* 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.
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere Stage #2: With Rochelle's salt In tetrahydrofuran at 0 - 20℃;
Preparation of 3-(4-chlorophenvDpropan-l-ol A slurry of LAH (2.10 g, 55.2 mmol) in dry THF (250 mL) is stirred at 0 °C under nitrogen and a solution of 3-(4-chlorophenyl)propionic acid (10.2 g, 55.2 mmol) in THF (10 mL) is added slowly. The reaction is allowed to warm to rt and stirred overnight. The reaction is cooled at 0 °C and a saturated solution of potassium sodium tartrate (20 mL) is added carefully. The mixture is then stirred at rt for 4 h, diluted with ethyl acetate and filtered through Celite. The salts are washed with ethyl acetate and the filtrate is concentrated to give 9.20 g (97percent) of desired product as clear colorless oil. NMR (400 MHz, CDC ) δ 1.89 (2 H, m), 2.71 (2 H, m), 3.69 (2 H, t,), 7.15 (2 H, d,), 7.27 (2 H, d); HPLC retention time: 3.44 min. (Method A).
Reference：
[1] Patent: WO2011/126567, 2011, A1, . Location in patent: Page/Page column 163-164
[2] Organic Letters, 2012, vol. 14, # 3, p. 840 - 843
[3] Journal of the American Chemical Society, 2003, vol. 125, # 23, p. 6977 - 6985
[4] Patent: US2003/158177, 2003, A1,
[5] Patent: US2002/58660, 2002, A1,
[6] Patent: US4489094, 1984, A,
[7] Patent: US4489094, 1984, A,
[8] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 8, p. 2426 - 2431
[9] Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9427 - 9440
[10] Journal of the American Chemical Society, 2015, vol. 137, # 12, p. 4010 - 4013
2
[ 1615-02-7 ]
[ 6282-88-8 ]
Yield
Reaction Conditions
Operation in experiment
98%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran for 12 h; Inert atmosphere; Cooling with ice; Reflux Stage #2: With hydrogenchloride; water In tetrahydrofuran at 0 - 20℃; for 0.5 h;
9.1 3-(4-Chloro-phenyl)-propan-1-olTo a suspension of lithium aluminium hydride (20.26 g, 37.95 mmol) in THF (tetrahy- drofuran) (300 mL) under nitrogen atmosphere was slowly added a solution of 3-(4- chloro-phenyl)-acrylic acid (65.00 g, 355.96 mmol) in THF (500 mL) under cooling with an ice bath. The resulting mixture was stirred until it reached room temperature and then refluxed for 12 h. After cooling to room temperature, a 10percent HCI solution was added at 0° C and the resultant solution was stirred for 0.5 h. The mixture was then extracted with MTBE (methyl tert-butyl ether) and the organic layers were washed with water, dried and evaporated. The title compound was obtained as a brown oil (70.0 g, 98percent).
Stage #1: With sodium hydrogencarbonate In DMF (N,N-dimethyl-formamide) at 50℃; for 7 h; Stage #2: With sodium tetrahydroborate In DMF (N,N-dimethyl-formamide) at 5℃; for 0.5 h;
EXAMPLE 1Pd Coupling Reaction and Reduction of Aldehyde 95.38 g (400 mmol) of p-chloroiodobenzene, 34.85 g (600 mmol) of ally alcohol, 0.089 g (0.4 mmol) of palladium acetate and 47.99 g (2,000 mmol) of sodium hydrogencarbonate, were added to 200 ml of dimethylformamide (DMF), followed by heating until the internal temperature of the suspension became 50° C. The heating was continued for 7 hours, and after confirming the formation of the aldehyde compound by gas chromatogram, the suspension was cooled to 5° C. Then, 4.54 g (120 mmol) of sodium borohydride was added, followed by stirring for 30 minutes. Then, 100 ml of a saturated ammonium chloride aqueous solution, 100 ml of water and 200 ml of toluene were added, followed by stirring for one hour. After removing insolubles by Celite filtration, liquid separation was carried out, and the water layer was extracted again with 200 ml of toluene. The tolune layers were put together, concentrated and then distilled (107° C./1 mmHg) to obtain 63.4 g (y 93percent) of 3-(p-chlorophenyl)-1-propanol {compound (1)} as a colorless oily substance. From the analysis by gas chromatography, this product was found to contain 6percent of the branched isomer.
