* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With sodium tetrahydroborate In tetrahydrofuran at 20 - 30℃; for 0.666667 h; Stage #2: With iodine In tetrahydrofuran at 20 - 30℃; for 2 h;
Method 2: Sodium borohydride (1.2 g, 31.7 mmol) was added to a flask containing tetrahydrofuran (THF) (40 mL) stirred under nitrogen. 4-Biphenylacetic acid (5.0 g, 23.6 mmol) was then added slowly over 20 min while the stirred reaction mixture was maintained at 20-30 0C. A THF rinse (5 mL) was then added, and the resulting mixture was stirred for 20 min. A solution of iodine (2.9 g, 11.4 mmol) in THF (10 mL) was then added slowly over about an hour while the stirred reaction mixture was maintained at 20-30 0C. Stirring at that temperature was continued for about an hour, at which time chromatographic analysis revealed complete conversion of 4-biphenylacetic acid. The reaction mixture was then quenched by addition of 5 wt percent aqueous sodium hydroxide (26 mL). After the resulting mixture had been mixed well, the phases were allowed to separate, and the lower phase was drained from the upper phase. The lower (aqueous) phase was extracted with isopropyl acetate (2 x 25 mL). The upper (organic) phases were combined, washed with deionized water (4 x 20 mL), and evaporated at reduced pressure to provide 2-(biphenyl-4'-yl)ethanol as a light yellow crystalline residue (4.6 g, 98.5percent). Alternatively, product may be crystallized by exchange of isopropyl acetate with heptane as described in Method 1 above.
96%
Stage #1: With borane-THF In tetrahydrofuran at 0 - 65℃; for 3 h; Stage #2: With methanol In tetrahydrofuran at 0℃;
Example 2.62: Preparation of l-{4'-[2-((λ)-2-Methyl-pyrrolidin-l-yl)-ethyI]-biphenyl-4- suIfonyl}-piperidine-4-carboxylic Acid Ethyl Ester (Compound 90); Step A: Preparation of Intermediate 2-Biphenyl-4-yl-ethanoI; To a 1000 mL round-bottomed flask containing 4-biphenylacetic acid (20.0 g, 94.2 mmol) in THF (250 mL) at 0 0C was added borane THF complex (240 mL, 240 mmol) via an addition funnel. The reaction was then heated to 65 0C for 3 h and then cooled to 0 0C. The reaction was slowly quenched with MeOH (250 mL) and concentrated. The product was diluted with EtOAc (500 mL) and washed with 1 M HCl (200 mL), saturated NaHCO3 (200 mL) and brine (200 mL). The organics were dried with MgSO4, filtered and concentrated to furnish the title compound (18.0 g, 96percent yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.92 (t, J= 6.44 Hz, 2 H), 3.91 (t, /= 6.57 Hz, 2 H), 7.29 - 7.37 (m, 3 H), 7.40 - 7.47 (m, 2 H), 7.52 - 7.61 (m, 4 H).
96%
Stage #1: With borane-THF In tetrahydrofuran at 0 - 65℃; for 3 h; Stage #2: With methanol In tetrahydrofuran at 0℃;
Step A: Preparation of Intermediate 2-Biphenyl-4-yl-ethanol.To a 1000 mL round-bottomed flask containing 4-biphenylacetic acid (20.0 g, 94.2 mmol) in THF (250 mL) at 0 0C was added borane THF complex (240 mL, 240 mmol) via an addition funnel. The reaction was then heated to 65 0C for 3 h and then cooled to 0 0C. The reaction was slowly quenched with MeOH (250 mL) and concentrated. The product was diluted with EtOAc (500 mL) and washed with 1 M HCl (200 mL), saturated NaHCO3 (200 mL) and brine (200 mL). The organics were dried with MgSO4, filtered and concentrated to afford the title compound (18.0 g, 96percent yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.92 (t, J= 6.44 Hz, 2 H), 3.91 (t, J= 6.57 Hz, 2 H), 7.29 - 7.37 (m, 3 H), 7.40 - 7.47 (m, 2 H), 7.52 - 7.61 (m, 4 H).
87%
With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether at 20℃; for 4 h; Inert atmosphere
Under nitrogen atmosphere, to a cooled (0 °C) suspension of LiA1H4 (2.0 M in THF solution, 5.65 mL, 11.3 mmol) in dry Et20 (20 mL), commercially available 4-biphenyl-acetic acid (0.6 g, 2.83 mmol) in dry Et20 (8.0 mL) was added dropwise. The resulting reaction mixture was stirred at r.t. for 4 h, and then cooled to 0 °C. H20 (0.50 mL) was slowly added, followed by 3.0 M KOH solution (0.50 mL) and additional H20 (1.5 mL). The mixture wasstirred at 0 °C for 1 h and then filtered off. The organic layer was dried over Na2504, filtered and concentrated to dryness, affording the title compound (0.53 g, 87percent), which was used in the next step without any further purification. ‘H NMR (DMSO-d6) ö 7.67—7.61 (m, 2H), 7.59—7.54 (m, 2H), 7.50—7.42 (m, 2H), 7.3 8—7.28 (m, 3H), 4.64 (t, 1H, J= 5.2 Hz), 3.78—3.53 (m, 2H), 2.76 (t, 2H, J= 7.0 Hz).
