100 ml of ether. The ether layers were combined, extracted with dilute NaHCO3 solution, dried (CaSO4), and distilled to give 4.95 g of 80% pure product, boiling point 139-142 (0.15 torr) and 0.87 g of about 97% pure product, boiling point 142-143 (0.15 torr). [Infrared analysis of the lower-boiling impurity indicated it to be bi(m-cumenyl)]. Anal. Calc'd. for 97% C14 H19 NO2 -3% C18 H22; C, 72.60; H, 8.24; N, 5.82. Found: C, 72.60; H, 8.46; N, 5.84.
With magnesium; In water;
EXAMPLE 50 Preparation of Ethyl beta-Amino-m-Isopropylcinnamate. To the Grignard reagent prepared from 39.5 g (0.198 mol) of <strong>[5433-01-2]m-bromocumene</strong> and 4.9 g (0.20 mol) of magnesium in 150 ml of ether was added 11.2 g (0.099 mol) of ethyl cyanoacetate dropwise with stirring at 10. The mixture was stirred at reflux for 22 hours and was allowed to stand at 23 for four days. Then, 10.6 g (0.20 mol) of NH4 Cl in 60 ml of water was added with stirring at 10-15, followed by 0.20 mol of 2 N, HCl at 0. The layers were separated, and the water layer was extracted with 100 ml of ether. The ether layers were combined, extracted with dilute NaHCO3 solution, dried (CaSO4), and distilled to give 4.95 g of 80% pure product, boiling point 139-142 (0.15 torr) and 0.87 g of about 97% pure product, boiling point 142-143 (0.15 torr). [Infrared analysis of the lower-boiling impurity indicated it to be bi(m-cumenyl)]. Anal. Calc'd. for 97% C14 H19 NO2 -3% C18 H22: C, 72.60; H, 8.24; N, 5.82. Found: C, 72.60; H, 8.46; N, 5.84.
Example 3; N-{1-(3,5-Difluoro-bthetanzyl)-3-[1-ethyl-4-(3-isopropyl-phe?yl)-2-oxo-pipbetaridin-4- ylami?o]-2-hydroxy-propyl}-acbetatamide ( alternate synthesis ); Referring to Scheme 1c, intermediate compounds 14,16, 23, 24, 25, 26, 27 and the Me ester of 17 were prepared according to the following procedures:; In a 250 ml round bottom flask with reflux condenser and N2 cap, a solution of 25 gm (125.6 mmol) <strong>[5433-01-2]1-bromo-3-isopropylbenzene</strong> and 45 gm (502.5 mmol) copper cyanide in 50 ml of pyridine was heated in a 150 0C oil bath for 2 hr where upon a dark brown homogeneous solution was formed. The reaction mixture was heated at this temperature for 11 hrs. The refluxing solution was treated with benzene and allowed to cool. The reaction mixture was partitioned between 400 ml cone NH4OH and 200 ml of benzene and was then stirred for 30 min. The mixture was poured through a small pad of silica to remove any remaining solids. The organic phase was removed and the aqueous layer was washed several times with methylene chloride. The combined organic layers were washed with saturated brine and then dried and evaporated to afford 18 gm (100%) of 3-isopropylbenzonitrile. NMR (400 MHz, CDCI3) delta 7.5-7.2 (m, 3H), 2.9 (m, 1H), 1.2 (d, 6H) ppm
100%
With pyridine; at 180℃; for 24h;
3-isopropyl-benzonitrile 5.15 g (25.87 mmol) m-bromo-isopropyl-benzene and 2.69 g (30.04 mmol) copper cyamide are stirred in 2.50 ml of pyridine for 24 hours at 180 C. Then 15 ml of water, 15 ml of toluene and 15 ml conc. ammonia solution are added, then the mixture is extracted. The organic phase is dried and evaporated to dryness. Yield: 5.00 g (100% of theoretical)
100%
