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[ CAS No. 37595-74-7 ] {[proInfo.proName]}

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Chemical Structure| 37595-74-7
Chemical Structure| 37595-74-7
Structure of 37595-74-7 * Storage: {[proInfo.prStorage]}
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Product Details of [ 37595-74-7 ]

CAS No. :37595-74-7 MDL No. :MFCD00000404
Formula : C8H5F6NO4S2 Boiling Point : -
Linear Structure Formula :- InChI Key :DIOHEXPTUTVCNX-UHFFFAOYSA-N
M.W : 357.25 Pubchem ID :142176
Synonyms :
N-Phenyltrifluoromethanesulfonimide
Chemical Name :1,1,1-Trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide

Calculated chemistry of [ 37595-74-7 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 21
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.25
Num. rotatable bonds : 5
Num. H-bond acceptors : 10.0
Num. H-bond donors : 0.0
Molar Refractivity : 58.96
TPSA : 88.28 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.31 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.8
Log Po/w (XLOGP3) : 3.06
Log Po/w (WLOGP) : 6.88
Log Po/w (MLOGP) : 0.44
Log Po/w (SILICOS-IT) : 0.55
Consensus Log Po/w : 2.55

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 1.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.86
Solubility : 0.0488 mg/ml ; 0.000137 mol/l
Class : Soluble
Log S (Ali) : -4.58
Solubility : 0.00939 mg/ml ; 0.0000263 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -3.31
Solubility : 0.174 mg/ml ; 0.000486 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.41

Safety of [ 37595-74-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P264-P280-P302+P352-P305+P351+P338-P332+P313-P337+P313-P362+P364 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 37595-74-7 ]

* 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.

  • Downstream synthetic route of [ 37595-74-7 ]

[ 37595-74-7 ] Synthesis Path-Downstream   1~94

  • 1
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  • [ 62-53-3 ]
  • [ 456-64-4 ]
  • 2
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  • [ 61995-20-8 ]
  • [ 149108-73-6 ]
  • 3
  • [ 37595-74-7 ]
  • [ 38923-57-8 ]
  • [ 143225-17-6 ]
YieldReaction ConditionsOperation in experiment
100% Under argon, a solution of diisopropylamine (2.51 g, 24.8 mmol) in tetrahydrofuran (150 mL) was cooled in an ice water bath. A solution of n-butyllithum in hexanes (2.5 M, 9.7 mL, 24 mmol) was added dropwise over 2 min, and the resulting solution was stirred for 10 additional min. The solution was then cooled to -78C in a C02:acetone bath, and methyl 2,2-dimethyl-3- oxobutanoate (3.2 g, 22 mmol) was added dropwise over 30 s. The solution was stirred for an additional 15 min, and /V-phenyl-bis(trifluoromethanesulfonimide) (8.4 g, 23.5 mmol) was added as a solution in tetrahydrofuran (20 mL) via cannula over 5 min, washing with an additional portion of tetrahydrofuran (10 mL). The resulting solution was stirred for 10 min and was removed from the cold bath. After stirring an additional 1 h, the reaction mixture was concentrated in vacuo and diluted with diethyl ether (150 mL). The organic phase was washed with 1 M aqueous sodium hydroxide (1 x 100 mL, 1 x 30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound (6.2 g, 100%) as an amber liquid that was used without further purification.
Under argon, a solution of diisopropylamine (2.51 g, 24.8 mmol) in tetrahydrofuran (150 mL) was cooled in an ice water bath. A solution of n-butyllithum in hexanes (2.5 M, 9.7 mL, 24 mmol) was added dropwise over 2 min, and the resulting solution was stirred for 10 additional min. The solution was then cooled to -78 C. in a CO2:acetone bath, and <strong>[38923-57-8]methyl 2,2-dimethyl-3-oxobutanoate</strong> (3.2 g, 22 mmol) was added dropwise over 30 s. The solution was stirred for an additional 15 min, and N-phenyl-bis(trifluoromethanesulfonimide) (8.4 g, 23.5 mmol) was added as a solution in tetrahydrofuran (20 mL) via cannula over 5 min, washing with an additional portion of tetrahydrofuran (10 mL). The resulting solution was stirred for 10 min and was removed from the cold bath. After stirring an additional 1 h, the reaction mixture was concentrated in vacuo and diluted with diethyl ether (150 mL). The organic phase was washed with 1 M aqueous sodium hydroxide (1×100 mL, 1×30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound (6.2 g, 100%) as an amber liquid that was used without further purification.
  • 4
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  • [ 5751-20-2 ]
  • [ 456-64-4 ]
  • [ 154499-77-1 ]
  • 5
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  • [ 66171-50-4 ]
  • [ 163276-23-1 ]
  • 6
  • [ 37595-74-7 ]
  • [ 61995-20-8 ]
  • [ 149108-73-6 ]
  • 5-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester [ No CAS ]
  • 7
  • [ 1885-38-7 ]
  • [ 37595-74-7 ]
  • [ 128073-42-7 ]
  • (3S,4aR,8aR)-6-((E)-2-Cyano-1-phenyl-vinyl)-3,4,4a,5,8,8a-hexahydro-1H-isoquinoline-2,3-dicarboxylic acid 3-ethyl ester 2-methyl ester [ No CAS ]
  • (3S,4aS,8aR)-6-((E)-2-Cyano-1-phenyl-vinyl)-3,4,4a,7,8,8a-hexahydro-1H-isoquinoline-2,3-dicarboxylic acid 3-ethyl ester 2-methyl ester [ No CAS ]
  • 8
  • [ 1885-38-7 ]
  • [ 37595-74-7 ]
  • [ 128073-42-7 ]
  • (3S,4aR,6S,8aR)-6-(2-Cyano-1-phenyl-ethyl)-octahydro-isoquinoline-2,3-dicarboxylic acid 3-ethyl ester 2-methyl ester [ No CAS ]
  • 9
  • [ 37595-74-7 ]
  • [ 5513-40-6 ]
  • [ 183070-41-9 ]
  • 10
  • [ 37595-74-7 ]
  • [ 130200-58-7 ]
  • [ 188616-78-6 ]
  • 11
  • [ 23432-43-1 ]
  • [ 37595-74-7 ]
  • Trifluoro-methanesulfonic acid 6-chloro-quinolin-4-yl ester [ No CAS ]
  • 12
  • [ 37595-74-7 ]
  • [ 67342-99-8 ]
  • (Z)-3-Trifluoromethanesulfonyloxy-dodec-2-enoic acid ethyl ester [ No CAS ]
  • 13
  • [ 37595-74-7 ]
  • [ 24589-98-8 ]
  • 4-Formyl-3-trifluoromethanesulfonyloxy-benzoic acid methyl ester [ No CAS ]
  • 14
  • [ 37595-74-7 ]
  • [ 119-60-8 ]
  • cyclohexyl(cyclohexenyliden)methyl trifluoromethanesulfonate [ No CAS ]
  • 15
  • [ 13196-11-7 ]
  • [ 37595-74-7 ]
  • [ 227752-25-2 ]
YieldReaction ConditionsOperation in experiment
69% In dichloromethane; for 72h; [00132] The benzofuranyl carbonyl moiety was prepared by protecting the hydroxyl groupof compound 13 by reacting with tert-butyldimethylsilyl chloride (1.0 equivalents) andtriethylamine (TEA, 1.1 equivalents) in acetone, to give compound 14 in 79percent yield. A solutionof compound 14 in methanol was then treated with sodium borohydride (1.0 equivalent) at roomtemperature overnight. The reaction was quenched with an addition of acetone, stirred at roomtemperature for a further 2.5 hours, aqueous HC1 (4N) was added with the temperature controlledto below 28 °C, tetrahydrofuran (THF) was added, and the solution stirred overnight under argonand in the absence of light. The product, compound 15, was isolated quantitatively by extractioninto methylene chloride, concentrated at low heat, and used without further purification. Thetriflate ester, compound 16, was produced in 69percent yield from compound 15 by reacting it with Nphenyl-bis(trifluoromethanesulfonimide) (1.0 equivalent) in methylene chloride for 72 hours.Compound 16 in a mixture of DMF, methanol, and triethylamine, was added to a preparedsolution of palladium acetate, 1,3-Bis(diphenylphosphino)propane (dppp), DMF and methanol inan autoclave. Carbon monoxide was charged into the autoclave to a pressure of 8 bar, and the reaction mixture was heated at 70 °C for 6 hours. After workup, compound 17 was isolated in 91percent yield. Lithium hydroxide (4 equivalents) in methanol and water was used to hydrolyze the ester and permit the isolation of compound 18? in 97percent yield.
  • 17
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  • [ 713-95-1 ]
  • [ 445462-86-2 ]
  • 18
  • [ 19090-04-1 ]
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  • [ 194665-78-6 ]
  • 19
  • [ 37595-74-7 ]
  • [ 185099-67-6 ]
  • [ 185099-68-7 ]
YieldReaction ConditionsOperation in experiment
95% To a solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 4.2 mmol) in THF (21.1 mL) was added LHMDS (4.64 mL, 4.64 mmol) dropwise under N2 at-50 C and the solution was warmed to-30 C and stirred for 1 h. 1,1,1-trilluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.66 g, 4.64 mmol) in THF (1.0 mL) was added dropwise at-30 C and the resulting mixture was warmed to 25 C and stirred for 4 h. Aqueous sat. NH4CI (10 mL) was added to the reaction mixture and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0 - 30 %) EtOAc in hexanes to afford the title compound (2.2 g, 95 % yield)MS (ES+) C13H18F3NO5S requires: 357, found 358 [M+H]+.
90% To a solution of N-Boc-nortropinone (6 g, 26.6 mmol) in THF (70 ml) at -78C was added LDA (2 M in haptane/TBF/ethyl benzene, 20ml, 40 mmol) slowly and the reaction mixture was stirred for 10 min. A solution of N-phenylbis(trifluoromethanesulfonimide) (10.5 g, 29.3 mmol) in THF (48 ml) was added. The reaction mixture was stirred at -78C for 30 min and the cooling bath was removed to warm it up to room temperature for 1.5 h until all N-Boc- nortropinone was utilized. Saturated NH4CI solution (~10 mL) was added and stirring was continued for 5 minutes before the reaction mixture was transferred to a separatory funnel using EtOAc (150 mL). The organics were then extracted with EtOAc (2 x 125 ml), and washed with water (2 x 30 ml), brine (1 x 30 ml), and dried over MgS04. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution withEtOAc/Hexanes (0-35%) gave the desired product, tert-butyl 3-(trifluoromethylsulfonyloxy)-8- azabicyclo[3.2.1]oct-3-ene-8-carboxylate (8.5 g, 90%).
84% Example 108 - Preparation of Intermediate 35 The synthesis of Intermediate 35 followed the procedure of General Procedure 23 following: Intermediate 35 To a cooled solution (-78C) of tert-butyl-3-oxo-8-azabicyclo[3.2.1]octane-8- carboxylate (30 g, 133.3 mmol) in dry THF (300 mL) was added LiHMDS (lithium hexamethyldisilazide, 1M in THF, 146 mL, 146.7 mmol). After stirring for 30 minutes, a solution of N-phenyl-bis(trifluoromethanesulfonimide) (PhNTf2, 52 g, 146.7 mmol) in dry THF (30 mL) was added and the mixture stirred at room temperature for 5 hours. The reaction mixture was quenched with saturated ammonium chloride solution (80 mL), and extracted with EtOAc (2 x 300 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100-200 mesh), eluting with 3-5% EtOAc/n-hexane, to afford tert- butyl-3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate (Intermediate 35, 40 g, yield: 84%) as a pale yellow liquid; TLC System: 20% ethyl acetate in hexane. Rf-0.5.
79% under nitrogen protection,3-Oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.2 g, 5.3 mmol)The 15 mL THF solution was cooled to -70 C.LDA (1M in THF, 8 mL, 8.0 mmol) was added dropwise with stirring.The temperature of the control system is around -70 C.After stirring the system for 1 h, N-phenylbis(trifluoromethanesulfonyl)imide (1.9 g, 5.3 mmol) was added portionwise.After the addition, the system was naturally warmed under stirring and stirred at room temperature overnight.TLC showed that after completion of the reaction, the reaction system was poured into 100 mL of saturated ammonium chloride solution and extracted with EA (50 mL x 3).The organic phase is washed with saturated brine.Dry anhydrous Na2SO4 and concentrate under reduced pressure.The crude product was purified by column (PE:EA=20:1) to give 1.5 g.(yield: 79%) of the target compound,It is a white solid.
72.6% (0519) Tert-butyl 3-oxo-8-azabicyclo[3.2.1]octan-8-carboxylate (8.5 g, 37.8 mmol) was dissolved in tetrahydrofuran (80 mL), and a solution of lithium diisopropylamide in tetrahydrofuran/ n-heptane/ ethylbenzene (28 mL, 56 mmol, 2 M) was added slowly to the system at -78 C. After stirring for 10 min, a solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (14.8 g, 41.6 mmol) in tetrahydrofuran (50 mL) was added. After stirring for 30 min, the reaction was carried out at room temperature for 2 h. After the reaction, the mixture was concentrated to get the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20:1) to get the title compound (9.8 g, yield: 72.6%).
63% A. A 300 mL round bottom flask was charged with Compound 6a (1.0 g,4.44 mmol) and THF (30 mL). The mixture was cooled to -78 0C using a dry ice/acetone bath. A 20% solution of LiN(SiMe3)2 in THF (5.OmL, 5.32 mmol) was added dropwise over 15 min. The mixture was stirred at- 78 0C for 40 min. A solution of PhN(SO2CF3)2 (1.6 g, 4.48 mmol) in THF (33 mL) was added dropwise via addition funnel. The mixture was stirred for 18 h with gradual warming to room temperature. The mixture was concentrated in vacuo and purified via flash chromatography (230-400 mesh silica gel 60, 95:5 hexanes:EtOAc ) to give 1.O g (63%) of Compound 6b as a white solid. 1H NMR (300 MHz, CDCI3) delta 6.08 (d, J = 5.3 Hz, 1 H), 4.31-4.45 (m, 2 H), 3.04-3.21 (m, 2 H), 1.97-2.24 (m, 4 H), and 1.46 (s, 9 H).
63.0% 1360A. tert-Butyl 3-(((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate To a stirred solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 4.44 mmol) in tetrahydrofuran (10 mL) at -78 C. was added LDA (3.33 mL, 6.66 mmol) and stirred at that temperature for 30 min. Then N,N-bis(trifluoromethylsulfonyl) aniline (1.586 g, 4.44 mmol) in tetrahydrofuran (5 mL) was added and stirred for 1 h. The reaction mixture was warmed to room temperature and stirred for 2 h. Reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (2*100 mL). The organic layer was washed with brine solution (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get the crude, which was purified by silica gel flash chromatography to afford 1360A (brown oil, 1 g, 2.80 mmol, 63.0% yield).
A solution of 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (15.8 g, 70.0 mmol) and THF (150 mL) was cooled to -78 C. and 1.0 M sodium hexamethyldisilazane in THF (84 mL) was added dropwise over 5 min. The reaction mixture was stirred for 1 h and then N-phenylbis(trifluoromethane-sulphonimide) (25.0 g, 70.0 mmol) was added and the reaction mixture was stirred for 1 h. The solution was warmed to room temperature, 1.0 N NaOH (100 mL) was added, and the reaction mixture was stirred for 15 min. Approximately 75 mL of solvent was evaporated. The resulting solution was diluted with ethyl acetate:hexanes (100 mL:100 mL) and water (100 mL), extracted and washed with 1.0 N NaOH (2*200 mL). The organic layer was washed with saturated NaCl solution (200 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (18.2 g) as a dark oil, which was used without further purification.
