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With C17H14O*Pd*C26H24P2S2; In melt; at 100℃; for 6h;Inert atmosphere; Green chemistry;
General procedure: The melt of catalyst (5 mole %) and appropriate aryl thiophenol (1 equiv.) was stirred under N2 atmosphere at 100 C for 6 hours. The progress of reaction was monitored by thin layer chromatography. After 6 hours the reaction mixture was diluted with ethyl acetate and filtered through a sintered glass funnel. The filtrate was further washed with brine (X 3) and dried over Na2SO4 and concentrated under reduced pressure. The oily mass obtained was purified by column chromatography using hexane afford the desired compounds 2a-k.
With sulfuryl dichloride; In dichloromethane; at 0℃; for 0.5h;
i) l J '-dithiobis(2-fluorobenzene')Sulfuryl chloride (0.7ml) was added dropwise to a solution of 2-fluorobenzenethiol (1.5ml) in DCM (20ml) at O0C. The reaction mixture was stirred for 30 min, then concentrated under EPO <DP n="35"/>reduced pressure. The residue was purified by chromatography on silica eluting with isohexane to give the sub-title compound as an oil, yield 1.7g. MS: APCI(+ve) 254 (M+H)
With N-chloro-succinimide; In dichloromethane; at 20℃; for 0.5h;
General procedure: To the stirred solution of thiols (5 mmol) in dichloromethane (10 mL),NCS (0.5 eq.) was added. The mixture was then stirred for 30 min. The progressof the reaction was monitored by TLC. After completion of the reaction, CH2Cl2(10 mL) was added and the mixture was washed successively with water (2×20mL).The organic layer was separated and dried by adding anhydrous Na2SO4.Evaporation of the solvent under reduced pressure gave almost pure product.Further purication was achieved by column chromatography on silica gel (ethyl acetate:hexane (1:30)) to give pure product in good to excellent yield.
3-(3-Fluoro-phenyl)-N-[2-(2-{3-(3-fluoro-phenyl)-2-[(E)-hydroxyimino]-propionylamino}-ethyldisulfanyl)-ethyl]-2-[(E)-hydroxyimino]-propionamide[ No CAS ]
3-(3-fluoro-phenyl)-<i>N</i>-[2-(2-fluoro-phenyldisulfanyl)-ethyl]-2-hydroxyimino-propionamide[ No CAS ]
Preparation of Sch 425084 Compound 29. To a solution of N,N,N-Trimethylethylenediamine (1.2 mL, 8.6 mmol) in THF (8 mL) at -20 C. was added n-BuLi (1.6 M, 5.4 mL, 8.6 mmol) dropwise. After 15 min 4-trifluoromethoxybenzaldehyde (1.5 g, 7.8 mmol) in THF (8 mL) was added. The mixture was stirred for 15 minutes and additional n-BuLi (1.6M, 14.6 mL, 23 mmol) was added. The reaction mixture was stirred at -20 C. for 1 h, then placed in the freezer at -20 C. for 20 h. The mixture was cooled to -40 C, and a solution of bis(2-fluorophenyl)disulfide (4.0 g, 15.7 mmoles) in 30 mL THF was added. The reaction mixture was stirred at -35 C. for 3 h. The reaction mixture was poured into 0.5 N HCl and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated to an oil. Purification by sgc (3percent EtOAc/hexanes) gave 1.55 g (62percent) of Compound 29 as a solid.
To a solution of N, N, N'- Trimethylethylenediamine (1.2 mL, 8.6 mmoles) in THF (8 mL) AT-20°C was added n-BuLi (1.6 M, 5.4 mL, 8.6 mmoles) dropwise. After 15 minutes 4- trifluoromethoxybenzaldehyde (1.5 g, 7.8 mmoles) in THF (8 mL) was added. The mixture was stirred for 15 minutes and more of n-BuLi (1.6M, 14.6 mL, 23 mmole) was added. The reaction mixture was stirred AT-20°C for 1 H, then placed in the freezer at-20°C for 20h. The mixture was COOLED TO-40°C, followed by addition OF SOLUTION OF O-FLUOROBENZENEDISULFIDE (4.0 g, 15.7 mmoles) in 30 mL THF and stirred AT-40°C TO-35°C for 3 h. The reaction was poured into 0.5 N HCI and extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over NA2SO4, filtered and concentrated to give yellow oil. It was purified by silica-gel column chromatography (3 percent ETHYLACETATE/HEXANES) to give light yellow solid 1.55g (62 percent).
