* 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 magnesium In tetrahydrofuran at 55 - 60℃; for 2.5 h; Inert atmosphere Stage #2: at 55 - 60℃; for 2.5 h; Inert atmosphere
Bromobenzene (37.7g, 0.24mol) and 200mL THF (tetrahydrofuran) were uniformly mixed into a pressure-equalizing dropping funnel. Under nitrogen, a 1L flask was added three pieces of magnesium (6.1g, 0.25mol) and was heated at 55-60°C. 20mL of the above mixture was added dropwise THF and bromobenzene at 55-60°C for the Grignard reaction initiator for 0.5 hours. The reaction was incubated at 55-60°C and stirred for 2 hours. 9-fluorenone (36.0,0.20mol) mixed with 100mL THF was added dropwise to the homogeneous reaction system for 0.5 hours. . The reaction was incubated at 55-60°C and stirred for 2 hours. Ammonium chloride aqueous solution (200mL, 2.5mol / L) was added to the reaction system after the completion of the reaction. The reaction was quenched and left to stand for liquid separation. It was then washed with deionized water, solvent was removed, and recrystallized from toluene or ethanol to give a pale yellow solid 9-phenyl-9-fluorenol, yield 88percent.
74.7%
Stage #1: With iodine; magnesium In tetrahydrofuran at 40 - 80℃; for 4 h; Inert atmosphere Stage #2: for 15 h; Inert atmosphere; Reflux
(1) 250mL three-necked flask,In a nitrogen-purged atmosphere,Join 0.05mol raw material U1,0.06molMg powder,Dissolved in 60 ml of dry tetrahydrofuran,Add 0.0004mol elemental I2,Heated to 40 ° C and stirred until the solution changed from yellow to colorless,The above mixed solution was heated to 80 ° C,The reaction was stirred for 4 hours,No magnesium powder left,Reaction is complete,Generate format reagent intermediates V1,Without purification,Go directly to the next step. (2) 250mL three-necked flask,In a nitrogen-purged atmosphere,0.03 mol of 9-fluorenone was added,Dissolved in 40 ml of dry tetrahydrofuran,Slowly add the above format reagent intermediate V1 solution,Heated to reflux for 15 hours,Generate a lot of white precipitate,Then cooled to room temperature,The addition of saturated NHCl4 converts the salt of form into alcohol;After the reaction is completed,Ether extraction,Drying and steaming,After the silica gel column,A slightly yellow solid tert-alcohol intermediate W1 was obtained,HPLC purity 99.2percentYield 74.7percent.
74.7%
Stage #1: With iodine; magnesium In tetrahydrofuran at 40 - 80℃; for 4 h; Inert atmosphere Stage #2: for 15 h; Inert atmosphere; Reflux
(1) 250mL three bottle,In a nitrogen atmosphere, 0.05 mol of U1, 0.06 mol of Mg powder was added.Dissolve in 60ml of dry tetrahydrofuran and add 0.0004mol of elemental I2.Heat to 40°C and stir until the solution turns from yellow to colorless,The mixed solution was heated to 80°C and the reaction was stirred for 4 hours.No magnesium powder remained and the reaction was complete. The reagent intermediate V1 was generated in the format without further purification, and the next step was performed directly.(2) A 250 mL three-necked flask, under a nitrogen atmosphere,0.03 mol of 9-fluorenone was added, dissolved in 40 ml of dry tetrahydrofuran, and the solution of the above-mentioned reagent intermediate V1 was slowly added dropwise, and the mixture was heated under reflux for 15 hours.Generate a lot of white precipitate,It is then cooled to room temperature and saturated salt NHCl4 is added to convert the format salt to alcohol;After the reaction is completed, ether is extracted, dried and evaporated.Through a silica gel column, a slightly yellowish solid tertiary alcohol intermediate W1 is obtained.HPLC purity 99.2percent, yield 74.7percent.