With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; n-heptane; at -60 - 20℃; for 24.25h; 10 ml of a 2.5N solution n-butyl lithium in hexane are added, dropwise to a solution of 3.73 ml of diisopropylamine in 100 ml of tetrahydrofuran cooled to -60 C., in a 500 ml three-necked flask under nitrogen. After stirring for 1/4 hour, 5 g of N-tert-butyloxycarbonyl nortropinone in tetrahydrofuran (50 ml) at 0 C. are added. Finally, still at 0 C., 8.32 g of N-phenyltrifluoromethanesulfonimide are added. After stirring for 24 hours at ambient temperature, the tetrahydrofuran is evaporated off and the product is purified by rapid filtration over alumina, using a 2/1 mixture of heptane/ethyl acetate as eluent. 6.13 g of tert-butyl 3-[(trifluoromethyl)sulfonyl]oxy}-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate are obtained.
1.1/3-Trifluoromethanesulfonyloxy-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester 3-Oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (5 g, 22.2 mmol) is placed in 24 ml of anhydrous THF and the solution is cooled to -70 C. under nitrogen, 1N lithium bis(trimethylsilyl)amide in THF (24.4 ml, 24.4 mmol) is added dropwise. After stirring for 45 min at -70 C., N-phenyltrifluoromethane-sulfonimide (8.7 g, 24.4 mmol) placed in 25 ml of anhydrous THF is added dropwise. The temperature of the reaction medium is left to rise slowly. Stirring is maintained for 16 h at ambient temperature. After concentration to dryness, the crude product obtained is chromatographed on silica gel, elution being carried out with a cyclohexane/ether mixture (90/10). 10.2 g of expected 3-trifluoromethanesulfonyloxy-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester are obtained. [M+H+]=258 (-OtBu)
To a solution of N-Boc-nortropinone (6 g, 26.6 mmol) in THF (70 ml) at -78C was added LDA (2 M in haptane/THF/ethyl benzene, 20ml, 40 mmol) slowly and the reaction mixture was stirred for 10 min. A solution of N~phenylbis(trifluoromethanesulfonimide) (10.5 g, 29.3 mmol) in THF (48 ml) was added. The reaction mixture was stirred at -78C for 30 min and the cooling bath was removed to warm it up to room temperature for 1.5 h until all N-Boc- nortropinone was utilized. Saturated NH4C1 solution (-10 mL) was added and stirring was continued for 5 minutes before the reaction mixture was transferred to a separatory funnel using EtOAc (150 mL). The organics were then extracted with EtOAc (2 x 125 ml), and washed with water (2 x 30 ml), brine (1 x 30 ml), and dried over MgS04 The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution withEtOAc/Hexanes (0-35%) gave the desired product, tert-butyl 3-(trifluoromethylsulfonyloxy)-8- azabicyclo[3.2. l]oct-3-ene-8-carboxylate.
To a solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (10 g, 44.4 mmol) in tetrahydrofuran (100 mL) was added 2M lithium diisopropylamide (26.6 mL, 53.3 mmol) dropwise at -60C under argon and the mixture was stirred at -60C for 1 hour. A solution of 1, 1,1-trifluoro-N- phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (17.44 g, 48.8 mmol) in tetrahydrofuran (100 mL) was added dropwise at -60C and the mixture was stirred at -60C for 30 minutes, and was allowed to warm to room temperature. The mixture was stirred under argon overnight, quenched with water (200 mL), and extracted with ethyl acetate (three times). The organic extracts were washed with 5% aqueous citric acid (twice) and stirred with 1M aqueous sodium hydroxide (200 mL) for 30 minutes. The wash process was repeated one additional time. The organic phase was dried over sodium sulfate, filtered, concentrated, and purified by flash chromatography on silica gel using an ISCO Companion eluting with ethyl acetate/petroleum ether (1 :20) to provide the title compound.
To a 250 mL 3-necked round-bottom flask was placed a solution of (lR,5S)-tert- butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (5.00 g, 22.2 mmol) in tetrahydrofuran (100 mL). Lithium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 26.6 mL, 26.6 mmol) was added dropwise at -78C. The mixture was stirred at -78C for 1 hour. Then a solution of l,l,l-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (9.51 g, 26.6 mmol) in tetrahydrofuran (30 mL) was added at -78C. The mixture was stirred for an additional 16 h at ambient temperature. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (100 mL), washed with water (2 x 50 mL) and brine (50 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue purified on silica, eluting with ethyl acetate/petroleum ether (5: 100) to afford the title compound. LRMS (ESI) calc'd for Ci3Hi9F3N05S [M + H]+: 358, found 358; 1H NMR (400 MHz, CDC13) 56.08 (d, / = 5.4 Hz, 1H), 4.59-4.33 (m, 2H), 3.12-2.94 (m, 1H), 2.31-2.13 (m, 1H), 2.09-1.93 (m, 3H), 1.79-1.63 (m, 1H), 1.46 (s, 9H).
Starting material 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (6.0 g, 26.63 mmol, 1.0 eq)Dissolved in anhydrous tetrahydrofuran solution (30 mL),Nitrogen protection drops to -70 C ~ -60 C,A solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1 mol/L, 32 mL, 1.2 eq) was added dropwise.After the drop, stir at -70 C ~ -60 C for 1 h,A solution of N-phenylbis(trifluoromethanesulfonyl)imide (11.4 g, 31.96 mmol, 1.2 eq) in tetrahydrofuran (30 mL).After the addition of 0 C or less, the reaction was carried out for 3 h, and the mixture was naturally stirred at room temperature for 12 h.The mixture was cooled to 0 C to 10 C, and brine (50 mL) and brine (50 mL)The filtrate was concentrated under reduced pressure to give a product.
To a solution of ferf-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (Int 23a) (1.00 g, 4.33 mmol) in THF (10 mL) was added LDA (2 N, 3.3 mL) at -78 C and the mixture was stirred for 10 min at the same temperature. A solution of N- phenylbis(trifluoromethanesulfonimide) (1.75 g, 4.88 mmol) in THF (8 mL) was added. The mixture was stirred at -78 C for 30 min. The cooling bath was removed and the mixture was stirred for 1.5 h. Saturated aqueous NH4CI (30 mL) was added and stirring was continued for 5 min. The mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (EtOAc/PE = 1 :2) to give the title compound as a yellow oil.

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  • [ 110-89-4 ]
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  • [ 51029-15-3 ]
  • [ 456-64-4 ]
  • piperidinium trifluoromethanesulfonate [ No CAS ]
  • 21
  • [ 110-91-8 ]
  • [ 37595-74-7 ]
  • [ 456-64-4 ]
  • 1-(trifluoromethanesulfonyl)morpholine [ No CAS ]
  • morpholinium trifluoromethanesulfonate [ No CAS ]
  • 22
  • [ 110-85-0 ]
  • [ 37595-74-7 ]
  • [ 456-64-4 ]
  • 1-(trifluoromethanesulfonyl)piprazine [ No CAS ]
  • 1,4-bis(trifluoromethanesulfonyl)piprazine [ No CAS ]
  • piperazinium trifluoromethanesulfonate [ No CAS ]
  • 23
  • [ 39093-93-1 ]
  • [ 37595-74-7 ]
  • [ 456-64-4 ]
  • 4-(trifluoromethanesulfonyl)-1λ6,4-thiazinane-1,1-dione [ No CAS ]
  • 1,1-dioxo-1λ6,4-thiazinan-4-ium trifluoromethanesulfonate [ No CAS ]
  • 24
  • [ 37595-74-7 ]
  • [ 21906-39-8 ]
  • [ 625382-97-0 ]
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  • [ 37595-74-7 ]
  • [ 703-67-3 ]
  • [ 556107-58-5 ]
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  • [ 37595-74-7 ]
  • [ 1138-52-9 ]
  • [ 155064-25-8 ]
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  • [ 37595-74-7 ]
  • [ 19832-98-5 ]
  • [ 851485-48-8 ]
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  • [ 4629-80-5 ]
  • [ 37595-74-7 ]
  • [ 862911-54-4 ]
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  • [ 7651-82-3 ]
  • [ 37595-74-7 ]
  • [ 149353-93-5 ]
  • 30
  • [ 37595-74-7 ]
  • [ 207989-87-5 ]
  • [ 207989-88-6 ]
YieldReaction ConditionsOperation in experiment
96% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; DIEA (2.89 mL, 16.6 mmol) was added to a solution of 5-(4-hydroxyphenyl)-2- pyrrolidinone (1.47 g, 8.30 mmol) andiV-phenyltrifluoromethanesulfonimide (4.45 g, 12.45 mmol) in 10 mL of DMF, and the mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc (100 mL) and washed with brine (50 mL), H2O (3 x 50 mL), and brine (50 mL). The organic layer was separated, dried over MgStheta4, and concentrated. Chromatography on a Biotage 40+M cartridge using EtOAc as the eluant afforded 2.45 g (96 %) of the title EPO <DP n="34"/>compound as a white solid: 1 H NMR delta 1.90-1.98 (m, IH), 2.38-2.51 (m, 2H), 2.57-2.65 (m, IH), 4.81 (t, J = 7.1, IH), 6.92 (br. s, IH), 7.27-7.30 (m, 2H), 7.38-7.42 (m, 2H).
  • 31
  • [ 37595-74-7 ]
  • [ 130312-02-6 ]
  • benzyl 4-(trifluoromethylsulfonyloxy)-2,3-dihydro-1H-pyrrole-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% 212A. Preparation of benzyl 4-(trifluoromethylsulfonyloxy)-2,3-dihydro-1H-pyrrole-1-carboxylate A solution of <strong>[130312-02-6]benzyl 3-oxopyrrolidine-1-carboxylate</strong> (300 mg, 1.4 mmol) in THF (10 mL) was treated with lithium bis(trimethylsilyl)amide (1.5 mL, 1M in THF, 1.5 mmol) at -78 C. After stirring 15 minutes at -78 C., N-phenyltrifluoromethanesulfonimide (600 mg, 1.7 mmol) was added. The reaction mixture was then warmed to room temperature. The reaction was quenched with the addition of saturated aqueous NaHCO3 (10 mL), and then extracted with ethyl ether (10 mL). The organic layer was washed with saturated aqueous NaCl solution (10 mL), and then dried over Na2SO4. The crude mixture was filtered, concentrated and purified by flash chromatography (SiO2, 30% ethyl acetate/hexane) to afford the title compound (400 mg, 82%). 1H-NMR (500 MHz, CDCl3) delta 7.26 (m, 5H), 5.50 (s, 1H), 4.76 (s, 2H), 3.20 (m, 2H).
  • 32
  • [ 37595-74-7 ]
  • [ 81382-46-9 ]
  • [ 945761-93-3 ]
  • 33
  • [ 369-57-3 ]
  • [ 174899-83-3 ]
  • C8H5F6NO4S2 [ No CAS ]
  • [ 37595-74-7 ]
  • 34
  • [ 369-57-3 ]
  • [ 174899-83-3 ]
  • C8H5F6NO4S2 [ No CAS ]
  • [ 462-06-6 ]
  • [ 37595-74-7 ]
  • 35
  • [ 23681-89-2 ]
  • [ 37595-74-7 ]
  • [ 189035-25-4 ]
YieldReaction ConditionsOperation in experiment
96% With sodium t-butanolate; In tetrahydrofuran; at 0℃; for 1h; Add to a solution of <strong>[23681-89-2]2,3-dihydrobenzofuran-6-ol</strong> (0.180 g, 1.32 mmol) and N-phenyl- bis(trifluoromethanesulfonimide) (0.520 g, 1.45 mmol) in tetrahydrofuran (6.61 mL). Cool to 0 °C was added sodium tert-butoxide (0.140 g, 1.45 mmol) and stir at 0 °C for for 1 h. Warm to room temperature and stir for 1 h. Dilute with ethyl acetate (100 mL) and wash with water (3 x 50 mL), saturated aqueous sodium chloride (2 x 50 mL), dry (sodium sulfate), filter, concentrate and purify (HPLC, eluting with 9: 1 hexanes:ethyl acetate) to give the title compound as a pale yellow oil (340 mg, 96.0percent). HRMS m/z Calculated: 269.0095; Found: 269.0099
  • 36
  • [ 37595-74-7 ]
  • [ 548-83-4 ]
  • trifluoromethanesulfonic acid 3,5-dihydroxy-4-oxo-2-phenyl-4H-chromen-7-yl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
91 mg (61%) With triethylamine; In dichloromethane; EXAMPLE 141 Trifluoromethanesulfonic acid 3,5-dihydroxy-4-oxo-2-phenyl-4H-chromen-7-yl ester To a solution of <strong>[548-83-4]galangin</strong> (100 mg, 0.00037 mmol) and triethylamine (0.103 mL, 0.740 mmol) in CH2Cl2 (6 mL) was added N-phenyltrifluoro-methanesulfonimide (132 mg, 0.37 mmol). After 24 h the reaction was concentrated to yield a yellow semisolid and purified via Biotage chromatography with gradient elution from 100% hexanes to 25% EtOAc/hexanes to yield 91 mg (61%) of trifluoromethanesulfonic acid 3,5-dihydroxy-4-oxo-2-phenyl-4H-chromen-7-yl ester. Tf is CF3SO2-. 1H NMR (CDCl3, 400 MHz) delta12.64 (s, 1H), 10.19 (s, 1H), 8.24 (d, 2H), 7.59-7.51 (c, 41H), 6.97 (d, 1H).
  • 37
  • [ 37595-74-7 ]
  • [ 116247-92-8 ]
  • [ 199682-34-3 ]
YieldReaction ConditionsOperation in experiment
54% To a stirred solution of N-(pyrimid-2-yl)-piperidin4-one (0.177 g, 1.0 mmol) in tetrahydrofuran (5 ml) at -70 C. under argon was added LDA (1.92M in THF) (0.57 ml, 1.1 mmol). The solution was stirred for 20 minutes, then a solution of N-phenyl-bis(trifluoromethane-sulfonimide) (0.382 g, 1.07 mmol) in THF (3 ml) was slowly added. The solution was stirred overnight with warming to ambient temperature. The solution was evaporated to dryness and purified by alumina MPLC [using a mixture of 5% ethyl acetate/hexane as eluant] to afford the title product. Yield=0.166 g (54%). NMR (250 MHz, CDCl3): delta: 2.55 (s, 2H), 4.10 (t2H), 4.39 (m, 2H), 5.88 (s, 1H), 6.55 (t, 1H), 8.35 (d, 2H). MS: ESP+(M+H)=310.