3-isopropyl-benzonitrile 5.15 g (25.87 mmol) m-bromo-isopropyl-benzene and 2.69 g (30.04 mmol) copper cyanide are stirred in 2.50 ml of pyridine for 24 hours at 180 C. Then 15 ml of water, 15 ml of toluene and 15 ml conc. ammonia solution are added, then the mixture is extracted. The organic phase is dried and evaporated to dryness. Yield: 5.00 g (100% of theoretical)
With sulfuric acid; sodium nitrite; In ethanol; water;
1-Bromo-3-isopropylbenzene To a mixture of 1000 ml of 96% ethanol and 94 ml of 98% H2SO4, 117 g (0.55 mol) of 2-bromo-4-isopropylaniline was added over 15 min. with vigorous stirring at -5 C. Then, a solution of 63 g of NaNO2 in 125 ml of water was added at this temperature over 1 h, and the resulting mixture was stirred for about 30 min longer. Then, 12 g of copper powder was added. The reaction mixture was refluxed for 4 h and filtered through a glass frit (G3). The filtrate was poured into 2500 cm3 of cold water. The organic product was extracted with 4*400 ml of dichloromethane. The combined extract was dried over K2CO3 and evaporated to dryness. Fractional distillation gave the title product, b.p. 64-67 C./3 mm Hg. Yield 117.4 g (75%) of yellowish oil. Anal. calc. for C9H11Br: C, 54.30; H, 5.57. Found: C, 54.44; H, 5.49. 1H NMR (CDCl3): delta 7.37 (m, 1H, 2-H), 7.28-7.34 (m, 1H, 5-H), 7.15-7.16 (m, 1H, 6-H), 7.14 (d, J=1.0 Hz, 1H, 2-H), 2.87 (sept, J=6.9 Hz, 1H, CHMe2), 1.24 (d, J=6.9 Hz, 6H, CHMe2).
7-Bromo-5-isopropyl-2-methyl-1-indanone To a mixture of 34.9 g (0.26 mol) of AlCl3 and 350 ml of dichloromethane, a solution of 50.9 g (0.22 mol) of 2-bromo-2-methylpropanoyl bromide in 120 ml of dichloromethane was added dropwise with vigorous stirring at -10 C. Then, a solution of 40.0 g (0.20 mol) of <strong>[5433-01-2]1-bromo-3-isopropylbenzene</strong> in 70 ml of dichloromethane was added dropwise at this temperature. The resulting mixture was refluxed for 12 h and then poured onto 2000 cm3 of ice. The organic product was extracted with 4*300 ml of dichloromethane. The combined extract was dried over K2CO3 and evaporated to dryness. Fractional distillation gave the title product, b.p. 130-135 C./1.5 mm Hg. Yield 36.2 g (67%). Anal. calc. for C13H15BrO: C, 58.44; H, 5.66. Found: C, 58.40; H, 5.67. 1H NMR (CDCl3): delta 7.37 (s, 1H, 6-H), 7.23 (s, 1H, 4-H), 3.31 (dd, J=16.7 Hz, J=8.0 Hz, 1H, 3-H), 2.94 (sept, J=6.8 Hz, 1H, CHMe2), 2.71 (m, 1H, 2-H), 2.65 (m, 1H, 3'-H), 1.30 (d, J=7.4 Hz, 3H, 2-Me), 1.27 (d, J=6.8 Hz, 6H, CHMe2).
tetrakis(triphenylphosphine) palladium(0); In 1-methyl-pyrrolidin-2-one; at 125℃; for 2.5h;
1 -Bromo-3-isopropylbenzene (200 g, 954 mmol, 1 eq) is dissolved in 1 I of 1-methyl-2-pyrro- lidone. Zinc cyanide (114 g, 954 mmol, 1 eq) and Pd(PPh3)4 (28.7 g, 24.8 mmol, 0.03 eq) are added under nitrogen. The reaction mixture is heated to 125C, stirred at this temperature for 150 min, then cooled to rt and filtered over Hyflo Super Gel, and the filtrate is diluted with H2O and EtOAc. The organic layer is washed with water, 1 N HCI solution and brine, dried -~ over sodium sulfate, filtered and concentrated. The residue is purified by column chromatography using DCM/hexane in a ratio of 1 to 3 to give the product. <n="103"/>HPLC (Nucleosil C18HD, 4x70 mm, 3 mum, 20-100% MeCN (6 min), 100% MeCN (3 min)) retention time: 5.06 min.1H-NMR (400 MHz, CDCI3): 7.57 (s, 1H), 7.53-7.48 (m, 2H), 7.43 (t, 1H), 3.01-2.92 (m, 1H), 1.29 (d, 6H).