With tert.-butyl lithium; In tetrahydrofuran; hexanes; at -78℃; for 1.25h;
In a flame dried flask under N2 blanket, compound B (440 mg, 1.3 [MMOL)] was dissolved in dry THF (20 mL) and cooled to-78 [°C.] A solution of t-butyl lithium (1.5 M in hexanes, 1.7 mL, 2.5 [MMOL)] was added and the reaction mixture was stirred for 15 min. 2-fluorophenyl disulfide (0.32 g, 1.3 [MMOL)] in THF (5 mL) was added and the reaction mixture was stirred at-78 [°C] for 1 h before slowly warming up to 0 [°C.] The reaction mixture was then quenched with saturated aqueous [NH4CI] (50 mL). Ethyl acetate (100 mL) was added and the layers were separated. The organic layer was washed with brine, then dried over [NA2SO4,] and concentrated to dryness. The crude product of compound C was used without further purification.
[3-(2-fluoro-phenylsulfanyl)-1H-indol-7-yloxy]-acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride; In DMF (N,N-dimethyl-formamide); at 20℃; for 2.2h;
To a solution of (LH-INDOL-7-YLOXY)-ACETONITRILE (0.244 g. , 1.42 mmol) in 15 mL anhydrous dimethylformamide was added sodium hydride (0.062 g. of a 60percent suspension in mineral oil, 1.56 mmol) portion wise). The solution was stirred with a magnetic stirrer at room temperature for 20 minutes. Bis- (2-fluorophenyl) disulfide (0.396 g. , 1.56 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2 x 25 mL) and the combined organic fractions were washed with water (2 x 25 mL) and brine (2 x 25 mL). After drying over MGS04, the organic fraction was concentrated in vacuo and the resulting dark red residue was purified by flash chromatography (chromatography (95: 5 ethyl acetate: hexanes to 85: 15 ethyl acetate: hexanes over 30 minutes) to give 0. 196 g. of [3-(2-fluoro-phenylsulfanyl)-lH-indol-7-yloxy]-acetonitrile as a clear oil. ms: (M-H)--= 297. 1
Example 7; Step 1: Indole (2.4 g, 20 mmol) was added to a DMF solution (100 ml_)containing NaH (0.78g) at 0°C. After stirring the solution for 15 minutes, 2-fluorophenyldisulfide (5.2g, 20 mmol) was added and the reaction mixture wasallowed to warm up to room temperature over a period of 4 h. The solvent wasremoved and the crude product was redissolved in ethyl acetate (100 ml_) andthen was washed sequentially with water (50 mL) and brine (50 ml_). The organicphase was dried and concentrated. The resulting product was recrystallized froma hexane:ethyl acetate mixture, thereby providing (7a) as a white solid (3.7 g).
Step 4: n-butyllithium (1.6 M, 0.59 ml) was added to a solution oftrifluoroacetamide (1c) (0.16 g, 0.42 mmol) in THF at -78°C. The reaction mixturewas stirred for 0.5 h, and then 2-fluorophenyldisulfide (0.16 g, 0.63 mmol) in THF(0.6 mL) was added. The resulting mixture was stirred at -78°C for 2 h. Waterwas then added, the mixture was warmed to room temperature, and extractedwith EtOAc. The organic phases were combined, washed with water and brine,dried (anhydrous MgSO4), filtered, and concentrated under vacuum. Theconcentrated product was purified by silica gel chromatography (35percentEtOAc/hexanes) to provide a racemic intermediate product (0.13 g, 0.25 mmol).The racemic intermediate product was dissolved in DCE without furtherpurification or isolation, and m-CPBA (0.21 g, 0.84 mmol) was added thereto. Theresulting reaction mixture was stirred for 17 h at room temperature, diluted withCHaCIa, washed with water and brine, dried (anhydrous MgSO4), filtered, andconcentrated under vacuum. The resulting concentrated product was purified bysilica gel preparative plate chromatography (45percent EtOAc/hexanes) to provide (1d)(0.067 g, 0.12 mmol).
Step 7: n-butlyllithium (1.8 M, 0.67 ml_) was added to a solution oftrifluoroacetamide (1g) (0.21 g, 0.54 mmol) in THF (2 ml_) which was cooled to-78°C. The reaction mixture was stirred for 30 minutes and then 2-fluorophenyldisulfide (0.17 g, 0.68 mmol) in THF (0.8 ml) was added. Thereaction mixture was allowed to slowly warm to room temperature over 17 h.Saturated NH4CI was then added, and the reaction mixture was extracted withEtOAc. The organic phases were combined and washed with water and brine,dried (anhydrous MgSO4), filtered, and concentrated under vacuum. The resultingpurified product was purified by silica gel chromatography (30percent EtOAc/hexanes)to provide a mixture of starting trifluoroacetamide and the desired thioetherproduct (0.13 g). The mixture was taken up into DCE (2 mL) without furtherpurification, and m-CPBA (0.22 g, 0.90 mmol) was added. The resulting mixturewas stirred at room temperature for 22 h. The reaction mixture was then dilutedwith CH2Cl2, washed with water and brine, dried (anhydrous MgSCU), filtered, andconcentrated under vacuum. The concentrated product was purified by silica gelchromatography (30-40percent EtOAc/hexanes) to provide (1h) (0.034 g, 0.061 mmol).