49% B. Triflate: To a solution of LDA (prepared from diopropylamine (167.4 mg, 1.658 mmol) and n-BuLi (2.5 M in hexanes, 0.663 ml, 1.658 mmol) at -780C, was added a solution of the above l-pyrimidin-2-yl-piperidin-4-one (320 mg, 1.382 mmol). The mixture was stirred at the same temperature for 1 hour, followed by the addition of PhNTf2 (543.1 mg, 1.52 mmol). The reaction mixture was warmed up to room temperature and stirred for 3 hours before it was quenched with the addition of saturated ammonium chloride (15 ml) and ethyl acetate (40 ml). After separation of the layers, the aqueous phase was extracted with ethyl acetate (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (20% ethyl acetate/hexanes) to give the corresponding triflate (210.7 mg, 49%) as a white solid as long with recovered starting material (142.9 mg): 1H NMR (CDCl3, 400 MHz) delta 8.37 (d, J= 6.4 Hz, 2 H), 6.59 (t, J= 6.4 Hz, 1 H), 5.91 (m, 1 H), 4.41 (m, 2 H), 4.11 (t, J= 5.6 Hz, 2 H), 2.55 (m, 2 H); MS calc'd for C10HnF3N3O3S [M+H]+: 310; Found: 310.
49% B. Triflate:; To a solution of LDA (prepared from diopropylamine (167.4 mg, 1.658 mmol) and n-BuLi (2.5 M in hexanes, 0.663 ml, 1.658 mmol) at -780C, was added a solution of the above l-pyrimidin-2-yl-piperidin-4-one (320 mg, 1.382 mmol). The mixture was stirred at the same temperature for 1 hour, followed by the addition of PhNTf2 (543.1 mg, 1.52 mmol). The reaction mixture was warmed up to room temperature and stirred for 3 hours before it was quenched with the addition of saturated ammonium chloride (15 ml) and ethyl acetate (40 ml). After separation of the layers, the aqueous phase was extracted with ethyl acetate (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (20% ethyl acetate/hexanes) to give the corresponding triflate (210.7 mg, 49%) as a white solid as long with recovered starting material (142.9 mg): 1H NMR (CDCl3, 400 MHz) delta 8.37 (d, J= 6.4 Hz, 2 H), 6.59 (t, J= 6.4 Hz, 1 H), 5.91 (m, 1 H), 4.41 (m, 2 H), 4.11 (t, J= 5.6 Hz, 2 H), 2.55 (m, 2 H); MS calc'd for C10HnF3N3O3S [M+H]+: 310; Found: 310.
49% 6.8. Preparation of Biphenyl-4-yl-fl-pyrimidin-2-yl-l,2,3i6-tetrahydro- pyridin-4-vl)-methanone; To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 8O0C overnight and concentrated under reduced pressure. The residue was treated with EtOAc (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40% EtOAc/hexanes) to give l-pyrimidin-2-yl- piperidin-4-one (320 mg, 53%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) delta 8.38 (d, J = 6.4 Hz, 2 H), 6.61 (t, J = 6.4 Hz, 9 H), 4.16 (t, J= 5.6 Hz, 2 H), 2.53 (t, J= 5.6 Hz, 2 H); To a solution of LDA (prepared from diopropylamine (167.4 mg, 1.658 mmol) and n-BuLi (2.5 M in hexanes, 0.663 ml, 1.658 mmol) at -780C, was added a solution of the above l-pyrimidin-2-yl-piperidin-4-one (320 mg, 1.382 mmol). The mixture was stirred at the same temperature for 1 hour, followed by the addition OfPhNTf2 (543.1 mg, 1.52 mmol). The reaction mixture was warmed up to room temperature and stirred for 3 hours before it was quenched with the addition of saturated ammonium chloride (15 ml) and EtOAc (40 ml). After separation of the layers, the aqueous phase was extracted with <n="55"/>EtOAc (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (20% EtOAc/hexanes) to give the corresponding triflate (210.7 mg, 49%) as a white solid as long with recovered starting material (142.9 mg): 1U NMR (CDCl3, 400 MHz) delta 8.37 (d, J= 6.4 Hz, 2 H), 6.59 (t, J = 6.4 Hz, 1 H), 5.91 (m, 1 H), 4.41 (m, 2 H), 4.11 (t, J= 5.6 Hz, 2 H), 2.55 (m, 2 H); MS calc'd for CiOHnF3N3O3S [M+H]+: 310; Found: 310.
49% To a solution of LDA (prepared from diisopropylamine (167.4 mg, 1.658 mmol) and n-BuLi (2.5 M in hexanes, 0.663 ml, 1.658 mmol) at -78 C., was added a solution of the above <strong>[116247-92-8]1-pyrimidin-2-yl-piperidin-4-one</strong> (320 mg, 1.382 mmol). The mixture was stirred at the same temperature for 1 hour, followed by the addition of PhNTf2 (543.1 mg, 1.52 mmol). The reaction mixture was warmed up to room temperature and stirred for 3 hours before it was quenched with the addition of saturated ammonium chloride (15 ml) and EtOAc (40 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2*10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (20% EtOAc/hexanes) to give the corresponding triflate (210.7 mg, 49%) as a white solid as long with recovered starting material (142.9 mg): 1H NMR (CDCl3, 400 MHz) delta 8.37 (d, J=6.4 Hz, 2 H), 6.59 (t, J=6.4 Hz, 1 H), 5.91 (m, 1 H), 4.41 (m, 2 H), 4.11 (t, J=5.6 Hz, 2 H), 2.55 (m, 2 H); MS calc'd for C10H11F3N3O3S [M+H]+: 310; Found: 310.

  • 38
  • [ 37595-74-7 ]
  • [ 101385-93-7 ]
  • [ 630121-86-7 ]
  • [ 456-64-4 ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; at -78 - 20℃; for 14.25h; Example 16; (2,3-Dihydrobenzo[1,4]oxazin-4-yl)[3-(4-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl]methanone (Compound No. 159); 16.1: tert-Butyl 3-trifluoromethanesulfonyloxy-2,5-dihydropyrrole-1-carbamate; 27 ml of a 2.5N solution of n-butyllithium in hexane are added dropwise, in a 500 ml three-necked flask under nitrogen, to a solution of 9.86 ml of diisopropylamine in 40 ml of tetrahydrofuran cooled to -78 C. After stirring for ¼ of an hour, a solution of 10 g of tert-butyl 3-oxopyrrolidine-1-carbamate in 40 ml of tetrahydrofuran is added dropwise at -78 C. Finally, still at -78 C., 21.22 g of N-phenyltrifluoromethanesulfonimide are added. After stirring at ambient temperature for 14 hours, the tetrahydrofuran is evaporated and the product is purified on silica gel using a cyclohexane/ether 9/1 mixture as eluent. 10.2 g of tert-butyl 3-trifluoromethanesulfonyloxy-2,5-dihydropyrrole-1-carbamate are obtained as a 1/1 mixture with C,C,C-trifluoro-N-phenylmethanesulfonamide.(M-tbu)+H+=262
  • 39
  • [ 37595-74-7 ]
  • [ 5985-24-0 ]
  • dimethyl 4-trifluoromethanesulfonyl-oxy-1,3-benzenedicarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With dmap; triethylamine; In dichloromethane; at 20 - 23℃; Intermediate T4T4.1 [0314] Dimethyl 4-(trifluoromethylsulfonyloxy)isophthalate (T4.1). To a stirred solution of <strong>[5985-24-0]dimethyl 4-hydroxyisophthalate</strong> (commercially available from Chem Service)(37.7 g, 179 mmol) in DCM (256 mL, 179 mmol) at 23°C was added TEA (30 mL, 215 mmol), and a catalytic amount of DMAP. N-phenyltriflimide (70 g, 197 mmol) was then added to the mixture and the mixture was stirred at room temperature for 21 hours. The solvent was removed, and the residue was purified on silica gel (0-10percent EtOAc in hexanes) to yield T4.1 dimethyl 4-(trifluoromethylsulfonyloxy)isophthalate as a colorless oil (59.00 g, 96percent yield). MS ESI (pos.) m/e: 360.0 (M+H20)+, 343.0 (M+H)+.
96% With triethylamine;dmap; In dichloromethane; at 20 - 23℃; for 21h; Dimethyl 4-(trifluoromethylsulfonyloxy)isophthalate (T9.2). To a stirred solution of <strong>[5985-24-0]dimethyl 4-hydroxyisophthalate</strong> T9.1 (commercially available from Chem Service) (37.7 g, 179 mmol) in DCM (256 mL, 179 mmol) at 23°C was added TEA (30 mL, 215 mmol), and a catalytic amount of DMAP. N-phenyltriflimide (70 g, 197 mmol) was then added, and stirring was continued at room temperature for 21 hours. The solvent was removed, and the residue was purified on silica gel (0-10percent EtOAc in hexanes) to yield T9.2 dimethyl 4-(trifluoromethylsulfonyloxy)isophthalate as a colorless oil (59.00 g, 96percent yield). MS ESI (pos.) m/e: 360.0 (M+H20)+, 343.0 (M+H)+.
  • 40
  • [ 37595-74-7 ]
  • [ 391-92-4 ]
  • [ 928264-54-4 ]
YieldReaction ConditionsOperation in experiment
5-FLUOROSALICYLIC acid methyl ester (28.2g, 166MMOL) was dissolved in dry dimethylformamide (165ML) and stirred as sodium hydride (60percent in oil) (7. 30G, L. LEQ) was added portionwise over 30 mins at 0°C. The reaction mixture was stirred for a further 30 mins at room temperature, then N-PHENYL TRIFLUOROMETHANESULFONIMIDE (62.8g, 1. 05eq) was added in portions over 30 mins, then left to stir for 3 hours. The mixture was diluted with diethyl ether and washed successively with water, then brine. The organic layers were combined, dried (MGS04), filtered and the solvent removed in vacuo. The resulting oil was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (10: 90 to 40: 60), to give the title compound as an oil.
5-Fluorosalicylic acid methyl ester (28.2g, 166mmol) was dissolved in dry dimethylformamide (165mL) and stirred as sodium hydride (60percent in oil) (7. 30g, l. leq) was added portionwise over 30 mins at 0°C. The reaction mixture was stirred for a further 30 mins at room temperature, then N-phenyl trifluoromethanesulfonimide (62.8g, 1. 05eq) was added in portions over 30 mins, then left to stir for 3 hours. The mixture was diluted with diethyl ether and washed successively with water, then brine. The organic layers were combined, dried (MgS04), filtered and the solvent removed in vacuo. The resulting oil was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (10: 90 to 40: 60), to give the title compound as an oil.
  • 41
  • [ 37595-74-7 ]
  • [ 1067915-34-7 ]
  • [ 851314-41-5 ]
YieldReaction ConditionsOperation in experiment
100% To a suspension of NaH (about 60% in oil, 0.27 g, about 6.8 mmol) in THF (20 mL) was added compound T" (1.01 g, 3.4 mmol) in THF (15 mL), at 0C. After 30 min the ice bath was removed and Tf2NPh (1.82 g, 5.1 mmol) was added. The mixture was heated at 45 C for 72 h. The mixture was allowed to cool to rt, ice was added, and the THF was evaporated under reduced pressure. EtOAc was added, the phases were separated and the organic phase was washed with aq. 10% Na2C03 (lx). The org. extracts were dried over MgS04, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 5: 95 o 1: 9) yielded the title compound (1.46 g, quantitative yield). LC-MS: Rt = 1. 13 min, ES+: 430.13.
  • 42
  • [ 37595-74-7 ]
  • [ 53400-41-2 ]
  • [ 890028-85-0 ]
  • 43
  • [ 37595-74-7 ]
  • [ 16806-93-2 ]
  • C9H7F3O4S [ No CAS ]
  • 45
  • [ 37595-74-7 ]
  • [ 13482-23-0 ]
  • [ 1092938-89-0 ]
YieldReaction ConditionsOperation in experiment
Diisopropylamine (1.5 mL, 10.0 mmol) was taken up in 25 mL of THF and chilled to -78 0C. Butyllithium, 2.5 M in hexanes (4.1 mL, 10.0 mmol) was added slowly. After 5 minutes, <strong>[13482-23-0]4-methoxycyclohexanone</strong> (1.1 g, 8.6 mmol) was added slowly in 7 mL of THF. After 10 minutes, n-phenyltriflimide (3.4 g, 9.4 mmol) was added slowly in 7 mL of THF. After 15 minutes, the mixture was warmed to room temperature. The mixture was stirred for 90 minutes, then quenched with 25 mL of aq NH4Cl. The mixture was then diluted with 20 mL of water and extracted twice with 30 mL of ether. The combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (1% to 10% EtOAc/hexanes) afforded 4-methoxy- 1 -cyclohexen- 1 -yl trifluoromethanesulfonate as a clear oil.
  • 46
  • [ 37595-74-7 ]
  • [ 98977-36-7 ]
  • [ 456-64-4 ]
  • [ 180691-65-0 ]
YieldReaction ConditionsOperation in experiment
5-Trifluoromethanesulfonyloxy-3,6-dihydro-2/-/-pyridine-1-carboxylic acid tert-butyl ester[372] To solution of LDA (7.20 mmol) in THF (10 mL) was added a solution of 1-Boc-3- piperidone (1.20 g, 6.00 mmol) in THF (2 mL) dropwise at -78 C. The mixture was warmed up to rt and stirred for 30 min. The reaction mixture was then cooled down to -78 C again and added a solution of N-phenylbis(trifluoromethanesulfonimide) (2.79 g, 7.80 mmol) in 13 mL THF. The resulting mixture was stirred for another 2.5 h. The resulting mixture was quenched by sat. aq. NaHCO3 (20 mL), diluted with EtOAc (40 mL), washed with water again(20 mL x 3) and brine (20 mL). The organic layer was dried over Na2SO4, concentrated in vacuo and purified by silica gel (eluent: Hexanes: EtOAc 9:1 ) to afford a mixture of the desired product and N-phenyl trifluoromethanesulfonimide (1 :1 ). 1H NMR (400 MHz, CDCI3): delta = 1.48(s, 9 H), 2.28 (m, 2 H), 3.48 (t, J = 5.6 Hz, 2 H), 3.95-4.13 (m, 2 H), 5.92 (t, J = 4.2 Hz, 1 H).
  • 47
  • [ 37595-74-7 ]
  • [ 147905-77-9 ]
  • [ 1257998-20-1 ]
YieldReaction ConditionsOperation in experiment
Step C - Synthesis oflnt-18dEthyl l -methyM-oxocyclohexanecarboxylate (Int-18c, 2.65 g, 14.39 mmol) was dissolved in dry THF (10 mL) and added into LDA (17.28 mmol) in THF (20 mL) at -78 0C. The resulting mixture was stirred for 30 min and N- phenyltrifluoromethanlsulfonimide (5.66 g, 15.8 mmol) on THF (10 mL) was added at-78 0C. The resulting mixture was allowed to warm up to room temperature and stirred overnight. NH4CI (aq.) was added to quench the reaction which was extracted with ethyl acetate. The organics were dried and concentrated and purified on a column(silica gel, 0-30% EA in hexane) to give ethyl l-methyl-4-(trifluoromethylsulfonyloxyJcyclohex-S-enecarboxylate (Int-18d) (3.36 g).
LDA (17.28 mmol) in THF (20 mL) was cooled to -78 C and the ketone (2.65 g, 14.39 mmol) in THF (10 mL) was added dropwise and stirred for 30 min. Then N- phenylbis(trifluoromethanesulfonimide) (5.66 g, 15.8 mmol) in THF (10 mL) was added. The resulting mixture was allowed to warm up to room temperature and stirred overnight. The NH4Cl(aq.) was added to quench the reaction and extracted with EtOAc. The organics was dried over Na2S04, concentrated and purified with column (0-30%) to give the product (3.36 g).
