3-(4-Chlorophenyl)propan-1-ol

Colorless liquid.

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).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).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.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).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 MgSO(e) p-Toluenesulfonic acid [3-(4-chlorophenyl)propyl] ester 285 g of p-toluenesulfonic acid [3-(4-chlorophenyl)propyl] ester are obtained as a viscous, yellowish oil from 150 g of (f) 135 ml of pyridine are added dropwise to 150 g of 3-(4-Chlorophenyl)propan-1-ol (610 mg, 3.58 mmol) was dissolved in chloroform (3.22 ml) and cooled to 0oC. Pyridine (0.5 ml) was added to the vessel prior to the addition of tosyl chloride (989 mg, 5.19 mmol) in small portions. The reaction was maintained at 0oC for 2.5 hours. Diethyl ether (4 ml) was added and the solution was washed with H2O (4 ml), 2M HCl (4 ml) and 5% NaHCO3 (4 ml). The organic layer was dried over anhydrous Na2SO4, concentrated and purified via flash chromatography on silica gel (using a gradient of 5% to 15% of ethyl acetate in hexanes as the eluent). 3-(4-Chlorophenyl)propyl tosylate (86% yield) was obtained as a colorless oil and used directly in the subsequent step.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 (97%) of desired product as clear colorless oil. NMR (400 MHz, CDC ) delta 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).1) After a mixture of 3-(4-chlorophenyl)propionic acid (5.00 g, 27.0 mmol) and thionyl chloride (3 ml) was refluxed for 2 hours, an excess of the thionyl chloride was distilled away under reduced pressure. The resultant residues were dissolved in tetrahydrofuran (200 ml), dropped slowly to a suspension of LiAlH4 in tetrahydrofuran at 0 C. and stirred at room temperature for 1 hour. Water and 1 N aqueous sodium hydroxide were added to the reaction mixture, and after insolubles were filtered off, the filtrate was dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, whereby 4.6 g Preparation of 4-[[3-(p-Chlorophenyl)propyl]methylamino]benzoic acid, ethyl ester A 550 ml. portion of 1M diborane in tetrahydrofuran is placed in a flask under nitrogen and cooled in an ice bath. An 82.5 g. portion of 3-(p-chlorophenyl)propionic acid in 250 ml. of dry tetrahydrofuran is added dropwise over a period of one hour. The cooling bath is removed, and the mixture is allowed to stand overnight and is then poured slowly into 1.5 liters of ice water with swirling. The mixture is extracted with three 500 ml. portions of ether. The ether extracts are combined, washed with 250 ml. of brine, dried over magnesium sulfate, and evaporated, yielding 72.9 g. of A 1.5 liter portion of 1M diborane in tetrahydrofuran is placed in a flask, under argon, and cooled in an icewater bath. A solution of 171.8 g. of 3-(p-chlorophenyl)propionic acid (prepared as described above) in 500 ml. of dry tetrahydrofuran is added slowly with stirring. The bath is removed, and the mixture is stirred overnight at room temperature. The solution is poured into 2 liters of stirred ice water and then extracted with three 650 ml. portions of ether. The ether extracts are combined, washed with 500 ml. of water, dried over magnesium sulfate, and condensed to an oil. This oil is distilled in a Kugelrohr apparatus, collecting the fraction with a boiling range of 100-115 C. (140 mm.), giving 128.2 g. of To a solution of 3-(4-chlorophenyl)propanoic acid (190 mg, 1 mmol) in THF (5 ml) cooled to 0 oC was added BH3.SMe2 (285 mul, 3 mmol) dropwise. After complete addition, the mixture was maintained at 0 oC for an additional 30 minutes, allowed to reach room temperature and stirred for 18 hours. The reaction mixture was then cooled to 0 oC, treated with methanol (1.8 ml) and concentrated under a reduced pressure. Diethyl ether (3.5 ml) was added and the mixture washed successively with 10% NaOH (4 ml) and brine (4 ml). The organic layer dried over anhydrous Na2SO4 and the solvent removed under reduced pressure to afford General procedure: To a stirred solution of 3- or 4-substituted phenylpropanoic acid 51-63 (7.0 mmol) in dry THF (35 ml), borane dimethyl sulfide (21.0 mmol) was added dropwise at 0 oC. The reaction mixture was stirred for 18h at room temperature, quenched with H2O and concentrated in vacuo. The resulting residue was re-dissolved in diethyl ether (25 ml), and washed with 10%NaOH (30ml) and brine. The organic fraction was dried over Na2SO4, filtered, and concentrated in vacuo to give 3-phenylpropan-1-ol derivatives that were used in the next step without further purification.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 % ethyl acetate/hexane) to give 6.15 g (97%) of the desired product as clear colorless oil. NMR (400 MHz, CDC13) delta 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).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 83%) of the desired 3-(p-chlorophenyl)-1-propyl bromide {compound (2)) as a colorless oily substance (85-89 C./0.3 MmHg)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 47% 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, 35%).