Reference：
[1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 6, p. 947 - 957
[2] Journal of Organic Chemistry, 2018, vol. 83, # 11, p. 6162 - 6170
[3] Patent: CN105541747, 2016, A, . Location in patent: Paragraph 0041; 0042; 0043
[4] Patent: CN107337680, 2017, A, . Location in patent: Paragraph 0046; 0047; 0048; 0049; 0054
[5] Patent: CN107573356, 2018, A, . Location in patent: Paragraph 0061; 0063; 0064; 0065
[6] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1990, # 12, p. 2167 - 2177
[7] Journal of Organic Chemistry, 1985, vol. 50, # 8, p. 1239 - 1246
[8] Organic Syntheses, 1993, vol. 71, p. 220 - 220
2
[ 486-25-9 ]
[ 100-58-3 ]
[ 25603-67-2 ]
Yield
Reaction Conditions
Operation in experiment
76%
Stage #1: at 0 - 20℃; for 16 h; Inert atmosphere Stage #2: With ammonium chloride In tetrahydrofuran; water
Under nitrogen atmosphere, a solution of 9-fluorenone (18.2 g, 100 mmol) in 150 mL of dry tetrahydrofuran (THF) was dropwise added at 0° C. to 100 mL of a 1M solution of phenylmagnesium bromide solution in THF. At the end of addition, the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was poured into 100 mL of saturated solution of ammonium chloride. The mixture was extracted twice with diethyl ether. The combined ether solution was dried over MgSO4 and the solvent was removed under reduced pressure to provide 19.5 g (76percent) of intermediate (I1). 1H NMR (CDCl3) δ: 7.72=7.73 (m, 2H), 7.27-7.57 (m, 11H). 13C NMR (CDCl3) δ: 150.74, 143.5, 139.87, 135.02, 129.38, 128.75, 128.53, 127.51, 125.71, 125.12124.69, 120.619, 120.39.
70%
at 0 - 20℃; for 24 h;
Preparation of compound 3-19-fluorenone (20.0 g, 111.0 mmol) was dissolved in THF (554.0 mL) in a flask and phenylmagnesium bromide (36.9 mL) was slowly added thereto at 0 °C. The mixture was stilTed at room temperature for 24 hrs. After completing the reaction, the organic layer was extracted with EA and dried by removing the remaining moisture with MgSO4. The layer was separated by column chromatography to obtain compound 3-1(20.0 g, 70 percent).
70%
at 0 - 20℃; for 24 h;
Preparation of compound 3-1[118]After 9-fluorenone (20.0 g, 111.0 mmol) was dissolved in THF (554 mL) in a flask, phenyl magnesium bromide (36.9 mL) was slowly added thereto at 0°C and the mixture was stirred at room temperature for 24 hrs. After completing the reaction, the organic layer was extracted with EA, was dried by removing the remaining moisture with MgSO4, and was separated through column chromatography to obtain compound 3-1 (20.0 g, 70 percent).
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1986, p. 405 - 408
[2] Patent: US2016/16872, 2016, A1, . Location in patent: Paragraph 0037
[3] Patent: WO2015/84021, 2015, A1, . Location in patent: Paragraph 179; 180; 181; 182
[4] Patent: WO2015/167199, 2015, A1, . Location in patent: Paragraph 117; 118
[5] Patent: JP2005/120030, 2005, A, . Location in patent: Page/Page column 44
[6] Journal of Organic Chemistry, 2010, vol. 75, # 12, p. 4124 - 4130
3
[ 486-25-9 ]
[ 591-51-5 ]
[ 25603-67-2 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 0 - 20℃; for 16 h; Inert atmosphere; Schlenk technique
To a stirred solution of 9-fluorenone (540 mg, 3 mmol) in THF (1.5 mL), PhLi in n-Bu2O (2mL, 1.8 M, 3.6 mmol) was added dropwise at 0 °C. The reaction mixture was warmed toroom temperature and stirred over 16 h. The reaction mixture was then cooled to 0 °C,diluted with Et2O (~3 mL) before being quenched with NH4Claq (~3 mL). The product wasextracted with Et2O (3 x ~5 mL). The combined organic layer was sequentially washed withH2O (~5 mL), then brine, dried over Na2SO4 and concentrated under reduced pressure. Theresidual was passed through a short silica plug (hexanes:EtOAc = 20:1) to afford the 9-phenyl-9-fluorenol in quantitative yield as a white solid. To a stirred solution of 9-phenyl-9-fluorenol (258 mg, 1 mmol) in DCM (5 mL) cooled to 0 °C, trifluoroacetic acid (0.3 mL, 4mmol) and then Et3SiH (0.4 mL, 2.5 mmol) were added dropwise. The reaction mixture wasstirred at 0 °C for 10 min. before being quenched with Na2CO3aq (~4 mL). The product wasextracted with DCM (3 x ~10 mL). The combined organic layer was washed with brine,dried over Na2SO4, and passed through a silica plug (hexanes:EtOAc = 20:1) to afford thetitled compound 5a in 82percent yield (197 mg) as a white solid.
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1987, vol. 23, # 4, p. 657 - 661[2] Zhurnal Organicheskoi Khimii, 1987, vol. 23, # 4, p. 730 - 735
[3] Chemische Berichte, 1905, vol. 38, p. 292
[4] Journal of the American Chemical Society, 1958, vol. 80, p. 5449,5452
[5] Zeitschrift fuer Naturforschung, B: Chemical Sciences, 1991, vol. 46, # 9, p. 1223 - 1226
[6] Tetrahedron Letters, 2004, vol. 45, # 41, p. 7645 - 7649
[7] Chemische Berichte, 1905, vol. 38, p. 292
5
[ 86-73-7 ]
[ 108-90-7 ]
[ 25603-67-2 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 42, p. 8488 - 8498
6
[ 486-25-9 ]
[ 100-59-4 ]
[ 25603-67-2 ]
Reference：
[1] Patent: US6162824, 2000, A,
7
[ 76-84-6 ]
[ 25603-67-2 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 4, p. 1365 - 1370
[2] Journal of the American Chemical Society, 1971, vol. 93, # 23, p. 6158 - 6166
[3] Chemische Berichte, 1905, vol. 38, p. 292
[4] Chemische Berichte, 1905, vol. 38, p. 292
8
[ 486-25-9 ]
[ 26138-28-3 ]
[ 25603-67-2 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1983, vol. 32, # 11, p. 2351 - 2356[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1983, # 11, p. 2615 - 2620
Reference：
[1] Journal of Organic Chemistry, 2017, vol. 82, # 12, p. 6044 - 6053
11
[ 52744-72-6 ]
[ 25603-67-2 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1986, p. 405 - 408
12
[ 100-58-3 ]
[ 25603-67-2 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1986, p. 405 - 408
13
[ 134-20-3 ]
[ 25603-67-2 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1986, p. 405 - 408
14
[ 486-25-9 ]
[ 25603-67-2 ]
Reference：
[1] Chemische Berichte, 1904, vol. 37, p. 73
[2] Chemische Berichte, 1905, vol. 38, p. 292
[3] Chemische Berichte, 1904, vol. 37, p. 73
[4] Chemische Berichte, 1905, vol. 38, p. 292
[5] Bulletin de la Societe Chimique de France, 1973, p. 562 - 569
[6] Bulletin de la Societe Chimique de France, 1971, p. 1526 - 1533
[7] Journal of the Chemical Society, 1961, p. 3052 - 3058
[8] Journal of Organic Chemistry, 1963, vol. 28, p. 1479 - 1484
[9] Journal of Organic Chemistry, 1977, vol. 42, # 1, p. 19 - 28
[10] Journal of the Chemical Society [Section] B: Physical Organic, 1971, p. 503 - 507
[11] Journal of the American Chemical Society, 1943, vol. 65, p. 49[12] Journal of the American Chemical Society, 1944, vol. 66, p. 376
[13] Journal of the American Chemical Society, 1984, vol. 106, p. 1432
[14] Canadian Journal of Chemistry, 1975, vol. 53, p. 1635 - 1641
[15] Journal of Medicinal Chemistry, 1994, vol. 37, # 15, p. 2334 - 2342
[16] Angewandte Chemie - International Edition, 2007, vol. 46, # 26, p. 4937 - 4939
[17] Tetrahedron Letters, 2003, vol. 44, # 48, p. 8649 - 8652
15
[ 55135-66-5 ]
[ 25603-67-2 ]
Reference：
[1] Chemische Berichte, 1905, vol. 38, p. 292
16
[ 25022-99-5 ]
[ 25603-67-2 ]
Reference：
[1] Journal of the Chemical Society, 1961, p. 3052 - 3058
17
[ 24300-00-3 ]
[ 25603-67-2 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1992, # 12, p. 2083 - 2090
Reference：
[1] Journal of the American Chemical Society, 1913, vol. 35, p. 202[2] Chemische Berichte, 1913, vol. 46, p. 225
20
[ 25603-67-2 ]
[ 55135-66-5 ]
Yield
Reaction Conditions
Operation in experiment
82%
With hydrogen bromide In toluene at 50 - 60℃; for 48 h; Large scale
(1) Prepare a 10L reactor, add 6L of toluene first, and stir; at 20-25°C,Slowly add 9-phenyl-9-fluorenol (1kg, 3.87mol), stir and dissolve, the solution was milky white;(2) Add a solution of 48percent HBr (2.9L, 25.5mol) in one portion at 20-25°C.The reaction solution was light yellow and cloudy;(3) The reaction solution was heated to 50-60°C in a water bath, and the reaction was continued for 48 h and the color of the solution was gradually deepened;(4) GC confirmed the reaction, the main raw material 9-phenyl-9-sterol content of 3percent, the termination of the reaction;(5) Remove the water bath, cool to room temperature, and transfer the reaction solution to a 20L reactor for post-treatment: stirring and standing.The layers were separated; the lower aqueous phase was extracted once with 2 L of toluene, and the organic toluene solution was combined and washed sequentially with 4 L saturated sodium carbonate solution, 4 L water, once with 4 L saturated brine, and finally with the organic phase. 100G anhydrous magnesium sulfate dehydrated and dried;(6) After drying for 4 hours, the mixture was suction-filtered, and the filter cake was discarded. The filtrate was concentrated at 45° C. and concentrated to dryness to give a white solid.1.1kg, GC test purity content 96percent;(7) Recrystallization purification of 9-bromo-9-phenyl hydrazine: 1.1 kg of crude product is added to a 10 L reaction vessel, and 7 L of hexene is added.Alkane, stirring, and then heated to reflux, the solution was transparent, and then added 50G activated carbon decolorization, stirring 30min, 65 °C hot pressure filtration, naturally cooled to room temperature, the final ice salt bath was cooled to -5 ~ -10 °C, set aside for 4h The white crystals were obtained by suction filtration, and the wet weight was 1.25 kg. After vacuum drying at 50° C. for 12 hours, 1.02 kg of a yellow crystalline powder was obtained. The purity of the GC was 99percent, MP: 99 to 100° C., and the total yield was 82percent.
73.5%
With hydrogen bromide In water; toluene at 20 - 25℃; for 24 h;
(3) 250mL three-necked flask,0.02 mol of intermediate W1 was added,Dissolved in 50 ml of toluene,Slowly add 48percent HBr aqueous solution (40ml)The reaction was stirred at 25 ° C for 24 hours,After the reaction liquid separation,The aqueous phase is extracted with toluene,After combining the organic phases with anhydrous sodium sulfate,Suction filtration,The filter cake was rinsed with ethyl acetate,The filtrate and rinse were swirled to solventless,After the silica gel column,Intermediate M1 was obtained,HPLC purity 99.4percentYield 73.5percent.
73.5%
With hydrogen bromide In water; toluene at 25℃; for 4 h;
250mL three-necked bottle, add 0.02mol intermediate W1,Dissolved in 50 ml of toluene,48percent HBr aqueous solution (40 ml) was slowly added dropwise.Stir the reaction at 25 °C for 24 hours,Separating after the reaction,The aqueous phase is extracted with toluene.The organic phases were combined and dried over anhydrous sodium sulfate and suction filtered.The cake was rinsed with ethyl acetate and the filtrate and rinse were evaporated to solvent-free.The silica gel column gave intermediate Ml-I, HPLC purity 99.4percent, yield 73.5percent.
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 11, p. 6162 - 6170
[2] Organic Syntheses, 1993, vol. 71, p. 220 - 220
[3] Patent: CN107573208, 2018, A, . Location in patent: Paragraph 0022; 0023; 0024; 0025; 0026; 0027; 0028-0032
[4] Patent: CN107337680, 2017, A, . Location in patent: Paragraph 0050; 0051; 0054
[5] Patent: CN107573356, 2018, A, . Location in patent: Paragraph 0062; 0066; 0067
[6] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1992, # 12, p. 2083 - 2090
[7] Journal of the Chemical Society, 1930, p. 708,711
[8] Chemische Berichte, 1906, vol. 39, p. 3065
[9] Journal of the Chemical Society, 1964, p. 1895 - 1906
[10] Journal of Organic Chemistry, 1963, vol. 28, p. 1479 - 1484
[11] Journal of Organic Chemistry, 1985, vol. 50, # 8, p. 1239 - 1246
21
[ 506-96-7 ]
[ 25603-67-2 ]
[ 55135-66-5 ]
Reference：
[1] Journal of the American Chemical Society, 1930, vol. 52, p. 3287,3288, 3289[2] Journal of the American Chemical Society, 1933, vol. 55, p. 2135,2139
With triethylsilane; trifluoroacetic acid; In dichloromethane; at 0℃; for 0.166667h;Inert atmosphere; Schlenk technique;
To a stirred solution of 9-fluorenone (540 mg, 3 mmol) in THF (1.5 mL), PhLi in n-Bu2O (2mL, 1.8 M, 3.6 mmol) was added dropwise at 0 C. The reaction mixture was warmed toroom temperature and stirred over 16 h. The reaction mixture was then cooled to 0 C,diluted with Et2O (~3 mL) before being quenched with NH4Claq (~3 mL). The product wasextracted with Et2O (3 x ~5 mL). The combined organic layer was sequentially washed withH2O (~5 mL), then brine, dried over Na2SO4 and concentrated under reduced pressure. Theresidual was passed through a short silica plug (hexanes:EtOAc = 20:1) to afford the <strong>[25603-67-2]9-phenyl-9-fluorenol</strong> in quantitative yield as a white solid. To a stirred solution of <strong>[25603-67-2]9-phenyl-9-fluorenol</strong> (258 mg, 1 mmol) in DCM (5 mL) cooled to 0 C, trifluoroacetic acid (0.3 mL, 4mmol) and then Et3SiH (0.4 mL, 2.5 mmol) were added dropwise. The reaction mixture wasstirred at 0 C for 10 min. before being quenched with Na2CO3aq (~4 mL). The product wasextracted with DCM (3 x ~10 mL). The combined organic layer was washed with brine,dried over Na2SO4, and passed through a silica plug (hexanes:EtOAc = 20:1) to afford thetitled compound 5a in 82% yield (197 mg) as a white solid.
With chloro-trimethyl-silane; sodium iodide; In acetone; at 20℃; for 12h;Absence of light;
PREPARATIVE EXAMPLE 4;-Preparation of the compound according to formula IIIA; The antioxidant precursor compound according to formula IIIA was obtained in a one-pot synthesis. 9-Phenyl-9-fluorenol (1.0 g, 3.87 mmol) was dissolved in dry, freshly distilled acetone (over CaH2). This solution was added drop-wise to a solution of previously reacted trimethylsilyl chloride (0.51 mL, 1.2 eq. ) and excess NaI (2.9 g, 5 eq. ) in acetone, all under inert atmosphere (argon) at room temperature. The solution turned brown from the initial addition and darkened as the reaction was stirred overnight (12hrs). After evaporation by rotovap, the residue was washed between dichloromethane (100 mL) and 100mL of 10% Na2S203 (aq.) (the aqueous phase was clear and the dichloromethane layer was opaque with a white suspension). Simple filtration of this bilayer afforded the desired product (which was washed several times with ice cold acetone) to afford 480 mg of product as a white powder. (51 % yield) mp 176-185 C (decomposition from pink powder to dark red liquid),'H NMR (CDC13,200 MHz): 8 7.59-7. 46 (6H), 7.30-7. 09 (m, 16H), 6.93 (broad s,-2H), 6.57 (broad s, ~2H) ppm. 13C NMR: 8 147.5, 146.3, 141.5, 140.9, 131.5, 129.4, 129.2, 128.3, 127.7, 127.6, 127.6, 127.3, 127.2, 126.7, 126.4, 126.0, 119.8, 119.5, 93.5 ppm. MS (EI) m/z 241 [M/2] + (100%). HRMS calculated for C19H13+ (M/2+) 241.1012, found 241.1037. An overview of this preparative method is shown in reaction scheme 9.
With hydrogen bromide; In toluene; at 50 - 60℃; for 48h;Large scale;
(1) Prepare a 10L reactor, add 6L of toluene first, and stir; at 20-25C,Slowly add <strong>[25603-67-2]9-phenyl-9-fluorenol</strong> (1kg, 3.87mol), stir and dissolve, the solution was milky white;(2) Add a solution of 48% HBr (2.9L, 25.5mol) in one portion at 20-25C.The reaction solution was light yellow and cloudy;(3) The reaction solution was heated to 50-60C in a water bath, and the reaction was continued for 48 h and the color of the solution was gradually deepened;(4) GC confirmed the reaction, the main raw material 9-phenyl-9-sterol content of 3%, the termination of the reaction;(5) Remove the water bath, cool to room temperature, and transfer the reaction solution to a 20L reactor for post-treatment: stirring and standing.The layers were separated; the lower aqueous phase was extracted once with 2 L of toluene, and the organic toluene solution was combined and washed sequentially with 4 L saturated sodium carbonate solution, 4 L water, once with 4 L saturated brine, and finally with the organic phase. 100G anhydrous magnesium sulfate dehydrated and dried;(6) After drying for 4 hours, the mixture was suction-filtered, and the filter cake was discarded. The filtrate was concentrated at 45 C. and concentrated to dryness to give a white solid.1.1kg, GC test purity content 96%;(7) Recrystallization purification of 9-bromo-9-phenyl hydrazine: 1.1 kg of crude product is added to a 10 L reaction vessel, and 7 L of hexene is added.Alkane, stirring, and then heated to reflux, the solution was transparent, and then added 50G activated carbon decolorization, stirring 30min, 65 C hot pressure filtration, naturally cooled to room temperature, the final ice salt bath was cooled to -5 ~ -10 C, set aside for 4h The white crystals were obtained by suction filtration, and the wet weight was 1.25 kg. After vacuum drying at 50 C. for 12 hours, 1.02 kg of a yellow crystalline powder was obtained. The purity of the GC was 99%, MP: 99 to 100 C., and the total yield was 82%.