LDA (17.28 mmol) in THF (20 mL) was cooled to -78 C and the ketone (2.65 g, 14.39 mmol) in THF (10 mL) was added dropwise and stirred for 30 min. Then N- phenylbis(1xifluoromethanesulfonimide) (5.66 g, 15.8 mmol) in THF (10 mL) was added. The resulting mixture was allowed to warm up to room temperature and stirred overnight. The- 59 - NH4Cl(aq.) was added to quench the reaction and extracted with EtOAc. The organics was dried over Na2S04, concentrated and purified with column (0~30%) to give the product (3.36 g).
With lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - 20℃; for 3.5h;Cooling with acetone-dry ice; Step 4. Preparation of ethyl 1-methyl-4-(trifluoromethylsulfonyloxy)cyclohex-3-enecarboxylate (i-le). The mixture of ethyl l-methyl-4-oxocyclohexanecarboxylate (i-ld) (3.0 g, 16.3 mmol) in anhydrous THF (20 mL) was cooled to -78 C in a dry ice-acetone bath and LiHMDS (18 mL, 17.9 mmol) was added dropwise. The mixture was stirred at -78C for 30min. Then the solution of trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide 5 (5.37 g, 14.7 mmol) in anhydrous THF (20 mL) was added dropwise. The resulted solution was warmed to room temperature and continued to stir for 3h. Saturated NH C1 solution (50 mL) was added to quench the reaction and the aqueous layer was extracted with EA (3x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04 and concentrated. The residue was chromatographed on silica gel (PE:EA 100: 1) to get the desired product as a colorless oil. LCMS (ESI) calc'd for CnHi5F305S [M+H]+: 317, found: 317;
Step 4. Preparation of ethyl l-methyl-4-(trifluoromethylsulfonyloxy)cyclohex-3- enecarboxylate (i-le).A mixture of ethyl i-methyl-4-oxocyclohexanecarboxylate (i-ld) (3.0 g, 16.3 mmol) in anhydrous THF (20 mL) was cooled to -78C in a dry ice-acetone bath and LiHMDS (18 mL, 17.9 mmol) was added dropwise. The mixture was stirred at -78C for 30mm. Then a solution of trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide 5 (5.37 g, 14.7 mmol) in anhydrous THF (20 mL) was added dropwise. The resulting solution was warmed to room temperature and continued to stir for 3h. Saturated NH4C1 solution (50 mL) was added to quench the reaction and the aqueous layer was extracted with EA (3x50 mL). The combinedorganic layers were washed with brine (50 mL), dried over anhydrous Na2504 andconcentrated. The residue was chromatographed on silica gel (PE:EA 100:1) to obtain the+desired product as a colorless oil. LCMS (ESI) calcd for C11H15F3055 [M+H] :317, found:317;
Step 4. Preparation of ethyl 1-methyl-4-(trifluoromethylsulfonyloxy)cyclohex-3-enecarboxylate (i-1e) [0262] A mixture of <strong>[147905-77-9]ethyl 1-methyl-4-oxocyclohexanecarboxylate</strong> (i-1d) (3.0 g, 16.3 mmol) in anhydrous THF (20 mL) was cooled to -78 C. in a dry ice-acetone bath and LiHMDS (18 mL, 17.9 mmol) was added dropwise. The mixture was stirred at -78 C. for 30 min. Then a solution of trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide 5 (5.37 g, 14.7 mmol) in anhydrous THF (20 mL) was added dropwise. The resulting solution was warmed to room temperature and continued to stir for 3 h. Saturated NH4Cl solution (50 mL) was added to quench the reaction and the aqueous layer was extracted with EA (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was chromatographed on silica gel (PE:EA 100:1) to obtain the desired product as a colorless oil. LCMS (ESI) calc'd for C11H15F3O5S [M+H]+: 317. found: 317.
Step 4. Preparation of ethyl l-methyl-4-(((trifluoromethyl)sulfonyl)oxy)cvclohex-3- enecarboxylate (i-23d) [00197] To a solution of LDA (20.4 mL, 2.0 M in THF, 40.8 mmol) in THF (30 mL) cooled at -78 C was added ethyl l-methyl-4-oxocyclohexanecarboxylate (5.00 g, 27.1 mmol) in THF (10 mL) dropwise. After stirring at this temperature for 30 min, N,N- bis(trifluoromethylsulfonyl)aniline (10.67 g, 29.9 mmol) in THF (20 mL) was added. The mixture was warmed to room temperature and stirred for 16 h. The mixture was quenched with NH4CI (aq.) (30 mL), extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine (40 mL*2), dried over Na2SC>4, filtered and concentrated. The residue was purified by column chromatography on silica gel (Petro. ether: EtOAc = 100: 1-50: 1) to afford the title compound. NMR (CD3OD, 400 MHz) delta 5.71 (s, 1H), 4.04-4.21 (m, 2H), 2.62-2.75 (m, 1H), 2.27-2.48 (m, 2H), 2.01-2.19 (m, 2H), 1.68-1.75 (m, 1H), 1.14-1.25 (m, 6H).
To a solution of LDA (20.4 mL, 2.0 M in THF, 40.8 mmol) in THF (30 mL) cooled at -78 OC was added <strong>[147905-77-9]ethyl 1-methyl-4-oxocyclohexanecarboxylate</strong> (5.00 g, 27.1 mmol) in THF (10 mL) drop wise. After stirring at this temperature for 30 min, N,N-bis(trifluoromethylsulfonyl)aniline (10.67 g, 29.9 mmol) in THF (20 mL) was added. The mixture was warmed to room temperature and stirred for 16 h. The mixture was quenched with NH4Cl (aq.) (30 mL), extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine (40 mL*2), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (Petro. ether:EtOAc=100:150:1) to afford the title compound. 1H NMR (CD3OD, 400 MHz) delta 5.71 (s, 1H), 4.04-4.21 (m, 2H), 2.62-2.75 (m, 1H), 2.27-2.48 (m, 2H), 2.01-2.19 (m, 2H), 1.68-1.75 (m, 1H), 1.14-1.25 (m, 6H).
To a solution of LDA (20.4 mL, 2.0 M in THF, 40.8 mmol) in THF (30 mL) cooled to -78 C. was added <strong>[147905-77-9]ethyl 1-methyl-4-oxocyclohexanecarboxylate</strong> (5 .00 g, 27.1 mmol) was added dropwise. After stirring at this temperature for 30 minutes, N, N-bis (trifluoromethylsulfonyl) aniline (10.67 g, 29.9 mmol) in THF (20 mL) was added. The mixture was warmed to room temperature and stirred for 16 h. The mixture was quenched with NH 4 Cl (aq) (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (40 mL × 2), Dried over Na 2 SO 4, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether: EtOAc = 100: 1 to 50: 1)To give the title compound.
To a solution of ethyl l -methyl-4-oxocyclohexanecarboxylate (14 g) in tetrahydrofuran (150 mL) was added potassium hexamethyidisilazide (1 M tetrahydrofuran solution, 129 mL) at -78 C. The reaction mixture was stirred at -78 C for 1 hour and a solution of 1 ,1 ,1 -trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (34.6 g) in tetrahydrofuran was slowly added at -78 C. The mixture was stirred and allowed to warm to 25 C in the period of 15 hours. The reaction was quenched with aqueous NH4CI solution (100 mL), extracted with ethyl acetate (2 x 200 mL). The combined organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether and ethyl acetate = 100 : 1-10 : 1) to give the title compound.

  • 48
  • [ 37595-74-7 ]
  • [ 20870-90-0 ]
  • C10H7BrF3NO3S [ No CAS ]
  • 49
  • [ 37595-74-7 ]
  • [ 51786-11-9 ]
  • [ 1338327-04-0 ]
YieldReaction ConditionsOperation in experiment
74.8% With potassium carbonate; In tetrahydrofuran; at 18 - 25℃; for 50.0h; ntermediate 25: 2-Chloro-3-cvanophenyl trifluoromethanesulfonate Potassium carbonate (1.350 g, 9.77 mmol) was added to <strong>[51786-11-9]2-chloro-3-hydroxybenzonitrile</strong> (Intermediate 25a; 0.5 g, 3.26 mmol) and 1,1,1-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl)methanesulfonamide (1.163 g, 3.26 mmol) in THF (40 mL) at 20C. The resulting suspension was stirred at 20 C for 50 hours. The reaction mixture was evaporated to dryness and redissolved in EtOAc (25 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried over Na2S04, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 2-chloro-3-cyanophenyl trifluoromethanesulfonate (0.696 g, 74.8 %) as a colourless liquid. 1H NMR (400 MHz, CDC13) 7.47 7.53 (1H, m), 7.62 (1H, dd), 7.73 (1H, dd). m z (ES-) (M-H)- = 284
  • 50
  • [ 37595-74-7 ]
  • [ 156001-68-2 ]
  • [ 156001-69-3 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 25℃; for 12.0h; DESCRIPTION FOR D22methyl 3-cyano-4-[(trifluoromethyl)sulfonyl]oxy}benzoate (D22)To a solution of <strong>[156001-68-2]methyl 3-cyano-4-hydroxybenzoate</strong> (D21) (1.3 g) and 1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (3.28 g) in acetonitrile (50 mL) at room temperature was added DIPEA (1.602 mL). Then the reaction mixture was stirred at 25 C. for 12 h. The solvent was removed under reduced pressure and the crude product was purified by column chromatography to afford methyl 3-cyano-4-[(trifluoromethyl)sulfonyl]oxy}benzoate (D22) (1.9 g) as a colorless oil. MS (ES): C10H6F3NO5S requires 309. found 309.9 (M+H+).
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20 - 25℃; for 12.0h; To a solution of <strong>[156001-68-2]methyl 3-cyano-4-hydroxybenzoate</strong> (D21) (1.3 g) and 1 ,1 ,1-trifluoro- /V-phenyl-A/-[(trifluoromethyl)sulfonyl]methanesulfonamide (3.28 g) in acetonitrile (50 mL) at room temperature was added DIPEA (1.602 mL). Then the reaction mixture was stirred at 25 C for 12 h. The solvent was removed under reduced pressure and the crude product was purified by column chromatography to afford methyl 3-cyano- 4-[(trifluoromethyl)sulfonyl]oxy}benzoate (D22) (1.9 g) as a colorless oil. MS (ES): doHeFsNOsS requires 309; found 309.9 (M+H+).
  • 51
  • [ 37595-74-7 ]
  • [ 81382-45-8 ]
  • [ 1246307-56-1 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;Inert atmosphere; In a 250 ml round-bottomed flask, a mixture of 645 mg of <strong>[81382-45-8]1H-indazol-4-ol</strong> obtained according to the preceding stage, 1.08 g of N-phenylbis(trifluoromethanesulphonimide) and 1.24 ml of diisopropylethylamine in 40 ml of tetrahydrofuran is stirred under argon at ambient temperature. After 3 hours, 0.9 g of N-phenylbis(trifluoromethanesulphonimide) and 0.6 ml of diisopropylethylamine are added and the stirring is continued overnight. The following day, the reaction medium is evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40 mum), elution being carried out with a mixture of ethyl acetate and cyclohexane (20:80 v/v). 863 mg of trifluoromethanesulphonic acid 1H-indazol-4-yl ester are obtained in the form of a white solid, the characteristics of which are the following:1H NMR spectrum (400 MHz, delta in ppm, DMSO-d6): 7.24 (d, J=7.6 Hz, 1H); 7.49 (t, J=7.9 Hz, 1H); 7.70 (d, J=8.3 Hz, 1H); 8.17 (s, 1H); 13.68 (broad s, 1H).Mass spectrum (LC/MS method C): Retention time Tr (min)=0.90; [M+H]+: m/z 267; [M-H]-: m/z 265
  • 52
  • [ 37595-74-7 ]
  • [ 117565-57-8 ]
  • [ 1268816-83-6 ]
YieldReaction ConditionsOperation in experiment
42% [Example 73] tert-Butyl 3-ethyl-4-[2-(5-methanesulfonylindol-1-ylmethyl)pyridin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1) tert-Butyl 3-ethyl-4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylate Under N2 atmosphere, a solution of 1.0M lithium bis(trimethylsilyl)amide-tetrahydrofuran solution (4.3 mL, 4.3 mmol) in dry tetrahydrofuran (20 mL) was cooled to -78C. To this was added dropwise a solution of <strong>[117565-57-8]tert-butyl 3-ethyl-4-oxopiperidine-1-carboxylate</strong> (881 mg, 3.88 mmol) in dry tetrahydrofuran (5 mL). After stirring at - 78C for 30 minutes, the reaction mixture was added dropwise a solution of N-phenylbis(trifluorometanesulfonimide) (1.4 g, 3.88 mmol) in dry tetrahydrofuran (5 mL). The reaction mixture was slowly warmed up to 0C. After stirring for 1 hour, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/chloroform = 8/1 ? 0/100), to give the title compound as a colorless oil (581 mg, yield 42%). 1H NMR (CDCl3 400 MHz): delta= 1.01 (3H, t, J = 7 Hz), 1.48 (9H, s), 1.3-1.6 (1H, m), 1.6-1.8 (1H, m), 2.2-2.5 (1H, m), 3.2-3.5 (1H, m), 3.7-4.0 (2H, m), 4.0-4.5 (1H, m), 5.74 (1H, br s).
  • 53
  • [ 37595-74-7 ]
  • [ 16881-33-7 ]
  • (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)-phenyl)propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
79% With magnesium sulfate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; Prepared using General Procedure 9: A stirred solution of <strong>[16881-33-7]<strong>[16881-33-7](S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate</strong> hydrate</strong> (25 g, 64.2 mmol) in DCM (100 mL) was treated with magnesium sulfate (4.01 g, 33.7 mmol). After 15 min, the mixture was filtered and washed with DCM (2 x 20 mL). The organics were treated with N-ethyl-N-isopropylpropan-2-amine (17.41 g, 134.7 mmol) and stirred. This solution was treated with 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (26.44 g, 74.01 mmol) and the mixture was allowed to stir overnight at RT. The mixture was treated with water (50 mL) and saturated aqueous NaHC03 (20 mL) and stirred vigorously for 10 min. The layers were separated and the organic layer was further washed with saturated aqueous NaHC03 (2 x 50 mL), water (50 mL), and saturated aqueous NaHC03 (50 mL) and concentrated. The compound was purified by chromatography (EA / hexanes) to afford 26.85 g (79%) of {S)-tert- vXy 2-(((benzyloxy)carbonyl)amino)-3-(4- (((trifluoromethyl)sulfonyl)oxy)phenyl) propanoate INT-5. LCMS-ESI (m/z) calculated for C22H24F3NO7S: 503.1; found 526.1 [M + Na]+, = 4.12 min (Method 3).
  • 54
  • [ 13314-85-7 ]
  • [ 37595-74-7 ]
  • [ 1442104-28-0 ]
YieldReaction ConditionsOperation in experiment
68% With triethylamine; In dichloromethane; at 20℃; for 2h; <strong>[13314-85-7]2-methyl-1H-indol-5-ol</strong> (43, 0.41 g, 2.78 mmol), triethylamine (0.71 g, 6.96 mmol), and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl) methanesulfonamide PhN(SO2CF3)2 (1.49 g, 4.17 mmol) were dissolved in CH2Cl2 (20 mL), and the mixturewas stirred at RT. After 2 h the mixture was diluted with CH2Cl2 (100 mL), washed with 10% aqueous Na2CO3, dried over MgSO4 and concentrated to give the crude product. Purification was performed using flash chromatography on silica gel (isooctane/ethyl acetate, gradient) to give the title compound in 68% yield (0.53 g, 1.89 mmol). MS m/z(relative intensity, 70 eV) 279 (M+, 53),146 (bp),118 (66),117 (27), 91(11). 1H NMR (CDCl3, 400 MHz) delta: 2.45 (s, 3H), 6.26 (dd, J = 2.15,0.98 Hz, 1H), 6.99 (dd, J = 8.79, 2.54 Hz, 1H), 7.25 (d, J = 4.69 Hz, 1H),7.39 (d, J = 2.34 Hz, 1H), 8.03 (br s, 1H). 13C NMR (CDCl3, 101 MHz) delta: 13.77, 101.26, 110.94, 111.95, 113.94, 114.09, 117.28, 120.47, 123.66,129.38, 134.84, 137.94, 143.70.
