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CAS No. : | 1875-88-3 | MDL No. : | MFCD00002899 |
Formula : | C8H9ClO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HZFRKZWBVUJYDA-UHFFFAOYSA-N |
M.W : | 156.61 | Pubchem ID : | 74647 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 42.39 |
TPSA : | 20.23 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.25 cm/s |
Log Po/w (iLOGP) : | 2.0 |
Log Po/w (XLOGP3) : | 1.41 |
Log Po/w (WLOGP) : | 1.87 |
Log Po/w (MLOGP) : | 2.46 |
Log Po/w (SILICOS-IT) : | 2.64 |
Consensus Log Po/w : | 2.08 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.01 |
Solubility : | 1.53 mg/ml ; 0.00974 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.44 |
Solubility : | 5.7 mg/ml ; 0.0364 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.23 |
Solubility : | 0.0916 mg/ml ; 0.000585 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.07 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.9% | With phosphorus tribromide In cyclohexane at -10 - 80℃; for 3.75 - 8.25 h; | The volume efficiency was 1.76 L per Kg of 2-(4'-chlorophenyl)ethanol starting material or 758 g of 2-(4'-chlorophenyl)ethyl bromide product (assay corrected) per liter.Process DescriptionTo a reactor affixed with a vent to a caustic scrubber to capture HBr gas that might evolve during the reaction was added 2-(4'-chlorophenyl)ethanol (1.00 Kg, 6.39 moles, 1.00 equiv.). The reactor contents were cooled to 0° C. The feed pump and line were rinsed with cyclohexane (0.019 Kg), and the rinses were directed to waste disposal. To the cooled solution was added phosphorous tribromide (0.869 Kg, 3.21 moles, 0.503 equiv.) while the stirred reactor contents were maintained at 0-10° C. The resulting reaction was highly exothermic and was controlled by the addition rate with a jacket temperature of -5° C. to -10° C. The feed pump and line was rinsed with cyclohexane (0.019 Kg), and the rinses were directed to waste disposal. The resulting reaction mixture was heated to 25° C. (20° C. to 30° C.), and stirring was continued at this temperature for 2 hours (1 to 3 hours). After this time, the reaction mixture was slowly heated to 80° C. (75 to 85° C.) over 60 minutes (45 to 75 minutes), and stirring at that temperature was continued for 3 hours (2 to 4 hours). A slightly turbid emulsion was formed upon heating. The reactor contents were cooled to 22° C. and then a sample of the reaction mixture was analyzed for reaction completion (>99percent by HPLC peak area). The reaction mixture was a thick but easily stirred emulsion. A receiver vented to a caustic scrubber was charged with purified water (0.514 Kg). The receiver contents were cooled to 5-20° C. The reaction mixture was transferred from the reactor to the receiver at a rate sufficiently slow to maintain the stirred receiver contents at about 15° C. The receiver contents were warmed to 35-40° C. and filtered through a polishing filter. The reactor was washed with additional purified water (0.085 Kg), and the washings were passed through the filter into the aqueous product mixture. The phases were allowed to separate at 35-40° C. The lower phase was drained from the upper phase. The lower phase weighed about 1.39 Kg and was about 96percent pure 2-(4'-chlorophenyl)ethyl bromide, which was therefore obtained in about 94.9percent yield (assay corrected). |
94.9% | at 0 - 30℃; for 3 h; | The present invention uses SM-A and LCS-1 condensation to prepare Impurity F.Specific operations are as follows: 40g of p-chlorophenylacetic acid was added to 400ml of tetrahydrofuran,Stirring at room temperature dissolved; lithium aluminum hydride in batches, temperature control at 25 ~ 30 ,After the reaction was stirred for 20 hours, 200 ml of water was added slowly and the addition was completed.Add ethyl acetate 400ml stirred 30min, liquid separation, organic phase plus 200ml saturated brine and dried over 20g anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure 40 ~ 45 ,36.7 g of oil (S2) was obtained; S2 was added to the reaction flask, the temperature was lowered to 0 to 5 ° C in ice water,Slowly dropping phosphorus tribromide, dropping temperature during the course of 0 ~ 5 , the dropwise addition is completed,Heated to 25 ~ 30 , incubated for 3h,Add water 80ml, stirred 30min, liquid separation, the aqueous phase was extracted with dichloromethane 100ml × 2,The organic phases were combined and concentrated under reduced pressure to give an oil (S3): 48.8 g. Yield: 94.9percent. |
65.2% | With pyridine; dibromo sulfoxide In water; toluene | EXAMPLE 5 Preparation of 4-chlorophenethyl bromide A 500 ml. 3 neck round bottomed flask under nitrogen was charged 15.65 g. of 4-chlorophenethanol (1.0 eq., 0.10 moles) in 60 ml. toluene. To the reaction was added dropwise 41.6 g of thionyl bromide (2.0 eq., 0.20 moles) in 15 ml. of toluene maintaining the temp. below 25 C. Finally, 8.7 g. pyridine (1.1 eq., 0.11 moles) in 20 ml. toluene was added dropwise again keeping the temperature below 30° C. with an external ice bath. The reaction was monitored by GLC and after 1 hr. an additional 14.0 g of thionyl bromide (0.67 eq. 0.067 moles) was added followed three hours later by 9.7 gms. (1.1 eq., 0.11 moles). Subsequently 4.3 g. of pyridine was added (0.55 eq., 0.055 moles) after which GLC indicated all the alcohol was consumed. The reaction was quenched by the addition of 300 ml of water while cooling with an ice bath after which 400 ml. of ether was added. The ether was washed water three times with 250 ml.), dried over MgSO4 and concentrated to give 14.4 g of product as an oil (65.2percent yield). NMR (60 MHz): 2.9-3.7 (m, 4H) and 7.0-7.4 (ABq, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.9% | With phosphorus tribromide; In cyclohexane; at -10 - 80℃; for 3.75 - 8.25h; | The volume efficiency was 1.76 L per Kg of 2-(4'-chlorophenyl)ethanol starting material or 758 g of 2-(4'-chlorophenyl)ethyl bromide product (assay corrected) per liter.Process DescriptionTo a reactor affixed with a vent to a caustic scrubber to capture HBr gas that might evolve during the reaction was added 2-(4'-chlorophenyl)ethanol (1.00 Kg, 6.39 moles, 1.00 equiv.). The reactor contents were cooled to 0 C. The feed pump and line were rinsed with cyclohexane (0.019 Kg), and the rinses were directed to waste disposal. To the cooled solution was added phosphorous tribromide (0.869 Kg, 3.21 moles, 0.503 equiv.) while the stirred reactor contents were maintained at 0-10 C. The resulting reaction was highly exothermic and was controlled by the addition rate with a jacket temperature of -5 C. to -10 C. The feed pump and line was rinsed with cyclohexane (0.019 Kg), and the rinses were directed to waste disposal. The resulting reaction mixture was heated to 25 C. (20 C. to 30 C.), and stirring was continued at this temperature for 2 hours (1 to 3 hours). After this time, the reaction mixture was slowly heated to 80 C. (75 to 85 C.) over 60 minutes (45 to 75 minutes), and stirring at that temperature was continued for 3 hours (2 to 4 hours). A slightly turbid emulsion was formed upon heating. The reactor contents were cooled to 22 C. and then a sample of the reaction mixture was analyzed for reaction completion (>99% by HPLC peak area). The reaction mixture was a thick but easily stirred emulsion. A receiver vented to a caustic scrubber was charged with purified water (0.514 Kg). The receiver contents were cooled to 5-20 C. The reaction mixture was transferred from the reactor to the receiver at a rate sufficiently slow to maintain the stirred receiver contents at about 15 C. The receiver contents were warmed to 35-40 C. and filtered through a polishing filter. The reactor was washed with additional purified water (0.085 Kg), and the washings were passed through the filter into the aqueous product mixture. The phases were allowed to separate at 35-40 C. The lower phase was drained from the upper phase. The lower phase weighed about 1.39 Kg and was about 96% pure 2-(4'-chlorophenyl)ethyl bromide, which was therefore obtained in about 94.9% yield (assay corrected). |
94.9% | With phosphorus tribromide; at 0 - 30℃; for 3h; | The present invention uses SM-A and LCS-1 condensation to prepare Impurity F.Specific operations are as follows: 40g of p-chlorophenylacetic acid was added to 400ml of tetrahydrofuran,Stirring at room temperature dissolved; lithium aluminum hydride in batches, temperature control at 25 ~ 30 ,After the reaction was stirred for 20 hours, 200 ml of water was added slowly and the addition was completed.Add ethyl acetate 400ml stirred 30min, liquid separation, organic phase plus 200ml saturated brine and dried over 20g anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure 40 ~ 45 ,36.7 g of oil (S2) was obtained; S2 was added to the reaction flask, the temperature was lowered to 0 to 5 C in ice water,Slowly dropping phosphorus tribromide, dropping temperature during the course of 0 ~ 5 , the dropwise addition is completed,Heated to 25 ~ 30 , incubated for 3h,Add water 80ml, stirred 30min, liquid separation, the aqueous phase was extracted with dichloromethane 100ml × 2,The organic phases were combined and concentrated under reduced pressure to give an oil (S3): 48.8 g. Yield: 94.9%. |
65.2% | With pyridine; dibromo sulfoxide; In water; toluene; | EXAMPLE 5 Preparation of 4-chlorophenethyl bromide A 500 ml. 3 neck round bottomed flask under nitrogen was charged 15.65 g. of 4-chlorophenethanol (1.0 eq., 0.10 moles) in 60 ml. toluene. To the reaction was added dropwise 41.6 g of thionyl bromide (2.0 eq., 0.20 moles) in 15 ml. of toluene maintaining the temp. below 25 C. Finally, 8.7 g. pyridine (1.1 eq., 0.11 moles) in 20 ml. toluene was added dropwise again keeping the temperature below 30 C. with an external ice bath. The reaction was monitored by GLC and after 1 hr. an additional 14.0 g of thionyl bromide (0.67 eq. 0.067 moles) was added followed three hours later by 9.7 gms. (1.1 eq., 0.11 moles). Subsequently 4.3 g. of pyridine was added (0.55 eq., 0.055 moles) after which GLC indicated all the alcohol was consumed. The reaction was quenched by the addition of 300 ml of water while cooling with an ice bath after which 400 ml. of ether was added. The ether was washed water three times with 250 ml.), dried over MgSO4 and concentrated to give 14.4 g of product as an oil (65.2% yield). NMR (60 MHz): 2.9-3.7 (m, 4H) and 7.0-7.4 (ABq, 4H). |
32.6% | Production Example 6 Synthesis of 4-chlorophenethyl bromide 4-Chlorophenethyl alcohol (5 ml) was treated as in Production Example 1 to give the title compound (2.639 g) as a pale yellow oil (yield: 32.6%). (no NMR) | |
With phosphorus tribromide; In tetrachloromethane; | EXAMPLE 38 Preparation of 4-chlorophenethyl bromide STR52 Phosphorus tribromide (1.3 ml) was added, dropwise, to a solution of 4-chlorophenethyl alcohol (5.0 g) in carbon tetrachloride (30 ml). The mixture was stirred at room temperature for 10 minutes then heated under reflux for 2 hours. Ice (50 g) was added and the mixture partitioned between dichloromethane (50 ml) and 10% aqueous sodium carbonate (50 ml). The layers were separated and the aqueous layer extracted with dichloromethane (2*50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluding with dichloromethane. The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil, yield 3.0 g. 1 H N.M.R. (CDCl3) delta=7.35 (d, 2H); 7.20 (d, 2H); 3.60 (t, 2H); 3.20 (t, 2H) ppm. | |
With carbon tetrabromide; triphenylphosphine; In diethyl ether; at 20℃; for 16h; | To a solution of 2- (4-chlorophenyl) ethanol (15 g, 95.8 MMOL) in diethyl ether (225 ML) were added triphenylphosphine (31.2 g, 119 MMOL) and carbon tetrabromide (38.4 g, 116 MMOL). The mixture was stirred at room temperature for 16 hours, diluted with petroleum ether (bp 40-60 C, 360 ml), and filtered. The filter cake was washed with a mixture of diethyl ether/petroleum ether (1: 1,250 ML). The filtrate was concentrated, and the residue distilled in vacuo to the title compound as a colourless oil : bp 104-105C (0.25 mbar) ;'H NMR (CDCI3) 8 3.12 (t, 2H), 3.53 (t, 2H), 7.13 (d, 2H), 7.28 (d, 2H) ;'3C NMR (CDCI3) 8 33.0, 39.0, 129.1 (2C), 130.4 (2C), 133.2, 137.7. | |
With hydrogen bromide; at 91 - 96℃; under 517.552 - 1807.68 Torr;Product distribution / selectivity; | In a 1 L pressure vessel, 4-chlorophenylethanol (412.8 g, 2636 mmol) was stirred and heated to an internal temperature of -91 0C. The system was held under reduced pressure (~ - 0.98 bar) for ~2 min. Hydrogen bromide gas was gradually charged into the pressure vessel and the reaction was stirred at an internal pressure between +0.69 and +1.65 bar for 135 min. The vessel was allowed to slowly vent to a caustic scrubber and flushed with nitrogen gas for ~ 5 min. Conversion to the bromide was found to be 4.27% by HPLC. The reaction mixture was allowed to cool to ambient temperature overnight under nitrogen. The mixture was then heated once more in an oil bath set at 96 0C and the vessel was evacuated. The vessel was gradually filled with hydrogen bromide gas and stirred at an internal pressure between +1.38 and +1.65 bar for 2 h. Conversion to the bromide was found to be 92.67 % by HPLC. The reaction was held at a bath temperature of 96 0C at atmospheric pressure for 45 min. The vessel was then evacuated and slowly backfilled with hydrogen bromide gas over 15 min to +1.38 bar. After stirring for a further 2.5 h at +1.24 to +1.38 bar, the vessel was vented to the caustic scrubber and held at a bath temperature of 96 0C in closed system at atmospheric pressure. Conversion to the bromide was found to be 99.49% by HPLC with a peak area purity of 98.71%.In order to test stability and impurity formation, the pressure vessel was then evacuated and gradually back filled with hydrogen bromide gas to an internal pressure of +1.03 bar. The dark brown suspension was allowed to stir at +1.03 bar at a bath temperature of 96 0C. After 15 h the internal pressure had risen to +2.41 bar and the vessel was vented to the caustic scrubber, purged with nitrogen, and allowed to cool to ambient temperature. The peak area purity was found to be 96.06%. The reaction mixture was transferred to a seperatory funnel and allowed to separate at room temp. The upper product phase was washed with water (412 mL) in 2 portions to leave a milky beige suspension (563.4 g) with an HPLC peak area purity of 99.29%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride In dichloromethane at 0 - 20℃; for 1h; | 1.5. Synthesis of 1-chloro-4-(2-chloroethyl)benzene: To a solution of 1-chloro-4-(2-chloroethyl)ethanol (5mmol) in anhydrous dichloromethane (5ml) was added SOCl2 (15mmol, 1.1ml) drop-wise at 0oC. The reaction mixture was allowed to reach room temperature, stirred for 1h, and then cooled down to 0oC again. It was then carefully diluted with water, and neutralized with saturated NaCO3 sodiumNaHCO3. The reaction mixture was extracted with dichloromethane and washed with water to afford the product as a yellow oil in quantitative yield. 1H NMR (300MHz, CDCl3) δ 2.99 (t, J=7.2, 2H), 3.65 (t, J=7.2, 2H), 7.11 (d, J=8.4, 2H), 7.25 (d, J=8.1, 2H). 13C NMR (75MHz, CDCl3) δ 38.2, 44.6, 128.6 (2C), 130.1 (2C), 132.6, 136.4. |