(26-1) Synthesis of 1-(3-bromopropyl)-4-chlorobenzene (compound 26-1) [Show Image] 3-(4-Chlorophenyl)-1-propanol (1.00 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (1.66 g) and N-bromosuccinimide (1.11 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 6 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.30 g) as a colorless oil. 1H-NMR(CDCl3) delta (ppm): 2.10-2.18(2H, m), 2.76(2H, t, J=7.3Hz), 3.38(2H, t, J=6.5Hz), 7.13(2H, d, J=8.3Hz), 7.31-7.35(2H, m).General procedure: To a stirred solution of 3- or 4-substituted phenylpropanoic acid 51-63 (7.0 mmol) in dry THF (35 ml), borane dimethyl sulfide (21.0 mmol) was added dropwise at 0 oC. The reaction mixture was stirred for 18h at room temperature, quenched with H2O and concentrated in vacuo. The resulting residue was re-dissolved in diethyl ether (25 ml), and washed with 10%NaOH (30ml) and brine. The organic fraction was dried over Na2SO4, filtered, and concentrated in vacuo to give 3-phenylpropan-1-ol derivatives that were used in the next step without further purification. Triphenylphosphine (7.5 mmol) and carbon tetrabromide (7.1 mmol) were added to a stirred solution of the 3-phenylpropan-1-ol derivatives in dry CH2Cl2 at 0 oC. The reaction mixture was stirred for 18h at room temperature and quenched with brine. The organic fraction was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (10:1 n-hexane/EtOAc) to give the corresponding title compound (38-50) in a 64-73% yield (two steps). These are also all known, but commercially unavailable compounds for which the chemical structure of each could be identified from the 1H- and 13C-NMR spectra.General procedure: By the following method, it went 3-reduction of phenylpropionic acid (hydrogenation).Put a stir bar in a dry glass tube (25mL), further, 3-phenylpropionic acid (75.09mg, 0.5mmol), the rhenium complex 4 (7.07mg, 0.010mmol), potassium tetraphenylborate (17.92mg , accommodates 0.05 mmol), the tubes containing this mixture, was inserted into the autoclave. Then, after replacing the inside of the autoclave in an argon gas atmosphere was added while continuing flow of argon gas dehydration toluene (4.0mL). This autoclave through a stainless steel tube by introducing hydrogen gas from a hydrogen gas cylinder connected, the inside of the autoclave was replaced with hydrogen gas, then disconnect the hydrogen gas pressure from the leak valve. This operation - was repeated (substituted de substitution) five times. Finally, the hydrogen gas pressure in the autoclave was set to 4 MPa, using a constant temperature bath, and allowed to react for 12 hours at 180 C. After completion of the reaction, the autoclave was cooled by immersion in an ice bath, almost to room temperature. Then, carefully release the hydrogen gas that is inside in the draft. After removing the solvent, the reaction product was analyzed by 1H NMR using mesitylene (60.1 mg, 0.5 mmol) as an internal standard substance. As a result, 3-phenylpropyl alcohol, and 3-phenylpropionic acid 3-phenylpropyl The yield was 98% and 1%, respectively. In the above Examples 6-1, Substrate (carboxylic acid compounds), and hydrogenation conditions (hydrogen pressure), Except that to adopt the conditions described in Table 7-9, It has been reduced (hydrogenated) in the same manner as in Example 6-1.However, The entry 19-26 in Table 9, Using tetrahydrofuran (THF) as a solvent.The results are shown in Tables 7 to 9.5 kg of 3- (4-chlorophenyl) propan-1-ol was formulated into a 50 wt% toluene solution, raw material ;Preparation of 3- (piperidin-1-yl) propionic acid solution: 4.61kg of 3- (piperidin-1-yl) propionic acid was prepared into a 50% by weight toluene solution, raw material ;Reactor preparation: Fill the catalyst SO42- / Fe2O3 and raise the temperature to 40 C.Feed after the temperature is stable. Feedstock control the flow rate of 6 g / min, feedstock control of 5.53 g / min. A toluene solution of the intermediate is obtained in the collector, and the solvent is evaporated to obtain 9.2 kg of intermediate.9.2 kg of 3- (4-chlorophenyl) propyl 3- (piperidin-1-yl) propionate was dissolved in 40 kg of THF, 4.4 kg of NaBH4 was added, and 0.18 kg of I2 was added dropwise at about 25 C in a water bath. The temperature of the THF solution was raised to 60 C., and the reaction was carried out for 6 h. The reaction was completed. Saturated NH4Cl aqueous solution was added to the ice bath to quench it. After no longer foaming, centrifugation, centrifugation, water and EA extraction, washing, drying, temperature controlled dropwise addition of ethyl acetate hydrochloride solution, salt formation, crystallization, centrifugation, to obtain the product, baking Dry 7.15kg, yield 82.5%, purity 99.9%.

Molecular Weight:170.63
XLogP3:2.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:3
Exact Mass:170.0498427
Monoisotopic Mass:170.0498427
Topological Polar Surface Area:20.2
Heavy Atom Count:11
Complexity:97.7
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes