* 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.
Fourth Step: The compound (34) (52.3 g), formic acid (87percent; 58.6 ml), and toluene (200 ml) were mixed, and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to 30 °C, and then water (200 ml) and toluene (300 ml) were added and mixed thereto. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution obtained was purified by means of recrystallization from heptane and dried, giving 41.9 g of 1-(3-fluorophenyl)-cyclohexane-4-one (35). The yield based on a compound (34) was 98.5percent.
93.7%
With formic acid In toluene for 3 h; Inert atmosphere; Reflux
The compound (18) (61.9 g), formic acid (120 g) and toluene (120 ml) were put in a reaction vessel under a nitrogen atmosphere, heated under reflux for 3 hours, and cooled slowly to room temperature. Water (300 ml) and toluene (300 ml) were added and mixed thereto. The mixture was allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Then the solvent of the solution was distilled off under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene: ethyl acetate= 9:1 by volume) as an eluent and silica gel as a stationary phase powder and dried, giving 47.2 g of 4-(3-fluorophenyl)cyclohexanone (19). The yield based on the compound (18) was 93.7percent.
3.01 g
With hydrogenchloride In water; acetone at 20℃;
To a solution of 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (3.96 g) in acetone(30 ml) was added 6 mol/1 hydrochloric acid (3 ml) at room temperature. The mixturewas stirred at room temperature overnight. The solvent was evaporated under reducedpressure. To the mixture was added saturated brine, and the mixture was extracted withethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gelchromatography (ethyl acetate/hexane) to give the title compound (3.01 g).MS, found: 193.1.
Reference:
[1] Patent: EP2206695, 2010, A1, . Location in patent: Page/Page column 57-58
[2] Patent: EP2279990, 2011, A1, . Location in patent: Page/Page column 51
[3] Journal of the American Chemical Society, 2012, vol. 134, # 41, p. 17023 - 17026,4
[4] Journal of the American Chemical Society, 2012, vol. 134, # 41, p. 17023 - 17026
[5] Journal of the American Chemical Society, 2012, vol. 134, # 49, p. 20208 - 20208
[6] Patent: WO2017/135306, 2017, A1, . Location in patent: Paragraph 0138
2
[ 1073-06-9 ]
[ 40503-87-5 ]
Reference:
[1] Journal of the American Chemical Society, 2012, vol. 134, # 41, p. 17023 - 17026,4
[2] Journal of the American Chemical Society, 2012, vol. 134, # 41, p. 17023 - 17026
[3] Journal of the American Chemical Society, 2012, vol. 134, # 49, p. 20208 - 20208
[4] Patent: WO2014/140279, 2014, A1,
[5] Patent: CN107573212, 2018, A,
3
[ 4746-97-8 ]
[ 40503-87-5 ]
Reference:
[1] Journal of the American Chemical Society, 2012, vol. 134, # 41, p. 17023 - 17026,4
[2] Journal of the American Chemical Society, 2012, vol. 134, # 41, p. 17023 - 17026
[3] Journal of the American Chemical Society, 2012, vol. 134, # 49, p. 20208 - 20208
[4] Patent: WO2014/140279, 2014, A1,
[5] Patent: CN107573212, 2018, A,
[6] Patent: WO2018/54365, 2018, A1,
4
[ 17318-03-5 ]
[ 40503-87-5 ]
Reference:
[1] Journal of Medicinal Chemistry, 1972, vol. 15, # 12, p. 1239 - 1243
[2] Patent: WO2018/54365, 2018, A1,
5
[ 170011-47-9 ]
[ 40503-87-5 ]
Reference:
[1] Patent: WO2017/135306, 2017, A1,
6
[ 768-35-4 ]
[ 40503-87-5 ]
Reference:
[1] Patent: WO2017/135306, 2017, A1,
7
[ 680596-79-6 ]
[ 40503-87-5 ]
Reference:
[1] Patent: WO2018/54365, 2018, A1,
8
[ 1121-86-4 ]
[ 40503-87-5 ]
Reference:
[1] Patent: WO2018/54365, 2018, A1,
9
[ 40503-83-1 ]
[ 40503-87-5 ]
Reference:
[1] Journal of Medicinal Chemistry, 1972, vol. 15, # 12, p. 1239 - 1243
10
[ 13482-22-9 ]
[ 40503-87-5 ]
Reference:
[1] Journal of Medicinal Chemistry, 1972, vol. 15, # 12, p. 1239 - 1243
Fourth Step: The compound (34) (52.3 g), formic acid (87%; 58.6 ml), and toluene (200 ml) were mixed, and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to 30 C, and then water (200 ml) and toluene (300 ml) were added and mixed thereto. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution obtained was purified by means of recrystallization from heptane and dried, giving 41.9 g of 1-(3-fluorophenyl)-cyclohexane-4-one (35). The yield based on a compound (34) was 98.5%.
93.7%
With formic acid; In toluene; for 3h;Inert atmosphere; Reflux;
The compound (18) (61.9 g), formic acid (120 g) and toluene (120 ml) were put in a reaction vessel under a nitrogen atmosphere, heated under reflux for 3 hours, and cooled slowly to room temperature. Water (300 ml) and toluene (300 ml) were added and mixed thereto. The mixture was allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Then the solvent of the solution was distilled off under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene: ethyl acetate= 9:1 by volume) as an eluent and silica gel as a stationary phase powder and dried, giving 47.2 g of 4-(3-fluorophenyl)cyclohexanone (19). The yield based on the compound (18) was 93.7%.
3.01 g
With hydrogenchloride; In water; acetone; at 20℃;
To a solution of 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (3.96 g) in acetone(30 ml) was added 6 mol/1 hydrochloric acid (3 ml) at room temperature. The mixturewas stirred at room temperature overnight. The solvent was evaporated under reducedpressure. To the mixture was added saturated brine, and the mixture was extracted withethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gelchromatography (ethyl acetate/hexane) to give the title compound (3.01 g).MS, found: 193.1.
7
[ 40503-87-5 ]
[ 4009-98-7 ]
[ 1130351-00-6 ]
Yield
Reaction Conditions
Operation in experiment
93.7%
Fifth Step: Well-dried methoxymethyltriphenylphosphonium chloride (112.1 g) and THF (1000 ml) were mixed under a nitrogen atmosphere, and cooled to -30 C. Then, potassium t-butoxide (t-BuOK; 36.7 g) was put in thereto in twice in the temperature range of -30 C to 20 C. After the mixture had been stirred at -20 C for 30 minutes, the compound (35) (41.9g) dissolved in THF (200 ml) was added dropwise thereto in the temperature range of -30 C to -20 C. After the reaction had been stirred at -10 C for 30 minutes, it was poured into a mixture of water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The eluent obtained was concentrated under reduced pressure, giving 45.0 g of 1-(3-fluorophenyl)-4-methoxymethylenecyclohexane (36). The yield based on the compound (35) was 93.7%.
With sodium tetrahydroborate; In tetrahydrofuran; at 0℃; for 3h;Inert atmosphere;
Sodium borohydride (9.8 g) and THF (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to 0 C. The compound (19) (47.2 g) dissolved in THF (100 ml) was added dropwise thereto, with caution in the evolution of hydrogen gas, and the mixture was stirred for 3 hours. A saturated aqueous solution of ammonium chloride (400 ml) and ethyl acetate (400 ml) were added and mixed thereto. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed with brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene: ethyl acetate= 10:1 by volume) as an eluent and silica gel as a stationary phase powder, and dried, giving 40.9 g of 4-(3-fluorophenyl) cyclohexanol (20). The yield based on the compound (19) was 85.7%.
8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene[ No CAS ]
[ 40503-87-5 ]
Yield
Reaction Conditions
Operation in experiment
88.2%
43.1g of the cyclohexenyl intermediate was added to a 1L hydrogenation reactor, 400ml of ethanol was further added,5% palladium on carbon 3g. At hydrogen pressure of 0.3 ~ 0.5MPa,Hydrogenation temperature to 50C hydrogen absorption to the end. The reaction solution was filtered to remove the catalyst, ethanol was evaporated to dryness,The residue was transferred to 500ml three-necked flask, 150g of 85% formic acid, 150ml of toluene,Stir at reflux for 4h. Decompressing the formic acid and toluene under reduced pressure, the residue petroleum ether recrystallized,33.9 g of 4- (3-fluorophenyl) cyclohexanone was obtained, yielding 88.2% of total yield with 1,4-cyclohexanedione monoethylene ketal,GC purity 99.3%.
Step 4 (MS-54):Oxalyl chloride (7.1 g, 56.2 mmol) and aluminum chloride (7.5 g. 56.2 mmol) weresuccessively added to a solution of MS-53 (2.7 g, 14.0 mmol) in dichloromethane (60 mL) at -30C and the mixture was stirred for 2 h at room temperature. Methanol (20 mL) was added at -30C and the reaction mixture was warmed to room temperature and stirred for 12 h at this temperature. The reaction was quenched with ice water, basified with saturated sodium bicarbonate and extracted with dichloromethane. The separated organic layer was washedsuccessively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to afford the crude product. Purification by column chromatography over silica gel (60-1 2omesh) and using 15% ethyl acetate in pet ether as the eluent afforded 4.0 g (50%) of MS-S4 as an off white solid.
3'-fluoro-2,5-dihydro-[1,1'-biphenyl]-4(3H)-one[ No CAS ]
[ 40503-87-5 ]
Yield
Reaction Conditions
Operation in experiment
66%
With palladium 10% on activated carbon; hydrogen; In ethanol; under 3620.13 Torr; for 5h;
Step 3 (MS-53):A solution of MS-52 (4 g, 21.0 mmol) in absolute ethanol (100 mL) was hydrogenated over10% Pd-C in a Parr apparatus (70psi) for 5 h. The reaction mass was filtered through celiteand washed with ethanol. The combined filtrate and washing portion was concentrated underreduced pressure to afford the crude intermediate. Purification by column chromatographyover silica gel (60-i20mesh) and using 7% ethyl acetate in pet ether as the eluent afforded2.7 g (66%) of MS-53 as a colorless liquid.