100% | With thionyl chloride In dichloromethane at 0 - 20℃; for 1h; | |
97% | With thionyl chloride In toluene at 60 - 65℃; for 2h; | 1.1.A Example 1: Preparation of 2-Chloro-ΛL(4-chlorophenethyl)propan-l-amine (Compound VI) Hydrochloride.; Method 1; Step A: Preparation of l-ChIoro-4-(2-chloroethyl)benzene (Compound III). To a 4-L, jacketed glass reactor containing a solution of 2-(4-chlorophenyl)ethanol(Compound II) (591 g, 3774 mmol) dissolved in toluene (1250 mL) and N5N- dimethylformamide (41.4 g, 566 mmol) at 60 0C was charged thionyl chloride (302 mL, 4151 mmol) over 30 min. The addition was exothermic with significant gas evolution. The reaction mixture was stirred for 1.5 h at 60 to 65 0C. Reaction conversion was monitored by HPLC and 1H ΝMR. When the amount of 2-(4-chlorophenyl)ethanol remaining was < 1 area % by HPLC , the reaction mixture was cooled to 20 to 25 0C. Water (1000 mL) was charged to the reactor and the mixture was stirred for 15 min. The aqueous layer was removed and the organic phase was washed twice with saturated sodium bicarbonate solution (1000 mL). Evaporation of the organic phase afforded the title compound as a colorless to yellow oil (641 g, 97% yield, 100 area % by HPLC). 1H ΝMR (400 Hz, CDCl3) δ 3.06 (t, J= 7.2 Hz, 2H), 3.72 (t, J= 7.2 Hz, 2H), 7.19 (d, J = 10 Hz, 2H), 7.32 (d, J= 10 Hz, 2H). |
96% | With pyridine hydrochloride; triphenylphosphine; diethylazodicarboxylate In dichloromethane | |
86% | Stage #1: 2-(4-Chlorophenyl)ethanol With methanesulfonyl chloride; triethylamine In toluene at 0℃; for 1h; Stage #2: With lithium chloride In N,N-dimethyl-formamide at 20℃; for 24h; | |
With phosphorus pentachloride | ||
With thionyl chloride | ||
With pyridine; thionyl chloride | 24.a [4-(1H-Imidazol-4-yl)butyl] 4-chlorophenethyl sulfone Step a. 1-chloro-2-(4-chlorophenyl)ethane. To a solution of 4-chlorophenethyl alcohol (5 ml, 37 mmol) and pyridine (3.0 ml, 37.0 mmol) in a two-necked flask, equipped with a dropping funnel and a reflux condenser fitted with calcium chloride drying tube, was added thionyl chloride (5.39 ml, 74.0 mmol) dropwise over 1 h. The reaction was heated at reflux for 1.5 h before being cooled in an ice-bath. This led to the precipitation of a white solid which was filtered off rapidly and washed with a small quantity of cold diethyl ether. The organic material was then washed cautiously with water (1*30 ml), 2N sodium hydroxide solution (2*30 ml) and water (1*30 ml), dried over magnesium sulfate, filtered and the solvent evaporated to give the desired product as a pale yellow oil (5.73 g): 1H NMR (300 MHz, CDCl3) 7.29 (2H, d), 7.16 (2H, d), 3.70 (2H, t), 3.05 (2H, t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With lithium aluminum hydride In diethyl ether at 35℃; for 2h; | |
92% | With tin(II) trifluoromethanesulfonate; tris(2,4-pentanedionato)ruthenium(III); hydrogen; [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine] In water; toluene at 160℃; for 48h; Autoclave; | |
87% | With C25H42N6Rh(1+)*CF3O3S(1-); phenylsilane In tetrahydrofuran at 30℃; for 20h; Inert atmosphere; |
80% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | 24 4.1.4 Synthetic procedure 3: reduction of carboxylic acid with LiAlH4 In a 3-neck flask, LiAlH4 (8.0mmol) was dissolved in anhydrous tetrahydrofuran (THF) (10mL), under nitrogen atmosphere at 0°C. A solution of phenyl acetic acid (4.0mmol) in anhydrous THF (10mL), was added dropwise to the reaction mixture over 20min, followed by addition of 5mL of anhydrous THF. The mixture was allowed to warm to rt, after which the reaction was quenched with EtOAc (50mL) and water (50mL). The mixture was washed with water (3×50mL) and the organic layer was dried over MgSO4, filtered and the solvent was removed under reduced pressure. |
76% | With dimethylsulfide borane complex In tetrahydrofuran | |
With lithium aluminium tetrahydride In tetrahydrofuran | ||
With lithium aluminium tetrahydride | ||
With lithium aluminium tetrahydride In tetrahydrofuran for 4h; Heating; | ||
With lithium aluminium tetrahydride In diethyl ether | ||
With lithium aluminium tetrahydride In tetrahydrofuran Heating; | ||
Multi-step reaction with 2 steps 1: 89 percent / H2SO4 / 8 h / Heating 2: LiAlH4 / diethyl ether / 3 h / Heating | ||
Multi-step reaction with 2 steps 2: LiAlH4 | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 12 h / Reflux 2: lithium aluminium tetrahydride / diethyl ether / 0 °C / Reflux; Inert atmosphere | ||
Stage #1: 4-chlorophenylacetic Acid With lithium aluminium tetrahydride In tetrahydrofuran at 18 - 26℃; for 2h; Stage #2: With water; ammonium chloride In tetrahydrofuran | 4.2. General procedure for the synthesis of aldehydes General procedure: To a suspension of LiAlH4 in dry THF was added the corresponding acid dissolved in dry THF dropwisely at room temperature. Then the mixture was stirred for 2 h and quenched with saturated NH4Cl. The mixture was extracted with chloroform and dried over anhydrous Na2SO4. Then the solvent was evaporated and the product was used without further purification. The crude alcohol was dissolved in dry DCM and DMP (Dess-Martin Periodinane) was added. The resulting mixture was stirred at room temperature for 2 h and quenched with Na2S2O3/NaHCO3 (v/v=1/1). The aqueous phase was extracted with DCM and dried over anhydrous Na2SO4. The solvent was evaporated to afford the corresponding aldehydes. | |
With samarium diiodide; tributyl-amine; water In tetrahydrofuran at 23℃; Inert atmosphere; chemoselective reaction; | ||
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 6.5 h / Inert atmosphere; Reflux 2: diisobutylaluminium hydride; hydrogenchloride / tetrahydrofuran; hexane; water / 0 - 20 °C / pH 1 / Inert atmosphere | ||
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 4.5h; Reflux; | Preparation of phenylethyl alcohols General procedure: To a mixture of LiAlH4 (15 mmol) in anhydrous THF (25 mL) in an ice-bath was added dropwise a solution of phenylacetic acids (15 mmol) in THF (8 mL). This mixture was stirred at room temperature for 30 min, and then heated to reflux for 4 h. After it was cooled to room temperature, water (0.5 mL) was added, and then NaOH (15%, 0.5 mL) and water (1.5 mL) were added in sequence. After stirring for another 30 min, the mixture was filtered, dried over anhydrous Na2SO4 and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 50-85% yield by column chromatography. Alternative method: To a solution of phenylacetic acids (15 mmol) in MeOH (30 mL) was added SOCl2 (30 mmol). This mixture was heated to reflux for 3 h before evaporation. The residue was dissolved in DCM (30 mL), washed with aqueous NaHCO3, water and brine, dried over anhydrous Na2SO4, and concentrated to give 100% yield of crude methyl phenylacetates which were used to next step without further purification. To a solution of the methyl phenylacetates in THF (30 mL) was added NaBH4 (60 mmol). When the mixture was heated to gently reflux, MeOH (1.0 mL) was added dropwise from a syringe over 5 min. After refluxing for another 6 h, the mixture was cooled to room temperature and poured into 30 mL ice water, and extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 70-85% yield by column chromatography. | |
36.7 g | With lithium aluminium tetrahydride In tetrahydrofuran at 25 - 30℃; for 20h; | 2.3 The present invention uses SM-A and LCS-1 condensation to prepare Impurity F.Specific operations are as follows: 40g of p-chlorophenylacetic acid was added to 400ml of tetrahydrofuran,Stirring at room temperature dissolved; lithium aluminum hydride in batches, temperature control at 25 ~ 30 ,After the reaction was stirred for 20 hours, 200 ml of water was added slowly and the addition was completed.Add ethyl acetate 400ml stirred 30min, liquid separation, organic phase plus 200ml saturated brine and dried over 20g anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure 40 ~ 45 ,36.7 g of oil (S2) was obtained; S2 was added to the reaction flask, the temperature was lowered to 0 to 5 ° C in ice water,Slowly dropping phosphorus tribromide, dropping temperature during the course of 0 ~ 5 , the dropwise addition is completed,Heated to 25 ~ 30 , incubated for 3h,Add water 80ml, stirred 30min, liquid separation, the aqueous phase was extracted with dichloromethane 100ml × 2,The organic phases were combined and concentrated under reduced pressure to give an oil (S3): 48.8 g. Yield: 94.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With C30H34Cl2N2P2Ru; potassium methanolate; hydrogen; In tetrahydrofuran; at 100℃; under 38002.6 - 76005.1 Torr; for 5h;Glovebox; Autoclave; | General procedure: In a glove box, add a ruthenium complex Ia (0.3 to 0.7 mg, 0.0002 to 0.001 mmol) to a 300 mL autoclave,Potassium methoxide (35-700 mg, 0.5-10 mmol), tetrahydrofuran (4-60 mL), and ester compounds (10-200 mmol).After sealing the autoclave, take it out of the glove box and fill it with 50 100atm of hydrogen.The reaction kettle was heated and stirred in an oil bath at 100 C for 10 to 336 hours.After the reaction kettle was cooled in an ice-water bath for 1.5 hours, the excess hydrogen was slowly released.The solvent was removed from the reaction solution under reduced pressure, and the residue was purified with a short silica gel column to obtain an alcohol compound. The results are shown in Table 5. |
97.75% | With sodium tetrahydroborate; In tetrahydrofuran; isopropyl alcohol; for 28h;Reflux; | 490 g of ethyl p-chlorophenylacetate, 1500 ml of THF and 1500 ml of isopropanol were added to a 5000 ml three-necked flask, and after stirring at 200 r/s at reflux temperature, 190.2 g of NaBH4 was added in portions, and the reaction system remained sealed during the reaction. With the addition of NaBH4, gas gradually escapes, the solution changes from transparent to milky white. After the addition is completed, after 28 hours of reaction, the reaction is stopped, cooled to room temperature, acidified to a pH of about neutral, and the layer is allowed to stand, leaving the organic layer. The aqueous layer was extracted with ethyl acetate. The organic layer was combined, and the organic layer and organic phase were combined, and washed three times with saturated brine, and then evaporated under reduced pressure at 60 C. The solvent was evaporated to give a yield of 97.75% and a purity of 99.98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dichloro bis(acetonitrile) palladium(II); 1-hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadien-1-one)-μ-hydrotetracarbonyldiruthenium(II); water; isopropyl alcohol; p-benzoquinone; copper dichloride; <i>tert</i>-butyl alcohol at 85℃; | |
54% | With water; diphenyldisulfane; 9-(2-mesityl)-10-methylacridinium perchlorate In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; regioselective reaction; | |
With sulfuric acid In ethanol at 25℃; |
Multi-step reaction with 2 steps 1: 2,6-bis[1-((2,6-diethylphenyl)imino)ethyl]pyridine; iron(II) chloride; ethylmagnesium bromide / diethyl ether; tetrahydrofuran / 1 h / 20 °C / Inert atmosphere 2: potassium hydrogencarbonate; dihydrogen peroxide / tetrahydrofuran; water; methanol / 6 h / 20 °C | ||
With D-Glucose; oxygen In aq. phosphate buffer at 30℃; for 8h; Green chemistry; regioselective reaction; | ||
With cytochrome P450 [T121A-N201K-N209S-Y385H-E418G-A103L-M118L-R120H-V123I-I326V-V327M-H385V-M391L] variant; oxygen; nicotinamide adenine dinucleotide phosphate; isopropyl alcohol; alcohol dehydrogenase at 20℃; for 2h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 36.5% 2: 36.8% 3: 3% 4: 4.7% | With sodium hydroxide; oxygen; lead acetate In water at 90℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.6% | With triethylamine In dichloromethane at 20℃; | 7.1 4-chlorophenethyl methanesulfonate To a solution of 2-(4-chlorophenyl)ethanol (500 mg, 3.21 mmol) and TEA (650 mg, 6.43 mmol) in DCM (5 mL) was added methanesulfonyl chloride (548 mg, 4.81 mmol) at 0° C. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with DCM and water, and the phases were separated. The organic phase was washed with brine dried over sodium sulfate, filtered and concentrated to give product 4-chlorophenethyl methanesulfonate (570 mg, 75.6%) as white solid. 1H-NMR (CDCl3) δ 7.31-7.33 (d, 2H), 7.18-7.20 (d, 2H), 4.40-4.43 (t, 2H), 3.03-3.06 (t, 2H), 2.91 (s, 3H). |
With pyridine for 18h; | ||
With triethylamine In dichloromethane Yield given; |
With triethylamine | ||