  • 55
  • [ 37595-74-7 ]
  • [ 55704-60-4 ]
  • [ 1449661-70-4 ]
YieldReaction ConditionsOperation in experiment
53.4% With potassium hexamethylsilazane; In tetrahydrofuran; at -78 - 20℃; for 2.5h;Inert atmosphere; Step 1 Preparation of diethyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1,1-dicarboxylate A flask containing a solution of <strong>[55704-60-4]diethyl 4-oxocyclohexane-1,1-dicarboxylate</strong> (0.505 g, 2.084 mmol) and 1,1,1-Trifluoro-N-phenyl-N-(trifluoromethyl)sulfonyl methanesulfonamide (0.819 g, 2.293 mmol) in THF (10 mL) was cooled to -78 C. To the solution was added KHMDS (0.5M in toluene) (6.25 mL, 3.13 mmol). The mixture was stirred at -78 C. for 1.5 h then was warmed to rt and was stirred for 1 h. The reaction was quenched with sat. aq ammonium chloride (30 mL) and was extracted with ethyl acetate (3*30 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 0-20% ethyl acetate in hexanes gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give the product which still contained impurities. The residue was repurified using a 0-50% toluene in hexanes gradient followed by a 0-10% ethyl acetate in hexanes. The fractions containing the expected product were combined and concentrated under reduced pressure to give the expected product as a clear, colorless oil (0.417 g, 1.114 mmol, 53.4% yield). 1H NMR (500 MHz, chloroform-d) delta=5.82-5.75 (m, 1H), 4.29-4.18 (m, 4H), 2.84-2.75 (m, 2H), 2.50-2.41 (m, 2H), 2.35-2.30 (m, 2H), 1.31-1.26 (m, 6H).
  • 56
  • [ 37595-74-7 ]
  • [ 93413-62-8 ]
  • desvenlafaxine triflate [ No CAS ]
  • 57
  • [ 37595-74-7 ]
  • [ 193480-28-3 ]
  • [ 1613720-41-4 ]
YieldReaction ConditionsOperation in experiment
To a solution of 2-benzylpiperidin-4-one (BETAPHARMA, 0.868 g, 3 mmol) in anhydrous THF (10 mL) was added LiHMDS (1M solution in THF, 6 mL) dropwise at -78 C. After addition, the mixture was allowed to warm to -30 C. and stirred for 20 min. The mixture was cooled to -78 C. again and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (2.144 g, 6 mmol) was added. The mixture was allowed to warm to ambient temperature and stirred for 2 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel (eluting with 2% EtOAc in petroleum ether) to give tert-butyl 6-benzyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate as an oil (0.72 g, crude), which was used in the next step without further purification. TLC (eluting with 10% EtOAc/PE) Rf=0.5.
  • 58
  • [ 37595-74-7 ]
  • [ 58012-34-3 ]
  • [ 1166829-72-6 ]
YieldReaction ConditionsOperation in experiment
87% To a solution of commercially available <strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong> (SI-17) (1.0 g,5.43 mmol) in anhydrous THF (30 mL) was added LiHMDS (5.7 mL, 1.0 M in THF, 5.70mmol) at -78 C and the mixture was stirred for 1 hour. Then, PhN(SO2CF3)2 (2.04 g, 5.70mmol) in THF (20 mL) was added under N2 protection. After addition, the mixture wasstirred at room temperature overnight. Then, the reaction was quenched with aqueousKHSO4 and extracted with MTBE. The organic layer was washed with 1.0 M aqueousNaOH, aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered and concentratedto give Int. 8 (1.50 g, 87%) as a yellow oil. ESI-MS m/z 317 [M+H]+ calc. forC11H15F3O5S. 1H NMR (CDCl3, 400 MHz): delta 5.66 (s, 1H, C=CH), 4.12-4.05 (m, 2H, OCH2-CH3), 2.35-2.23 (m, 5H, cyclohexene and cyclohexene-CH2-CO), 2.21-2.03 (m, 1H,cyclohexene), 1.90-1.83 (m, 2H, cyclohexene), 1.49-1.42 (m, 1H, cyclohexene), 1.23-1.18(m, 3H, O-CH2-CH3).
35% Step 1. Ethyl 2-(4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-l-yl)acetate. To a solution of <strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong> (0.50 g, 2.71 mmol) in tetrahydrofuran (2.71 mL) was slowly added a solution of lithium bis(trimethylsilyl)amide in THF (4.07 mL, 1.00 M, 4.07 mmol). The reaction was cooled to -40C then stirred for 1 h then a solution of /V-phenyl- bis(trifluoromethanesulfonimide) (1.16 g, 3.26 mmol) in tetrahydrofuran (0.90 mL) was added dropwise at -40C. The reaction was allowed to warm up to room temperature and stirred for an additional 3 h. The reaction mixture was quenched with sat. NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated to give the crude product. The crude oil was purified via flash chromatography 0- 30% EtOAc/Heptanes to obtain the title compound as a colorless oil (300 mg, 35%). 'H NMR (400 MHz, CDCb) d 5.77 - 5.56 (m, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.50 - 2.39 (m, 1H), 2.33 (td, J = 2.6, 5.0 Hz, 2H), 2.29 (d, J = 7.1 Hz, 2H), 2.18 - 2.04 (m, 1H), 2.01 - 1.85 (m, 2H), 1.60 - 1.45 (m, 1H), 1.25 (t, / = 7.2 Hz, 3H). [M+H] = 317.1.
To a solution of commercially available <strong>[58012-34-3]ethyl 2-(4-oxocyclohexyl)acetate</strong> (1 .0 g, 5.43 mmol) in anhydrous THE (30 mL) was added LHMDS (5.7 mL, 1 .0 M in THE, 5.70 mmol) at -78C, then the mixture was stirred at the sametemperature for ihr, compound PhN(SO2CE3)2 (2.04 g, 5.70 mmol) in THE (20 mL) was added under N2 protection. After addition, the mixture was stirred at room temperature overnight until TLC showed the starting material was consumed completely, the mixture was quenched with aqueous KHSO4, extracted with MTBE, the organic layer was washed with 1 .0 M aqueousNaOH, aqueous NH4CI, brine, dried over anhydrous Na2SO4, concentrated to give the crude reagent R-27b (1 .50 g, 87%) as a yellow oil. ESI-MS (Mi-i):317 calc. for C11H1SE3OSS: 316.0.
  • 59
  • [ 37595-74-7 ]
  • 4-(5-fluoro-2-methoxyphenyl)-2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine [ No CAS ]
  • [ 81357-18-8 ]
  • 1-tert-butyl 2-methyl 4-(4-(5-fluoro-2-methoxyphenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2,3-dihydropyridine-1,2(6H)-dicarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
1-tert- Butyl 2-methyl 4-oxopiperidine- l,2-dicarboxylate (10 g, 38.9 mmol) was dissolved in tetrahydrofuran (80 ml) under nitrogen atmosphere, and the solution was chilled in a dry ice-acetone bath. To the stirred solution was added dropwise a IN solution of lithium bis(trimethylsilyl)amide in hexanes (42.8 ml, 42.8 mmol), and after the addition of base was completed, a solution of 1,1, 1- trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (14.58 g, 40.8 mmol) in tetrahydrofuran (20 ml) was added dropwise. The reaction was allowed to warm to room temperature, quenched with saturated aqueous NH4C1 (100 mL), and extracted with ethyl acetate (3 x 150 mL). The extracts were dried (Na2S04), filtered, and concentrated. The crude material was purified by flash chromatography (Analogix system, Grace 120g column, 60 mL/min, gradient from 0 to 20% ethyl acetate-heptanes over 60 minutes). The product was isolated as a mixture of the title compounds which was used without further purification in the subsequent reaction. The inseparable mixture of regioisomers from Example 855A (5.25 g, 9.44 mmol, combined mass of the two isomers, adjusted to account for the triflamide byproduct), bis(pinacolato)diboron (2.398 g, 9.44 mmol), PdCl2(l,r-bis(diphenylphosphino)ferrocene), complex with CH2C12 (0.321 g, 0.393 mmol) and potassium acetate (3.86 g, 39.3 mmol) were combined in dioxane (40 ml). The mixture was degassed with nitrogen, and then heated to reflux for 1.5 hours. The mixture was cooled to room temperature and then Example 87B (4 g, 7.87 mmol), additional PdCl2(l,l '- bis(diphenylphosphino)ferrocene), complex with CH2C12 (0.321 g, 0.393 mmol), and a solution of sodium carbonate (4.59 g, 43.3 mmol) in water (0.5 mL) were added. The reaction was heated to 65C overnight, then cooled to room temperature and partitioned between water (100 mL) and ethyl acetate (3 x 75 mL). The solution was dried (Na2SO/t), filtered, concentrated and purified by repeated flash chromatography (Analogix Intelliflash system, gradient from 0 to 40% ethyl acetate-heptanes over 45 minutes, Grace 80g column, 60 mL/min) to provide the title compound
  • 60
  • [ 37595-74-7 ]
  • [ 81357-18-8 ]
  • 1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydropyridine-1,2(6H)-dicarboxylate [ No CAS ]
  • 1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1,2(2H)-dicarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
1-tert- Butyl 2-methyl 4-oxopiperidine- l,2-dicarboxylate (10 g, 38.9 mmol) was dissolved in tetrahydrofuran (80 ml) under nitrogen atmosphere, and the solution was chilled in a dry ice-acetone bath. To the stirred solution was added dropwise a IN solution of lithium bis(trimethylsilyl)amide in hexanes (42.8 ml, 42.8 mmol), and after the addition of base was completed, a solution of 1,1, 1- trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (14.58 g, 40.8 mmol) in tetrahydrofuran (20 ml) was added dropwise. The reaction was allowed to warm to room temperature, quenched with saturated aqueous NH4C1 (100 mL), and extracted with ethyl acetate (3 x 150 mL). The extracts were dried (Na2S04), filtered, and concentrated. The crude material was purified by flash chromatography (Analogix system, Grace 120g column, 60 mL/min, gradient from 0 to 20% ethyl acetate-heptanes over 60 minutes). The product was isolated as a mixture of the title compounds which was used without further purification in the subsequent reaction.
  • 61
  • [ 37595-74-7 ]
  • [ 790667-49-1 ]
  • (S)-tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
  • (S)-tert-butyl 6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
A solution of (S)-tert-butyl-2-methyl-4-oxopiperdine-l-carboxylate (5 g, 23.44 mmol) in tetrahydrofuran (100 mL) was cooled to -78C and lithium bis(trimethylsilyl)amide (1M in hexanes, 28.1 mL, 28.1 mmol) was added dropwise. The mixture was stirred at -78C for 30 minutes and a solution of l,l,l-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl) methanesulfonamide (10.89 g, 30.5 mmol) in tetrahydrofuran (25 mL) was added dropwise. The mixture was allowed to warm to room temperature and after 24 hours, the reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The extracts were dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel eluting with 0-40% ethyl acetate-hexanes gave an oil as a mixture of enol isomers. This material also contained 25% by weight 1 , 1 , 1 -trifluoro-N- phenylmethanesulfonamide. The mixture was carried on in the next step without any further purification. MS (ESI) m/e 246.0 (M-BOC)+.
  • 62
  • [ 37595-74-7 ]
  • [ 790667-49-1 ]
  • 4-(5-fluoro-2-methoxyphenyl)-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine [ No CAS ]
  • (S)-tert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-methyl-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
  • (S)-tert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-6-methyl-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example 258D (S)-fert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-l-tosyl-lH-pyrrolo[2,3-b]pyridin-2-yl)-2-methyl-5,6- dihydropyridine- 1 (2H)-carboxylate and (S)-fert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-l-tosyl-lH- pyrrolo[2,3-b]pyridin-2-yl)-6-methyl-5,6-dihydropyridine-l(2H)-carboxylate (4: 1) A mixture of Example 258A (1.75 g, 6.89 mmol), bis(diphenylphosphino)ferrocene] dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (1.75 g, 28.7 mmol), and potassium acetate (2.82 g, 28.7 mmol) in dioxane (40 mL) was degassed and heated at reflux for 90 minutes. After cooling to room temperature, Example 258C (3 g, 5.74 mmol), additional bis(diphenylphosphino) ferrocene]dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol) and a solution of sodium carbonate (3.35 g, 31.6 mmol) in water (0.5 mL) was added and the mixture was heated to 65C for 24 hours. The mixture was partitioned between water and ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel eluting with 0-30% ethyl acetate in heptanes over 50 minutes provided the title compound as a mixture of regioisomers which was used in the next step without any further purification. MS (ESI) m/e 592.1 (M+l)+. A mixture of Example 258A (1.75 g, 6.89 mmol), bis(diphenylphosphino)ferrocene] dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (1.75 g, 28.7 mmol), and potassium acetate (2.82 g, 28.7 mmol) in dioxane (40 mL) was degassed and heated at reflux for 90 minutes. After cooling to room temperature, Example 258C (3 g, 5.74 mmol), additional bis(diphenylphosphino) ferrocene]dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol) and a solution of sodium carbonate (3.35 g, 31.6 mmol) in water (0.5 mL) was added and the mixture was heated to 65C for 24 hours. The mixture was partitioned between water and ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel eluting with 0-30% ethyl acetate in heptanes over 50 minutes provided the title compound as a mixture of regioisomers which was used in the next step without any further purification. MS (ESI) m/e 592.1 (M+l)+.