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; Inert atmosphere; Cooling with ice Stage #2: for 4 h; Reflux; Inert atmosphere
Yield: 23.3-88.0percent .Take 3-(4-chlorophenyl)propan-1-ol (3c) for example. To a suspension of lithium aluminum hydride (1.71 g, 45 mmol) in THF (30 mL), under nitrogen atmosphere and ice bath, the solution of 2.74 g (15 mmol) 3-(4-chlorophenyl)acrylic acid (2c) in THF was gently added in 30 min. the resulting mixture stirred until it reached ambient temperature and then it was reflux for 4h. When TLC analyses indicated the disappearance of the starting material, after cooling to ambient temperature, 15 ml methanol and 15 ml water was dropped slowly to quench the reaction, then the PH was adjusted to 3 with 10percent hydrochloric acid, The crude mixture was extracted with ethyl acetate (3 × 30 ml), organic layer was combined and dried over anhydrous MgSO4 and concentrated in vacuo. The resulting yellow oil was purified by chromatography on silica-gel column (n-hexane: ethyl acetate = 4:1, v/v) to obtain the product, yellow oil, yield 54.7percent. 1H NMR (300 MHz, CDCl3) δ: 7.27-7.22(m, 2H), 7.15-7.10 (m, 2H), 3.66(t, J=6.4Hz, 2H), 2.68(t, J=7.44Hz, 2H), 1.91-1.81(m, 2H).
54.7%
With lithium aluminium tetrahydride In tetrahydrofuran for 4.5 h; Inert atmosphere; Reflux; Cooling with ice
General procedure: To a suspension of lithium aluminum hydride (1.71g, 45mmol) in THF (30mL), under nitrogen atmosphere and ice bath, the solution of 15mmol 3-(4-substituted phenyl)acrylic acid (2a-h) in THF was gently added in 30min. the resulting mixture stirred until it reached ambient temperature and then it was reflux for 4h. When TLC analyses indicated the disappearance of the starting material, after cooling to ambient temperature, 15ml methanol and 15ml water was dropped slowly to quench the reaction, then the PH was adjusted to 3 with 10percent hydrochloric acid, The crude mixture was extracted with ethyl acetate (3×30 ml), organic layer was combined and dried over anhydrous MgSO4 and concentrated in vacuo. The resulting yellow oil was purified by chromatography on silica-gel column (n-hexane: ethyl acetate = 4:1, v/v) to obtain the product.
Reference：
[1] Chinese Chemical Letters, 2016, vol. 27, # 4, p. 555 - 558
[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 7, p. 1849 - 1853
[3] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 18, p. 4752 - 4756
5
[ 24393-52-0 ]
[ 6282-88-8 ]
Reference：
[1] Synthesis, 2009, # 4, p. 660 - 664
[2] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 18, p. 4752 - 4756
[3] European Journal of Organic Chemistry, 2006, # 20, p. 4573 - 4577
6
[ 7116-36-1 ]
[ 6282-88-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2006, # 20, p. 4573 - 4577
[2] Bulletin of the Chemical Society of Japan, 1959, vol. 32, p. 1135,1136
[3] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 18, p. 4752 - 4756
[4] Green Chemistry, 2018, vol. 20, # 14, p. 3191 - 3196
7
[ 104-88-1 ]
[ 6282-88-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 2002, vol. 45, # 16, p. 3549 - 3557
[2] Journal of the Indian Chemical Society, 2013, vol. 90, # 10, p. 1853 - 1860
[3] Chinese Chemical Letters, 2016, vol. 27, # 4, p. 555 - 558
[4] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 7, p. 1849 - 1853
8
[ 50561-69-8 ]
[ 6282-88-8 ]
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 12, p. 4010 - 4013
[2] Journal of Medicinal Chemistry, 2002, vol. 45, # 16, p. 3549 - 3557
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9427 - 9440
9
[ 1075-77-0 ]
[ 6282-88-8 ]
[ 24583-70-8 ]
[ 75677-02-0 ]
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 7, p. 2378 - 2381