5.18 gm (99.6%) | With triethylamine In tetrahydrofuran | B.XI 2-(4-chloro)phenyl-1-mesyloxyethane Preparation B-XI 2-(4-chloro)phenyl-1-mesyloxyethane To a stirring solution of 3.00 mL (22.16 mMol) 2-(4-chloro)phenyl-l-ethanol in 75 mL tetrahydrofuran at 0°C were added 4.63 mL (33.24 mMol) triethylamine followed by 1.89 mL (24.38 mMol) methanesulfonyl chloride. The reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was then poured into water and extracted well with ethyl acetate. The organic phases were combined, washed with water, dried over sodium sulfate and concentrated under reduced pressure to give 5.18 gm (99.6%) of the title compound. |
With triethylamine In tetrahydrofuran at 0 - 25℃; for 0.5h; | 18; 21 [000455j To a solution of Compound 18A (10.0 g, 64 mmol) in THF (100 mL) was added Et3N (19.4 g, 192 mmol). The mixture was cooled to 0 °C and MsC1 (8.1 g, 70.5 mmol) was added slowly. The mixture was stirred about half an hour at 25 °C. The mixture was diluted with ethyl acetate (500 mL), washed with water (100 mL x 2) and brine (100 mL), dried over sodium sulfate, and concentrated. The crude product was purified with column chromatography on silica gel (eluted with ethyl acetate in petroleum ether, from 10% to 20% v/v) to give Compound 18B. LC-MS (mlz): 235 [M+1] ‘H-NMR (DMSO-d6, 400 MHz): major characteristic peaks 5 (ppm) 2.99 (t, J= 6.8 Hz, 2H), 3.11 (s, 3H), 4.41 (t, J 7.2 Hz, 2H), 7.32-7.39 (m, 4H). | |
With triethylamine In dichloromethane at 0℃; for 2h; | 8.8A Example 8A: To a solution of 2-(4-chlorophenyl)ethanol (250 mg, 1.60 mmol, 215 μ, 1 eq) and Et3N (243 mg, 2.40 mmol, 333 μ, 1.50 eq) in DCM (5 mL) at 0 °C was added methanesulfonyl chloride (340 mg, 2.97 mmol, 230 μ, 1.86 eq). The solution was stirred at 0 °C for 2 hours. Water (30 mL) was added to the solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to afford the target compound (350 mg, 93% yield). The product can be used directly for the next step without further purification. MR (400 MHz, METHANOLS) δ 7.35 - 7.21 (m, 4H), 4.43 (t, J= 6.6 Hz, 2H), 3.04 (t, J= 6.6 Hz, 2H), 2.98 (s, 3H). | |
With triethylamine In dichloromethane at 20℃; Inert atmosphere; Schlenk technique; | ||
5.18 gm (99.6%) | With triethylamine In tetrahydrofuran | B.XI 2-(4-chloro)phenyl-1-mesyloxyethane Preparation B-XI 2-(4-chloro)phenyl-1-mesyloxyethane To a stirring solution of 3.00 mL (22.16 mMol) 2-(4-chloro)phenyl-l-ethanol in 75 mL tetrahydrofuran at 0°C were added 4.63 mL (33.24 mMol) triethylamine followed by 1.89 mL (24.38 mMol) methanesulfonyl chloride. The reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was then poured into water and extracted well with ethyl acetate. The organic phases were combined, washed with water, dried over sodium sulfate and concentrated under reduced pressure to give 5.18 gm (99.6%) of the title compound. |
5.18 gm (99.6%) | With triethylamine In tetrahydrofuran | B.XI 2-(4-chloro)phenyl-1-mesyloxyethane PREPARATION B-XI 2-(4-chloro)phenyl-1-mesyloxyethane To a stirring solution of 3.00 mL (22.16 mMol) 2-(4-chloro)phenyl-1-ethanol in 75 mL tetrahydrofuran at 0° C. were added 4.63 mL (33.24 mMol) triethylamine followed by 1.89 mL (24.38 mMol) methanesulfonyl chloride. The reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was then poured into water and extracted well with ethyl acetate. The organic phases were combined, washed with water, dried over sodium sulfate and concentrated under reduced pressure to give 5.18 gm (99.6%) of the title compound. |
5.18 gm (99.6%) | With triethylamine In tetrahydrofuran | XI 2-(4-chloro)phenyl-1-mesyloxyethane Preparation XI 2-(4-chloro)phenyl-1-mesyloxyethane To a stirring solution of 3.00 mL (22.16 mMol) 2-(4-chloro)phenyl-1-ethanol in 75 mL tetrahydrofuran at 0° C. were added 4.63 mL (33.24 mMol) triethylamine followed by 1.89 mL (24.38 mMol) methanesulfonyl chloride. The reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was then poured into water and extracted well with ethyl acetate. The organic phases were combined, washed with water, dried over sodium sulfate and concentrated under reduced pressure to give 5.18 gm (99.6%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.9% | With CoxMnyO4 (x/y=8); In toluene; at 60℃; for 6h; | Add 2-thiophene methanol (1 mmol) and toluene (2 mL) to a 10 mL reaction tube.The catalyst CoxMnyO4 (x/y=8) was added, and the reaction mixture was reacted at 60 C for 6 h.After the completion of the reaction, the target product is isolated by column chromatography to obtain the target product V.The yield was 99.9%. |
91% | With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; dihydrogen peroxide; In water; at 60℃; for 2h; | General procedure: A general experimental procedure is as follows: A mixtureof alcohol (1.0 mmol) and DBDMH (0.5 mmol, 0.14 g)in aqueous hydrogen peroxide (3.0 mmol, 35% aq. 0.09 mL)solution was stirred for 2 h at 60oC in the open vessel. Aftercooling the mixture to room temperature, the product wasextracted into dichloromethane (2 x 25 mL) and washed withwater. The combined organic layers were dried over MgSO4and evaporated under reduced pressure. The crude productwas purified by flash column chromatography (ethyl acetate/n-hexane = 1:3, v/v) to give the desired carbonyl compound. |
88% | With Dess-Martin periodane; In dichloromethane; at 20℃; for 2.25h;Inert atmosphere; | Example 15 4-Chlorophenylacetaldehyde (38) Dess-Martin periodinane (1.02 g, 2.4 mmol) was diluted in anhydrous CH2Cl2 (25 mL) under argon, and when solution was affected, 4-chlorophenethyl alcohol (33, 0.313 g, 2 mmol) was added dropwise. The mixture was stirred for 2 h and 15 min at room temperature, and was then quenched by addition of 20 mL sat. aq. Na2S2O3. After stirring at room temperature for 15 min, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The organic layer was washed with H2O and sat. aq. NaCl (50 mL each) and was dried over anhydrous sodium sulfate and concentrated. The resulting semisolid residue was triturated with 10% EtOAc in hexanes, and the solid was filtered and discarded. The filtrate was concentrated, and the oily residue was purified by flash column chromatography (SiO2), eluting with a gradient of hexanes to 15% EtOAc in hexanes to afford the title compound as a clear yellow volatile oil (0.211 g, 88%). 1H-NMR (500 MHz; CDCl3): delta 9.75 (t, J=2.1 Hz, 1H), 7.34 (d, J=8.3 Hz, 2H), 7.15 (d, J=8.2 Hz, 2H), 3.69 (d, J=2.0 Hz, 2H). |
88% | With Dess-Martin periodane; In dichloromethane; at 20℃; for 2.25h;Inert atmosphere; | 4-Chlorophenylacetaldehyde (38). Dess-Martin periodinane (1.02 g, 2.4 mmol) was diluted in anhydrous CH2Cl2 (25 mL) under argon, and when solution was affected, 4-chlorophenethyl alcohol (33, 0.313 g, 2 mmol) was added dropwise. The mixture was stirred for 2 h and 15 min at room temperature, and was then quenched by addition of 20 mL sat. aq. Na2S2O3. After stirring at room temperature for 15 min, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The organic layer was washed with H2O and sat. aq. NaCl (50 mL each) and was dried over anhydrous sodium sulfate and concentrated. The resulting semisolid residue was triturated with 10% EtOAc in hexanes, and the solid was filtered and discarded. The filtrate was concentrated, and the oily residue was purified by flash column chromatography (SiO2), eluting with a gradient of hexanes to 15% EtOAc in hexanes to afford the title compound as a clear yellow volatile oil (0.211 g, 88%). 1H-NMR (500 MHz; CDCl3): delta 9.75 (t, J=2.1 Hz, 1 H), 7.34 (d, J=8.3 Hz, 2 H), 7.15 (d, J=8.2 Hz, 2 H), 3.69 (d, J=2.0 Hz, 2 H). |
87% | With Dess-Martin periodane; In dichloromethane; for 2h;Inert atmosphere; | General procedure: To a stirred solution of the Dess-Martin reagent (DMP) (1.5mmol) in CH2Cl2 (10mL) under nitrogen, the alcohol (1.0mmol) was added dropwise. The reaction mixture was stirred for 2h and subsequently quenched with saturated aqueous sodium thiosulfate (20mL). After 15min of stirring the layers were separated, the organic layer was washed with water (50mL) and brine (2×50mL) and the aqueous layer was washed with EtOAc (2×25mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The thus obtained semisolid was triturated with 10% EtOAc in hexanes. The solid was removed by filtration. The filtrate was concentrated under reduced pressure to yield the final product. |
73% | 2-(4-Chlorophenyl)ethanol (1.00 g, 6.30 mmol) was added dropwise to a stirred solution of Dess-Martin periodinane (3.25 g, 7.66 mol) in dichloromethane (79 mL). After 2 hours, saturated aqueous sodium thiosulphate solution (63 mL) was added and stirring was continued for 15 minutes. The organic phase was separated and theaqueous phase was extracted with further dichloromethane. The combined organic extracts were washed with brine, dried and evaporated and the residue was purified by flash chromatography (hexanes/ethyl acetate) to give 0.708 g (73%) of the title compound as a white solid. Purity 100%.1 H NMR (400 MHz, Chloroform-d) 6 9.74 ppm (t, J = 2.1 Hz, 1 H), 7.32- 7.37 (m, 2H),7.13- 7.18 (m, 2H), 3.68 (d, J =2.1 Hz, 2H). HPLC/MS (3 mm) retention time 1 .33 mm.LRMS: m/z No ionization. | |
42% | With Dess-Martin periodane; In dichloromethane; at 20℃; | Example 3: Preparation of 1 -(4-chlorophenethyl)-5-cvclopropyl-8-methoxy-2, 3,5,6- tetrahydrobenzorbiri ,51diazocin-4(1 H)-one2-(4-chlorophenyl)acetaldehydeTo a solution of 2-(4-chlorophenyl)ethanol (2.00g, 12.77mmol) in dichloromethane (100ml) was added Dess-Martin periodinane (8.12g, 19.16mmol) and the mixture was stirred at room temperature over weekend. Then was added diethylether (150ml) and the resulting mixture was washed with a 1 :1 solution (150ml) of sodium carbonate (aqueous saturated) and sodium thiosulfate (aqueous saturated) and then with sodium bicarbonate (aqueous saturated) and finally with brine. The organic phase was then dried over sodium sulfate and evaporated. Silica gel flash chromatography (pentan/ethylacetate: 9/1 ) afforded the desired compound (0.834g, 42%) as a white solid.1H NMR (300MHz, CDCI3), delta 9.74 (t, J=2.0, 1 H), 7.34 (d, J=8.3, 2H), 7.15 (d, J=8.3, 2H), 3.68 (d, J=2.0, 2H). |
With Dess-Martin periodane; In dichloromethane; at 18 - 26℃; for 2h; | General procedure: To a suspension of LiAlH4 in dry THF was added the corresponding acid dissolved in dry THF dropwisely at room temperature. Then the mixture was stirred for 2 h and quenched with saturated NH4Cl. The mixture was extracted with chloroform and dried over anhydrous Na2SO4. Then the solvent was evaporated and the product was used without further purification. The crude alcohol was dissolved in dry DCM and DMP (Dess-Martin Periodinane) was added. The resulting mixture was stirred at room temperature for 2 h and quenched with Na2S2O3/NaHCO3 (v/v=1/1). The aqueous phase was extracted with DCM and dried over anhydrous Na2SO4. The solvent was evaporated to afford the corresponding aldehydes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 0 - 20℃; for 1.16667h; Inert atmosphere; | Alkyl Iodides 4; General Procedure A General procedure: To a solution of the appropriate alcohol (1.0 equiv) in CH2Cl2 (0.5 M), imidazole (1.2 equiv), PPh3 (1.1 equiv), and iodine (1.1 equiv) were sequentially added at 0 °C. After completion of the addition, the mixture was stirred at 0 °C for 10 min. The resulting mixture was warmed to r.t. and stirred for 1 h. The reaction was quenched by sat. aq Na2S2O3. The organic layer was separated and dried over anhydrous Na2SO4. After the solvent had been removed in vacuo, the crude product was purified by flash column chromatography (silica gel, hexane/EtOAc) to give the corresponding alkyl iodide 4. |
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane | ||
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 20℃; |
Multi-step reaction with 2 steps 1: aq. HBr 2: NaI | ||
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 0 - 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With chloroaluminium tetrahydroborate on poly(4-vinylpyridine) In ethanol for 10h; Heating; | |
85% | With ammonia borane; C28H28Cl2CoNP2; erbium(III) triflate In tetrahydrofuran at 45℃; for 8h; | |
84% | In isopropyl alcohol at 29.84℃; for 6h; Inert atmosphere; UV-irradiation; Sealed tube; |
58% | With bis(cyclopentadienyl)titanium dichloride; manganese; water In tetrahydrofuran at -20℃; for 0.5h; Inert atmosphere; chemoselective reaction; | |
44% | With N,N'-Dimethylurea; tris(pyrrolidino)phosphine oxide; lithium chloride In tetrahydrofuran at 0℃; for 4.5h; Inert atmosphere; Electrolysis; Glovebox; regioselective reaction; | |
Multi-step reaction with 2 steps 1: [(S)iPr(2,5-bis-(2-oxazolinyldimethylmethyl)pyrrole)NiF] / benzene-d6 / 36 h / 20 °C / Inert atmosphere 2: sodium hydroxide; water / methanol / 24 h / 20 °C / Inert atmosphere | ||
67 %Spectr. | With trimethylamine-N-oxide; [bis(hexamethylene)cyclopentadienone]iron tricarbonyl; hydrogen In toluene at 150℃; for 22h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-vinylbenzyl chloride With benzo[1,3,2]dioxaborole In toluene at 20℃; for 2h; Stage #2: With sodium hydroxide; water; dihydrogen peroxide In toluene at 20℃; for 2h; Title compound not separated from byproducts; | ||
Stage #1: 4-vinylbenzyl chloride With benzo[1,3,2]dioxaborole In toluene at 20℃; for 2h; Stage #2: With sodium hydroxide; water; dihydrogen peroxide In toluene at 20℃; for 2h; Title compound not separated from byproducts; | ||
Stage #1: 4-vinylbenzyl chloride With (S)-quinazolinap rhodium; benzo[1,3,2]dioxaborole In tetrahydrofuran at 20℃; for 2h; Stage #2: With sodium hydroxide; dihydrogen peroxide In tetrahydrofuran; ethanol at 0 - 20℃; Title compound not separated from byproducts; |
Stage #1: 4-vinylbenzyl chloride With (R)-2-tert-butyl-quinazolinap rhodium; benzo[1,3,2]dioxaborole In tetrahydrofuran at 20℃; for 2h; Stage #2: With sodium hydroxide; dihydrogen peroxide In tetrahydrofuran; ethanol at 0 - 20℃; Title compound not separated from byproducts; | ||