86.1%
Stage #1: With sodium tetrahydroborate In Isopropyl acetate at 0 - 25℃; for 1 h; Stage #2: With boron trifluoride diethyl etherate In Isopropyl acetate at -5 - 25℃; for 4 - 18.93 h; Stage #3: With sodium hydroxide; water In Isopropyl acetate at 1 - 48℃; for 0.516667 - 1 h;
Step A: Preparation of 2-Biphenyl-4-yl-ethanol.To dilute the hydrogen gas byproduct continuously vented from the reactor, a vigorous flow of nitrogen through the reactor is maintained throughout the entire preparation until the quench with aqueous sodium hydroxide is completed. To a 50 L reactor containing isopropyl acetate (16.7 L) is added sodium borohydride (0.762 Kg, 20.14 mole, 1.60 eq). The sodium borohydride is rinsed into the reactor with additional isopropyl acetate (1 L). 4-Biphenylacetic acid (2.67 Kg, 12.58 moles, 1.00 eq) is then added sufficiently slowly to maintain the stirred reactor contents at 0°-8°C with reactor jacket cooling. The biphenylacetic acid is rinsed into the reactor with additional isopropyl acetate (1 L). The reactor contents are then warmed to 25°C for one hour and then cooled again to -5°-0°C. Borontrifluoride diethyletherate (3.584 Kg, 25.25 moles, 2.01 eq) is then added at a constant rate over a three hour period while the stirred reactor contents are maintained at 0°-5°C with reactor jacket cooling. The reactor contents are warmed to 20°-25°C, and stirring at that temperature is continued until substantially complete 4-biphenylacetic acid conversion is verified by liquid chromatography. (Substantially complete conversion is typically achieved in 1-12 hours.) A solution of sodium hydroxide (3.355 Kg, 83.9 moles, 6.67 eq) in water (15.0 L) is then added sufficiently slowly to maintain the stirred reactor contents at 10°-20°C with reactor jacket cooling. The reactor contents are heated to 400C, and stirring at that temperature is continued for one hour or until substantially all solids are dissolved. The stirred mixture is then cooled to 15°-20°C, and the phases are allowed to separate. The aqueous phase is drained, and the organic (upper) phase is washed with water (4 x 5.0 L). The upper organic phase is concentrated by vacuum distillation to 8 L volume at temperatures rising to no more than 6O0C. The reactor contents are cooled to 2O0C, and heptane (20 L) is added. The stirred reactor contents are concentrated by vacuum distillation to 16 L <n="70"/>volume at temperatures rising to no more than 4O0C. The stirred reactor contents are cooled to200C, stirred at that temperature for at least 2 hours, and then filtered. The filtered solid is washed with heptane (5 L) and vacuum dried at 250C to provide the title compound 2-biphenyl- 4-yl-ethanol. The yield is about 2.148 Kg (10.83 moles, 86.1percent).; Method 1: To dilute and vent the hydrogen gas byproduct, the reactor was purged with nitrogen throughout the entire preparation until the quench with aqueous sodium hydroxide had been completed. To a 50 L reactor containing isopropyl acetate (16.7 L) was added sodium borohydride (0.762 kg, 20.14 mol). The sodium borohydride was rinsed into the reactor with additional isopropyl acetate (1 L), and the stirred reactor contents were cooled to 2 0C. 4- Biphenylacetic acid (2.67 kg, 12.58 mol) was then added sufficiently slowly to maintain the stirred reactor contents at 2-13 0C with reactor jacket cooling. The biphenylacetic acid was rinsed into the reactor with additional isopropyl acetate (1 L), and the stirred reactor contents were cooled to -4 0C. Borontrifluoride diethyletherate (3.2 L, 3.584 kg, 25.25 mol) was then added at a constant rate over two hours while the stirred reactor contents were maintained at -4 0C to 6 0C with reactor jacket cooling. The reactor contents were warmed to 20 0C, and LCTMS analysis revealed the 4-biphenylacetic acid conversion to be 95percent after 19 min. After the reaction mixture had been stirred at 15-22 0C for 16.6 h, it was cooled to 1 0C. Six liters of a 50 wt percent solution of sodium hydroxide in water was mixed with nine liters of deionized water. Eleven liters of the resulting diluted aqueous solution of sodium hydroxide was added to the stirred reaction mixture sufficiently slowly to maintain the reactor contents at 1-12 0C with reactor jacket cooling. The resulting mixture was stirred at 12-20 0C for 30 min and then heated to 400C. Stirring at 40-48 0C was continued for 31 minutes, and the mixture was then cooled to 22 0C. Sodium chloride (0.50 kg), deionized water (2.0 L), and methanol (500 mL) were added to the stirred mixture to facilitate phase separation. The phases were then allowed to separate. The aqueous phase was drained, and the organic (upper) phase was washed with deionized water <n="88"/>(4 x 5.0 L). The upper organic phase was concentrated by vacuum distillation to 11 L volume at temperatures rising to 59 0C. The reactor contents were cooled to 20 0C, and heptane (20 L) was added. The stirred reactor contents were concentrated by vacuum distillation to 16 L volume at temperatures rising to 36 0C. The stirred reactor contents were cooled to 200C, stirred at that temperature for 21.4 h, and then filtered. The filtered solid was washed with heptane (5 L) and vacuum dried at ambient temperature to provide the title compound (2.148 kg, 86.1percent).