  • 63
  • [ 37595-74-7 ]
  • [ 790667-49-1 ]
  • 4-(5-fluoro-2-methoxyphenyl)-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine [ No CAS ]
  • (S)-tert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-methyl-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
  • (S)-tert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-6-methyl-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example 258D (S)-fert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-l-tosyl-lH-pyrrolo[2,3-b]pyridin-2-yl)-2-methyl-5,6- dihydropyridine- 1 (2H)-carboxylate and (S)-fert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-l-tosyl-lH- pyrrolo[2,3-b]pyridin-2-yl)-6-methyl-5,6-dihydropyridine-l(2H)-carboxylate (4: 1) A mixture of Example 258A (1.75 g, 6.89 mmol), bis(diphenylphosphino)ferrocene] dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (1.75 g, 28.7 mmol), and potassium acetate (2.82 g, 28.7 mmol) in dioxane (40 mL) was degassed and heated at reflux for 90 minutes. After cooling to room temperature, Example 258C (3 g, 5.74 mmol), additional bis(diphenylphosphino) ferrocene]dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol) and a solution of sodium carbonate (3.35 g, 31.6 mmol) in water (0.5 mL) was added and the mixture was heated to 65C for 24 hours. The mixture was partitioned between water and ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel eluting with 0-30% ethyl acetate in heptanes over 50 minutes provided the title compound as a mixture of regioisomers which was used in the next step without any further purification. MS (ESI) m/e 592.1 (M+l)+. A mixture of Example 258A (1.75 g, 6.89 mmol), bis(diphenylphosphino)ferrocene] dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (1.75 g, 28.7 mmol), and potassium acetate (2.82 g, 28.7 mmol) in dioxane (40 mL) was degassed and heated at reflux for 90 minutes. After cooling to room temperature, Example 258C (3 g, 5.74 mmol), additional bis(diphenylphosphino) ferrocene]dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol) and a solution of sodium carbonate (3.35 g, 31.6 mmol) in water (0.5 mL) was added and the mixture was heated to 65C for 24 hours. The mixture was partitioned between water and ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel eluting with 0-30% ethyl acetate in heptanes over 50 minutes provided the title compound as a mixture of regioisomers which was used in the next step without any further purification. MS (ESI) m/e 592.1 (M+l)+. To a solution of Example 258D (3.06 g, 5.17 mmol) in dioxane (29.6 mL) was added a solution of sodium hydroxide (0.724 g, 18.1 mmol) in water (3.62 mL) and the mixture was heated at 90C for 24 hours. The mixture was cooled to room temperature, diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel eluting with 0-50% methanol in dichloromethane provided the title compound as a mixture of regioisomers which was used in the next step without any further purification. MS (ESI) m/e 438.1 (M+l)+.
  • 64
  • [ 37595-74-7 ]
  • [ 790667-49-1 ]
  • 4-(5-fluoro-2-methoxyphenyl)-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine [ No CAS ]
  • (S)-4-(5-fluoro-2-methoxyphenyl)-2-(6-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example 258D (S)-fert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-l-tosyl-lH-pyrrolo[2,3-b]pyridin-2-yl)-2-methyl-5,6- dihydropyridine- 1 (2H)-carboxylate and (S)-fert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-l-tosyl-lH- pyrrolo[2,3-b]pyridin-2-yl)-6-methyl-5,6-dihydropyridine-l(2H)-carboxylate (4: 1) A mixture of Example 258A (1.75 g, 6.89 mmol), bis(diphenylphosphino)ferrocene] dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (1.75 g, 28.7 mmol), and potassium acetate (2.82 g, 28.7 mmol) in dioxane (40 mL) was degassed and heated at reflux for 90 minutes. After cooling to room temperature, Example 258C (3 g, 5.74 mmol), additional bis(diphenylphosphino) ferrocene]dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol) and a solution of sodium carbonate (3.35 g, 31.6 mmol) in water (0.5 mL) was added and the mixture was heated to 65C for 24 hours. The mixture was partitioned between water and ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel eluting with 0-30% ethyl acetate in heptanes over 50 minutes provided the title compound as a mixture of regioisomers which was used in the next step without any further purification. MS (ESI) m/e 592.1 (M+l)+. A mixture of Example 258A (1.75 g, 6.89 mmol), bis(diphenylphosphino)ferrocene] dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (1.75 g, 28.7 mmol), and potassium acetate (2.82 g, 28.7 mmol) in dioxane (40 mL) was degassed and heated at reflux for 90 minutes. After cooling to room temperature, Example 258C (3 g, 5.74 mmol), additional bis(diphenylphosphino) ferrocene]dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol) and a solution of sodium carbonate (3.35 g, 31.6 mmol) in water (0.5 mL) was added and the mixture was heated to 65C for 24 hours. The mixture was partitioned between water and ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel eluting with 0-30% ethyl acetate in heptanes over 50 minutes provided the title compound as a mixture of regioisomers which was used in the next step without any further purification. MS (ESI) m/e 592.1 (M+l)+. To a solution of Example 258D (3.06 g, 5.17 mmol) in dioxane (29.6 mL) was added a solution of sodium hydroxide (0.724 g, 18.1 mmol) in water (3.62 mL) and the mixture was heated at 90C for 24 hours. The mixture was cooled to room temperature, diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel eluting with 0-50% methanol in dichloromethane provided the title compound as a mixture of regioisomers which was used in the next step without any further purification. MS (ESI) m/e 438.1 (M+l)+. To a solution of Example 258E (0.600 g, 1.37 mmol) in 4 mL 1 : 1 methanol: ethyl acetate was added 2M hydrogen chloride in diethyl ether (5 mL) and the mixture was stirred at 40C for 2 hours and concentrated. Purification by reverse phase-HPLC (Sunfire 5muMu, 50 X 250 mm) eluting with 5- 40% acetonitrile in water (containing 0.1% trifluoroacetic acid), provided the title compound as trifluoroacetate salt. To a solution of this salt in methanol was added 2M hydrogen chloride in diethyl ether. Concentration afforded the title compound as the hydrochloride salt. MS (ESI) m/e 338.1 (M+l)+.
  • 65
  • [ 37595-74-7 ]
  • [ 148404-28-8 ]
  • [ 1416313-05-7 ]
YieldReaction ConditionsOperation in experiment
To a solution of sodium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 14.65 mL, 14.65 mmol) in tetrahydrofuran (12 mL) at -78C was slowly added tert-butyl 5- oxohexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (3.00 g, 13.32 mmol) in tetrahydrofuran (7.5 mL). The mixture was stirred for 30 minutes and treated over 15 minutes with a solution of 1, 1, 1- trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (5.23 g, 14.65 mmol) in tetrahydrofuran (12 mL). The mixture was stirred at -78C for 90 minutes and allowed to warm to room temperature for 1 hour. The mixture was quenched with water (7.5 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 10-80% ethyl acetate/hexanes to afford the title compound (-75% purity), which was used in the next step without further purification. MS (ESI+) m/z 380 (M+Na)+.
To a solution of sodium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 14.65 mL, 14.65 mmol) in tetrahydrofuran (12 mL) at -78 C. was slowly added <strong>[148404-28-8]tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate</strong> (3.00 g, 13.32 mmol) in tetrahydrofuran (7.5 mL). The mixture was stirred for 30 minutes and treated over 15 minutes with a solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (5.23 g, 14.65 mmol) in tetrahydrofuran (12 mL). The mixture was stirred at -78 C. for 90 minutes and allowed to warm to room temperature for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Teledyne CombiFlash Rf, 10-80% ethyl acetate/hexanes) to afford the title compound (?75% purity), which was used in the next step without further purification. MS (ESI+) m/z 380 (M+Na)+.
Step A: LDA (2M, 1.0 mL, 2.0 eq.) was added to a solution of <strong>[148404-28-8]t-butyl 5-oxo-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate</strong> (226 mg, 1.0 mmol, 1.0 eq.) in anhydrous THF (20 mL) at -78C. The resulting mixture was stirredat -78C for 1 hour and further added with a solution of N,N-bis(trifluoromethanesulfonyl)aniline (467 mg, 1.2 mmol,1.2 eq.) in anhydrous THF (20 mL). The mixture was then warmed up to room temperature and stirred for 16 hours.The mixture was concentrated to dryness, and the residue was dissolved in DCM, successively, washed with asaturated aqueous NaHCO3 solution, dried over anhydrous MgSO4 and concentrated, to give t-butyl 5-(trifluoromethylsulfonyloxy)-3,3a,6,6-tetrahydro-1H-cyclopenta[c]pyrrole -2-carboxylate (360 mg, a crude product) as abrown oil, which was used directly in the next step.
  • 66
  • [ 37595-74-7 ]
  • [ 16881-33-7 ]
  • [ 145205-85-2 ]
YieldReaction ConditionsOperation in experiment
79% General procedure: (General Procedure 9: Formation of Trflate.[00420j A solution of the phenol (1.0 eq) in DCM (0.25 M) was treated with 1,1- trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1 .1 eq). The reaction mixture was stirred at room temperature until complete. The reaction was stirred with water and saturated aqueous NaHCO3. The organic layers was dried and concentrated. The material was purified by chromatography or alternatively used without purification.S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3- (4-(((trijluoromethyl)sulfonyl)oxy)- phenyl) propanoate (INT-5) [00491j Prepared using General Procedure 9: A stirred solution of (S)-tert-butyl 2- (((benzyloxy)carbonyl)amino)-3 -(4-hydroxyphenyl)propanoate hydrate (25 g, 64.2 mmol) in DCM (100 mL) was treated with MgSO4 (4.01 g, 33.7 mmol). After 15 mm, the mixture was filtered and washed with DCM (2 x 20 mL). The organics were treated with N-ethyl-N-isopropylpropan-2-amine (17.41 g, 134.7 mmol) and stirred. Thissolution was treated with 1,1,1 -trifluoro-N-phenyl-N((trifluoromethyl)sulfonyl)methanesulfonamide (26.44 g, 74.01 mmol) and the mixture was allowed to stir overnight at room temperature. The mixture was treated with water (50 mL) and saturated aqueous NaHCO3 (20 mL) and stirred vigorously for 10 mm. The layers were separated and the organic layer was further washed with saturated aqueous NaHCO3 (2 x 50 mL), water (50 mL), and saturated aqueous NaHCO3 (50 mL) and concentrated. The compound was purified by chromatography (EA / hexanes) to afford 26.85 g (79%) of (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3 -(4- (((trifluoromethyl)sulfonyl)oxy)phenyl) propanoate INT-5. LCMS-ESI (mlz) calculated for C22H24F3N07S: 503.1; found 526.1 [M + Na], tR = 4.12 mm (Method 3).
79% Prepared using General Procedure 9: A stirred solution of <strong>[16881-33-7]<strong>[16881-33-7](S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate</strong> hydrate</strong> (25 g, 64.2 mmol) in DCM (100 mL) was treated with MgSO4 (4.01 g, 33.7 mmol). After 15 min, the mixture was filtered and washed with DCM (2 x 20 mL). The organics were treated with N-ethyl-N-isopropylpropan-2-amine (17.41 g, 134.7 mmol) and stirred. This solution was treated with 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (26.44 g, 74.01 mmol) and the mixture was allowed to stir overnight at room temperature.The mixture was treated with water (50 mL) and saturated aqueous NaHCO3 (20 mL) and stirred vigorously for 10 min. The layers were separated and the organic layer was further washed with saturated aqueous NaHCO3 (2 x 50 mL), water (50 mL), and saturated aqueous NaHCO3 (50 mL) and concentrated. The compound was purified by chromatography (EA / hexanes) to afford 26.85 g (79%) of (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4- (((trifluoromethyl)sulfonyl)oxy)phenyl) propanoate INT-5. LCMS-ESI (m/z) calculated for C22H24F3NO7S: 503.1; found 526.1 [M + Na]+, tR = 4.12 min (Method 3).
  • 67
  • [ 37595-74-7 ]
  • [ 16801-63-1 ]
  • 4-(((benzyloxy)carbonyl)amino)cyclohex-1-en-1-yl trifluoromethanesulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
37.3% To a solution of sodium bis(trimethylsilyl)amide 1 M in THF (22.24 ml, 22.24 mmol) in dry THF (25 mL), previously cooled to -78 C, a solution of <strong>[16801-63-1]benzyl (4-oxocyclohexyl)carbamate</strong> (2.5 g, 10.11 mmol) in dry THF (25 mL) was slowly added. The solution was stirred for 30 mm at -78C and then a solution of 1,1,1-trifluoro-N- phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (7.58 g, 21.23 mmol) in dry THF (25 mL) was added. The reaction was stirred at -78C for 10 mm and then allowed to reach room temperature. Reaction was diluted with diethyl ether (200 mL) and organiclayer was washed with 1 M NaOH aqueous solution (100 mL). Organic phases were dried over Na2SO4, filtered and solvent was removed under reduced pressure. The product was purified by Biotage Si 50 g with a gradient of heptane and EtOAc to give the titled compound (1.43 g, 3.77 mmol, 37.3 % yield) as a white solid.UPLC-MS: 1.25 mm, 380 [M+H]+, method 9
37.3% To a solution of sodium bis(trimethylsilyl)amide 1 M in THF (22.24 ml, 22.24 mmol) in dry THF (25 mL), previously cooled to -78 C., a solution of <strong>[16801-63-1]benzyl (4-oxocyclohexyl)carbamate</strong> (2.5 g, 10.11 mmol) in dry THF (25 mL) was slowly added. The solution was stirred for 30 min at -78 C. and then a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (7.58 g, 21.23 mmol) in dry THF (25 mL) was added. The reaction was stirred at -78 C. for 10 min and then allowed to reach room temperature. Reaction was diluted with diethyl ether (200 mL) and organic layer was washed with 1 M NaOH aqueous solution (100 mL). Organic phases were dried over Na2SO4, filtered and solvent was removed under reduced pressure. The product was purified by Biotage Si 50 g with a gradient of heptane and EtOAc to give the titled compound (1.43 g, 3.77 mmol, 37.3% yield) as a white solid.UPLC-MS: 1.25 min, 380 [M+H]+, method 9
  • 68
  • [ 37595-74-7 ]
  • [ 873924-08-4 ]
  • tert-butyl 9-(((trifluoromethyl)sulfonyl)oxy)-3-azaspiro[5.5]undecan-8-ene-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% At -78 deg.C, under nitrogen atmosphere, Example 27C (2 g, 7.5 mmol) in tetrahydrofuran(20 mL) was added dropwise a solution of lithium diisopropylamide (2.5M, 1.22mL, 9 mmol). After the addition was complete, the reaction mixture was stirred for 2 hours. Was then added dropwise 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.67 g, 7.48 mmol, was dissolved in 5mL of THF) into the reaction solution, and stirred at -78 deg.C for 1.5 hours. The mixture was warmed to 10 deg.C and stirred for 2.5 hours, the reaction mixture was treated with ammonium chloride solution (30 mL) quenched (50mL × 2) and extracted with ethyl acetate. The organic layer (50 mL) and washed with brine, dried over Na2SO4 and concentrated to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give the title compound (2.3g, yield 77%) as a brown oil.
To a solution of <strong>[873924-08-4]tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate</strong> (1.0 g, 3.74 mmol) and in THF (20 mL) was added sodium bis(trimethylsilyl)amide (4.86 ml, 4.86 mmol) at -78C. After stirring at -78C for 30 min, 1 , 1 , 1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (1.60 g, 4.49 mmol) was added as solid and stirred for 50 minutes. To the reaction was added saturated aHC03 (100 mL) and the mixture was extracted with EtOAc (2X100 mL). The organic layer was washed with brine, dried over MgS04, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane to give the title compound.
Step A: tert-butyl 9-(((trifluoromethyl)sulfonyl)oxy)-3-azaspiro[5.5]undec-8-ene-3-carboxylate (1291) To a solution of <strong>[873924-08-4]tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate</strong> (1.0 g, 3.74 mmol) and in THF (20 mL) was added sodium bis(trimethylsilyl)amide (4.86 ml, 4.86 mmol) at -78 C. After stirring at -78 C. for 30 min, 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.60 g, 4.49 mmol) was added as solid and stirred for 50 minutes. To the reaction was added saturated NaHCO3 (100 mL) and the mixture was extracted with EtOAc (2×100 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane to give the title compound.
  • 69
  • [ 37595-74-7 ]
  • [ 59942-87-9 ]
  • pyrazolo[1,5-a]pyridin-2-yl trifluoromethanesulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% With sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil; for 1.0h; To a solution of 4a (3.10 g, 23.1 mmol) in THF (17 mL) and DMF (17mL) was added NaH (1.0 g, 25.4 mmol, 60% dispersion in oil) and Tf2NPh (9.90 g, 27.7 mmol) at 0 C. The mixture was stirred for 1 h, then it was added to ice-water and extracted with EtOAc. The organiclayer was washed with brine and dried (Na2SO4). The mixture was concentrated in vacuo. The crude material was purified by flash column chromatography (silica gel, hexane-EtOAc, 10:1) to give 3a as acolorless solid; yield: 6.10 g, 99%); mp 37-38 C.