Stage #1: 4-vinylbenzyl chloride With diethoxymethylane In toluene at 50℃; for 12h; Stage #2: With potassium fluoride; dihydrogen peroxide; potassium carbonate In tetrahydrofuran; methanol at 0℃; | ||
With bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; 1-(2-(diphenylphosphaneyl)naphthalen-1-yl)-4-((R)-1-phenylethoxy)phthalazine; benzo[1,3,2]dioxaborole In toluene at 20℃; for 2h; | ||
Stage #1: 4-vinylbenzyl chloride With pinacol borane; 4 A molecular sieve; chiral TADDOL-based reagent In 1,2-dimethoxyethane at 0 - 20℃; Stage #2: With sodium hydroxide; dihydrogen peroxide In methanol; 1,2-dimethoxyethane; water at 0 - 20℃; Title compound not separated from byproducts; | ||
Stage #1: 4-vinylbenzyl chloride With (S)-di(3,5-difluorophenyl)(1-(2-isopropyl-quinazolin-4-yl)(2-naphthyl))phosphine rhodium(1,5-cyclooctadeine) trifluoromethanesulfonate; benzo[1,3,2]dioxaborole In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; Stage #2: With water; dihydrogen peroxide; sodium hydroxide In tetrahydrofuran; ethanol at 0 - 20℃; Inert atmosphere; optical yield given as %ee; | ||
Stage #1: 4-vinylbenzyl chloride With CF3O3S(1-)*C45H39N2OPRh(1+); benzo[1,3,2]dioxaborole In tetrahydrofuran at 20℃; Inert atmosphere; Stage #2: With dihydrogen peroxide; sodium hydroxide In ethanol; water at 0 - 20℃; optical yield given as %ee; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 62% 2: 9% | Stage #1: 4-vinylbenzyl chloride With 1-bromo-butane; sodium tetrahydroborate; Aliquat 336 at 20℃; for 16h; Stage #2: With sodium hydroxide; dihydrogen peroxide at 40℃; for 1h; | |
With benzo[1,3,2]dioxaborole In tetrahydrofuran at 25℃; for 3h; | ||
With benzo[1,3,2]dioxaborole In tetrahydrofuran at 25℃; for 3h; |
1: 76 %Spectr. 2: 13 %Spectr. | Stage #1: 4-vinylbenzyl chloride With sodium tetrahydroborate; ethyl iodide In 1,2-dimethoxyethane at 25℃; for 20h; Stage #2: With dihydrogen peroxide; sodium hydroxide In water at 0 - 25℃; for 0.333333h; Overall yield = 89 percent; | Typical procedure for hydroboration of alkenes with borane from NaBH4 and ethyl iodide using the PV method (Condition C) General procedure: Ethyl iodide (380 mg, 2.4 mmol) and magnetic stirring bar were placed at the bottom of a test tube (15mm f × 130 mm), to which Galden HT-135 (2 mL) and Galden HT-200 (1 mL) were added slowly using a syringe in order. Subsequently, NaBH4 (84 mg, 2.2 mmol), a solution of 4-methylstyrene (1a) (240mg, 2.0 mmol) in DME (5.0 mL) were added slowly in order, forming four layers. A rubber septum was fitted to the test tube, and a needle equipped with a balloon, which acted as a reservoir of borane gas during the reaction, was then pricked into the septum. The air in the test tube was removed by a syringe until the balloon was completely flattened. The test tube was stirred slowly for 20 h at 25 °C, taking care not to mix the layers. The reaction mixture was then cooled to 0 °C with ice while stirring. An aqueous NaOH solution (1 M, 1.35 mL) was added slowly in ten portions. Verifying that organic layer was changed to basic condition using a pH test paper, H2O2 solution (30%, 0.5 mL) was added slowly in two portions. After 20 min stirring, the organic layer was taken up with a glass pipette to a separating funnel, and washed with water and brine three times. The organic layer was dried over Na2SO4. After filtration, the solvent was evaporated. The residue was then purified by column chromatography on silica gel,eluting hexane/ethyl acetate (8:2) afforded 2-(p-tolyl)-1-ethanol (2a) (247 mg, 91%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With hydrogenchloride; zinc(II) chloride In benzene | |
26.2 g (56%) | With sodium hydrogensulfite In benzene | 1.7.a 7-Chloro-1-(4-nitrophenyl)-isochromane Step a) 7-Chloro-1-(4-nitrophenyl)-isochromane 24.97 g (160 mM) of 2-(4-chlorophenyl)-ethanol and 24.17 g (160 mM) of 4-nitrobenzaldehyde were dissolved in 480 ml of anhydrous benzene, then 21.76 g (160 mM) of anhydrous zinc chloride were added. Dry HCl gas was led into the stirred suspension for 4 hours and stirring was continued overnight. The reaction mixture was first washed with water then with a solution of sodium bisulfite, dried, filtered and finally evaporated. The residue was recrystallized from ethanol. Yield 26.2 g (56%), m. p. 98-101° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With molecular sieve; pyridinium chlorochromate In dichloromethane at 20℃; for 8h; | |
39% | With manganese dioxide on aluminum silicate In cyclohexane at 80℃; for 16h; | substrate C (entry 22, Table 3) 105.2 mg (0.67 mmol, 1 eq.) 2-(4-chlorophenyl) ethanol was dissolved in 25 mL cyclohexane (abs.) and 5 g manganese dioxide on aluminum silicate was added. The black suspension was heated under reflux for 16 h.The suspension was cooled to rt and filtered through Celite and washed with copiious EtOAc. The solvent wasremoved under reduced pressure. The product was purified by column chromatography (eluent: cyclohexane:EtOAc 3: 1)1H NMR (300 MHz, CDCl3) δ ppm 7.52 (d, J = 8.35 Hz, 2 H) 7.83 (d, J = 8.64 Hz, 2 H) 9.99 (s, 1 H). 13C NMR (75MHz, CDCl3) δ ppm 191, 142, 135, 131, 128. FTIR (KBr disc.) cm-1 3089, 2860, 2855, 2769, 2759, 2745, 1919,1699, 1693, 1678, 1597, 1588, 1577, 1486, 1419, 1388, 1362, 1321, 1293, 1265, 1209, 1163, 1155, 1131, 1094,1081, 1012, 841, 817, 794, 705, 700, 629, 544, 481. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl di-t-butylphosphine; lithium hexamethyldisilazane In 1,2-dimethoxyethane at 100℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl di-t-butylphosphine; lithium hexamethyldisilazane In 1,2-dimethoxyethane at 100℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cyanomethylenetributyl-phosphorane In toluene at 100℃; for 4h; | 78.78a (Tributylphosphoranylidene)acetonitrile (1.31 g, 4.89 mmol) was added to a solution of toluene (12 mL) containing N-(4-hydroxybenzoyl)glycine ethyl ester (which is the compound disclosed in J. Med. Chem., (1999), 42, 1041-1052, 663 mg, 2.97 mmol) and 2-(4-chlorophenyl)ethanol (447 µL, 3.30 mmol). The mixture was stirred at 100°C for 4 hours, and then ethyl acetate was added thereto. The resulting mixture was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane to hexane : ethyl acetate, 4:1 to 3:1, and then ethyl acetate, v/v) to give a powder (1.23 g). All this powder was dissolved in ethanol (12 mL), and then a 2 M lithium hydroxide aqueous solution (3.00 mL, 6.00 mmol) was added thereto. The resulting mixture was stirred at 60°C for 30 minutes, and then 10% hydrochloric acid (2.1 mL) was added thereto under ice-cooling. The produced precipitate was collected by filtration, washed sequentially with water and diisopropyl ether, and then dried under reduced pressure to give 861 mg of the title compound (powder, yield: 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 20℃; | ||
With pyridine at 0 - 20℃; for 18h; | 169.i (i) Toluene-4-sulfonic acid 2-(4-chloro-phenyl)-ethyl ester (i) Toluene-4-sulfonic acid 2-(4-chloro-phenyl)-ethyl ester 5 g (31.9 mmol) of 2-(4-Chloro-phenyl)-ethanol was dissolved in 100 ml of pyridine and the solution was cooled to 0° C. 6.09 g (31.9 mmol) of para-toluene sulfonyl chloride was added to this solution and the reaction was stirred at 0° C. for 2 h, then at room temperature for 16 h. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed once with saturated aqueous sodium bicarbonate, once with water, and once with saturated aqueous sodium chloride. The organic phase was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The compound was recrystallized from n-heptane/ethyl acetate. Yield: 6.23 g MS (Cl+): m/e=311, chloro pattern. | |
With pyridine In chloroform at 0℃; for 2.5h; | Compound 3m: 4-chlorophenethyl alcohol (205 μl, 1.5 mmol) was dissolved in chloroform (1.35 ml) and cooled to 0 oC. Pyridine (250 μl) was added to the vessel prior to the addition of tosyl chloride (415 mg, 2.2 mmol) in small portions The reaction was maintained at 0 oC with continuous stirring. After 2.5 hours, diethyl ether was added to the solution and the organic phase was washed with H2O (2 ml), 2M HCl (2ml) and 5% NaHCO3 (2 ml). The organic layer dried over anhydrous Na2SO4, concentrated to afford 4-chlorophenethyl tosylate (88% yield) as a white solid and used directly in the subsequent step. |
With dmap; triethylamine In dichloromethane for 4h; | 3 Example 3: Synthesis of A/-(4-chlorophenethyl)prop-2-en-l-aminium chloride (5) from l-(2-hydroxyethyl)-4-chlorobenzene (7) Example 3: Synthesis of A/-(4-chlorophenethyl)prop-2-en-l-aminium chloride (5) from l-(2-hydroxyethyl)-4-chlorobenzene (7) : Into a flask equipped with magnetic stir bar was placed the starting material (7, 2 mL, 11 mmol) which was dissolved in dichloromethane (20 mL). Triethylamine (1.84 mL, 1.2 eq), 4-dimethylaminopyridine (134 mg, 0.1 eq) and para-toluenesulfonyl chloride (2.3 g, 1.1 eq) were added successively. The solution was stirred for 4 hours after allylamine (3.3 mL, 4 eq) was added and reaction was stirred at reflux overnight. The reaction was washed with saturated Na2C03 solution (30 mL). The dichloromethane phase was concentrated and the residue was re-dissolved in dichloromethane (30 mL) and the solution was washed with a 2/1 mixture of brine/HCI IN (40 mL). The water phase was re-extracted with dichloromethane (20 mL). The combined dichloromethane fractions were dried over Na2S04 and concentrated. The solid was suspended in isopropyl acetate (30 mL) to give pure product 5 (60% of yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 69 percent / HCl / -10 - -5 °C 2: 48 percent / conc. H2SO4 / 5 h / 80 - 90 °C | ||
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2.5 h / 20 °C / Inert atmosphere 1.2: Inert atmosphere 2.1: titanium tetrachloride / dichloromethane / 2.5 h / 0 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: dichloromethane / 2.5 h / 20 °C / Inert atmosphere 2: trimethylsilyl trifluoromethanesulfonate / acetonitrile / 3 h / 0 °C / Inert atmosphere |
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2.5 h / 20 °C / Inert atmosphere 2: titanium tetrachloride / dichloromethane / 2.5 h / 0 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 20 °C 2: trimethylsilyl trifluoromethanesulfonate / acetonitrile / 0 - 20 °C | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 0 - 20 °C / Inert atmosphere 2: trimethylsilyl trifluoromethanesulfonate / acetonitrile / 24 h / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: dichloromethane / 12 h / 0 - 20 °C / Inert atmosphere 2: trimethylsilyl trifluoromethanesulfonate / acetonitrile / 24 h / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2.5 h / 25 °C 2: trimethylsilyl trifluoromethanesulfonate / dichloromethane / 10 h / 0 - 25 °C | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 25 - 27 °C / Inert atmosphere 2: trimethylsilyl trifluoromethanesulfonate / acetonitrile / 25 - 27 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0 - 20 °C 2: trimethylsilyl trifluoromethanesulfonate / acetonitrile / 24 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20 - 30℃; | 1.B Preparation of methyl 2- [3- [2- (4-CHLOROPHENYL) ETHOXYPHENYLTHIOLISO- butyrate (ST2195) Method B The product was prepared starting from methyl 2- (3- hydroxyphenylthio) isobutyrate (prepared as described above) (1.00 g, 4.42 mmol), and 4-chlorophenetyl alcohol (0.692 g, 4.42 mmol) in 15 mL of anhydrous THF, to which were added DIAD (1. 16 g, 5.75 mmol) and triphenylphosphine (1.500 g, 5.75 mmol) piecemeal in small portions, keeping the temperature below 30°C. The reaction was left overnight under magnetic stirring at room temperature. After this time period, the solvent was evaporated and the residue purified by silica gel chromatography using hexane/AcOEt 9/1 as eluent. 1.146 g of oily product were obtained (yield: 71%) ; TLC: silica gel, eluent hexane/AcOEt 9/1, Fr = 0.28 ; 1H NMR (CDC13, 300 MHz) 8 : 7.25 (m, 6H), 7.00 (m, 1H), 6.90 (d, 1H), 4.15 (t, 2H), 3.65 (s, 3H), 3.08 (t, 2H), 1.55 (s, 6H); HPLC: Column: Inertisil ODS 3 (5 UM) 4.6 x 250 mm, T: 30°C, mobile phase CH3CN/H20 80/20 (v/v), pH: as is, flow rate: 0.75 mL/min, 205 nm UV detector, retention time 19.34 min; KF: 1.7% H20; E. A. conforming for C19H2LCLO3S. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20 - 30℃; | 3 Preparation of methyl 2-[4-[2-(4-chlorophenyl)ethoxy]phenylthio]iso- butyrate (ST1929) The title product was prepared according to the procedure described in Method B starting from methyl 2- (4-hydroxyphenyl- thio) isobutyrate (prepared as described above) (0.800 g, 3.54 mmol) and 4-chlorophenetyl alcohol (0.554 g, 3.54 mmol) in 20 mL of anhydrous THF. DEAD (0.801 g, 4.6 mmol) and triphenylphosphine (1.205 g, 4.6 mmol) were added piecemeal in small portions, maintaining the temperature below 30°C. The reaction was left overnight under magnetic stirring at room temperature. After this period, the solvent was evaporated and the residue purified by silica gel chromatography using hexane/ethyl acetate 9/1 as eluent. 0.416 g of oily product were obtained (yield : 32%); TLC: silica gel, eluent hexane/ethyl acetate 9/1, Fr: 0.32 ; IH NMR (CDC13, 300 MHz) 8 : 7.40-7. 19 (m, 6H), 6.80 (d, 2H), 4.15 (t, 2H), 3.65 (s, 3H), 3.08 (t, 2H) 1.45 (s, 6H); HPLC: Column: Symmetry-Cis, (5 UM) 4.6 x 250 mm, T: 30°C, mobile phase CH3CN/H20 70/30 (v/v), pH: as is, flow rate: 0.75 mL/min, 205 nm UV detector, retention time 31.40 min; KF: 0.4% H20; E. A. conforming for CL9H2LCLO3S. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In methanol at 50℃; for 48h; | 13 Example 13-2- [2- (4-CHLOROPHENYL) ETHOXY]-21, 31, 51-TRI-O- (TRIISOPROPYLSILYL)- adenosine; [62] A mixture of 2-chloro-2', 3', 5-TRIS-O-(TRIISOPROPYLSILYL) adenosine (Example 6,5. 