tetrakis(triphenylphosphine) palladium(0); In 1-methyl-pyrrolidin-2-one; at 125℃; for 2.5h;
a) 3-lsopropyl-benzonitrileTo a solution of 200 g (954 mmol) of 1 -bromo-3-isopropyl-benzene in 1 I of 1 -methyl-2-pyrro- lidone are added under a nitrogen atmosphere 1 14 g (954 mmol) of zinc cyanide and 28.7 g (24.8 mmol) of Pd(PPh3)4. The mixture is heated to 1259C, stirred at this temperature for 150 min, then cooled to rt and filtered through Hyflo Super Gel. The filtrate is diluted with water and EtOAc. The organic layer is washed with water, 1 N aq. HCI and brine, dried over sodium sulfate and concentrated. The residue is purified by column chromatography (DCM/he- xanes 1/3) to yield the title compound. <n="24"/>1H-NMR (400 MHz, CDCI3): 7.57 (s, 1 H), 7.53-7.48 (m, 2H), 7.43 (t, 1 H), 3.01 -2.92 (m, 1 H), 1.29 (d, 6H).
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; In toluene; for 12h;Heating / reflux;
Preparation Example 1-1: Preparation of 4-t-butyl-N- (4- isopropylphenyl ) benzenamine; As represented below in Reaction Scheme 1, 25g of 3-t- butylaniline (0.125mol) and 37.3g of 3-bromoisopropylbenzene(0.25mol) were dissolved in 25OmL of toluene, and 3.43g ofPd2(dba)3 (0.0037mol) was added thereto under a nitrogen atmosphere. Then, 14.4g of NaOBufc (0.15mol) and 1.157g of (t- Bu)3P (0.0075mol) were added to the reaction solvent, and the reaction mixture was refluxed and stirred for 12 hours. The reaction mixture was checked for the completion of the reaction by means of TLC, and if the reaction was completed, the reaction product was cooled down to room temperature. The reacted solution was poured onto a thin silica pad to perform short chromatography, and then was washed with methylene chloride (MC) . The washed solution was subjected to distillation under reduced pressure to thereby remove the solvent, and was chromatographed using n-hexane to thereby obtain a desired white solid product (29.4g, 88percent). [Reaction Scheme 1]
To 1.2 g (50 mmol) of magnesium turnings in 15 mL of dry THF is added a small crystal of iodine followed by 40 pL of dibromoethane. This mixture is placed in a water bath at 50 C and <strong>[5433-01-2]3-isopropylbromobenzene</strong> (5.0 g, 25 mmol) in 15 mL of dry tetrahydrofuran (THF) is added dropwise over 20 min, while the bath temperature is raised to 70 C. The mixture is stirred and refluxed for 40 additional min. The solution is cooled in an ice-water bath and cyclohexanone (2.0 mL, 19 mmol) in 10 mL of dry THF is added dropwise over 15 min. The ice bath is removed and the mixture is allowed to warm to ambient temperature over 1 h. The solution is decanted into aqueous saturated NH4C1 and combined with an ether wash of the residual magnesium turnings. The organic phase is washed twice more with aqueous NH4CI, dried over anhydrous sodium sulfate, filtered and concentrated. Chromatography on silica gel, eluting with 10% ethyl acetate in heptane, affords 2.7 g (12 mmol, 60%) of 1- (3-isopropylphenyl) cyclohexanol 5 as an oil : 1H NMR (CDC13) 8 7.39 (m, 1 H), 7.3 (m, 2 H), 7.12 (m, 1 H), 2.92 (m, 1 H), 1.84-1. 54 (m, 10 H), 1.26 (d, J = 7 Hz, 6 H).
58 - 60%
To 1.2 g (50 mmol) of magnesium turnings in 15 mL of dry THF is added a small crystal of iodine followed by 40, uL of dibromoethane. This mixture is placed in a water bath at 50 C and <strong>[5433-01-2]3-isopropylbromobenzene</strong> (5.0 g, 25 mmol) in 15 mL of dry tetrahydrofuran (THF) is added dropwise over 20 min, while the bath temperature is raised to 70 C. The mixture is stirred and refluxed for 40 additional min. The solution is cooled in an ice-water bath and cyclohexanone (2.0 mL, 19 mmol) in 10 mL of dry THF is added dropwise over 15 min. The ice bath is removed and the mixture is allowed to warm to ambient temperature over 1 h. The solution is decanted into aqueous saturated NH4CI and combined with an ether wash of the residual magnesium turnings. The organic phase is washed twice more with aqueous NH4CI, dried over anhydrous sodium sulfate, filtered and concentrated. Chromatography on silica gel, eluting with 10% ethyl acetate in heptane, affords 2.7 g (12 mmol, 60%) of 1- (3-isopropylphenyl) cyclohexanol 5 as an oil :'H NMR (CDCI3) ; 8 7.39 (m, 1 H), 7.3 (m, 2 H), 7.12 (m, 1 H), 2.92 (m, 1 H), 1.84-1. 54 (m, 10 H), 1.26 (d, J = 7 Hz, 6 H).