  • 70
  • [ 37595-74-7 ]
  • [ 51985-95-6 ]
  • methyl 1-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
3.92 g With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere; To a mixture of methyl 5-hydroxy-l-methyl-lH-pyrazole-3- carboxylate (2.404 g) , diisopropylethylamine (5.38 mL) and DMF (24 mL) was added N-phenyIbis (trifluoromethanesulfonimide) (6.05 g) at 0°C, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The. obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) and concentrated under reduced pressure to give the title compound (3.92 g) . H NMR (300 MHz, CDC13) delta 3.92 (3H, s) , 3.94 (3H, s) , 6.69 (1H, s) .
  • 71
  • [ 37595-74-7 ]
  • [ 116047-26-8 ]
  • [ 1116093-95-8 ]
YieldReaction ConditionsOperation in experiment
With potassium hexamethylsilazane; In tetrahydrofuran; at -78 - 20℃; for 16h; To a solution of compound Al 9-2 (3 g, 15 mmol) in dry THF (60 mL) at -78 C was added KHIVIDS (1 M in THF, 20 mL, 20 mmol) dropwise, followed by Tf2NPh (6.43 g, 18 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 hrs. Then the reaction was quenched with water, and neutralized with aqueous HC1 (2N) to pH=7. The organic layer wasseparated and the aqueous solution was extracted with EtOAc two times. The combined organic layers were washed with brine, dried over Na2504 and concentrated in vacuo to afford a residue, which was purified by column chromatography over silica gel to obtain compound A19-3. MS(ESI) m / e (M+H): 336.0/337.1.
  • 72
  • [ 37595-74-7 ]
  • [ 24985-85-1 ]
  • 2-formyl-1H-indol-5-yl trifluoromethanesulfonate [ No CAS ]
  • 73
  • [ 37595-74-7 ]
  • [ 26673-32-5 ]
  • (7-chloro-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate [ No CAS ]
  • 74
  • [ 37595-74-7 ]
  • [ 33668-25-6 ]
  • C10H13F3O5S [ No CAS ]
  • C10H13F3O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With lithium hexamethyldisilazane; In tetrahydrofuran; at -78℃; LiHMDS 1.5 M in THF (0.41 mL, 617 mupiiotaomicron) was added to a solution of ethyl-3-oxocyclohexanecarboxylate (100 mg, 588 muiotatauiotaomicron) in THF (1.3 mL) at - 78C. The resulting mixture was stirred at -78C for 1 h before the addition of PhNTf2 (220 mg, 617 muiotaetaomicron) in THF (1.3 mL). The mixture was stirred at -78C for 30 min and then allowed to warm to rt overnight. The mixture was quenched by addition of NH4C1 sat. (0.86 mL) and the solvent was removed under vacuum. Et20 and an aqueous solution of NaOH (0.3 M) were added and the layers were separated. The organic layer was washed with an aqueous solution of NaOH (0.3 M) (once), a saturated aqueous solution of NH4C1 (once) and brine (once), dried over MgS04, filtered and concentrated in vacuum to give 143 mg of a mixture of intermediate (R15a) and intermediate (R15b) as yellow oil. The crude product was used without further purification in the next step. Reaction scheme : (1199)
  • 75
  • [ 37595-74-7 ]
  • [ 22246-05-5 ]
  • 1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% With triethylamine; In dichloromethane;Inert atmosphere; Under a nitrogen atmosphere, Intermediate 158 (38.3 g, 235 mmol) was suspended in DCM (1 L), thenN-phenyl-bis(trifluoromethanesulfonimide) (84 g, 235 mmol) and triethylamine (33 mL, 235 mmol) were added. The mixture was stirred overnight, diluted with water, and the layers were separated. The aqueous layer was extracted with DCM (500 mL). The combined organic layers were washed with aqueous HC1 (1M) and water, then dried (Na2S04) and evaporated in vacuo. The residue was crystallised from diisopropyl ether, then dried in vacuo at 40C for 2 days, to afford the title compound (37.9 g, 55%). deltaEta (300 MHz, CDCb) 7.97 (s, 1H), 7.42-7.29 (m, 2H), 7.02 (s, 1H), 3.61 (td, J6.7, 2.9 Hz, 2H), 3.04 (t, J6.6 Hz, 2H)
  • 76
  • [ 37595-74-7 ]
  • [ 32263-70-0 ]
  • 6-(benzyloxy)-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% Step 2: 6-(Benzyloxy)-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate 129b To a solution of 129a (26.0 g, 103.05 mmol) in THF (300 mL) was added LiHMDS (1M THF solution, 165 mL, 165 mmol) at -78 C. under N2 atmosphere. The mixture was stirred for 30 minutes and PhNTf2 (55 g, 154.57 mmol) was added to the mixture. The reaction mixture was slowly warmed up to room temperature, and stirring was continued for 2 hours. Water (50 mL) was added to the reaction mixture and the mixture was extracted with DCM (500 mL*2) and two layers were separated. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography eluted with 0-10% EtOAc in petroleum ether to afford 129b (36 g, 91% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 7.42-7.33 (m, 5H), 7.26-7.24 (m, 1H), 6.84-6.80 (m, 2H), 5.85 (t, J=4.8 Hz, 1H), 5.06 (s, 2H), 2.82 (t, J=8.0 Hz, 2H), 2.49-2.44 (m, 2H).
72% Step 2: Preparation of (6-benzyloxy-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate To a solution of <strong>[32263-70-0]6-benzyloxytetralin-1-one</strong> (80 g, 317.07 mmol, 1.00 eq) in tetrahydrofuran (1000 mL) was added lithium diiso-propylamide (2 M, 237.8 mL, 1.50 eq) at -70 C. The mixture was stirred at -70 C. for 1 hour, then 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (124.6 g, 348.78 mmol, 1.10 eq) in tetrahydrofuran (300 mL) was added dropwise to the mixture. The reaction mixture was stirred at 20 C. for 1 hour. TLC (petroleum ether:ethyl acetate=10:1) showed most of the starting material was consumed. Saturated ammonium chloride (600 mL) was added to the mixture, the organic phase was separated. Ethyl acetate (600 mL) was added to the mixture, the resulting mixture was washed with brine (600 mL*2). The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (petroleum ether:ethyl acetate=1:0 to 50:1) to give (6-benzyloxy-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate (88 g, 228.95 mmol, 72% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) delta 7.46-7.33 (m, 5H), 7.27 (d, J=8.4 Hz, 1H), 6.87-6.83 (m, 2H), 5.88 (t, J=4.8 Hz, 1H), 5.09 (s, 2H), 2.85 (t, J=8.0 Hz, 2H), 2.52-2.47 (m, 2H).
  • 77
  • [ 37595-74-7 ]
  • [ 191805-29-5 ]
  • C15H22F3NO5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% A solution of 1M LiHMDS in THF (63 mL, 63 mmol, 2.0 eq) was added dropwise to a solution of l-oxo-8-Azaspiro[4.5]decane-8-carboxylic acid, 1,1-dimethylethyl ester (8.0 g, 31.6 mmol, 1.0 eq) in anhydrous THF (200 mL) at -78 C. The reaction mixture was stirred for 2h at -78 C, then a solution of N,N-bis(trifluoromethylsulfonyl)aniline (22.6 g, 63.0 mmol, 2.0 eq) in anhydrous THF (60 mL) was added dropwise. After complete addition, the cooling bath was replaced with a bath at 0 C and the reaction was maintained at 0 C overnight. The reaction was quenched with sat. Na2C03 and then was added diethyl ether, water and brine. The organic phase was separated, washed twice with sat. Na2C03, once with brine, dried over MgSC^, filtered and concentrated in vacuo to afford the crude product. The crude product was purified by normal phase flash chromatography (330g Si02) using EtOAc containing 1% Et3N and Heptane containing 1% Et3N as eluent (gradient: 0% to 10% EtOAc containing 1% Et3N; isocratic: 10% EtOAc containing 1% Et3N), to afford intermediate 525 as white solid (9.4 g, 24 mmol, yield: 78%)
  • 78
  • [ 37595-74-7 ]
  • [ 181269-69-2 ]
  • [ 34846-90-7 ]
  • 2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-amine [ No CAS ]
  • N-(isoxazol-3-yl)-2-oxooxazolidine-3-sulfonamide [ No CAS ]
  • (rac)-N-(isoxazol-3-yl)-7-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-sulfonamide [ No CAS ]
  • (rac)-N-(isoxazol-3-yl)-5-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-sulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
A 250-mL round-bottom flask was charged with (Rac)-tert-butyl 3-methy 1-4-oxopiperidine-1-carboxylate (5.00 g, 23.4 mmol) and purged with nitrogen. THF (47.0 ml) was introduced and the reaction mixture was cooled to -78 °C in a dry ice-acetone bath. A solution of potassium /er/-butoxide (1.6 M in THF, 19.0 mL, 29.9 mmol) was added to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to 0 °C in an ice-water bath. After 30 min, the reaction mixture was cooled to -78 °C. Methyl 3 -methoxy aery late (5.29 ml, 49.2 mmol) was added dropwise to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to ambient temperature. After 2 h, the resultant red reaction mixture was cooled was cooled to -78 °C. N-phenyl bis-trifluoromethane sulfonamide (13.2 g, 37.0 mmol) was added to the vigorously stirred, cooled reaction mixture in one portion and the reaction mixture was subsequently allowed to warm to 0 °C in an ice-water bath. After 1 h, saturated aqueous sodium bicarbonate solution (100 mL) and EtOAc (100 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography in two portions (100-g silica gel Biotage column, eluent: gradient, 0 to 30percent EtOAc in heptane) to afford a mixture of (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-2-methy 1-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (11.75 g, 27.4 mmol, 117 percent yield) as a yellow solid.A 20-mL vial was charged with a mixture of (Rac)-(E)-tert-buty 1 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((lrifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-buty\ 3-(3-methoxy-3-oxoprop-1 -en-1 -yl)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (716 mg, 1.668 mmol), 2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny 1]-4-amine (Preparation 4h, 352 mg, 1.39 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (101 mg, 0.174 mmol), cesium carbonate (1.36 g, 4.17 mmol), tris(dibenzylideneacetone)dipalladium(0) (63.9 mg, 0.07 mmol), and 1,4-dioxane (6.95 mL) then sparged with nitrogen for 10 min. The needle was then removed and the reaction was heated to 100 °C. After 3 h, the reaction mixture was allowed to cool to ambient temperature and was diluted with EtOAc (15 mL) and filtered through a Celite® pad. The pad was rinsed with EtOAc (3 x 15 mL). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (50-g silica gel Biotage column, eluent: gradient, 0 to 35percent 3:1 EtOAc/EtOH in heptane with DCM as a 10percent additive) to afford a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-l-(2,3',5'-trifluoro-5-methoxy-[l,r-biphenyl]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-bu\y\ 5-methy 1-2-oxo-1-(2,3',5'-lrifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (587 mg, 1.17 mmol, 84.0percent) as a brown solid,A 20-mL vial was charged with a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-butyl 5-methy 1-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxy late (587 mg, 1.173 mmol) and trifluoroacetic acid (5.86 mL) at ambient temperature. After 30 min, the reaction mixture was concentrated under reduced pressure, dissolved in DCM (15 mL) and carefully poured into saturated aqueous sodium bicarbonate solution (15 mL). The layers were separated and the aqueous layer extracted with additional DCM (3 x 15 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to afford a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-l-(2,3',5'-trifluoro-5-methoxy-[l,l'-biphenyl]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-butyl 5-methy 1-2-oxo-1-(2,3',5'-lrifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (400 mg, 1.00 mmol, 85.0percent) as a tan amorphous solid, which was used without further purification.20-mL vial was charged with a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-butyl 5-methy 1-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (400 mg, 1.00 mmol), N-(isoxazol-3-yl)-2-oxooxazol...
  • 79
  • [ 37595-74-7 ]
  • [ 181269-69-2 ]
  • [ 34846-90-7 ]
  • 2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-amine [ No CAS ]
  • (rac)-tert-butyl 7-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-carboxylate [ No CAS ]
  • (rac)-tert-butyl 5-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
A 250-mL round-bottom flask was charged with (Rac)-tert-butyl 3-methy 1-4-oxopiperidine-1-carboxylate (5.00 g, 23.4 mmol) and purged with nitrogen. THF (47.0 ml) was introduced and the reaction mixture was cooled to -78 °C in a dry ice-acetone bath. A solution of potassium /er/-butoxide (1.6 M in THF, 19.0 mL, 29.9 mmol) was added to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to 0 °C in an ice-water bath. After 30 min, the reaction mixture was cooled to -78 °C. Methyl 3 -methoxy aery late (5.29 ml, 49.2 mmol) was added dropwise to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to ambient temperature. After 2 h, the resultant red reaction mixture was cooled was cooled to -78 °C. N-phenyl bis-trifluoromethane sulfonamide (13.2 g, 37.0 mmol) was added to the vigorously stirred, cooled reaction mixture in one portion and the reaction mixture was subsequently allowed to warm to 0 °C in an ice-water bath. After 1 h, saturated aqueous sodium bicarbonate solution (100 mL) and EtOAc (100 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography in two portions (100-g silica gel Biotage column, eluent: gradient, 0 to 30percent EtOAc in heptane) to afford a mixture of (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-2-methy 1-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (11.75 g, 27.4 mmol, 117 percent yield) as a yellow solid.A 20-mL vial was charged with a mixture of (Rac)-(E)-tert-buty 1 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((lrifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-buty\ 3-(3-methoxy-3-oxoprop-1 -en-1 -yl)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (716 mg, 1.668 mmol), 2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny 1]-4-amine (Preparation 4h, 352 mg, 1.39 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (101 mg, 0.174 mmol), cesium carbonate (1.36 g, 4.17 mmol), tris(dibenzylideneacetone)dipalladium(0) (63.9 mg, 0.07 mmol), and 1,4-dioxane (6.95 mL) then sparged with nitrogen for 10 min. The needle was then removed and the reaction was heated to 100 °C. After 3 h, the reaction mixture was allowed to cool to ambient temperature and was diluted with EtOAc (15 mL) and filtered through a Celite® pad. The pad was rinsed with EtOAc (3 x 15 mL). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (50-g silica gel Biotage column, eluent: gradient, 0 to 35percent 3:1 EtOAc/EtOH in heptane with DCM as a 10percent additive) to afford a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-l-(2,3',5'-trifluoro-5-methoxy-[l,r-biphenyl]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-bu\y\ 5-methy 1-2-oxo-1-(2,3',5'-lrifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (587 mg, 1.17 mmol, 84.0percent) as a brown solid,
  • 80
  • [ 37595-74-7 ]
  • [ 181269-69-2 ]
  • [ 34846-90-7 ]
  • 2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-amine [ No CAS ]
  • C22H19F3N2O2 [ No CAS ]
  • C22H19F3N2O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
A 250-mL round-bottom flask was charged with (Rac)-tert-butyl 3-methy 1-4-oxopiperidine-1-carboxylate (5.00 g, 23.4 mmol) and purged with nitrogen. THF (47.0 ml) was introduced and the reaction mixture was cooled to -78 °C in a dry ice-acetone bath. A solution of potassium /er/-butoxide (1.6 M in THF, 19.0 mL, 29.9 mmol) was added to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to 0 °C in an ice-water bath. After 30 min, the reaction mixture was cooled to -78 °C. Methyl 3 -methoxy aery late (5.29 ml, 49.2 mmol) was added dropwise to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to ambient temperature. After 2 h, the resultant red reaction mixture was cooled was cooled to -78 °C. N-phenyl bis-trifluoromethane sulfonamide (13.2 g, 37.0 mmol) was added to the vigorously stirred, cooled reaction mixture in one portion and the reaction mixture was subsequently allowed to warm to 0 °C in an ice-water bath. After 1 h, saturated aqueous sodium bicarbonate solution (100 mL) and EtOAc (100 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography in two portions (100-g silica gel Biotage column, eluent: gradient, 0 to 30percent EtOAc in heptane) to afford a mixture of (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-2-methy 1-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (11.75 g, 27.4 mmol, 117 percent yield) as a yellow solid.A 20-mL vial was charged with a mixture of (Rac)-(E)-tert-buty 1 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((lrifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-buty\ 3-(3-methoxy-3-oxoprop-1 -en-1 -yl)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (716 mg, 1.668 mmol), 2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny 1]-4-amine (Preparation 4h, 352 mg, 1.39 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (101 mg, 0.174 mmol), cesium carbonate (1.36 g, 4.17 mmol), tris(dibenzylideneacetone)dipalladium(0) (63.9 mg, 0.07 mmol), and 1,4-dioxane (6.95 mL) then sparged with nitrogen for 10 min. The needle was then removed and the reaction was heated to 100 °C. After 3 h, the reaction mixture was allowed to cool to ambient temperature and was diluted with EtOAc (15 mL) and filtered through a Celite® pad. The pad was rinsed with EtOAc (3 x 15 mL). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (50-g silica gel Biotage column, eluent: gradient, 0 to 35percent 3:1 EtOAc/EtOH in heptane with DCM as a 10percent additive) to afford a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-l-(2,3',5'-trifluoro-5-methoxy-[l,r-biphenyl]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-bu\y\ 5-methy 1-2-oxo-1-(2,3',5'-lrifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (587 mg, 1.17 mmol, 84.0percent) as a brown solid,A 20-mL vial was charged with a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-butyl 5-methy 1-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxy late (587 mg, 1.173 mmol) and trifluoroacetic acid (5.86 mL) at ambient temperature. After 30 min, the reaction mixture was concentrated under reduced pressure, dissolved in DCM (15 mL) and carefully poured into saturated aqueous sodium bicarbonate solution (15 mL). The layers were separated and the aqueous layer extracted with additional DCM (3 x 15 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to afford a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-l-(2,3',5'-trifluoro-5-methoxy-[l,l'-biphenyl]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-butyl 5-methy 1-2-oxo-1-(2,3',5'-lrifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (400 mg, 1.00 mmol, 85.0percent) as a tan amorphous solid, which was used without further purification.
  • 81
  • [ 37595-74-7 ]
  • [ 3612-20-2 ]
  • [ 34846-90-7 ]
  • (E)-methyl 3-(1-benzyl-4-(((trifluoromethyl)sulfonyl)oxy)-1,2,5,6-tetrahydropyridin-3-yl)acrylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
66.4% A 250-mL round-bottom flask was charged with 1 -benzy 1-4-piperidone(Sigma Aldrich, 2.68 ml, 15.0 mmol) and purged with nitrogen. THF (75 ml) was introduced, and the resultant solution cooled to -78 °C in a dry ice-acetone bath. A solution of potassium /erZ-butoxide (1.0 M in THF, 18.0 mL, 18.0 mmol) was added to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to 0 °C in an ice-water bath. After 30 min, the reaction mixture was cooled to -78 °C. Methyl 3-methoxy aery late (22.8 mL, 212 mmol) was added dropwise to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to ambient temperature. After 1 h, the reaction mixture was cooled was cooled to -78 °C. N-phenyl bis-trifluoromethane sulfonimide (6.43 g, 159 mmol) was added to the vigorously stirred, cooled reaction mixture in one portion and the reaction mixture was subsequently allowed to warm to 0 °C in an ice-water bath. After 1 h, saturated aqueous sodium bicarbonate solution (50 mL) and EtOAc (50 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (100-g silica gel Biotage column, eluent: gradient, 0 to 30percent EtOAc in heptane) to afford (E)-methyl 3-(1-benzyl-4-(((trifluoromethyl)sulfonyl)oxy)-1,2,5,6-tetrahydropyridin-3-yl)acrylate (4.04 g, 9.97 mmol, 66.4 percent yield) as an orange oil.
  • 82
  • [ 37595-74-7 ]
  • [ 181269-69-2 ]
  • [ 34846-90-7 ]
  • (rac)-(E)-tert-butyl 3-(3-methoxy-3-oxoprop-1-en-1-yl)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
  • (rac)-(E)-tert-butyl 3-(3-methoxy-3-oxoprop-1-en-1-yl)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
A 250-mL round-bottom flask was charged with (Rac)-tert-butyl 3-methy 1-4-oxopiperidine-1-carboxylate (5.00 g, 23.4 mmol) and purged with nitrogen. THF (47.0 ml) was introduced and the reaction mixture was cooled to -78 °C in a dry ice-acetone bath. A solution of potassium /er/-butoxide (1.6 M in THF, 19.0 mL, 29.9 mmol) was added to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to 0 °C in an ice-water bath. After 30 min, the reaction mixture was cooled to -78 °C. Methyl 3 -methoxy aery late (5.29 ml, 49.2 mmol) was added dropwise to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to ambient temperature. After 2 h, the resultant red reaction mixture was cooled was cooled to -78 °C. N-phenyl bis-trifluoromethane sulfonamide (13.2 g, 37.0 mmol) was added to the vigorously stirred, cooled reaction mixture in one portion and the reaction mixture was subsequently allowed to warm to 0 °C in an ice-water bath. After 1 h, saturated aqueous sodium bicarbonate solution (100 mL) and EtOAc (100 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography in two portions (100-g silica gel Biotage column, eluent: gradient, 0 to 30percent EtOAc in heptane) to afford a mixture of (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-2-methy 1-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (11.75 g, 27.4 mmol, 117 percent yield) as a yellow solid.
  • 83
  • [ 37595-74-7 ]
  • [ 34846-90-7 ]
  • [ 79099-07-3 ]
  • (E)-tert-butyl 3-(3-methoxy-3-oxoprop-1-en-1-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% A 1-L round-bottom flask was charged with /ert-butyl 4-oxopiperidine-l- carboxylate (Sigma Aldrich, 20.0 g, 100 mmol) and purged with nitrogen. THF (57 ml) was introduced, and the resultant solution cooled to -78 °C in a dry ice-acetone bath. A solution of potassium /ert-butoxide (1.6 M in THF, 80 mL, 128 mmol, 1.28 equiv) was added to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to 0 °C in an ice-water bath. After 30 min, the peach colored reaction mixture was cooled to -78 °C. Methyl 3-methoxyacrylate (22.8 mL, 212 mmol, 2.11 equiv) was added dropwise to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to ambient temperature. After 2 h, the resultant red reaction mixture was cooled was cooled to -78 °C. N-phenyl bis-trifluoromethane sulfonimide (56.7 g, 159 mmol, 1.58 equiv) was added to the vigorously stirred, cooled reaction mixture in one portion and the resultant reaction mixture was subsequently allowed to warm to 0 °C in an ice-water bath. After 1 h, saturated aqueous sodium bicarbonate solution (200 mL) and EtOAc (200 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EtOAc (3150 mL), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography in two portions (340-g silica gel Biotage column, eluent: gradient, 0 to 30percent EtOAc in heptane with 1percent Et3N as an additive) to afford (E)-tert-butyl 3-(3-methoxy-3-oxoprop-1-en-1-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (38.0 g, 91 mmol, 91percent yield) as a off-white solid.
  • 84
  • [ 37595-74-7 ]
  • [ 70163-98-3 ]
  • methyl 3-fluoro-2-(triflate)benzoate [ No CAS ]
  • 85
  • [ 37595-74-7 ]
  • C17H26O7 [ No CAS ]
  • [ 456-64-4 ]
  • C18H25F3O9S [ No CAS ]
  • 86
  • [ 37595-74-7 ]
  • [ 954236-44-3 ]
  • [ 1227472-19-6 ]
YieldReaction ConditionsOperation in experiment
80% Potassium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran; 58.8 mL, 58.8 mmol) was added drop-wise to a -70 C. solution of <strong>[954236-44-3]tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate</strong> (10.0 g, 39.2 mmol) in tetrahydrofuran (250 mL). After the reaction mixture had been stirred at -70 C. for 30 minutes, a solution of 1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (18.2 g, 50.9 mmol) in tetrahydrofuran (100 mL) was slowly added. The reaction mixture was then warmed to 20 C. and stirred for 1 hour, whereupon it was quenched, via addition of saturated aqueous ammonium chloride solution (200 mL), and diluted with water (300 mL). The resulting mixture was extracted with ethyl acetate (3*300 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Repeated silica gel chromatography (Gradient: 0% to 10% ethyl acetate in petroleum ether), followed by final chromatographic purifications on silica gel (Gradient: 0% to 2% ethyl acetate in petroleum ether, followed by 100% ethyl acetate) afforded the product as a white solid. Yield: 12.2 g, 31.5 mmol, 80%. LCMS m/z 332.0 [(M-2-methylprop-1-ene)+H]+. 1H NMR (400 MHz, CDCl3) delta 5.75 (t, J=2.2 Hz, 1H), 4.65 (d, J=2.0 Hz, 2H), 3.84-3.69 (br m, 2H), 3.32-3.20 (m, 2H), 1.74-1.66 (m, 4H), 1.47 (s, 9H).
  • 87
  • [ 37595-74-7 ]
  • [ 29419-14-5 ]
  • 2-trifluoromethanesulfonyloxy-6-fluoro-1,4-dihydronaphthalene [ No CAS ]
YieldReaction ConditionsOperation in experiment
28% At -78 C, to LiHMDS (bis-trimethylsilylamide lithium, 1 M, 14.6 mL,14.6 mmol) of tetrahydrofuran (20 mL)A solution of <strong>[29419-14-5]6-fluoro-3,4-dihydronaphthalene-2(1H)-one</strong> (2 g, 12.2 mmol) in tetrahydrofuran (20 mL) was added dropwise.After one hour of reaction,A solution of N-phenylbis(trifluoromethanesulfonyl)imide (4.8 g, 13.4 mmol) in tetrahydrofuran (20 mL) was added dropwise.Stirring was continued for one hour at -78 C.It was then stirred at room temperature for 15 hours.The reaction was quenched with saturated sodium bicarbonate solution.Add 2M sodium hydroxide solution,Extract with ethyl acetate (3 × 100 mL), and wash with saturated brine.Dry over anhydrous sodium sulfate and spin dry to obtain crude product.Purified with petroleum ether to give compound 31A(1 g, 28% yield).
  • 88
  • [ 37595-74-7 ]
  • [ 126-07-8 ]
  • (2S,6'R)-7-chloro-2',4,6-trimethoxy-6'-methyl-3-oxo-3H-spiro[benzofuran-2,1'-cyclohexane]-2',4'-dien-4'-yl trifluoromethanesulfonate [ No CAS ]
  • 89
  • [ 37595-74-7 ]
  • [ 13916-98-8 ]
  • [ 870134-84-2 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine; In dichloromethane; at 20℃;Inert atmosphere; A solution of <strong>[13916-98-8]8-fluoronaphthalen-2-ol</strong> (640 mg, 3.87 mmol) and TEA (1.40 mL, 10.04 mmol) in anh. DCM(38 mL) is treated portionwise at RT with 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.678 g, 4.65 mmol) and the RM is stirred at RT, under nitrogen, overnight. The RM is then concentrated under reduced pressure. Purification by FC (from heptane to heptane/EtOAc = 7/3) affords 8-fluoronaphthalen-2-yl trifluoromethanesulfonate as a yellow oil (1.33 g, quantitative). LC-MS B: tR = 1.09 mm; no ionization.
  • 90
  • [ 37595-74-7 ]
  • [ 22080-96-2 ]
  • C10H9F3O6S [ No CAS ]
YieldReaction ConditionsOperation in experiment
77.1% With potassium carbonate; In acetone; at 35℃; for 48h; Embodiment 2 (S)-(1-(2,6-Dimethoxy-4-((2-methyl-biphenyl-3-yl)ethynyl)benzyl)pyrrolidin -2-yl)methanol 2 Synthetic route Synthesis of compound 2-f Potassium carbonate (304mg, 2.20mmol) was added to a solution of <strong>[22080-96-2]2,6-dimethoxy-4-hydroxybenzaldehyde</strong> (200mg, 1.10mmol) and N-phenylbis(trifluoromethanesulfonimide) (393mg, 1.10mmol) in acetone (10mL). The reaction solution was stirred at 35C for 48 hours, then evaporated under reduced pressure. The residue was diluted with ethyl acetate (20mL), then washed successively with water (20mL) and saturated brine (20mL). The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to give compound 2-f (266mg, yield 77.1%). 1H NMR (400 MHz, CDCl3) delta: 10.43 (s, 1H), 6.49 (s, 2H), 3.93 (s, 6H) ppm.
  • 91
  • [ 37595-74-7 ]
  • [ 127685-76-1 ]
  • trifluoromethanesulfonic acid 2-fluoro-6-methoxy-4-methylphenyl ester [ No CAS ]
  • 92
  • [ 37595-74-7 ]
  • [ 22245-98-3 ]
  • [ 897374-38-8 ]
  • 93
  • [ 37595-74-7 ]
  • [ 40594-34-1 ]
  • (4-(dimethylamino)cyclohex-1-en-1-yl)trifluoromethane sulphonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With lithium bis(dimethylsilyl)amide; In tetrahydrofuran; at -78 - 20℃;Inert atmosphere; a) 4-((dimethylamino)cyclohex-1-en-1-yl)trifluoromethane sulphonate <strong>[40594-34-1]4-dimethylaminocyclohexanone</strong> (500 mg, 3.54 mmol) was dissolved in anhydrous THF (10 mL), and N-phenylbis(trifluoromethanesulfonyl)imine (1.39 g, 3.9 mmol) was added. The atmosphere in the reaction system was replaced with nitrogen three times. After the temperature of the reaction system was lowered to -78 C, lithium dimethylsilylamide (4.3 mL, 4.25 mmol) was added dropwise slowly. After the addition was completed, the temperature was raised to rt and the mixture was stirred overnight. EA (20 mL) and water (5 mL) were added to the reaction solution for extraction and separation. The aqueous phase was extracted with EA (10 mL*2). The organic phases were combined, washed with a saturated saline solution (15 mL), dried with anhydrous sodium sulfate, filtered and concentrated at reduced pressure to obtain a crude product. Isolation and purification by column chromatography (silica gel, DCM: MeOH = 10:1 as an eluant) were performed to obtain the targeted compound (630 mg, 65% yield, pale yellow oily substance). LC-MS (ESI): m/z (M+1) 274.07.
  • 94
  • [ 37595-74-7 ]
  • [ 17396-35-9 ]
  • 1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl trifluoromethanesulfonate [ No CAS ]
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