0 g) and 15ML OF 2- (4-CHLOROPHENYL) ethyl alcohol was purged with nitrogen and heated to 50°C. Sodium hydride (1.56 g, 60% dispersion in mineral oil) was added at a rate so as to control gas evolution. After 48 hours of heating LC and LC/MS analysis showed a mixture of products with one and two protecting groups respectively (2 isomers). The reaction mixture was allowed to cool to room temperature and carefully quenched with 40 mL of water. The resulting mixture was extracted with ethyl acetate (70ml). The layers were separated and the aqueous layer was again extracted with ethyl acetate (2X50 mL). The combined organic phases were washed with brine (80 mL), dried over MGSO4 and concentrated under reduced pressure to afford a clear oil (18G). This was purified by silica gel chromatography eluting progressively with CH2CI2, 1%, 2%, 5% and then 10% MEOH in CH2C12. The fractions containing the desired products were combined and concentrated to yield 3.2g of a gummy white solid. This mixture of silylated displacement products was taken to the next stepExample 12-;2- [2- (4-Chlorophenyl) ethoxy] adenosine; [6 0] To a 250-mL, three-neck round bottom flask was added 2-chloro- 2', 3', 5-TRI-O-(TRIETHYLSILYL) adenosine (5.0 g, 7.8 mmol, Example 4) and 2- (4- chlorophenyl) ethanol (15 mL). The mixture was flushed with nitrogen for 5-10 minutes, then heated to 50 °C. To this mixture was added sodium hydride (1.56 g, 39 mmol, as a 60% dispersion in mineral oil) at such a rate as to avoid excessive gas evolution. The reaction was maintained at 50 °C for 20 hours, at which time HPLC indicated complete conversion to the fully deprotected, alkylated product. The reaction was then cooled to room temperature, carefully quenched with water (40 mL), and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine (120 mL), dried (MGS04), filtered, and concentrated under reduced pressure to afford a clear oil. This material was purified by passing through a plug of silica gel, eluting with CH2C12, 3% methanol in CH2C12, and 10% methanol in CH2Cl2. Those fractions containing products were combined and evaporated to dryness, affording the desired product as a white solid. 680 MG (21%). m. p.: 114-120 °C. [61] 1H-NMR (DMSO-D6) : 8 3.00 (t, 2H, J = 6.7 Hz), 3.43-3. 3 (m, 2H), 3.92 (q, 1H, J = 3.9 Hz), 4.02-4. 21 (m, 2H), 4.39 (5,2H, J = 6.7 Hz), 4.51-4. 66 (m, 1H), 5.03-5. 22 (m, 2H), 5.40 (d, 1H, J = 6.2 Hz), 5.78 (d, 1H, J = 6.1 Hz), 7.22 - 7. 48 (M, 6H), 8.14 (s, 1H). LC/MS: m/z = 422 (M+H); 95.4% purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; ethyl acetate; | 4-Chloro-3-[2-(4-chloro-phenyl)-ethoxy]-benzoic acid methyl ester g (5.36 mmol) of <strong>[166272-81-7]4-Chloro-3-hydroxy-benzoic acid methyl ester</strong> was dissolved in 40 ml of anhydrous tetrahydrofuran. To this solution was added 0.923 g (5.9 mmol) of 2-(4-chloro-phenyl)-ethanol, 5.35 g (equivalent to 16.1 mmol PPh3) of triphenylphosphine derivatized polystyrene and 2.80 g (16.1 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluding with ethyl acetate/n-heptane (1/5). Yield 1.6 g. LC-MS (ES+): m/e=325 (M)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; n-heptane; ethyl acetate; | EXAMPLE C STR22 2.40 g (15.2 mmol) of 2-(4-chlorophenyl)ethanol were added dropwise at 40 C. to a suspension of 680 mg (22.7 mmol) of sodium hydride (80% suspension in oil) in 40 ml of dry tetrahydrofuran, and the mixture was stirred until the evolution of hydrogen had ceased. The mixture was then allowed to cool to room temperature, whereupon 2.7 g (15.2 mmol) of <strong>[5018-38-2]<strong>[5018-38-2]4,6-dichloro-5-methoxypyrimidin</strong>e</strong> (Monatshefte Chem. 96, 1661 (1965) were added in portions. The mixture was stirred for 1 hour at room temperature and for 4 hours at 40 C. For work-up, the reaction mixture was poured into saturated ammonium chloride solution and extracted with diethyl ether. The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel using n-heptane/ethyl acetate (4:1). 4.0 g (88% of theory) of 4-[2-(4-chlorophenyl)ethoxy]-5-methoxy-6-chloropyrimidine was obtained in the form of a viscous oil which crystallized slowly upon drying (melting point 70-71 C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.2% | In N,N-dimethyl-formamide; | EXAMPLE 209 4-[2-(4-Chlorophenyl)ethoxy]-8-fluoroquinoline To 1.2 g of sodium hydride in 50 mL of DMF was added 3.9 g of 2-(4-chlorophenyl)ethyl alcohol. The mixture was stirred at room temperature for one hour, then 4.5 g of <strong>[63010-72-0]4-chloro-8-fluoroquinoline</strong> in 10 mL of DMF was added, the mixture was heated to reflux for two hours. Then the mixture was allowed to cool to room temperature while it was stirred for four hours, after which it was poured into an ice/water mixture. The mixture was filtered, and the filter cake was washed with H2 O. Recrystallization from pentane/ethyl acetate gave 0.840 g of the title product. Yield 11.2%. M.P. 139-140 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With lithium hexamethyldisilazane In 1,2-dimethoxyethane at 100℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With lithium hexamethyldisilazane In 1,4-dioxane at 20℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.3% | Part A. 2-(4-Chlorophenethoxy)-3-methoxypyrazine To a mixture of 2-(4-chlorophenyl)ethanol (1.246 g, 7.96 mmol) in THF was added 1.0 M sodium bis(trimethylsilyl)amide in THF (6.92 mL, 6.92 mmol). After stirring at RT under nitrogen for 18 hours, the reaction was diluted with a solution of saturated NaHCO3 (65 ml) and extracted with EtOAc 720 ml). The ethyl acetate layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane to 30% ethyl acetate) to elute 2-(4-chlorophenethoxy)-3-methoxypyrazine (1.25 g, 4.72 mmol, 68.3% yield) as clear oil. 1H NMR (500 MHz, CDCl3) ? ppm 7.61-7.64 (1 H, m), 7.59-7.61 (1 H, m), 7.26-7.30 (2 H, m), 7.20-7.24 (2 H, m), 7.15 (1 H, d, J=8.52 Hz), 4.49-4.63 (2 H, m), 4.02 (3 H, s), 3.12 (2 H, t, J=7.29 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With cyclooctadiene ruthenium(II) dichloride; potassium <i>tert</i>-butylate; 1,3-diisopropyl-1H-imidazol-3-ium chloride; tricyclopentylphosphonium tetrafluoroborate In toluene for 24h; Inert atmosphere; Reflux; | |
83% | With dichloro(1,5-cyclooctadiene)ruthenium(II); potassium <i>tert</i>-butylate; 1,3-diisopropyl-1H-imidazol-3-ium chloride; tricyclopentylphosphonium tetrafluoroborate In toluene at 110℃; for 24h; Inert atmosphere; | |
73% | With potassium <i>tert</i>-butylate In toluene for 24h; Inert atmosphere; Reflux; | 6 General Amidation Procedure Using Metathesis Catalysts: Hoveyda-Grubbs 1st generation catalyst (0.025 mmol), 1,3-diisopropylimidazolium chloride (0.025 mmol) and KOtBu (0.075 mmol) were weighted into an oven-dried Schlenk tube. A condenser was attached and vacuum applied before the flask was filled with argon (procedure repeated twice). Freshly distilled toluene (1 mL) was then added and the mixture was heated at reflux temperature for 20 min. The flask was removed from the oil bath and the alcohol (0.5 mmol) and the amine (0.5 mmol) were added. The flask was returned to the oil bath and heated at reflux for 24 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography to give the amide. Results are presented in FIG. 8. |
49% | With 3-methyl-butan-2-one; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; caesium carbonate; 1,4-di(diphenylphosphino)-butane In <i>tert</i>-butyl alcohol at 125℃; for 24h; Schlenk technique; Inert atmosphere; | Representative Procedure for Formation of Amides from Alcohols General procedure: To an oven-dried, nitrogen purged Schlenk tube containing [Ru(p-cymene)Cl2]2(46.9 mg, 0.075 mmol), dppb (64.0 mg, 0.15 mmol) and Cs2CO3(97.7 mg, 0.30 mmol) was added alcohol (3 mmol), amine (0.33 mmol),3-methyl-2-butanone (0.8 ml, 7.5 mmol) and tBuOH(3 ml) and the reaction heated at reflux for 24 h. On completion, the reaction was allowed to cool to room temperature before the solvent was removed invacuo. The crude product was purified by column chromatography (diethyl ether/petroleum ether (b.p. 40-60 °C) as eluent) before recyrstallization from(dichloromethane/hexane), to afford the corresponding amide in good yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: 2-(4-Chlorophenyl)ethanol With sodium hydride In N,N-dimethyl acetamide at 20℃; for 0.5h; Stage #2: 5-fluoro-N-[3-(methyloxy)phenyl]methyl}-4-oxo-3,4-dihydroquinazoline-2-carboxamide In N,N-dimethyl acetamide at 80℃; for 1h; | 190 Example 190; 5-hydroxy-N-[3-(methyloxy)phenyl]methyl}-4-oxo-3,4- dihydroquinazoline-2-carboxamide; To a solution of 2- (4-chlorophenyl)ethanol mg, 556 µmol) in DMA (5 mL) was added sodium hydride (60% in oil, 92 mg, 2.32 mmol), and the mixture was stirred at room temperature for 30 min. 5-Fluoro-N-[3-(methyloxy)phenyl]methyl}-4-oxo-3,4- dihydroquinazoline-2-carboxamide (150 mg, 463 pmol) obtained in Example 110 was added, and the mixture was stirred with heating at 80°C for 1 hr. The reaction mixture was cooled to room temperature, adjusted to pH 3-4 with 1N hydrochloric acid, and diluted with ethyl acetate. The organic layer was washed with water and saturated brine and, after drying over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure. The obtained concentrated residue was crystallized from ethanol to give the title compound as a pale-yellow powder (110 mg, 73%) . melting point: 187-189°C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: 2-(4-Chlorophenyl)ethanol With sodium hydride In tetrahydrofuran; mineral oil at 2℃; for 0.5h; Inert atmosphere; Stage #2: 3,6-dichloropyridazin-4-carboxylic acid In tetrahydrofuran; mineral oil at 2 - 60℃; Stage #3: diazomethyl-trimethyl-silane In methanol; hexane; dichloromethane | 2.3 To a stirred mixture of 60% sodium hydride in mineral oil (2.27 g, 59.0 mmol) in anhydrous THF (125 mL) under nitrogen, cooled in an ice-water bath at 2° C., was added 4-chlorophenethyl alcohol (3.71 mL, 27.5 mmol) drop-wise. After 30 min 3,6-dichloropyridazine-4-carboxylic acid (5.0 g, 26.2 mmol) was added as a solution in THF (40 mL) over 20 minutes. The cooling bath was removed and stirring was continued at room temperature for 1 h then at 60° C. for 24 h. The mixture was cooled to room temperature and solvent was removed in vacuo. The residue was partitioned between ethyl acetate (150 mL) and water (150 mL). The combined organic layer was washed with an aqueous solution of sodium chloride (100 mL) and dried (MgSO4). The resulting solution was concentrated to give a white solid which was dissolved in CH2Cl2 (150 mL) and methanol (25 mL) and cooled in an ice-water bath to 2° C. To this solution was added (trimethylsilyl) diazomethane solution (15 mL, 60 mmol, 2.0 M in hexanes) dropwise. Once N2 evolution was complete the solution was concentrated in vacuo and the crude solid formed triturated with 10% diethyl ether/isohexane (100 mL). The precipitated solid was filtered washing with further 10% diethyl ether/isohexane (2×25 mL) and air-dried to give 4.97 g (58% over two steps) of the title compound as a pale pink solid. 1H NMR δ (ppm)(DMSO-d6): 3.12 (3H, t, J=6.37 Hz), 3.89 (3H, s), 4.72 (3H, t, J=6.37 Hz), 7.29-7.46 (4H, m), 8.11 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: 2-(4-Chlorophenyl)ethanol With sodium hydride In tetrahydrofuran; mineral oil at 2℃; for 0.5h; Inert atmosphere; Stage #2: tert-Butyl 4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate In tetrahydrofuran; mineral oil at 20 - 60℃; for 18h; | 1.2 To a stirred mixture of 60% sodium hydride in mineral oil (0.19 g, 4.95 mmol) in anhydrous THF (40 mL) under nitrogen, cooled in an ice-water bath at 2° C., was added 4-chlorophenethyl alcohol (0.73 mL, 5.40 mmol) drop-wise. After 30 min tent-butyl 4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate (1.50 g, 4.5 mmol) was added as a solution in THF (15 mL). The cooling bath was removed and stirring was continued at room temperature for 2 h then at 60° C. for 16 h. The mixture was cooled to room temperature and solvent was removed in vacuo. The residue was partitioned between ethyl acetate (100 mL) and water (75 mL). The combined organic layer was washed with an aqueous solution of sodium chloride (75 mL) and dried via hydrophobic frit. The resulting solution was concentrated to give a cream solid. The residue was dissolved in the minimum amount of dichloromethane and purified by flash chromatography (silica gel, 20% EtOAc/isohexane) to give 1.21 g (63%) of the title compound as a white solid. 