[2] Journal of Organic Chemistry, 1998, vol. 63, # 7, p. 2378 - 2381
10
[ 20754-21-6 ]
[ 6282-88-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 2002, vol. 45, # 16, p. 3549 - 3557
11
[ 1073-67-2 ]
[ 201230-82-2 ]
[ 6282-88-8 ]
[ 59667-21-9 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1991, # 4, p. 233 - 234
Reference：
[1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 16, p. 4632 - 4636
14
[ 24583-70-8 ]
[ 6282-88-8 ]
Reference：
[1] Journal of the Indian Chemical Society, 2013, vol. 90, # 10, p. 1853 - 1860
15
[ 1615-02-7 ]
[ 6282-88-8 ]
[ 24583-70-8 ]
Reference：
[1] Synthesis, 2011, # 9, p. 1375 - 1382
16
[ 6048-06-2 ]
[ 6282-88-8 ]
Reference：
[1] Journal of the Indian Chemical Society, 2013, vol. 90, # 10, p. 1853 - 1860
17
[ 37556-13-1 ]
[ 6282-88-8 ]
Reference：
[1] Green Chemistry, 2018, vol. 20, # 14, p. 3191 - 3196
18
[ 6529-53-9 ]
[ 6282-88-8 ]
Reference：
[1] Green Chemistry, 2018, vol. 20, # 14, p. 3191 - 3196
19
[ 75-21-8 ]
[ 104-83-6 ]
[ 6282-88-8 ]
Reference：
[1] Journal of the Chemical Society, 1964, p. 1548 - 1553
20
[ 6282-88-8 ]
[ 64473-35-4 ]
Yield
Reaction Conditions
Operation in experiment
97%
With bromine; triphenylphosphine In dichloromethane at 0 - 20℃;
Preparation of l-(3-bromopropyl)-4-chlorobenzeneA solution of triphenylphosphine (7.42 g, 28.3 mmol) in DCM (200 mL) is cooled at 0 °C and a solution of bromine (1.46 mL, 28.3 mmol) in DCM (40 mL) is added slowly over a period of 30 min. A solution of 3-(4-chlorophenyl)propan-l-ol (4.6 g, 27 mmol) in DCM (20 mL) is then added and the reaction is allowed to warm to rt and stir for 24 h. The reaction mixture is then transferred to a separatory funnel; washed with saturated sodium bicarbonate, water and brine; and the organics are dried with anhydrous sodium sulfate and concentrated. The residue is subjected to silica gel chromatography (230-400 mesh, 350 g, elution with 7.5 percent ethyl acetate/hexane) to give 6.15 g (97percent) of the desired product as clear colorless oil. NMR (400 MHz, CDC13) δ 2.16 (2 H, m), 2.77 (2 H, t), 3.41 (2 H, t), 7.15 (2 H, d), 7.27 (2 H, d); HPLC retention time: 5.1 1 min. (Method A).
83%
With phosphorus tribromide In toluene at 20 - 90℃; for 3 h;
EXAMPLE 2 Bromination 66.0 g (387 mmol) of 3-(p-chlorophenyl)-1-propanol was dissolved in 350 ml of toluene, and a solution having 105 g (387 mmol) of phosphorus tribromide dissolved in 50 ml of toluene, was dropwise added thereto.. After the dropwise addition, the internal temperature of the reaction solution was raised to 90° C. and returned to room temperature 3 hours later. 250 ml of a 1N sodium hydroxide aqueous solution was added thereto, followed by shaking.. Then, the solution was left to stand still for liquid separation, and the water layer was extracted again with 150 ml of toluene.. The toluene layers were put together and washed with 150 ml of a saturated sodium chloride aqueous solution, followed by Celite filtration, and then the solvent was distilled off.. The residue was Idistilled to obtain 75.2 g (y 83percent) of the desired 3-(p-chlorophenyl)-1-propyl bromide {compound (2)) as a colorless oily substance (85-89° C./0.3 MmHg)
35%
With hydrogen bromide In water at 20℃; for 2 h;
9.2 1-(3-Bromo-propyl)-4-chloro-benzene3-(4-Chloro-phenyl)-propan-1-ol of step 9.1 (59.0 g, 170 mmol) was added to a solution of 47percent aqueous HBr (295 ml.) and the resulting mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with CH2CI2. The com- bined organic phases were washed with water, dried and evaporated. The crude residue was purified by flash chromatography on silica gel to give the title compound as a brown oil (28.1 g, 35percent).