70%
With lithium aluminium tetrahydride In tetrahydrofuran for 12 h; Cooling with ice; Heating
Dissolve LiAlH4 (1.1 eq) in anhydrous THF.Under ice bath conditions,Slowly add the compound of formula 1-1 (Biphenyl-4-carboxylic acid, 1.0 eq) in THF,After the addition was completed, the reaction solution was heated to a stirring reaction for 12 hours.The reaction was terminated and the reaction was quenched by the addition of 15percent NaOH solution.The resulting mixture was extracted with ethyl acetate.Filtered, concentrated and column chromatographyGet white flaky crystals,That is, the compound of the formula 1-2, the yield is 70percent.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 15, p. 4740 - 4749
[2] Patent: WO2008/48609, 2008, A1, . Location in patent: Page/Page column 86
[3] Patent: WO2008/5338, 2008, A1, . Location in patent: Page/Page column 101
[4] Patent: WO2008/48609, 2008, A1, . Location in patent: Page/Page column 55
[5] Patent: WO2014/144836, 2014, A2, . Location in patent: Paragraph 0519; 0520
[6] Patent: WO2008/48609, 2008, A1, . Location in patent: Page/Page column 67-68; 85-86
[7] Tetrahedron Asymmetry, 2001, vol. 12, # 4, p. 585 - 596
[8] Patent: CN108727213, 2018, A, . Location in patent: Paragraph 0094-0097
[9] Journal of the American Chemical Society, 1972, vol. 94, # 14, p. 4971 - 4977
[10] Journal of the American Chemical Society, 1978, vol. 100, p. 228 - 246
[11] Journal of Medicinal Chemistry, 1998, vol. 41, # 3, p. 358 - 378
[12] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 8, p. 2315 - 2319
[13] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 19, p. 5760 - 5763
[14] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 8, p. 2520 - 2524
[15] Patent: WO2006/20951, 2006, A1, . Location in patent: Page/Page column 109
With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0 - 20℃;
4-Biphenylethanol (see Kawasaki et al., Tetrahedron: Asymmetry 2001, 12, 585-596) (1.47 g, 7.41 mmol) and CBr4 (1.12 equiv) were dissolved in CH2Cl2 (25 mL), the mixture was cooled to 0 C and triphenylphosphine (1.1 equiv) was added in small portions. The reaction mixture was warmed at room temperature and stirred for 1 h before the solvent was removed in vacuo. Flash chromatography (0-5% EtOAc-hexanes) yielded 4-(2-bromoethyl)biphenyl (1.59 g, 82%). The title compound was prepared from S7 (55 mg, 0.27 mmol) and 4-(2-bromoethyl)biphenyl (280 mg, 1.07 mmol) by using general procedure D. Flash chromatography (SiO2, 1.5 x 18 cm, 50-100% EtOAc-hexanes) afforded the title compound (38 mg, 40%) as a white solid: 1H NMR (CDCl3, 500 MHz) delta 8.84 (dd, IH, J = 0.7, 4.7 Hz), 8.29 (d, IH, J = 7.9 Hz), 7.92 (dt, IH, J = 1.7, 7.8 Hz), 7.57 (m, 2H), 7.53 (m, 3H), 7.42 (t, 2H, J = 7.7 Hz), 7.33 (m, 3H), 3.60 (t, 2H, J = 7.5 Hz), 3.19 (t, 2H, J = 7.5 Hz); 13C NMR (CDCl3, 150 MHz) delta 186.2, 165.3, 161.3, 150.9, 142.7, 141.0, 139.6, 139.0, 137.5, 129.0, 128.9, 127.5, 127.3, 127.2, 126.9, 124.2, 41.7, 29.1 ; HRMS-ESI-TOF m/z 356.1392 ([M+H]+, C22H17N3O2 requires 356.1393).
With carbon tetrabromide; triphenylphosphine; In dichloromethane;
Synthesis of the thioether, sulfoxide and sulfone linkers was achieved using theprocess described in Scheme 14. Reduction of biphenyl acetic acid to alcohol followedby conversion of the alcohol to bromo leaving group allowed conversion of thefunctional group to a thioether. The nitro group was then reduced and acylated to affordoxazolidine intermediate. The thioether could then be further functionalized beforedeprotection of the Boc and oxazolidine protecting groups. The free alcohol was thenconverted into the desired final phosphate product.
Method 2: Sodium borohydride (1.2 g, 31.7 mmol) was added to a flask containing tetrahydrofuran (THF) (40 mL) stirred under nitrogen. 4-Biphenylacetic acid (5.0 g, 23.6 mmol) was then added slowly over 20 min while the stirred reaction mixture was maintained at 20-30 0C. A THF rinse (5 mL) was then added, and the resulting mixture was stirred for 20 min. A solution of iodine (2.9 g, 11.4 mmol) in THF (10 mL) was then added slowly over about an hour while the stirred reaction mixture was maintained at 20-30 0C. Stirring at that temperature was continued for about an hour, at which time chromatographic analysis revealed complete conversion of 4-biphenylacetic acid. The reaction mixture was then quenched by addition of 5 wt % aqueous sodium hydroxide (26 mL). After the resulting mixture had been mixed well, the phases were allowed to separate, and the lower phase was drained from the upper phase. The lower (aqueous) phase was extracted with isopropyl acetate (2 x 25 mL). The upper (organic) phases were combined, washed with deionized water (4 x 20 mL), and evaporated at reduced pressure to provide 2-(biphenyl-4'-yl)ethanol as a light yellow crystalline residue (4.6 g, 98.5%). Alternatively, product may be crystallized by exchange of isopropyl acetate with heptane as described in Method 1 above.
96%
Example 2.62: Preparation of l-{4'-[2-((lambda)-2-Methyl-pyrrolidin-l-yl)-ethyI]-biphenyl-4- suIfonyl}-piperidine-4-carboxylic Acid Ethyl Ester (Compound 90); Step A: Preparation of Intermediate 2-Biphenyl-4-yl-ethanoI; To a 1000 mL round-bottomed flask containing 4-biphenylacetic acid (20.0 g, 94.2 mmol) in THF (250 mL) at 0 0C was added borane THF complex (240 mL, 240 mmol) via an addition funnel. The reaction was then heated to 65 0C for 3 h and then cooled to 0 0C. The reaction was slowly quenched with MeOH (250 mL) and concentrated. The product was diluted with EtOAc (500 mL) and washed with 1 M HCl (200 mL), saturated NaHCO3 (200 mL) and brine (200 mL). The organics were dried with MgSO4, filtered and concentrated to furnish the title compound (18.0 g, 96% yield) as a white solid. 1H NMR (400 MHz, CDCl3) delta 2.92 (t, J= 6.44 Hz, 2 H), 3.91 (t, /= 6.57 Hz, 2 H), 7.29 - 7.37 (m, 3 H), 7.40 - 7.47 (m, 2 H), 7.52 - 7.61 (m, 4 H).
96%
Step A: Preparation of Intermediate 2-Biphenyl-4-yl-ethanol.To a 1000 mL round-bottomed flask containing 4-biphenylacetic acid (20.0 g, 94.2 mmol) in THF (250 mL) at 0 0C was added borane THF complex (240 mL, 240 mmol) via an addition funnel. The reaction was then heated to 65 0C for 3 h and then cooled to 0 0C. The reaction was slowly quenched with MeOH (250 mL) and concentrated. The product was diluted with EtOAc (500 mL) and washed with 1 M HCl (200 mL), saturated NaHCO3 (200 mL) and brine (200 mL). The organics were dried with MgSO4, filtered and concentrated to afford the title compound (18.0 g, 96% yield) as a white solid. 1H NMR (400 MHz, CDCl3) delta ppm 2.92 (t, J= 6.44 Hz, 2 H), 3.91 (t, J= 6.57 Hz, 2 H), 7.29 - 7.37 (m, 3 H), 7.40 - 7.47 (m, 2 H), 7.52 - 7.61 (m, 4 H).
87%
With lithium aluminium tetrahydride; In tetrahydrofuran; diethyl ether; at 20℃; for 4h;Inert atmosphere;
Under nitrogen atmosphere, to a cooled (0 C) suspension of LiA1H4 (2.0 M in THF solution, 5.65 mL, 11.3 mmol) in dry Et20 (20 mL), commercially available 4-biphenyl-acetic acid (0.6 g, 2.83 mmol) in dry Et20 (8.0 mL) was added dropwise. The resulting reaction mixture was stirred at r.t. for 4 h, and then cooled to 0 C. H20 (0.50 mL) was slowly added, followed by 3.0 M KOH solution (0.50 mL) and additional H20 (1.5 mL). The mixture wasstirred at 0 C for 1 h and then filtered off. The organic layer was dried over Na2504, filtered and concentrated to dryness, affording the title compound (0.53 g, 87%), which was used in the next step without any further purification. ?H NMR (DMSO-d6) oe 7.67-7.61 (m, 2H), 7.59-7.54 (m, 2H), 7.50-7.42 (m, 2H), 7.3 8-7.28 (m, 3H), 4.64 (t, 1H, J= 5.2 Hz), 3.78-3.53 (m, 2H), 2.76 (t, 2H, J= 7.0 Hz).
86.1%
Step A: Preparation of 2-Biphenyl-4-yl-ethanol.To dilute the hydrogen gas byproduct continuously vented from the reactor, a vigorous flow of nitrogen through the reactor is maintained throughout the entire preparation until the quench with aqueous sodium hydroxide is completed. To a 50 L reactor containing isopropyl acetate (16.7 L) is added sodium borohydride (0.762 Kg, 20.14 mole, 1.60 eq). The sodium borohydride is rinsed into the reactor with additional isopropyl acetate (1 L). 4-Biphenylacetic acid (2.67 Kg, 12.58 moles, 1.00 eq) is then added sufficiently slowly to maintain the stirred reactor contents at 0-8C with reactor jacket cooling. The biphenylacetic acid is rinsed into the reactor with additional isopropyl acetate (1 L). The reactor contents are then warmed to 25C for one hour and then cooled again to -5-0C. Borontrifluoride diethyletherate (3.584 Kg, 25.25 moles, 2.01 eq) is then added at a constant rate over a three hour period while the stirred reactor contents are maintained at 0-5C with reactor jacket cooling. The reactor contents are warmed to 20-25C, and stirring at that temperature is continued until substantially complete 4-biphenylacetic acid conversion is verified by liquid chromatography. (Substantially complete conversion is typically achieved in 1-12 hours.) A solution of sodium hydroxide (3.355 Kg, 83.9 moles, 6.67 eq) in water (15.0 L) is then added sufficiently slowly to maintain the stirred reactor contents at 10-20C with reactor jacket cooling. The reactor contents are heated to 400C, and stirring at that temperature is continued for one hour or until substantially all solids are dissolved. The stirred mixture is then cooled to 15-20C, and the phases are allowed to separate. The aqueous phase is drained, and the organic (upper) phase is washed with water (4 x 5.0 L). The upper organic phase is concentrated by vacuum distillation to 8 L volume at temperatures rising to no more than 6O0C. The reactor contents are cooled to 2O0C, and heptane (20 L) is added. The stirred reactor contents are concentrated by vacuum distillation to 16 L <n="70"/>volume at temperatures rising to no more than 4O0C. The stirred reactor contents are cooled to200C, stirred at that temperature for at least 2 hours, and then filtered. The filtered solid is washed with heptane (5 L) and vacuum dried at 250C to provide the title compound 2-biphenyl- 4-yl-ethanol. The yield is about 2.148 Kg (10.83 moles, 86.1%).; Method 1: To dilute and vent the hydrogen gas byproduct, the reactor was purged with nitrogen throughout the entire preparation until the quench with aqueous sodium hydroxide had been completed. To a 50 L reactor containing isopropyl acetate (16.7 L) was added sodium borohydride (0.762 kg, 20.14 mol). The sodium borohydride was rinsed into the reactor with additional isopropyl acetate (1 L), and the stirred reactor contents were cooled to 2 0C. 4- Biphenylacetic acid (2.67 kg, 12.58 mol) was then added sufficiently slowly to maintain the stirred reactor contents at 2-13 0C with reactor jacket cooling. The biphenylacetic acid was rinsed into the reactor with additional isopropyl acetate (1 L), and the stirred reactor contents were cooled to -4 0C. Borontrifluoride diethyletherate (3.2 L, 3.584 kg, 25.25 mol) was then added at a constant rate over two hours while the stirred reactor contents were maintained at -4 0C to 6 0C with reactor jacket cooling. The reactor contents were warmed to 20 0C, and LCTMS analysis revealed the 4-biphenylacetic acid conversion to be 95% after 19 min. After the reaction mixture had been stirred at 15-22 0C for 16.6 h, it was cooled to 1 0C. Six liters of a 50 wt % solution of sodium hydroxide in water was mixed with nine liters of deionized water. Eleven liters of the resulting diluted aqueous solution of sodium hydroxide was added to the stirred reaction mixture sufficiently slowly to maintain the reactor contents at 1-12 0C with reactor jacket cooling. The resulting mixture was stirred at 12-20 0C for 30 min and then heated to 400C. Stirring at 40-48 0C was continued for 31 minutes, and the mixture was then cooled to 22 0C. Sodium chloride (0.50 kg), deionized water (2.0 L), and methanol (500 mL) were added to the stirred mixture to facilitate phase separation. The phases were then allowed to separate. The aqueous phase was drained, and the organic (upper) phase was washed with deionized water <n="88"/>(4 x 5.0 L). The upper organic phase was concentrated by vacuum distillation to 11 L volume at temperatures rising to 59 0C. The reactor contents were cooled to 20 0C, and heptane (20 L) was added. The stirred reactor contents were concentrated by vacuum distillation to 16 L volume at temperatures rising to 36 0C. The stirred reactor contents were cooled to 200C, stirred at that temperature for 21.4 h, and then filtered. The filtered solid was washed with heptane (5 L) and vacuum dried at ambient temperature to provide the title compound (2.148 kg, 86.1%).
70%
With lithium aluminium tetrahydride; In tetrahydrofuran; for 12h;Cooling with ice; Heating;
Dissolve LiAlH4 (1.1 eq) in anhydrous THF.Under ice bath conditions,Slowly add the compound of formula 1-1 (Biphenyl-4-carboxylic acid, 1.0 eq) in THF,After the addition was completed, the reaction solution was heated to a stirring reaction for 12 hours.The reaction was terminated and the reaction was quenched by the addition of 15% NaOH solution.The resulting mixture was extracted with ethyl acetate.Filtered, concentrated and column chromatographyGet white flaky crystals,That is, the compound of the formula 1-2, the yield is 70%.
With borane; In tetrahydrofuran;
Synthesis of the thioether, sulfoxide and sulfone linkers was achieved using theprocess described in Scheme 14. Reduction of biphenyl acetic acid to alcohol followedby conversion of the alcohol to bromo leaving group allowed conversion of thefunctional group to a thioether. The nitro group was then reduced and acylated to affordoxazolidine intermediate. The thioether could then be further functionalized beforedeprotection of the Boc and oxazolidine protecting groups. The free alcohol was thenconverted into the desired final phosphate product.
With thionyl chloride; N,N-dimethyl acetamide; In n-Butyl chloride; at 12 - 55℃; for 11h;
Step B: Preparation of 4'-(2-Chloro-ethyl)-biphenyl-4-sulfonic Acid.To a 30 L reactor containing 1 -chlorobutane (11.4 L) stirred under nitrogen and vented to an aqueous sodium hydroxide scrubber was added 2-biphenyl-4-yl-ethanol (1.9323 Kg, 9.75 moles, 1.00 eq) and N,N-dimethylacetamide (DMA, 84.3 g, 0.968 mole, 0.099 eq). Thionyl chloride (1.468 Kg, 12.34 mole, 1.27 eq) was then added sufficiently slowly to maintain the stirred reactor contents at 12-20C with reactor jacket cooling. The thionyl chloride was rinsed into the reactor with additional 1 -chlorobutane (50 mL). The reactor contents were heated to 55C, and stirring at that temperature was continued for 11 hours until conversion of 2- biphenyl-4-yl-ethanol to 4-(2-chloro-ethyl)-biphenyl was verified to be substantially complete by liquid chromatography. More 1 -chlorobutane (3.9 L) was added, and the reactor contents were cooled to -5C. Chlorosulfonic acid (1.648 Kg, 14.14 moles, 1.45 eq) was then added sufficiently slowly to maintain the stirred reactor contents at -5 to 1C with reactor jacket cooling. The chlorosulfonic acid was rinsed into the reactor with additional 1 -chlorobutane (50 mL). The reactor contents were warmed to 20-23C, and stirring at that temperature was continued for 17 hours until conversion of 4-(2-chloro-ethyl)-biphenyl to 4'-(2-chloro-ethyl)- biphenyl-4-sulfonic acid was verified to be substantially complete by liquid chromatography. The reaction mixture was filtered, and the filtered solids were washed with 1 -chlorobutane (11.5 L) and vacuum dried at 550C to constant weight to provide 4'-(2-chloro-ethyl)-biphenyl-4- sulfonic acid (2.674 Kg, 9.01 moles, 92.4% yield), which, if allowed to remain in contact with air, will absorb a considerable amount of water.
With triethylamine; In dichloromethane; at -30 - 25℃; for 2h;
Step B: Preparation of Intermediate Methanesulfonic Acid 2-Biphenyl-4-yI-ethyl Ester; To a 250 mL round-bottomed flask containing 2-birhohenyl-4-yl-ethanol (5.00 g, 25.2 mmol) in dichloromethane (50 mL) was added triefhylamine (3.52 mL, 25.2 mmol) and mesyl chloride (2.16 mL, 27.7 mmol). This was stirred at -30 0C allowing to warm to 25 0C over 2 h. The reaction was filtered and diluted with EtOAc (100 mL). This was washed with water (50 mL), 1 M HCl (50 mL), saturated NaHCO3 (50 mL) and brine (50 mL). The organics were dried with MgSO4, filtered and concentrated to furnish title compound as a cream colored solid (5.93 g, 85% yield). 1H NMR (400 MHz, CDCl3) delta 2.89 (s, 3 H), 3.11 (t, J= 6.82 Hz, 2 H), 4.46 (t, J= 6.95 Hz, 2 H), 7.29 - 7.34 (m, 2 H), 7.34 - 7.38 (m, 1 H), 7.41 - 7.47 (m, 2 H), 7.54 - 7.60 (m, 4 H).
85%
With triethylamine; In dichloromethane; at -30 - 25℃; for 2h;
Step B: Preparation of Intermediate Methanesulfonic Acid 2-Biphenyl-4-yl-ethyl Ester.To a 250 mL round-bottomed flask containing 2-biphenyl-4-yl-ethanol (5.00 g, 25.2 mmol) in DCM (50 mL) was added triethylamine (3.52 mL, 25.2 mmol) and mesyl chloride (2.16 mL, 27.7 mmol). This was stirred at -30 0C and allowed to warm to 25 0C over 2 h. The reaction was filtered and diluted with EtOAc (100 mL). This was washed with water (50 mL), IM HCl (50 mL), saturated NaHCO3 (50 mL) and brine (50 mL). The organics were dried with MgSO4, filtered and concentrated to afford the title compound (5.93 g, 85% yield) as a cream colored solid. 1H NMR (400 MHz, CDCl3) delta ppm 2.89 (s, 3 H), 3.11 (t, J = 6.82 Hz, 2 H), 4.46 (t, J= 6.95 Hz, 2 H), 7.29 - 7.34 (m, 2 H), 7.34 - 7.38 (m, 1 H), 7.41 - 7.47 (m, 2 H), 7.54 - 7.60 (m, 4 H).
With triethylamine; In tetrahydrofuran; at 5 - 20℃; for 6h;
(1-3) Preparation of 4- (2-iodoethyl) biphenyl A solution of methanesulfonyl chloride (9.54 g) in tetrahydrofuran (150 ml) was added dropwise to a solution 2- (biphenyl-4-yl) ethanol (5.53 g) and triethylamine (10.18 g) in tetrahydrofuran (150 ml) at 5C under nitrogen atmosphere. After stirring at room temperature for 6 hours, the precipitated crystals were collected by filtration. The filtrate was concentrated under reduced pressure and the resultant residue was purified with silica-gel column chromatography using a 1 : 1 mixture of hexane/ethyl acetate to give methanesulfonate of 2- (BIPHENYL-4-YL) ethanol as a colorless liquid. Sodium iodide (6.23 g) was added to a solution of the methanesulfonate in 2-butanone (150 ml) and stirred at 70C for 3 hours. The precipitate was filtered off and 5% aqueous sodium thiosulfate (30 ml) was added to the filtrate and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the resultant residue was purified with silica-gel column chromatography using a 5: 1 mixture of hexane and ethyl acetate to give the title compound (7.31 g) as a colorless liquid.
(1-2) Preparation of 2- (BIPHENYL-4-YL) ethanol A solution of 9-borabicyclo [3,3, 1] NONANE in tetrahydrofuran (0.5 MOL/1 tetrahydrofuran, 120 ml, 60 mmol) was added dropwise to a solution of 4-vinylbiphenyl (5.41 g) in tetrahydrofuran (43 ml) at 5C under nitrogen atmosphere. After stirring at room temperature for 12 hours, water (10 ml) was added, and further stirred at room temperature for 12 hours. 3 M aqueous sodium hydroxide solution (30 ml) and 30% hydrogen peroxide solution (30 ml) were added dropwise to the reaction solution, which stood for 48 hours. After the solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate, washed with an aqueous saturated saline solution, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resultant residue was purified with silica-gel column chromatography using a 1: 1 mixture of hexane and ethyl acetate to give the title compound (5.53 g) as a colorless liquid.
With hydrogenchloride; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water; N,N-dimethyl-formamide; toluene;
EXAMPLE 85 4-[2-(1,1'-biphenyl)-4-ylethoxy]quinazoline To a solution of 0.53 g of sodium hydride in 200 ml of DMF was added 2.2 g of 2-[(1,1'-biphenyl)-4-yl]ethanol, and the mixture was stirred at room temperature for one hour. Then 1.8 g of 4-chloroquinazoline in 20 ml of DMF were added, and the mixture was stirred at room temperature for another three hours. The mixture was then poured into a mixture of ice in water. The solid phase was collected and washed with water. TLC showed two spots. The product was purified using HPLC (silica gel, CH2 Cl2) giving 1.1 g of the title product. Yield: 30.6%. M.P. 72-74 C. The following is another, preferred process for preparing the title product: A suspension of 8.2 g of 4-chloroquinazoline and 9.9 g of 2-[(1,1'-biphenyl)-4-yl]ethanol in 250 mL of toluene saturated with HCl gas was heated to 50 C. for four hours. Then an additional 3.6 g of 4-chloroquinazoline were added, and heating to 50 C. was continued for one hour. Then the mixture was cooled, ice water was added, and the pH was adjusted to 8.5 using dilute sodium hydroxide. The toluene layer was separated, washed with brine, and filtered through phase separating paper. The toluene solution was placed in a freezer overnight. A small amount of hydroxyquinazoline crystallized, and was separated by filtration.
With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 0 - 20℃;
2-biphenyl ethanol (1 g, 5 mmol), 4-nitrophenol (834 mg, 6 mmol), andtriphenylphosphine (1.59 g, 6 mmol) was dissolved in 20 mL dichloromethane. Thesolution was chilled in an ice-water bath prior to the addition of diethylazodicarboxylate(949 i, 6 mmol). The reaction was then stirred overnight, and the ice-water bath slowlywarmed to room temperature. Crude product was purified by flash chromatography toyield 640 mg crystalline solid. ]H NMR (400 MHz, DMSO-d6) 5 8.1 (d), 7.6 (m), 7.47-7.41 (m), 7.34 (m), 7.17 (m), 4.39 (t, 2H), 3.13 (t, 2H).
With Dess-Martin periodane; In dichloromethane; for 2.5h;Cooling with ice; Heating;
The compound of formula 1-2 (1.0 eq) was dissolved in dichloromethane.Under ice bath conditions,Slowly add Dess-Martin Oxidizer (2.5 eq), after the addition,The reaction solution was heated to a stirring reaction for 2.5 hours to terminate the reaction.Slowly add saturated NaS2O3 solution and saturation to the reaction system.NaHCO3 solution,The resulting mixture was extracted with EtOAc.After concentration and column chromatography, a pale yellow solid was obtained as a compound of formula 1-3, yield 56%.
1-(4-phenylphenyl)ethyl 2-pyridyl carbonate[ No CAS ]
2-(4-phenylphenyl)ethyl 2-oxopyridine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; In dichloromethane; at 20℃; for 16h;Inert atmosphere;
Under nitrogen atmosphere, to a stirred solution of 2-(4-phenylphenyl)-ethanol (0.30 g,1.41 mmol) in dry CH2C12 (15 mL), DMAP (0.014 g, 0.11 mmol) and 2-DPC (0.37 g, 1.70mmol) were added. The reaction mixture was stirred at r.t. for 16h, then diluted with CH2C12 (15mL) and sequentially washed with sat. NH4C1 solution (15 mL) and sat. NaHCO3 solution (315 mL). The organic layer was dried over Na2SO4, filtered and concentrated to dryness giving an oily residue (0.46 g), as a mixture (1:1.7 ratio) of 2-(4-phenylphenyl)-ethyl-2-pyridyl carbonate and 2-(4-phenylphenyl)-ethyl-2-oxopyridine- 1 -carboxylate. The mixture of isomers was not separated and used in the next step without any further purification. R = 2.63 mm. MS (ESI)m/z: 244 [M-H], 266 [M-Na]. MS (ESI) m/z: 242 EM-Hr.
With potassium peroxomonosulfate; N,O-bis(diethylhydrogensilyl)trifluoroacetamide; acrylic acid; at 20 - 50℃; for 36h;Inert atmosphere;
Compound 30:Acrylic acid (13.5 mg, 0.05 mmol) was added sequentially to a 25 mL two-necked flask,2-biphenylethyl alcohol (49.5 mg, 0.25 mmol),N, O-bis (diethylsilyl) trifluoroacetamide (213.6 mg, 0.75 mmol)Potassium peroxy monosulfonate (307.0 mg, 0.50 mmol)The gas was replaced with dry N2 for 3 times,Finally, dry tetrahydrothiopyran (0.5 mL) was added under N2.Stirred at room temperature and heated to 50 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 15.0 mL three times,The combined organic phase was distilled under reduced pressure and the product was purified by column chromatography in 65% yield.
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