1H NMR δ (ppm)(DMSO-d6): 1.42 (9H, s), 3.05-3.18 (6H, m), 3.20-3.25 (4H, m), 4.66 (2H, t, J=6.13 Hz), 6.94 (1H, s), 7.38 (4H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 2-(4-Chlorophenyl)ethanol With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 0.333333h; Stage #2: recorcinol In tetrahydrofuran for 18h; | 68 EXAMPLE 68; 4-Amino-3-{3-[2-(4-chloro-phenyl)-ethoxy]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester; DEAD (2.0 g, 11.5 mmol) (Aldrich) was added to a stirred solution of triphenylphosphine (3.01 g, 11.5 mmol) (Aldrich) in tetrahydrofuran (80 mL) at room temperature. After stirring for 10 minutes, p-chlorophenethyl alcohol (1.40 g, 8.9 mmol) (Aldrich) was added. After stirring for 10 minutes resorcinol (2.92 g, 26.55 mmol) (Aldrich) in tetrahydrofuran (20 mL) was added quickly and mixture stirred for another 18 hours. The reaction mixture was concentrate and the residue was purified by flash chromatography eluting with 20-40% ethyl acetate in hexanes to give 3-[2-(4-chloro-phenyl)-ethoxy]-phenol. (Yield 1.44 g, 65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Step 1: 3-(4-Chlorophenethoxy)-6-iodopyridazine (Compound A)[0273] To a stirred mixture of 60% sodium hydride in mineral oil (0.96 g, 25.0 mmol) in anhydrous THF (30 mL) under nitrogen, cooled in an ice-water bath at 2 0C, was added 4- chlorophenethyl alcohol (3.10 mL, 22.9 mmol) drop-wise. After 30 min 3-chloro-6- iodopyridazine (5.00 g, 20.8 mmol) was added as a solution in THF (70 mL). The cooling bath was removed and stirring was continued at room temperature for 0.5 h then at 60 0C for 1.5 h. The mixture was cooled to room temperature and solvent removed in vacuo. The residue was partitioned between ethyl acetate (250 mL) and water (150 mL). The combined organic layer was washed with an aqueous solution of sodium chloride (150 mL) and dried via hydrophobic frit. The resulting solution was concentrated to give a yellow solid. The residue was triturated (Et2theta/isohexane 1 :10, 75 rnL) and filtered to give 6.53 g (88%) of the title compound as a white solid; 1H NMR delta (ppm)(DMSO-d6): 3.11 (2 H, t, J = 6.58 Hz),4.64 (2 H, t, J = 6.58 Hz), 7.01 (1 H, d, J = 9.14 Hz), 7.32-7.42 (4 H, m), 7.99 (1 H, d, J = 9.14 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In tetrahydrofuran; mineral oil at 50℃; for 48h; | 235.2 Step 2: N-{(3aR,4S,6R,6aS)-6-[2-[2-(4-Chloro-phenyl)-ethoxy]-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-4-yl}-propionamide The title compound is prepared by adding N-{(3aR,4S,6R,6aS)-6-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-4-yl}-propionamide (example 235, step 1) to a premixed solution of sodium hydride (60% in oil) and 2-(4-chloro-phenyl)-ethanol (1 equivalent) in dry THF. The reaction is stirred at 50° C. for 48 hours, before quenching residual sodium hydride with excess aqueous ammonium chloride. The reaction mixture id then partitioned between ethyl acetate and water; the organic phase is washed consecutively with water and brine before drying over magnesium sulfate. Filtration and removal of the volatile components under reduced pressure yields the crude product; purification by column chromatography/crystallisation affords the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 20 - 50℃; Inert atmosphere; | 9.A (9A) Ethyl 3-{4-[2-(4-chlorophenyl)ethoxy]phenyl}-3-ethoxypropionate Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and 2-(4-chlorophenyl)ethanol (99 mg, 0.630 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a yellow oily substance (151 mg, yield: 95%). 1H NMR (CDCl3, 400 MHz): δ1.13 (3H, t, J=7.0 Hz), 1.23 (3H, t, J=7.0 Hz), 2.55 (1H, dd, J=5.0, 15.2 Hz), 2.79 (1H, dd, J=9.0, 15.2 Hz), 3.06 (2H, t, J=7.0 Hz), 3.30-3.38 (2H, m), 4.14 (4H, t, J=7.3 Hz), 4.68 (1H, dd, J=5.0, 8.9 Hz), 6.86 (2H, d, J=8.6 Hz), 7.22 (2H, d, J=8.3 Hz), 7.24 (2H, d, J=8.6 Hz), 7.28 (2H, d, J=8.6 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 0 - 20℃; | 71 Example 71 Genera. Procedure for the Synthesis of Ethers by the SN2 alkylation or Mitsunobu Reaction; [0401] To a stirred solution of the phenol (3.89 mmol), the primary alcohol, (3.89 mmol), and triphenyl phosphine (4.28 mmol) in anhydrous THF (15 mL) at 0 °C was added DEAD (40% in toluene, 4.28 mmol, 1.95 mL) dropwise. The yellow solution was allowed to warm to room temperature and stirring was continued overnite. After evaporating the solvent under reduced pressure the crude residue was dissolved in DCM (15 mL). The organic layer was washed with 10% NaOH (2 x 10 mL), water and brine. The organic phase was dried (Na2S04), filtered and evaporated under reduced pressure. The crude residue was purified by column chromatography on silica gel using hexanes EtOAc as the eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: bis(trichloromethyl) carbonate; tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate With triethylamine In 1,2-dichloro-ethane at 80℃; for 1h; Stage #2: 2-(4-Chlorophenyl)ethanol In 1,2-dichloro-ethane at 100℃; for 18h; | 120.a To a stirred solution of (RS)-tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate (100 mg, CAS 908334-28-1) in dichloroethane (4 ml) were added sequentially triethylamine (0.62 ml) and triphosgene (44 mg) and the mixture was heated at 80° C. for 1 h. To the resulting mixture was added 4-chlorophenethyl alcohol (0.06 ml, CAS 1875-88-3) and the mixture was heated at 100° C. for 18 h. The mixture was then cooled to room temperature and diluted with dichloromethane. The mixture was washed with water, then the phases were separated and the organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (RS)-3-{-4-[2(4-chloro-phenyl)-ethoxycarbonylamino]-phenyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (104 mg, 63%) as an orange solid. MS (ISP): 464.3 ([{37Cl}M+NH4]+), 462.3 ([{35Cl}M+NH4]+). 391.2 ([{37Cl}M+H-C4H8]+), 389.2 ([{35Cl}M+H-C4H8]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-(4-Chlorophenyl)ethanol With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.5h; Cooling with ice; Stage #2: Methyl 4-(bromomethyl)benzoate In N,N-dimethyl-formamide; mineral oil at 20℃; for 3h; | 146.1 [Example 146] {1-[(4-[2-(4-chlorophenyl)ethoxy] methyl} phenyl)carbpnyl]isoquinolin-4-yl}acetic acid (1) To a solution of 4-chlorobenzyl alcohol (4.10 g) in N,N-dimethylformamide (110 ml), sodium hydride (60 to 72%, 952 mg) was added in an ice bath, and the mixed solution was stirred for 30 min. Then, to the resulting solution, 4-(bromomethyl)benzoic acid methyl ester (5,00 g) was added, and the mixed solution was stirred at room temperature for three hours. To the resulting solution, ethyl acetate was added. The resulting solution was washed with water and with a saturated saline solution, sequentially, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH type silica gel, ethyl acetate / n-hexane = 5 to 9%) to give methyl 4-[2-(4-chlorophenyl)ethoxy]methyl}benzoate (5.25 g). 1H NMR (600 MHz, CHLOROFORM-d) d ppm 2.90 (t, J=6.6 Hz, 2 H), 3.68 (t, J=6.6 Hz, 2 H), 3.31 (s,3 H), 4.56 (s, 2 H), 7.11 - 7.37 (m, 6 H), 7.92 - 8.05 (m, 2 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tributylphosphine; diamide In tetrahydrofuran at 20℃; for 18h; | 141.1 Example 141] [1-({4-[2-(4-chlorophenyl)ethoxy]phenyl} carbonyl)isoquinolin-4-yl]acetic acid (1) To a solution of the compound (100 mg) obtained in Example 134-(4) in tetrahydrofuran (2 ml), 2-(4-chlorophenyl)ethanol, tri-n-butyl phosphine (0.116 ml) and tetramethyl azodicarboxyamide (80 mg) were added. The mixed solution was stirred at room temperature for 18 hours. To the reaction solution, water was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH type silica gel, ethyl acetate / n-hexane = 10 to 50%) to give methyl [1-({4-[2-(4-chlorophenyl)ethoxy]phenyl}carbonyl)isoquinolin-4-yl]acetate (41 mg) as a colorless oily substance. 1H NMR (600 MHz, CHLOROFORM-d) d ppm 3.09 (t, J=6.8 Hz, 2 H), z (s, 3 H), 4.10 (s, 2 H), 4.22 (t, J=6.8 Hz, 2 H), 6.89 - 8.52 (m, 13 H) (2) The same procedure as used in Example 135-(6) was carried out using the compound (38 mg) obtained in Example 141-(1) to give the titled compound (35 mg) as a colorless amorphous substance. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; | 32.2 Step 2: 2-chloro-4-(4-chlorophenethoxy)phenyl)-6-methylpyrimidine 4-(2-chloro-6-methylpyrimidin-4-yl)phenol (30 mg, 0.14 mmol) and triphenylphosphine (PPh3, 47.7 mg, 0.182 mmol) was dissolved and 4-chlorophenylethanol (0.02 ml, 0.16 mmol) and diisopropylazodicarboxylate (DIAD, 0.04 ml, 0.182 mmol) were added. The reaction mixture was stirred at room temperature by thin layer chromatography (TLC) until 4-(2-chloro-6-methylpyrimidin-4-yl)phenol disappeared, and then diluted with water. The reaction product diluted in water was extracted with ethyl acetate, and the extracted organic layer was washed with brine and dried over magnesium sulfate. The dried organic layer was concentrated under reduced pressure, and the concentrated reaction product was purified by column chromatography (silica gel, ethyl acetate:n-hexane=1:4) to obtain the target compound (32 mg, 64%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With but-2-enenitrile; dodecacarbonyl-triangulo-triruthenium; 2,2'-bis(diphenylphosphino)biphenyl; zinc(II) chloride In tert-Amyl alcohol at 130℃; for 3h; Inert atmosphere; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium phosphate; C43H59NO2PPd(1+)*CH3O3S(1-) In <i>tert</i>-butyl alcohol at 110℃; for 1.5h; Inert atmosphere; | |
92% | With potassium phosphate; C44H59F3NO5PPdS In <i>tert</i>-butyl alcohol at 110℃; for 1.5h; Inert atmosphere; | 7 General Procedure for Arylation of Primary Amides General procedure: An oven-dried, resealable tube equipped with a magnetic stir bar and Teflon septum was charged with OTf-tBuBrettPhos precatalyst (9.1 mg, 1 mol %), K3PO4 (297 mg, 1.40 mmol, 1.40 eq), aryl halide (1.00 mmol, 1.00 eq) and amide (1.20 mmol, 1.20 eq) if they are solids. The tube was sealed and evacuated and backfilled with argon. This process was repeated three times. Then the aryl halide and amide were added if they are liquids, followed by tBuOH (2 mL). The reaction was heated at 110° C. and monitored by thin-layer chromatography or gas chromatography, observing the disappearance of aryl halide. After completion, the reaction was cooled to room temperature and diluted with ethyl acetate and water. The phases were separated and the aqueous phase was back extracted with ethyl acetate (2×5 mL). The combined organic phases were dried over sodium sulfate, concentrated via rotary evaporation and the crude product was purified by column chromatography. See FIG. 17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane at 20℃; for 2.5h; Inert atmosphere; | General procedure for start materials: General procedure: A mixture of the substituted phenylethyl alcohol (10 mmol), Chloromethyl methyl ether (15mmol) and N,N-diisopropylethylamine (20 mmol) in dry dichloromethane (25 mL)was stirred under nitrogen atmosphere for 2.5 h at rt. The reaction mixture wasthen washed with water (2×50 mL), dried (NaSO4) and the solvent wasremoved in vacuo. The crude MOM acetal was dissolved in dried CH3CN (25mL) and added to cooled (0 oC) solution of Trimethylsilyltrifluoromethanesulfonate (TMSOTf) (10 mmol). The reaction was carried outunder nitrogen atmosphere for 3 h. Then the mixture was quenched by theaddition of l M NaHCO3 (20 mL ). The orgnic phase was washed withbrine (2×50 mL), dried (NaSO4) and evaporated under reducedpressure. Purification by FC afforded relevant substituted isochromans. | |
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; | ||
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; |
In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | ||
With N-ethyl-N,N-diisopropylamine In dichloromethane at 25 - 27℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 2-phenylethynylbenzaldehyde p-toluenesulphonylhydrazone With silver trifluoromethanesulfonate In 1,2-dichloro-ethane at 60℃; for 3h; Stage #2: 2-(4-Chlorophenyl)ethanol With potassium phosphate; Dess-Martin periodane In dichloromethane; 1,2-dichloro-ethane at 60℃; | 1 4.2.2 General procedure: Silver trifluoromethanesulfonate (0.03 mmol), N0-(2-alkynylbenzylidene)hydrazide 1 (0.30 mmol, 1.0 equiv), and anhydrousdichloroethane (2.0 mL) were added into a tube equippedwith a magnetic stirring bar under sealing plug. The mixture wasstirred at 60 C for 3 h. When N0-(2-alkynylbenzylidene)hydrazide 1disappeared as indicated by TLC, the solutionwas cooled to rt, thenDMP(0.6 mmol, 2.0 equiv), aromatic alcohol 2 (0.6 mmol, 2.0 equiv),K3PO4 (0.9 mmol, 3.0 equiv), and anhydrous dichloromethane(2.0 mL) were added into the solution. The mixture was stirred at60 C. After completion of the reaction as indicated by TLC, the reactionwas quenched with water (10 mL), extracted with EtOAc(310 mL), dried by anhydrous Na2SO4. Evaporation of the solventfollowed by purification on silica gel provided the correspondingproduct 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: C23H20N2O3S With silver trifluoromethanesulfonate In 1,2-dichloro-ethane at 60℃; for 3h; Stage #2: 2-(4-Chlorophenyl)ethanol With potassium phosphate; Dess-Martin periodane In dichloromethane; 1,2-dichloro-ethane at 60℃; | 1 3p General procedure: Silver trifluoromethanesulfonate (0.03 mmol), N0-(2-alkynylbenzylidene)hydrazide 1 (0.30 mmol, 1.0 equiv), and anhydrousdichloroethane (2.0 mL) were added into a tube equippedwith a magnetic stirring bar under sealing plug. The mixture wasstirred at 60 C for 3 h. When N0-(2-alkynylbenzylidene)hydrazide 1disappeared as indicated by TLC, the solutionwas cooled to rt, thenDMP(0.6 mmol, 2.0 equiv), aromatic alcohol 2 (0.6 mmol, 2.0 equiv),K3PO4 (0.9 mmol, 3.0 equiv), and anhydrous dichloromethane(2.0 mL) were added into the solution. The mixture was stirred at60 C. After completion of the reaction as indicated by TLC, the reactionwas quenched with water (10 mL), extracted with EtOAc(310 mL), dried by anhydrous Na2SO4. Evaporation of the solventfollowed by purification on silica gel provided the correspondingproduct 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; | 23 4.2.9.23 Methyl 6-(4-chlorophenethoxy)-2-oxo-2H-chromene-3-carboxylate (48) A mixture of the appropriate hydroxycoumarin (13-22; 2.0mmol), triphenyl phosphine (1.04g, 4.0mmol), the corresponding alcohol (3.0mmol) and THF (30ml) was cooled to 0°C. DEAD (0.52g, 0.49mL, 3.0mmol) or DIAD (0.61g, 0.59mL, 3.0mmol) was added dropwise and the solution was stirred overnight at room temperature. The volume was reduced in vacuo the residue was diluted with EtOAc (100mL), washed with 1N NaOH (3× 100mL) and brine (80mL), dried over Na2SO4 and evaporated to dryness. The products were obtained either after recrystallization or column chromatography. Methyl 6-hydroxy-2-oxo-2H-chromene-3-carboxylate (14, 440 mg) was reacted with 2-(4-chlorophenyl)ethanol (470 mg) and DIAD. The residue was recrystallized from MeOH (30 mL) to give the product as light green needles (249 mg, 35%): mp 142-143 °C; 1H NMR (500 MHz, DMSO-d6) δ 3.05 (t, 2H, 3J = 7.0 Hz, CH2), 3.82 (s, 3H, CH3), 4.22 (t, 2H, 3J = 7.0 Hz, O-CH2), 7.30 (dd, 1H, 4J = 2.9 Hz, 3J = 8.8 Hz, 6-H), 7.36 (m, 5H, arom.H), 7.48 (d, 1H, 4J = 2.9 Hz, 5-H), 8.68 (s, 1H, 4-H); 13C NMR (125 MHz, DMSO-d6) δ 34.1, 52.5, 68.7, 112.9, 117.4, 117.8, 118.3, 122.9, 128.4, 131.0, 131.2, 137.3, 148.9, 149.2, 154.9, 156.2, 163.3. Anal. Calcd for C19H15ClO5: C, 63.61; H, 4.21. Found: C, 63.27; H, 4.46. LC-MS (ESI) (90% H2O to 100% MeOH in 10 min, then 100% MeOH to 20 min, DAD 220-400 