Reference：
[1] Patent: WO2011/126567, 2011, A1, . Location in patent: Page/Page column 164
[2] Patent: US6407298, 2002, B1, . Location in patent: Page column 5
[3] Patent: WO2010/146111, 2010, A1, . Location in patent: Page/Page column 114
[4] Journal of Medicinal Chemistry, 2002, vol. 45, # 16, p. 3549 - 3557
[5] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 18, p. 4752 - 4756
[6] Patent: EP2168944, 2010, A1, . Location in patent: Page/Page column 71
[7] Green Chemistry, 2018, vol. 20, # 14, p. 3191 - 3196
21
[ 6282-88-8 ]
[ 558-13-4 ]
[ 64473-35-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
With triphenylphosphine In dichloromethane at 0 - 20℃;
Example 502-[3-(4-chlorophenyl)propyl]-N-hydroxy-1-oxo-1,2-dihydroisoquinoline-7-carboxamide Compound I-131 Step 1: 1-(3-bromopropyl)-4-chlorobenzeneTo a solution of 3-(4-chlorophenyl)propan-1-ol (0.25 g, 1.46 mmol) in dichloromethane (5.5 mL) cooled at 0° C. was added triphenylphosphine (0.42 g, 1.6 mmol) and carbon tetrabromide (0.51 g, 1.5 mmol) and the reaction was stirred at rt overnight. The reaction was quenched with water and extracted with DCM (2.x.). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0percent to 70percent EtOAc/hexanes) to afford 1-(3-bromopropyl)-4-chlorobenzene (0.34 g, quant.). LC-MS: (FA) ES+234.
With sulfur trioxide pyridine complex; triethylamine; In dichloromethane; dimethyl sulfoxide; at 0 - 20℃; for 6.5h;
A solution of <strong>[6282-88-8]3-(4-chlorophenyl)propan-1-ol</strong> (2.0 g, 0.012 mol) in dry CH2CI2 (25 ml) was added DMSO (6 ml)and EhN (3.56 g, 0.0358 mmol). The reaction mixture was cooled to ooc and added a solution of pyridine sulfurtrioxide (2.8 g, 0.018 mol) in DMSO (6 ml). The reaction mixture was stirred at O"C for 0.5 hand then at RT for 6 h. The reaction mixture was concentrated in vacuum and the residue was diluted with Et20 (100 ml) and H20(100 ml). The organic layer was separated and the aqueous layer was extracted with Et20 (3 x 50 ml). Thecombined organic layers were dried over anhydrous Na2S04, filtered and concentrated under reducedpressure. The obtained crude compound was purified by silica gel (60-120) column chromatography and elutedat 10% EtOAc/pet ether the title compound (1.0 g, 50%) as a colourless oil.
44.2%
With pyridinium chlorochromate; In dichloromethane; at 20℃; for 1h;
Yield: 44.2-90.3 %. Take 3-(4-chlorophenyl)propanal (4c) for example. To a mixture of pyridinium chlorochromate (PCC) (2.55 g, 11.8 mmol) and dichloromethane (50 mL), the corresponding alcohol <strong>[6282-88-8]3-(4-chlorophenyl)propan-1-ol</strong> (1.4 g, 8.21 mmol) was added. The resulting mixture was stirred for 1 h under ambient temperature, when TLC analyses indicated the disappearance of the starting material. The mixture was filtered over silica gel under vacuum, washing with dichloromethane. The solvent was totally removed under reduced pressure, resulting in a yellow oil, which was purified by column chromatography on silica-gel column (n-hexane: ethyl acetate = 3:1, v/v) to obtain the product, yellow oil, yield 44.2 %. 1H NMR (300 MHz, CDCl3) delta 9.81 (t, J=1.2Hz, 1H), 7.28-7.23 (m, 2H), 7.16-7.07 (m, 2H), 2.92 (t, J=7.4Hz, 2H), 2.77 (dt, J=7.2Hz, 1.2Hz, 2H).
44.2%
With pyridinium chlorochromate; In dichloromethane; at 20℃; for 1h;
General procedure: To a mixture of pyridinium chlorochromate (PCC) (2.55 g, 11.8 mmol) and dichloromethane (50 mL), the corresponding alcohol 3a-h (8.21 mmol) was added. The resulting mixture was stirred for 1 h under ambient temperature, when TLC analyses indicated the disappearance of the starting material. The mixture was filtered over silica gel under vacuum, washing with dichloromethane. The solvent was totally removed under reduced pressure, resulting in a yellow oil, which was purified by column chromatography on silica-gel column (n-hexane: ethyl acetate = 3:1, v/v) to obtain the product 4a-h. 3-phenylpropanal (4a).