73.5%
With hydrogen bromide; In water; toluene; at 20 - 25℃; for 24h;
(3) 250mL three-necked flask,0.02 mol of intermediate W1 was added,Dissolved in 50 ml of toluene,Slowly add 48% HBr aqueous solution (40ml)The reaction was stirred at 25 C for 24 hours,After the reaction liquid separation,The aqueous phase is extracted with toluene,After combining the organic phases with anhydrous sodium sulfate,Suction filtration,The filter cake was rinsed with ethyl acetate,The filtrate and rinse were swirled to solventless,After the silica gel column,Intermediate M1 was obtained,HPLC purity 99.4%Yield 73.5%.
73.5%
With hydrogen bromide; In water; toluene; at 25℃; for 4h;
250mL three-necked bottle, add 0.02mol intermediate W1,Dissolved in 50 ml of toluene,48% HBr aqueous solution (40 ml) was slowly added dropwise.Stir the reaction at 25 C for 24 hours,Separating after the reaction,The aqueous phase is extracted with toluene.The organic phases were combined and dried over anhydrous sodium sulfate and suction filtered.The cake was rinsed with ethyl acetate and the filtrate and rinse were evaporated to solvent-free.The silica gel column gave intermediate Ml-I, HPLC purity 99.4%, yield 73.5%.
Bromobenzene (37.7g, 0.24mol) and 200mL THF (tetrahydrofuran) were uniformly mixed into a pressure-equalizing dropping funnel. Under nitrogen, a 1L flask was added three pieces of magnesium (6.1g, 0.25mol) and was heated at 55-60C. 20mL of the above mixture was added dropwise THF and bromobenzene at 55-60C for the Grignard reaction initiator for 0.5 hours. The reaction was incubated at 55-60C and stirred for 2 hours. 9-fluorenone (36.0,0.20mol) mixed with 100mL THF was added dropwise to the homogeneous reaction system for 0.5 hours. . The reaction was incubated at 55-60C and stirred for 2 hours. Ammonium chloride aqueous solution (200mL, 2.5mol / L) was added to the reaction system after the completion of the reaction. The reaction was quenched and left to stand for liquid separation. It was then washed with deionized water, solvent was removed, and recrystallized from toluene or ethanol to give a pale yellow solid 9-phenyl-9-fluorenol, yield 88%.
80%
First, a mixture of bromobenzene (13.0 g, 83.31 mmol) and Mg (2.23 g, 91.64 mmol) was carefully added to a 100 mL three-neck round bottom flask under a nitrogen atmosphere.The reaction flask was stirred at 60 C. in anhydrous tetrahydrofuran (15 mL) for 2 hours. then,The Grignard reagent was transferred to a 250 mL flask with fluorenone (5.0 g, 27.77 mmol). The reaction mixture was stirred at 85 C in anhydrous tetrahydrofuran (10 mL) for 6 hours. After cooling to room temperature, carefully pour the mixture into a flask filled with water to quench the mixture. The reaction was extracted with dichloromethane, the two phases were separated and the aqueous phase was extracted twice with dichloromethane. The filtrate was concentrated in vacuo by means of a rotary evaporator to obtain a crude product. The combined organic extracts were dried over MgSO4, evaporated, and purified using silica gel column chromatography (gradient elution: dichloromethane-petroleum ether (1: 4)) to give PFOH as a pale yellow solid (7.2 g, 80% ).
77%
After adding bromobenzene (60 mmol) and 200 mL of tetrahydrofuran to the reaction vessel,The vessel was cooled to -78 C under a nitrogen atmosphere.Then n-butyllithium (2.5 M, 60 mmol) was slowly added dropwise to the mixture.After the mixture was stirred at -78 C for 30 minutes, it was stirred at room temperature for 3 hours.And cooled to -78 C.Thereafter, 9-fluorenone (60 mmol) dissolved in 200 mL of tetrahydrofuran was slowly added dropwise to the mixture.After the addition, the reaction temperature was slowly raised to room temperature, and the mixture was stirred for 16 hours.Next, an aqueous ammonium chloride solution is added to the reaction solution to complete the reaction, and acetic acid B is used.The ester extraction reaction solution.The extracted organic layer was then dried using magnesium sulfate, and the solvent was removed using a rotary evaporator.The residue was purified by column chromatography to give Compound 1-1 (11.94 g, yield: 77%, MW: 258.42).