nm), 100% purity, m/z = 359.12 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; | 22 4.2.9.22 Methyl 7-(4-chlorophenethoxy)-2-oxo-2H-chromene-3-carboxylate (47) A mixture of the appropriate hydroxycoumarin (13-22; 2.0mmol), triphenyl phosphine (1.04g, 4.0mmol), the corresponding alcohol (3.0mmol) and THF (30ml) was cooled to 0°C. DEAD (0.52g, 0.49mL, 3.0mmol) or DIAD (0.61g, 0.59mL, 3.0mmol) was added dropwise and the solution was stirred overnight at room temperature. The volume was reduced in vacuo the residue was diluted with EtOAc (100mL), washed with 1N NaOH (3× 100mL) and brine (80mL), dried over Na2SO4 and evaporated to dryness. The products were obtained either after recrystallization or column chromatography. Methyl 7-hydroxy-2-oxo-2H-chromene-3-carboxylate (13, 440 mg) was reacted with 2-(4-chlorophenyl)ethanol (470 mg) and DIAD. The residue was recrystallized from MeOH (35 mL) to give the product as white needles (496 mg, 69%): mp 143-145 °C; 1H NMR (500 MHz, DMSO-d6) δ 3.06 (t, 2H, 3J = 6.6 Hz, CH2), 3.80 (s, 3H, CH3), 4.34 (t, 2H, 3J = 7.0 Hz, O-CH2), 6.97 (dd, 1H, 4J = 2.5 Hz, 3J = 8.8 Hz, 6-H), 7.02 (d, 1H, 4J = 2.6 Hz, 8-H), 7.36 (m, 4H, arom.H), 7.80 (d, 1H, 3J = 8.9 Hz, 5-H), 8.72 (s, 1H, 4-H); 13C NMR (125 MHz, DMSO-d6) δ 33.9, 52.3, 68.9, 101.0, 111.6, 113.2, 113.7, 128.4, 131.0, 131.2, 131.8, 137.1, 149.5, 156.3, 157.1, 163.5, 164.0. Anal. Calcd for C19H15ClO5: C, 63.61; H, 4.21. Found: C, 63.26; H, 4.37. LC-MS (ESI) (90% H2O to 100% MeOH in 10 min, then 100% MeOH to 20 min, DAD 220-400 nm), 98.8% purity, m/z = 359.13 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; sodium hydrogencarbonate In toluene at 110℃; for 72h; Inert atmosphere; | General Procedure for the Preparation of 3 General procedure: To a solution of [Cp*IrCl2]2 (0.0025 mmol), amino acid 2(0.65 mmol), and NaHCO3 (0.05 mmol) in toluene (3 mL) under an atmosphere of argon was added alcohol 1 (0.5mmol). The resulting mixture was stirred at 110 °C for a certain period of time. The reaction mixture was cooled tor.t., and H2O (5 mL) was then added. The resulting solution was extracted with EtOAc. Purification on silicon gel afforded the desired products 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: 2-(4-Chlorophenyl)ethanol With sodium at 60℃; for 0.5h; Stage #2: 2-chloropyrido[3,4-d]pyrimidin-4-ol at 90℃; | 174 Example 174: 2- [2-(4-chlorophenyl)ethoxy]pyrido [3 ,4-d]pyrimidin-4-ol A mixture of 2-(4-Chloro-phenyl)-ethanol (2 mL) and Na (95 mg, 5 eq, 4.14 mmol) was stirred and heated at 60 °C for 0.5 h until Na disappeared. 2-Chloro-pyrido[3,4- d]pyrimidin-4-ol (150 mg, 0.83 mmol) was added to the mixture and the mixture was stirred overnight at 90 °C. The reaction mixture was concentrated and the residue was purified by gel chromatography (20:1, DCM :MeOH) to afford 195 mg (59%) of the title compound as a white solid. ‘H NMR (400 MHz, DMSO-d6): ö 3.07 (t, J= 6.8 Hz, 2H), 4.62 (t, J= 6.8 Hz, 2H), 7.38 (s, 4H), 7.83 (d, J= 6.8 Hz, 1H), 8.49 (d, J= 5.2 Hz, 1H). 8.84 (s, 1H), 12.64(s, 1H). [M+H] Calc’d for C,5H,2C1N302, 302; Found, 302. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium <i>tert</i>-butylate In toluene at 120℃; for 24h; Inert atmosphere; Schlenk technique; | 2.4 General procedure for heterogeneous catalyst experiment Under N2 atmosphere, ethanol derivatives (1.0mmol), PPT-RuAl2O3 catalyst (0.1mol%, 2 % loading, w/w) and KOtBu (0.5 equiv.) were introduced in a Schlenk tube (25mL), successively. The tube was evacuated and refilled with high purity nitrogen for three times. Then the Schlenk tube was closed and the resulting mixture was stirred at 120°C for 24h under toluene (2.0mL) conditions. After cooling down to room temperature, water was added to quench the reaction, then filter to obtain mother liquor and extracted with ethyl acetate, the organic phase was concentrated by removing the solvent under vacuum. Finally, the residue was purified by column chromatography with petroleum ether as eluent to give the desired product. |
Multi-step reaction with 2 steps 1: trichloroisocyanuric acid; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / dichloromethane / 0.25 h / 0 °C 2: potassium hydroxide / ethanol / 4 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27.9% | Stage #1: 2-(4-Chlorophenyl)ethanol; (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate With diethylazodicarboxylate In tetrahydrofuran at 20℃; for 18h; Stage #2: With methanol; sodium hydroxide at 75℃; for 16h; | 26 Example 26 10245]Example 2610246] To a stirred solution of (5)-ethyl 2-(tert-butoxy)-2- (4-(4,4-dimethylpiperidin- 1 -yl)-5-(4-hydroxyphenyl)-2,6- dimethylpyridin-3-yl)acetate (20 mg, 0.043 mmol), 2-(4- chiorophenyl)ethanol (33.4 mg, 0.2 13 mmol) and Ph3P-resin (55.8 mg, 0.213 mmol) in THF (2 mE) was added DEAD (0.014 mE, 0.085 mmol) at it. Afier 18 h, mixture was filteredremove polymer, concentrated and treated with iN NaOH (0.854 mE, 0.854 mmol) in MeOH (1 mE) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPEC to afford (S)-2-(tert-butoxy)-2-(5-(4-(4-chlorophenethoxy)phenyl)-4- (4,4-dimethylpiperidin-1 -yl)-2,6-dimethylpyridin-3-yl)ace-acid (6.9 mg, 0.012 mmol, 27.9% yield). ‘H NMR (500 MHz, DMSO-d5) ö7.21 (d, J=8.4 Hz, 1H), 7.07-6.93 (m, 3H), 5.83 (s, 1H), 4.34-4.19 (m, 2H), 3.34 (br. s., 1H), 3.28 (bt s., 1H), 3.06 (t, J=6.6 Hz, 2H), 2.79 (t, J=12.1 Hz, 1H), 2.43 (s, 3H), 2.18 (d, J=9.2 Hz, 1H), 2.05 (s, 3H), 1.98-1.93 (m, 1H),1.91 (s, 3H), 1.49 (bt s., 1H), 1.29 (bt s., 1H), 1.18 (d, J=1 1.7 Hz, 1H), 1.12 (s, 9H), 1.02 (d, J=13.9 Hz, 1H), 0.85 (s, 3H), 0.60 (s, 3H). ECMS (M+H)=579.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With oxygen; sodium t-butanolate In tetrahydrofuran at 20℃; for 17h; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With ytterbium(III) triflate In nitromethane at 120℃; | Esterification of caffeic acid General procedure: To a mixture of caffeic acid fine powder (1.0 g, 5.56 mmol), various phenethyl alcohols (5.56 mmol) in CH3NO2 (125 mL) was added Yb(OTf)3 (34.4 mg, 0.056 mmol). After 5 min of ultrasonic shake, the mixture was stirred on a 120 °C oil bath for 40-120 min. The reaction mixture was cooled to room temperature, washed with 2% NaHCO3 (30 mL) and brine, dried over anhydrous Na2SO4, and concentrated to give crude products, which were purified by column chromatography to give the compounds 1-26 in 18-61% yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; 1-methyl-2-phenyl-3-(diphenylphosphino)-1H-indole; potassium carbonate In 1-methyl-pyrrolidin-2-one at 120℃; for 24h; Schlenk technique; Inert atmosphere; Sealed tube; | General procedure A (conditions A). General procedure: Two runs were set side by side. A Schlenck tube was loadedwith [RuCl2(p-cymene)]2 (3.1 mg, 5 mol, 1 mol%), L3 (3.9 mg, 0.01 mmol, 2 mol%), and K2CO3(173 mg, 1.25 mmol). The tube was backfilled with Ar (3 ×). Under light backflow of Ar, NMP (2.5mL), followed by the required substrate (1a-1d, 1f) (0.6 mmol) and p-chloroanisole (2a; 62 L, 71 mg,0.5 mmol). The tube was sealed and the reaction mixture was stirred at 120 °C for 24 hours. Aftercooling to room temperature, the reaction mixtures from both tubes were combined in H2O (40 mL)and EtOAc (20 mL). The organic phase was separated and washed with H2O (3 × 30 mL), dried(MgSO4), filtered, and concentrated under reduced pressure. The monoarylated products (major) wereisolated after flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap In dichloromethane at 20℃; for 6h; | 4.4. General procedure for the synthesis of 4'-ethyloxycarbonyloxyferulate 11b-l General procedure: Ethyl chloroformate (0.76 mL, 8 mmol) and TEA (1.1 mL, 8 mmol) were added to a suspension of ferulic acid (0.737 g, 3.8 mmol) in DCM (10 mL) and stirred for 1 h at -15 °C until TLC analysis revealed a total consumption of starting material. Alcohol (8 mmol) and DMAP (0.030 g, 0.08 mmol) were then added and the mixture stirred at room temperature for 6 h. The solvent was evaporated under reduced pressure to afford the crude product. This product was purified by silica gel column chromatography using mixtures of n-hexane/ethyl acetate or toluene/ethyl acetate as eluents. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With methanesulfonic acid; chloranil In acetonitrile at 20℃; for 4h; Inert atmosphere; regioselective reaction; | General Procedure General procedure: To a solution of the aldehyde 1 (1.0 equiv) in the mixture of anhydrous MeCN/HFIP (1/1, 1.0 M) was added alcohol (10 equiv), MeSO3H (30 mol%) and chloranil (1.0 equiv) at room temperature. The whole solution was stirred at room temperature under argon atmosphere until TLC revealed the consumption of aldehyde 1. The reaction mixture was quenched by sat. Na2CO3 and extracted with EtOAc. The whole organic layer was washed by brine and dried over MgSO4. The organic solution was filtered and concentrated by the rotary evaporator. The residue was purified by a silica gel flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With tert.-butylhydroperoxide; ferrocene; phenylsilane at 20 - 80℃; for 6h; Inert atmosphere; | 21 Example 21 Compound 21:Ferrocene (5.5 mg, 0.025 mmol) was added sequentially to a 25 mL two-necked flask,4-chlorophenylethanol (46.5 mg, 0.25 mmol),Phenyl silane (109 [mu] L, 0.75 mmol)Tert-butyl hydroperoxide (88 [mu] L, 0.75 mmol)The gas was replaced with dry N2 for 3 times,Finally, dry tetrahydropyran (2.0 mL) was added under N2.The mixture was stirred at room temperature and heated to 80 ° C to carry out the reaction,Until the thin layer chromatography monitoring of raw materials is completed.At the end of the reaction, 15.0 mL of NaCl solution was added at room temperature,Extracted with ether 15.0mL three times, combined with organic phase decompression steaming,The product was purified by column chromatography in 85% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 30℃; for 12h; | 1.2.2 General procedure for the preparation of compounds (D11-D14 and D17) General procedure: To a solution of 4-hydroxy-1-indanone (1a) (1.0 g, 1.0 equiv), R2-OH (1.3 equiv) and triphenylphosphine (2.28 g, 1.3 equiv) in tetrahydrofuran was added tert-butyl azodicarboxylate (2.02 g, 1.3 equiv) in the ice bath, and the reaction mixture was stirred for 12 hours at 30°C . Then, the reaction mixture was washed by saturated salt water and extracted with ethyl acetate (2×15 mL). The combined organic phases were concentrated in vacuo and the residue was dried and purified by silica gel chromatography to give corresponding target product (11b-14b and 17b).To a solution of acetic acid (0.2 mL) and (11b-14b and 17b) (0.95 g, 1.0 equiv) in CH2Cl2 was added propargylamine (0.35 mL, 0.77 equiv), the mixture was stirred for 2h at room temperature. After that, sodium acetate (0.2 g, 0.82 equiv) was added to the mixture and the mixture was stirred for 24 h at room temperature, followed by filtration. The filtrate was stirred for 4 h at 25°C with Sodium triacetoxyborohydride (STAB) (1.0 g, 0.75 equiv), followed by filtration. Adjusting pH < 2 by adding hydrogen chloride methanol solution (6 mL), then the resultant was collected and washed with ethyl acetate, dried over MgSO4 and purified to afford the corresponding target product (D11-D14 and D17). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With [Mn(HN(C2H4PiPr2)2)(CO)2Br]; sodium hydroxide In 5,5-dimethyl-1,3-cyclohexadiene at 145℃; for 16h; Schlenk technique; Inert atmosphere; | |
61% | With tris(triphenylphosphine)ruthenium(II) chloride; 1,3-bis-(diphenylphosphino)propane; sodium t-butanolate In toluene at 111℃; for 24h; Inert atmosphere; | |
Multi-step reaction with 2 steps 1.1: trichloroisocyanuric acid / dichloromethane / 0.08 h / 0 °C 1.2: 0.17 h / 20 °C 2.1: potassium hydroxide / ethanol / 12 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.5% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 5h; | General procedure: 2.5mmol thiazole-4-carboxyli acid and 2.0mmol alcohol were dissolved in 25mL dichloromethane (DCM) in a dry flask with continuous stirring, followed by the addition of 2.5mmol 3-(3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride. When the temperature of the reaction system cooled to 0°C, 0.2mmol 4-dimethylaminopyridine was added dropwise and reacted for 1hat 0°C. Then the temperature was elevated to room temperature for another 4h reaction. The reaction was stopped by adding 25mL saturated NaHCO3 solution and extracted twice with 20mL dichloromethane (2×20mL). The extracted organic layers were first dried by anhydrous Na2SO4, and then filtered and concentrated under vacuum distillation, obtaining the crude products. Finally, the crude products were further purified using column chromatography (ethy lacetate:petroleum ether, 1:5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With C57H63N4OP2Ru(1+)*Cl(1-); potassium <i>tert</i>-butylate at 60℃; for 22h; Inert atmosphere; | Method A: Hydroalkoxylation of 3-buten-2-ol (1a) (Table 2) General procedure: To an argon-purged reaction tube equipped with J-Young stop valve was added Ru6 (0.03 mmol), KOBut (0.06 mmol),3-buten-2-ol (1a) (2.0 mmol), and alcohols (8.6 mmol)as a substrate and solvent. The mixture was degassed by usingFPT cycles and then purged with argon again. The reaction mixture was stirred at the corresponding temperature for 22h. Then, to the mixture was added triphenylmethane (0.2 mmol) as an internal standard for NMR yield. After a part ofthe solution was evaporated and carefully dried under the vacuum, the yield was measured by 1H NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