With pyridinium chlorochromate; In dichloromethane; at 20℃;
3-(4-Chlorophenyl)propan-1-ol (2.0 g, 11.7 mmol) was dissolved in 35 ml dichloromethane. Pyridinium chlorochromate (3.8 g, 17.7 mmol) was added and thedark mixture was stirred overnight at room temperature. The mixture was filtered through a plug of Celite. The mixture was partitioned between water and dichloromethane, forming a dark residue. The organic phase was separated and was diluted with hexane to precipitate more dark oily residue. Anhydrous sodium sulphate was added to adsorb the dark oil and the mixture was filtered and evaporated underreduced pressure. The residue was partially purified by flash chromatography (dichloromethane-hexane gradient) to give 0.41 g of the crude title compound as a colourless oil. Purity 73%1H NMR (300 MHz, Chloroform-d) ppm 9.83 (s, 1H), 7.35-7.21 (m, 2H), 7.15 (d, J =8.5 Hz, 2H), 3.03 - 2.88 (m, 2H), 2.87 - 2.72 (m, 2H).
Yield: 23.3-88.0% .Take 3-(4-chlorophenyl)propan-1-ol (3c) for example. To a suspension of lithium aluminum hydride (1.71 g, 45 mmol) in THF (30 mL), under nitrogen atmosphere and ice bath, the solution of 2.74 g (15 mmol) 3-(4-chlorophenyl)acrylic acid (2c) in THF was gently added in 30 min. the resulting mixture stirred until it reached ambient temperature and then it was reflux for 4h. When TLC analyses indicated the disappearance of the starting material, after cooling to ambient temperature, 15 ml methanol and 15 ml water was dropped slowly to quench the reaction, then the PH was adjusted to 3 with 10% hydrochloric acid, The crude mixture was extracted with ethyl acetate (3 × 30 ml), organic layer was combined and dried over anhydrous MgSO4 and concentrated in vacuo. The resulting yellow oil was purified by chromatography on silica-gel column (n-hexane: ethyl acetate = 4:1, v/v) to obtain the product, yellow oil, yield 54.7%. 1H NMR (300 MHz, CDCl3) delta: 7.27-7.22(m, 2H), 7.15-7.10 (m, 2H), 3.66(t, J=6.4Hz, 2H), 2.68(t, J=7.44Hz, 2H), 1.91-1.81(m, 2H).
54.7%
With lithium aluminium tetrahydride; In tetrahydrofuran; for 4.5h;Inert atmosphere; Reflux; Cooling with ice;
General procedure: To a suspension of lithium aluminum hydride (1.71g, 45mmol) in THF (30mL), under nitrogen atmosphere and ice bath, the solution of 15mmol 3-(4-substituted phenyl)acrylic acid (2a-h) in THF was gently added in 30min. the resulting mixture stirred until it reached ambient temperature and then it was reflux for 4h. When TLC analyses indicated the disappearance of the starting material, after cooling to ambient temperature, 15ml methanol and 15ml water was dropped slowly to quench the reaction, then the PH was adjusted to 3 with 10% hydrochloric acid, The crude mixture was extracted with ethyl acetate (3×30 ml), organic layer was combined and dried over anhydrous MgSO4 and concentrated in vacuo. The resulting yellow oil was purified by chromatography on silica-gel column (n-hexane: ethyl acetate = 4:1, v/v) to obtain the product.
(S)-(2-{3-[((9S,12S)-12-Cyclohexyl-11,14-dioxo-2-oxa-10,13-diaza-tricyclo[17.2.2.13,7]tetracosa-1(22),3,5,7(24),19(23),20-hexaene-9-carbonyl)-amino]-2-oxo-hexanoylamino}-acetylamino)-phenyl-acetic acid[ No CAS ]
EXAMPLE 1Pd Coupling Reaction and Reduction of Aldehyde 95.38 g (400 mmol) of p-chloroiodobenzene, 34.85 g (600 mmol) of ally alcohol, 0.089 g (0.4 mmol) of palladium acetate and 47.99 g (2,000 mmol) of sodium hydrogencarbonate, were added to 200 ml of dimethylformamide (DMF), followed by heating until the internal temperature of the suspension became 50 C. The heating was continued for 7 hours, and after confirming the formation of the aldehyde compound by gas chromatogram, the suspension was cooled to 5 C. Then, 4.54 g (120 mmol) of sodium borohydride was added, followed by stirring for 30 minutes. Then, 100 ml of a saturated ammonium chloride aqueous solution, 100 ml of water and 200 ml of toluene were added, followed by stirring for one hour. After removing insolubles by Celite filtration, liquid separation was carried out, and the water layer was extracted again with 200 ml of toluene. The tolune layers were put together, concentrated and then distilled (107 C./1 mmHg) to obtain 63.4 g (y 93%) of 3-(p-chlorophenyl)-1-propanol {compound (1)} as a colorless oily substance. From the analysis by gas chromatography, this product was found to contain 6% of the branched isomer.