With 50% palladium on charcoal; hydrogen; In ethyl acetate; at 20℃; under 3000.3 Torr; for 6h;
To a solution of 3'-fluoro-2,5-dihydro- [1, 1'-biphenyl] -4 (3H) -one (5 g, 26.3mmol) in ethyl acetate: EA=1: 1 (100 mL) was added Pd/C (2.5 g, 50%) and the mixture was stirred for 6 hours at room temperature under H2 (0.4 Mpa). Then filtered to remove Pd/C and the filtrate was evaporated under reduced pressure to give crude product, which was used for next step without further purification.To a solution of 3'-fluoro-2, 5-dihydro- [1, 1'-biphenyl] -4 (3H) -one (4.0 g, 21 mmol) in methol (100 mL) was added Pd/C (0.4 g, 10%) and the mixture was stirred for 6 hours at room temperature under H2(0.1 Mpa) . Then filtered to remove Pd/C and the filtrate was evaporated under reduced pressure to give a crude product.1H NMR (400 MHz, DMSO-d6) deltaH7.32-7.38 (m, 1H) , 7.15 (d, J = 8.0 Hz, 2H) , 7.00-7.05 (m, 1H) , 3.06-3.14 (m, 1H) , 2.53-2.62 (m, 2H) , 2.25-2.29 (m, 2H) , 2.04-2.10 (m, 2H) and 1.84-1.94 (m, 2H) , MS (ESI) m/e [M+1]+=193.1.
With L-Selectride; In tetrahydrofuran; at -78 - 0℃; for 2h;
To <strong>[40503-87-5]4-(3-fluorophenyl)cyclohexanone</strong> (380 mg) in THF (15 ml) was added lithiumtri(sec-butyl)borohydride 1 mol/1 THF solution (3.95 ml) at -78C. The mixture wasstirred at ooc for 2 hr. To the reaction mixture was added saturated aqueousammonium chloride solution, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography (ethyl acetate/hexane) to give the title compound(325 mg).1H NMR (300 MHz,CDCb)6 1.31(1H,s),1.60-1.76(4H,m), 1.77-1.98(4H,m),2.45-2.62(1H,m), 4.10-4.18(1H,m), 6.82-6.97(2H,m), 7.01(1H,d,J=7.6Hz),7.18-7.26(1H,m).
1-fluoro-3-(4-propylenecyclohexyl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
500ml reaction flask was added propyl triphenylphosphine bromide 77g (0.2mol), THF200ml. Cooled to -10C ,Temperature control does not exceed 0C , potassium tert-butoxide 24.7g (0.22mol). After the addition was stirred 20min,A solution of 33.9 g (0.177 mol) of 4- (3-fluorophenyl) cyclohexanone in 60 ml of THF was added dropwise thereto,Temperature control below -5C 2h. Dropping 10g of water, the solvent was evaporated to dryness under reduced pressure,After adding petroleum ether 240ml to the residue and stirring well,Washed twice with 150 ml each of 50% methanol solution,The petroleum ether layer was washed with water and the petroleum ether was evaporated to dryness under reduced pressure to give 36.2 g of 1-fluoro-3- (4-propylenecyclohexyl) benzene, 94% of this step, GC purity of 99.5%.
N'-(4-(3-fluorophenyl)cyclohexylidene)-4-methylbenzenesulfonohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7 g
In methanol; at 20℃;
To a solution of 4- (3-fluorophenyl) cyclohexan-1-one (4.5 g, 23.3mmol) in methol (50 mL) was added 4-methylbenzenesulfonohydrazide (4.3 g, 23.3 mmol) at room temperature and the mixture was stirred for overnight. The solvent was evaporate under reduced pressure and the residue was purified by column chromatography (PE: EA=4: 1) to give product (7 g) as a white solid. [M+1] +=361. To a solution of 4- (3-fluorophenyl) cyclohexan-1-one (21 mmol) in methol (100 mL) was added 4-methylbenzenesulfonohydrazide (3.9 g, 21 mmol) at room temperature and the mixture was stirred for overnight. Evaporate half the solvent under reduced pressure and then filtered to give product as a white solid (5.0 g in 66%yield) .1H NMR (400 MHz, DMSO-d6) deltaH10.19 (s, 1H) , 7.74 (d, J= 8.0 Hz, 2H) , 7.40 (d, J= 8.0 Hz, 2H) , 7.29-7.34 (m, 1H) , 7.31 (s, 1H) , 7.05 (d, J= 4.8 Hz, 1H) , 6.98-7.02 (m, 1H) , 2.79-2.93 (m, 2H) , 2.39 (s, 3H) , 2.20-2.27 (m, 2H) , 1.90-1.97 (m, 3H) and 1.43-1.60 (m, 2H) . MS (ESI) m/e [M+1]+=361.1.