128.5 g | Stage #1: para-dichlorobenzene With ethyl bromide; magnesium In 2-methyltetrahydrofuran; water at 60 - 80℃; Inert atmosphere; Stage #2: oxirane In 2-methyltetrahydrofuran; water at 15 - 25℃; Inert atmosphere; | 1 A method for synthesizing p-chlorobenzene ethanol in this embodiment,Include the following steps: (1) To the equipped with a mechanical stirrer,800g of four round bottom reaction flask with reflux condenser and thermometer 2-methyltetrahydrofuran and 29.4 g of magnesium turnings,The mass fraction of water in the 2-methyltetrahydrofuran is 0.01%.Replace the air in the reaction flask with nitrogen.Stirring and controlling the temperature in the reaction flask is 60-65°C,Ethyl bromide 1.5g is added,The reaction solution in the reaction bottle changes from light yellow to light gray.Continue stirring, control the temperature of the reaction material 75-80 °C,147 g of p-dichlorobenzene was added dropwise using a dropping funnel.The dropwise addition of dichlorobenzene is controlled for 2.5-3 hours.After completion of dropping, keep warm to 75-80°C and stir for 4-5 hours.That is, the reaction solution A containing p-chlorophenyl magnesium chloride Grignard reagent; (2) The above reaction liquid A is cooled to 15-20°C,44 g of ethylene oxide was introduced into the bottom of the reaction solution while stirring.Control the completion of 5-6 hoursAfter the completion of the control of the material temperature is 20-25 °C,Stir and continue to react for 2-3 hours,After the reaction is completed, the temperature of the material is controlled30-50°C,Control the vacuum in the reaction flask to -0.09MPa,Concentrate under reduced pressure to recover 2-methyltetrahydrofuran,Reduce material temperatureAfter 10-15°C, 400 mL of dichloromethane was added.10-15°CInsulation while stirring while adding1mol/L sulfuric acid aqueous solution to the reaction solution pH = 6,Let stand for liquid separation, and add 50 mL of water to the organic phase to stir.Wash to pH=7 and then separateThe organic phase was stirred and dried with 12 g of anhydrous sodium sulfate for 3 hours, filtered, and the filtrate was concentrated under reduced pressure to recover dichloromethane and distilled under reduced pressure.Fractions of 110-115°C/0.5 mmHg were collected to give 128.5 g of a pale yellow liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With tetrabutylammomium bromide; sodium hydroxide In water; chlorobenzene at 110℃; for 16h; Inert atmosphere; | 175.1 Step 1: 4-chloro-5-(4-chlorophenethoxy)-2-nitroaniline [00666] A mixture of 4,5-dichloro-2-nitroaniline (2 g, 9.7 mmol), 2-(4-chlorophenyl)ethanol (3 g, 19.3 mmol), TBAB (218 mg, 0.68 mmol) and NaOH (1.2 g, 29.1 mmol) in PhCl (40 mL) and H20 (20 mL) was stirred for 16 h at 110 °C under N2 atmosphere. The reaction was quenched with water (30 mL), and then extracted with EtOAc (100 mL). The organic phase was dried over Na2S04, filtered, and concentrated in vacuo to give the residue. The residue was purified by silica gel column to give 4-chloro-5-(4-chlorophenethoxy)-2-nitroaniline (0.65 g , 20%) as a yellow solid. ESI-MS (EI+, m/z): 327 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Stage #1: bis(trichloromethyl) carbonate; 2-(4-Chlorophenyl)ethanol With triethylamine In dichloromethane at 22℃; for 1h; Stage #2: tert-butyl N-(azetidin-3-ylmethyl)carbamate In dichloromethane at 0 - 22℃; for 12h; | 16.1 Step 1 : To the stirred solution of 2-(4-chlorophenyl)ethan-1 -ol (0.1 mL, 0.80 mmol, 1 equivalent) in dichloromethane (15 mL), was added triphosgene (0.142 g, 0.48 mmol, 1 .0 equivalent) followed by triethylamine (0.28 mL, 2 mmol, 2.5 equivalent) and the resulting mixture was stirred at room temperature (22 °C) for 1 h. The reaction mixture was then cooled to 0 °C, fert-butyl (azetidin-3-ylmethyl)carbamate (0.15 g, 0.8 mmol, 1 .0 equivalent) was added, and the reaction mixture was stirred at room temperature (22 °C) for 12 h. After completion of the reaction, a mixture of saturated aqueous sodium bicarbonate solution (5 mL) and water (10 mL) was added. The resulting mixture was extracted with dichloromethane (3 x 30 mL). The combined organic layer was dried over anhydrous sodium sulphate, concentrated and the resulting crude material was purified by silica gel column chromatography using 30 % ethyl acetate in hexane to afford 4- chlorophenethyl 3-(((fert-butoxycarbonyl)amino)methyl)azetidine-1 -carboxylate (0.17 g, 57 % yield) as sticky solid. LCMS (ES) m/z = 313 [M+H]+-56. NMR (400 MHz, DMSO-d6): δ ppm 1 .35 (s, 9 H), 2.53 - 2.60 (m, 1 H), 2.82 - 2.85 (m, 2 H), 3.06 - 3.09 (m, 2 H), 3.50 - 3.54 (m, 2 H), 3.80 - 3.84 (m, 2 H), 4.09 - 4.13 (m, 2 H), 6.97 - 7.05 (m, 1 H), 7.17 - 7.18 (m, 1 H), 7.24 - 7.33 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: tert-butyl N-(5-fluoro-2-nitro-phenyl)-N-methyl-carbamate With sodium hydride In N,N-dimethyl-formamide at 0℃; Stage #2: 2-(4-Chlorophenyl)ethanol In N,N-dimethyl-formamide at 20℃; | 1.2.11 General procedure for the preparation of intermediates h1 - h22. General procedure: Dissolved e1 - e3 (1.0 equiv) completely in dry DMF, then added NaH (2.2 equiv) to the reaction slowly at 0 °C and the resulting mixture was stirred for 20 minutes, and then corresponding R2(CH2)nOH or g1 - g5 (1.2 equiv) was added and the reaction mixture was stirred for 1 h at room temperature. Then it was quenched by H2O, washed with brine and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by chromatography on a silica gel chromatography (petroleum ether/ ethyl acetate = 8:1 to 4:1) to give corresponding products h1 - h22 (yield 75% - 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With C24H24IrN4O4(1+)*BF4(1-); sodium t-butanolate at 140℃; for 24h; Sealed tube; Inert atmosphere; | General procedure for bis-NHC-Ir-catalyzed β-methylationof primary alcohols General procedure: To a sealed tube (35 mL) equipped witha stir bar, Ir-NHC catalyst 5d (0.05 mol%), methanol (1 mL),tBuONa (2 mmol) and primary alcohol (1 mmol) were addedunder nitrogen atmosphere. The solution was heated at140 °C for 24 h. 1,3,5-Trimethoxybenzene was added as aninternal standard, and sent for nuclear magnetic resonance(NMR) measurement. Pure products were obtained by columnchromatography over silica gel using ethyl acetate/petroleum ether mixture as eluent. |
76% | With [Mn(HN(C2H4PiPr2)2)(CO)2Br]; sodium methylate at 150℃; for 14h; Inert atmosphere; Autoclave; Green chemistry; regioselective reaction; | |
73% | With potassium <i>tert</i>-butylate; C37H36Cl2NPRuS2 at 135℃; for 36h; Sealed tube; Inert atmosphere; Green chemistry; |
With trimethylamine-N-oxide; (1,4-dimethyl-5,7-diphenyl-1,2,3,4-tetrahydro-6H-cyclopenta[b]pyrazin-6-one) irontricarbonyl complex3; sodium hydroxide at 130℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With methyl 3-pyridinecarboxylate In acetonitrile at 60℃; for 6h; | Procedure S (Standard) General procedure: To the freshly-prepared dimethyl phosphoenolpyruvate (300 μmol, 3.0 equiv.), were added sequentiallyacetonitrile (0.10 M), substrate (100 μmol, 1.0 equiv.), and methyl nicotinate (13.7 mg, 100 μmol, 1.0 equiv.).The mixture was warmed to 60 °C and stirred for 6 h. Then the reaction mixture was cooled to r.t. andconcentrated. After adding saturated Na2CO3 aq., the mixture was washed three times with diethyl ether. The aqueous layer was acidified with concentrated HCl to pH 1, and extracted five times with dichloromethane. Thecombined organic layers were dried over with Na2SO4, filtered and concentrated to afford crude product, whichwas purified by preparative HPLC to afford the corresponding phosphorylated product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79 %Spectr. | With C28H32IrN4(1+)*I(1-); sodium t-butanolate In tert-Amyl alcohol at 140℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.06% | With tributylphosphine; diamide In N,N-dimethyl-formamide at 0 - 20℃; for 4h; Inert atmosphere; | 30 Example 30. Preparation of Compounds 216 and 218 To a stirred solution of 5-[3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl]-4-methyl-2H-1,2,4-triazol-3-one (150.00 mg, 0.424 mmol, 1.00 equiv.) and 4-(2-hydroxyethyl)-chlorobenzol (79.67 mg, 0.509 mmol, 1.20 equiv.) in DMF (4.00 mL, 51.687 mmol, 121.92 equiv.) was added Bu3P (256.92 mg, 1.272 mmol, 3.00 equiv.) at rt. To the solution was added TMAD (219.00 mg, 1.272 mmol, 3.00 equiv.) at 0°C under nitrogen atmosphere. The solution was stirred at rt for 4 h. The residue was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20 - 40 um, 330 g; Mobile Phase A: Water (plus 10 mM NH4HCO3); Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 5% - 5% B, 5 min, 75% B - 95% B gradient in 20 min; Detector: 254 nm. The fractions containing the desired product were collected at 80 % B and concentrated under reduced pressure to afford 5-[3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl]-2-[2-(4-chlorophenyl)ethyl]-4-methyl-1,2,4-triazol-3-one (140 mg, 67.06%) as an off-white solid. The mixture product (130 mg) was purified by PREP CHIRAL HPLC with the following conditions (Column: CHIRALPAK IG, 20*250mm, 5 um; Mobile Phase A:, Mobile Phase B:; Flow rate:18 mL/min; Gradient:% B; 220/254 nm; RT1:10.663; RT2:14.359; Injection Volume:0.8 mL; Number Of Runs:7) to afford 5-[(4S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydropyrazol-1-yl]-2-[2-(4-chlorophenyl)ethyl]-4-methyl-1,2,4-triazol-3-one (52.5 mg) as an off-white solid and afford 5-[(4R)-3-(4-chlorophenyl)-4- phenyl-4,5-dihydropyrazol-1-yl]-2-[2-(4-chlorophenyl)ethyl]-4-methyl-1,2,4-triazol-3-one (66.6 mg) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 3h; | 28.2 Step 2: Preparation of methyl 6-(4-(4-chlorophenethoxy)phenyl)nicotinate methyl 6- (4-hydroxyphenyl) nicotinate (36 mg, 0.16 mmol) and triphenylphosphine (PPh3, 55 mg, 0.21 mmol) prepared in step 1 were dissolved in tetrahydrofuran (2 ml) and , 2-(4-chlorophenyl)ethanol (0.028 ml, 0.21 mmol) and diisopropylazodicarboxylate (DIAD, 0.041 ml, 0.21 mmol) were added. The reaction mixture was stirred at room temperature by thin film chromatography (TLC) until methyl 6-(4-hydroxyphenyl)nicotinate disappeared, and then diluted with water. The reaction product diluted in water was extracted with ethyl acetate, and the extracted organic layer was washed with brine and dried over magnesium sulfate. The dried organic layer was concentrated under reduced pressure, and the concentrated reaction product was purified by column chromatography (silica gel, ethyl acetate:n-hexane=1:6) to obtain the target compound (42 mg, 71%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: 2-(4-Chlorophenyl)ethanol; caffeic acid With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 36h; Stage #2: With anhydrous zinc chloride In ethanol at 20℃; for 18h; | Synthetic method of Scheme 4 General procedure: Add 25 ml of ultra-dry THF, 1 mmol caffeic acid, 1.2 mmolR-OH, and 1.5 mmol triphenylphosphine (TPP) to thereaction flask, and then add 1.5 mmol diisopropyl azodicarboxylate(DIAD) in an ice bath. After reacting at roomtemperature for 36 h, the reaction was monitored by TLC.After the reaction, it was concentrated in vacuo to removeTHF, re-dissolved in absolute ethanol, added 3.5 mmolZnCl2, and reacted at room temperature for 18 h to removetriphenylphosphorus oxide and monitored by TLC. Afterthe reaction, the precipitate was removed by filtration. Thefiltrate was concentrated in vacuo, EA (3 × 30 ml) wasextracted three times, the organic layer was dried overanhydrous Na2SO4, and purified by column chromatography(PE:EA = 5:1). |
56% | Stage #1: 2-(4-Chlorophenyl)ethanol; caffeic acid With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 36h; Stage #2: With anhydrous zinc chloride In ethanol at 20℃; for 18h; | Synthetic method of Scheme 4 General procedure: Add 25 ml of ultra-dry THF, 1 mmol caffeic acid, 1.2 mmolR-OH, and 1.5 mmol triphenylphosphine (TPP) to thereaction flask, and then add 1.5 mmol diisopropyl azodicarboxylate(DIAD) in an ice bath. After reacting at roomtemperature for 36 h, the reaction was monitored by TLC.After the reaction, it was concentrated in vacuo to removeTHF, re-dissolved in absolute ethanol, added 3.5 mmolZnCl2, and reacted at room temperature for 18 h to removetriphenylphosphorus oxide and monitored by TLC. Afterthe reaction, the precipitate was removed by filtration. Thefiltrate was concentrated in vacuo, EA (3 × 30 ml) wasextracted three times, the organic layer was dried overanhydrous Na2SO4, and purified by column chromatography(PE:EA = 5:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dicobalt octacarbonyl; Tributylphosphine oxide; carbon monoxide; hydrogen In toluene at 120℃; for 24h; Sealed tube; Autoclave; Green chemistry; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With 4-dimethylaminopyridine; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 2h; Inert atmosphere; | 4-chlorophenethyl 2-iodobenzoate (2) To a solution of 2-iodobenzoic acid (200 mg,0.8 mmol) in dry CH2Cl2 (10 mL) under N2 was added 2-(4-chlorophenyl)ethan-1-ol(131 mg, 0.84 mmol), DCC (185 mg, 0.9 mmol) and DMAP (10 mg, 0.08 mmol). Themixture was stirred at room temperature for 2 h, then the solvent was removed underreduced pressure and the residue was purified by flash column chromatography on silicagel (EtOAc/n-Hex (1:6)) to yield compound 2 (230 mg, 59%) as a white solid: MP 56 C.1H NMR (CDCl3): 3.06 (t, J = 6.9 Hz, 2H), 4.52 (t, J = 6.9 Hz, 1H), 7.26 (m, 6H), 7.69 (dd,J = 7.8, 1.7 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H). 13C NMR (CDCl3): 34.4, 65.8, 94.2, 128.0, 128.7,130.4, 130.9, 132.5, 132.7, 135.0, 132.7, 136.2, 141.4, 166.4; HRMS (ESI) calcd. for C15H12ClIO2408.9463 [M + Na]+, found 408.9469. |
[ 1875-87-2 ]
2-(2,5-Dichlorophenyl)ethan-1-ol
Similarity: 0.89
[ 5468-97-3 ]
1-(4-Chlorophenyl)-2-methylpropan-2-ol
Similarity: 0.86
[ 1875-87-2 ]
2-(2,5-Dichlorophenyl)ethan-1-ol
Similarity: 0.89
[ 5468-97-3 ]
1-(4-Chlorophenyl)-2-methylpropan-2-ol
Similarity: 0.86
[ 1875-87-2 ]
2-(2,5-Dichlorophenyl)ethan-1-ol
Similarity: 0.89
[ 5468-97-3 ]
1-(4-Chlorophenyl)-2-methylpropan-2-ol
Similarity: 0.86
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Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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