1005201 Step A: Preparation of 1-chloro-4-(3-methoxypropyl)benzene: A suspension of sodium hydride (0.444 g, 17.6 mmol) in dry THF (25 mL) was cooled to 0 C and 3-(4- chlorophenyl)propan-l-ol (2.00 g, 11.7 mmol) was added. The mixture was stirred for 5 minutes, allowed to reach ambient temperature and stirred for 15 minutes. The mixture was cooled to 0 C and methyl iodide (0.879 mL, 14.1 mmol) was added. The reaction mixture was stirred for 5 minutes, allowed to reach ambient temperature and stirred for 7 hours. The reaction mixture was slowly poured into 1M HCI (30 mL) containing crushed ice (30 mL) and mixed. The mixture was extracted with Et20 (3X) and the combined extracts were washed with H20 (2X), saturated NaC1 and dried over MgSO4lactivated charcoal. The dried solution was eluted through a Si02 plug (Et20 elution) and concentrated to provide the title compound as a colorless oil (2.13 g, 98%). ?H NMR (CDC13) 67.24 (d, J8.3 Hz, 2H), 7.11 (d, J8.2 Hz, 2H), 3.36 (t, J=6.3 Hz, 2H), 3.33 (s, 3H), 2.66 (t, J=7.4 Hz, 2H), 1.85 (m, 2H) ppm.
86%
In tetrahydrofuran; water;
EXAMPLE 2 Preparation of 3-(4-chlorophenyl)propyl methyl ether To a stirred solution of <strong>[6282-88-8]3-(4-chlorophenyl)propanol</strong> (9,61 g, 54,17 mmol) and methyl iodide (7,0 ml, 112 mmol) in dry tetrahydrofuran (85 ml) under nitrogen was added 60% sodium hydride (2,83 g, 70,8 mmol) in portions. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was treated with ice/water (150 ml), extracted with methylene chloride (3*250 ml), and the combined organic extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. Chromatography of the residual yellow oil on silica gel eluding with hexane afforded the title compound as a yellow oil (8,69 g, 86% from 3-(4-chlorophenyl)propionic acid) which was characterized by NMR spectral analysis.
With hydrogenchloride; triethylamine; In dichloromethane;
A solution of 128 g. of <strong>[6282-88-8]3-(p-chlorophenyl)propanol</strong> and 114 g. of triethylamine in 1.5 liters of dichloromethane is cooled to -10 C. A 9.5 g. portion of methane sulfonyl chloride is added dropwise with stirring, and the temperature is maitained at -10 C. The bath is removed, and the mixture is stirred for one hour. The dichloromethane is extracted with 400 ml. each of ice cold water, 10% hydrochloric acid, saturated sodium bicarbonate solution, and brine. The dichloromethane layer is then dried and evaporated, giving 188 g. of 3-(p-chlorophenyl)propyl mesylate.
9.1 3-(4-Chloro-phenyl)-propan-1-olTo a suspension of lithium aluminium hydride (20.26 g, 37.95 mmol) in THF (tetrahy- drofuran) (300 mL) under nitrogen atmosphere was slowly added a solution of 3-(4- chloro-phenyl)-acrylic acid (65.00 g, 355.96 mmol) in THF (500 mL) under cooling with an ice bath. The resulting mixture was stirred until it reached room temperature and then refluxed for 12 h. After cooling to room temperature, a 10% HCI solution was added at 0 C and the resultant solution was stirred for 0.5 h. The mixture was then extracted with MTBE (methyl tert-butyl ether) and the organic layers were washed with water, dried and evaporated. The title compound was obtained as a brown oil (70.0 g, 98%).
With triphenylphosphine; In dichloromethane; at 0 - 20℃;
Example 502-[3-(4-chlorophenyl)propyl]-N-hydroxy-1-oxo-1,2-dihydroisoquinoline-7-carboxamide Compound I-131 Step 1: 1-(3-bromopropyl)-4-chlorobenzeneTo a solution of <strong>[6282-88-8]3-(4-chlorophenyl)propan-1-ol</strong> (0.25 g, 1.46 mmol) in dichloromethane (5.5 mL) cooled at 0 C. was added triphenylphosphine (0.42 g, 1.6 mmol) and carbon tetrabromide (0.51 g, 1.5 mmol) and the reaction was stirred at rt overnight. The reaction was quenched with water and extracted with DCM (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 70% EtOAc/hexanes) to afford 1-(3-bromopropyl)-4-chlorobenzene (0.34 g, quant.). LC-MS: (FA) ES+234.
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