74.7%
(1) 250mL three-necked flask,In a nitrogen-purged atmosphere,Join 0.05mol raw material U1,0.06molMg powder,Dissolved in 60 ml of dry tetrahydrofuran,Add 0.0004mol elemental I2,Heated to 40 C and stirred until the solution changed from yellow to colorless,The above mixed solution was heated to 80 C,The reaction was stirred for 4 hours,No magnesium powder left,Reaction is complete,Generate format reagent intermediates V1,Without purification,Go directly to the next step. (2) 250mL three-necked flask,In a nitrogen-purged atmosphere,0.03 mol of 9-fluorenone was added,Dissolved in 40 ml of dry tetrahydrofuran,Slowly add the above format reagent intermediate V1 solution,Heated to reflux for 15 hours,Generate a lot of white precipitate,Then cooled to room temperature,The addition of saturated NHCl4 converts the salt of form into alcohol;After the reaction is completed,Ether extraction,Drying and steaming,After the silica gel column,A slightly yellow solid tert-alcohol intermediate W1 was obtained,HPLC purity 99.2%Yield 74.7%.
74.7%
(1) 250mL three bottle,In a nitrogen atmosphere, 0.05 mol of U1, 0.06 mol of Mg powder was added.Dissolve in 60ml of dry tetrahydrofuran and add 0.0004mol of elemental I2.Heat to 40C and stir until the solution turns from yellow to colorless,The mixed solution was heated to 80C and the reaction was stirred for 4 hours.No magnesium powder remained and the reaction was complete. The reagent intermediate V1 was generated in the format without further purification, and the next step was performed directly.(2) A 250 mL three-necked flask, under a nitrogen atmosphere,0.03 mol of 9-fluorenone was added, dissolved in 40 ml of dry tetrahydrofuran, and the solution of the above-mentioned reagent intermediate V1 was slowly added dropwise, and the mixture was heated under reflux for 15 hours.Generate a lot of white precipitate,It is then cooled to room temperature and saturated salt NHCl4 is added to convert the format salt to alcohol;After the reaction is completed, ether is extracted, dried and evaporated.Through a silica gel column, a slightly yellowish solid tertiary alcohol intermediate W1 is obtained.HPLC purity 99.2%, yield 74.7%.
The 100 mL three-neck round bottom flask was subjected to anhydrous anoxic treatment, and magnesium shavings (30 mmol, 3 equivalents) and iodine (2 mmol,10% equivalent), bromobenzene (30 mmol, 1.5 equivalents) was dissolved in re-distilled tetrahydrofuran and slowly added dropwise through a constant pressure dropping funnel.The reaction was carried out at 65 C in a round bottom flask. After 2 hours, 9-fluorenone was dissolved in tetrahydrofuran and slowly added to the reaction system.Continue to react overnight. After the reaction is completed, a saturated ammonium chloride solution is added to the system for quenching, and then ethyl acetate (3)×30 mL), the organic phase is combined, washed once with brine, and then the organic phase is dried over anhydrous sodium sulfate to remove the organic phase.The reagent was separated by column chromatography to give 9-phenylindole-9-ol.
Take magnesium shavings (1.09g, 48.8mmol), a small amount of iodine in a two-necked reaction flask and place it in a nitrogen atmosphere.Take 15ml tetrahydrofuran solution of distilled water and bromobenzene (7.04g, 44.8mmol), and slowly add a small amount of each under stirring.Initiate with a heating gun until it turns from a brown to a colorless solution, then move into ice water and add other solutions and bromobenzene. When there are no more bubbles, transfer to a 45 C oil bath for 2 hours.This process is a Grignard reagent preparation. Take fluorenone (5) (5.38g, 29.9mmol) in a dry two-necked reaction flask,After protecting in a nitrogen atmosphere, add about 50 ml of freshly distilled tetrahydrofuran and stir to fully dissolve. After the Grignard reaction is complete, add the fluorenone solution while hot, and react at 80 C for about 24 hours.At this point the solution changed from dark brown to milky white, and the reaction stopped after spot monitoring.Saturated ammonium chloride solution was used for extraction, anhydrous sodium sulfate was removed by spin-steaming, and it was separated on a 200-300 mesh silica gel column.Petroleum ether / dichloromethane was separated and purified at a volume ratio of 6: 1, and the product 9-phenyl tertiary alcohol was obtained as a white solid (6.85 g, 89%) by recrystallization with petroleum ether
Under nitrogen atmosphere, a solution of 9-fluorenone (18.2 g, 100 mmol) in 150 mL of dry tetrahydrofuran (THF) was dropwise added at 0 C. to 100 mL of a 1M solution of phenylmagnesium bromide solution in THF. At the end of addition, the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was poured into 100 mL of saturated solution of ammonium chloride. The mixture was extracted twice with diethyl ether. The combined ether solution was dried over MgSO4 and the solvent was removed under reduced pressure to provide 19.5 g (76%) of intermediate (I1). 1H NMR (CDCl3) delta: 7.72=7.73 (m, 2H), 7.27-7.57 (m, 11H). 13C NMR (CDCl3) delta: 150.74, 143.5, 139.87, 135.02, 129.38, 128.75, 128.53, 127.51, 125.71, 125.12124.69, 120.619, 120.39.