Step 11: n-butyllithium (1.8 M, 0.80 mL) was added to a solution of (1j)(0.25 g, 0.64 mmol) in THF (2.1 ml), maintained at -78°C. The reaction mixturewas stirred at -78 °C for 25 minutes. 2-fluorophenyldisulfide (0.24 g, 0.96 mmol)in THF (0.8 mL) was then added to the reaction mixture. The reaction mixturewas allowed to slowly warm to room temperature over 19 h. Saturated NHUCI wasthen added, and the reaction mixture was extracted with EtOAc. The organicphases were combined and washed with water and brine, dried (anhydrousMgSdi), filtered, and concentrated under vacuum. The residue was purified bysilica gel chromatography (30percent EtOAc/hexanes) to provide the thioether (0.23 g,0.44 mmol). The thioether was taken up into DCE (3 mL) without furtherpurification or isolation, then m-CPBA (0.38 g, 1.54 mmol) was added and themixture stirred at room temperature for 24 h. CH2CI2 was then added to themixture, and the mixture was washed with water and brine, and the organic layerwas dried (anhydrous MgSO4), filtered, and concentrated under vacuum. Theresidue was purified by silica gel chromatography (35percent EtOAc/hexanes) toprovide (1k) (0.13 g, 0.23 mmol).
(+)-(4AR)-(10BR)-8-(2-fluorophenylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 17 (+)-(4aR)-(10bR)-8-(2-fluorophenylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one A 700 mg portion of the same starting material used in Example 5 was reacted with 2.4 g of bis(2-fluorophenyl)-disulfide under the conditions of Example 5 to obtain 640 mg of the desired product. mp 196°-198° FDMS: m/e=341. alpha[D]589 =+84.2, alpha[D]365 =+300.8 (chloroform).
EXAMPLE 17 (+)-(4aR)-(10bR)-8-(2-fluorophenylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one STR31 A 700 mg portion of the same starting material used in Example 5 was reacted with 2.4 g of bis(2-fluorophenyl)disulfide under the conditions of Example 5 to obtain 640 mg of the desired product. mp 196°-198° FDMS: m/e=341. alpha[D]589 =+84.2, alpha[D]365 =+300.8 (chloroform).
EXAMPLE 17 (+)-(4aR)-(10bR)-8-(2-fluorophenylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one A 700 mg portion of the same starting material used in Example 5 was reacted with 2.4 g of bis(2-fluorophenyl)disulfide under the conditions of Example 5 to obtain 640 mg of the desired product. mp 196°-198° FDMS: m/e=341. alpha[D]589 =+84.2, alpha[D]365 =+300.8 (chloroform).
i) 4-bromo-2-fluoro- 1 - [Y.sum.-fluorophenvDthioibenzene4-Bromo-2-fluoro-l-iodobenzene (1.67g) was added to a solution of isopropylmagnesium chloride (2.79ml, 2M solution in THF) in THF (8ml), which was cooled to O0C and stirred for a further 2h. The mixture was then added to a solution of the product of step (i) in THF (5ml). The reaction was allowed to reach RT overnight, then stirred at 4O0C for 1 hour and 500C for a further 1 hour. The reaction was cooled to RT, diluted with ammonium chloride and extracted with diethylether. The diethylether fractions were dried (MgSO4) and evaporated under reduced pressure, yield 1.9g. Used directly without further purification. MS: APCI(+ve) 302 (M+H)
Compound 10. In a flame dried flask under N2 blanket, Compound 5 (21.55 g, 50.7 mmol) was dissolved in anhyd THF (300 mL) and cooled in a dry ice/IPA bath. A solution of methyllithium (1.6 M in Et2O, 32 mL, 51 mmol) was added, followed by n-BuLi (2.5 M in hexanes, 20.3 mL, 50.7 mmol) and the reaction mixture was stirred for 10 min. A solution of bis-(2-fluorophenyl) disulfide (14.2 g, 55.7 mmol) dissolved in THF was added and the reaction mixture was stirred for 2 h at -78 C. The ice bath was removed and the reaction mixture was allowed to warm to rt and left stirring overnight. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried with Na2SO4 and the solvents were evaporated. The crude product was purified via sgc (25percent EtOAc/hexanes) to give 23.2 g of a solid. This material was dissolved in CH2Cl2 (400 mL) and cooled in an ice bath. MCPBA (60percent, 30.3 g) was added in several portions and the reaction mixture was stirred for 1 h. The ice bath was removed and the reaction mixture was left stirring overnight. The reaction mixture was partitioned between CH2Cl2 and 5percent aq Na2CO3. The organic layer was washed with water and dried with Na2SO4. The solvents were evaporated and the crude product was purified via sgc (25percentEtOAc/hexanes) to give 10.84 g (44percent) of Compound 10.
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