A solution of 3-bromoisopropylbenzene (25 mmol) in 20 mL of dry THF is added dropwise over 20 min to 1.22 g (50 mmol) of magnesium turnings in 10 mL of refluxing THF under nitrogen and the mixture is refluxed for an additional 25 min to form the Grignard reagent. The Grignard solution is cooled and added by cannula to a suspension of CuBr-dimethylsulfide complex (0.52 g, 2.5 mmol) in dry THF at-25 C. The suspension is stirred at-25 C for 20 min, and then a solution of 1,4 cyclohexanedione, monoethylene ketal (3.9 g, 25 mmol) in 15 mL of THF is added dropwise over 5 min. The mixture is allowed to gradually warm to ambient temperature. After chromatography over silica gel, eluting with 20% to 30% ethyl acetate in heptane, alcohol 62 (5.6 g, 20 mmol, 80%) as a colorless oil which crystallizes to a white solid on cooling : H NMR (CDCl3) No. 7.39 (s, 1 H), 7.33 (m, 1 H), 7.28 (t, J=7. 5Hz, 1 H), 7.13 (d, J=7. 5Hz, 1 H), 4.0 (m, 4 H), 2.91 (hept, J = 7 Hz, 1 H), 2.15 (m, 4H), 1.82 (brd, J=11. 5Hz, 2H), 1.70 (brd, J=11. 5Hz, 2H), 1.25 (d, J = 7 Hz, 6 H); MS (CI) m/z 259.2
80%
A solution of 3-bromoisopropylbenzene (25 mmol) in 20 ml_ of dry THF was added dropwise over 20 min to 1.22 g (50 mmol) of magnesium turnings in 10 mL of refluxing THF under nitrogen and the mixture was refluxed for an additional 25 min to form the Grignard reagent. The Grignard solution was cooled and added by cannula to a suspension of CuBr-dimethylsulfide complex (0.52 g, 2.5 mmol) in dry THF at -25 C. The suspension was stirred at -25 C for 20 min, and then a solution of 1,4 cyclohexanedione, monoethylene ketal (3.9 g, 25 mmol) in 15 ml of THF was added dropwise over 5 min. The mixture was allowed to gradually warm to ambient temperature. After chromatography over silica gel, eluting with 20% to 30% ethyl acetate in heptane, alcohol 1 (5.6 g, 20 mmol, 80%) as a colorless oil which crystallized to a white solid on cooling: 1H NMR (CDCIs) 8 7.39 (s, 1 H), 7.33 (m, 1 H), 7.28 (t, J= 7.5 Hz, 1 H), 7.13 (d, J= 7.5 Hz, 1 H), 4.0 (m, 4 H), 2.91 (hept, J=7Hz, 1 H), 2.15 (m, 4 H), 1.82 (br d, J= 11.5 Hz, 2 H), 1.70(br d, J = 11.5 Hz, 2 H), 1.25 (d, J = 7 Hz, 6 H); MS (Cl) m/z 259.2 (M-OH).
Method B: Ethyl 3-isopropyIbenzoate (C-b). To a solution of l-bromo-3- isopropylbenzene (2.43 g, 12.5 mmol) in THF (18 ml) was added magnesium wire (0.296 g, 1 eq.). The mixture was heated to 50 to 600C until the magnesium was dissolved. To this was added a THF solution of ethyl chloro formate (1.3 ml, 1.1 eq.) at -78C and the mixture was allowed to warm up to room temperature . The reaction mixture was diluted with IM aq. HCl. The product was extracted into DCM, the organic layer was dried over MgSO4 and evaporated. Column chromatography (silica gel) using hexanes afforded the desired ethyl ester (1.04 g, 43 %). 1H-NMR (CDCl3) delta (ppm) 7.94 (s, IH), 7.89 (d, IH), 7.44 (d, IH), 7.38 (t, IH), 4.41 (q, 2H), 3.00.(m, IH), 1.42 (t, 3H), 1.30 (d, 6H).
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