70%
In tetrahydrofuran; at 0 - 20℃; for 24h;
Preparation of compound 3-19-fluorenone (20.0 g, 111.0 mmol) was dissolved in THF (554.0 mL) in a flask and phenylmagnesium bromide (36.9 mL) was slowly added thereto at 0 C. The mixture was stilTed at room temperature for 24 hrs. After completing the reaction, the organic layer was extracted with EA and dried by removing the remaining moisture with MgSO4. The layer was separated by column chromatography to obtain compound 3-1(20.0 g, 70 %).
70%
In tetrahydrofuran; at 0 - 20℃; for 24h;
Preparation of compound 3-1[118]After 9-fluorenone (20.0 g, 111.0 mmol) was dissolved in THF (554 mL) in a flask, phenyl magnesium bromide (36.9 mL) was slowly added thereto at 0C and the mixture was stirred at room temperature for 24 hrs. After completing the reaction, the organic layer was extracted with EA, was dried by removing the remaining moisture with MgSO4, and was separated through column chromatography to obtain compound 3-1 (20.0 g, 70 %).
Take a freshly dried 500mL double-necked flask, and under nitrogen protection, add 8.8g (34.1mmol) of <strong>[25603-67-2]9-phenyl-9-fluorenol</strong>, 1.9g (11.4mmol) of carbazole, and then add 200mL of dry methylene chloride .After stirring at room temperature for 1 h, 30 mL of a mixed solution in which 4.8 g (34.1 mmol) of boron trifluoride ether complex was dissolved was added dropwise. After the addition was complete, stirring was continued for 20 h. After the reaction was stopped, 50 mL of absolute ethanol was slowly added, and then 50 mL of water was slowly added to quench.The reaction system was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated and then separated by silica gel column chromatography.Petroleum ether: dichloromethane = 10: 1 was used for elution, and the eluent was concentrated to obtain an off-white solid A-1, 5.3 g, with a yield of 72 %
S-(9-Phenyl-9H-fluoren-9-yl)-D,L-cysteine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(i) S-(9-Phenyl-9H-fluoren-9-yl)-D,L-cysteine from <strong>[25603-67-2]9-phenyl-9H-fluoren-9-ol</strong> (Example 1b) and D,L-cysteine as a yellow powder.
1-(9-phenyl-9-fluorenyl)-1-vinylcyclopropane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With toluene-4-sulfonic acid;silica gel; In toluene;
Step 2 1-(9-Phenyl-9-fluorenyl)-1-vinylcyclopropane 1-Hydroxy-1-vinylcyclopropane is added to a suspension of <strong>[25603-67-2]9-phenyl-9-fluorenol</strong> (1eq) and AW-300 molecular sieves in anhydrous toluene under an argon atmosphere. p-Toluenesulfonic acid (catalytic amount) is added in one portion. The resulting suspension is heated at 90 C. until the disappearance of starting material is observed by thin layer chromatography. The mixture is filtered to remove the sieves. The resulting filtrate is concentrated in vacuo and the concentrate is purified by flash chromatography on silica gel using hexanes-ethyl acetate as eluent.
Method A Nalpha -(9-Fluorenylmethoxycarbonyl)--O--(9-phenyl-9H -fluoren-9-yl)-L-serine methyl ester A solution of 6.2 g (24 mmol) of 9-phenyl-9H-fluoren-9-ol (Example 1b) and 6.8 g (20 mmol) of Nalpha -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester in benzene (150 mL) was placed in a round bottomed flask fitted with a Dean-Stark trap. Two drops of concentrated sulfuric acid were added and the mixture heated under reflux with stirring for 1 h. Removal of the solvent under vacuo gave the crude Nalpha -(9-fluorenylmethoxycarbonyl)--O--(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester which was subjected to the Fmoc deprotection in Step 2 without further purification.
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