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Chemical Structure| 37595-74-7 Chemical Structure| 37595-74-7
Chemical Structure| 37595-74-7

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Synonyms: N-Phenyltrifluoromethanesulfonimide

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Product Citations

Henderson, Ian M. ; Zeng, Fanxun ; Bhuiyan, Nazmul H. ; Luo, Dan ; Martinez, Maria ; Smoake, Jane , et al.

Abstract: Interest in development of potent, selective inhibitors of the phosphatase from the receptor type protein tyrosine phosphatase PTPRD as antiaddiction agents is supported by human genetics, mouse models and studies of our lead compound PTPRD phosphatase inhibitor, 7-butoxy illudalic acid analog 1 (7-BIA). We now report structure-activity relationships for almost 70 7-BIA-related compounds and results that nominate a 7- cyclopentyl methoxy analog as a candidate for further development. While efforts to design 7-BIA analogs with substitutions for other parts failed to yield potent inhibitors of PTPRDs phosphatase, ten 7-position substituted analogs displayed greater potency at PTPRD than 7-BIA. Several were more selective for PTPRD vs the receptor type protein tyrosine phosphatases S, F and J or the nonreceptor type protein tyrosine phosphatase N1 (PTPRS, PTPRF, PTPRJ or PTPN1/PTP1B), phosphatases at which 7-BIA displays activity. In silico studies aided design of novel analogs. A 7-position cyclopentyl methoxy substituted 7-BIA analog termed NHB1109 displayed 600-700 nM potencies in inhibiting PTPRD and PTPRS, improved selectivity vs PTPRS, PTPRF, PTPRJ or PTPN1/PTP1B phosphatases, no substantial potency at other protein tyrosine phosphatases screened, no significant potency at any of the targets of clin.-useful drugs identified in EUROFINS screens and significant oral bioavailability. Oral doses up to 200 mg/kg were well tolerated by mice, though higher doses resulted in reduced weight and apparent ileus without clear organ histopathol. NHB1109 provides a good candidate to advance to in vivo studies in addiction paradigms and toward human use to reduce reward from addictive substances.

Keywords: Receptor type protein tyrosine phosphatase ; Cell adhesion molecule ; Addiction ; Drug reward ; Opiates ; Stimulants

Alternative Products

Product Details of N,N-Bis(trifluoromethylsulfonyl)aniline

CAS No. :37595-74-7
Formula : C8H5F6NO4S2
M.W : 357.25
SMILES Code : C1=C(N([S](C(F)(F)F)(=O)=O)[S](C(F)(F)F)(=O)=O)C=CC=C1
Synonyms :
N-Phenyltrifluoromethanesulfonimide
MDL No. :MFCD00000404
InChI Key :DIOHEXPTUTVCNX-UHFFFAOYSA-N
Pubchem ID :142176

Safety of N,N-Bis(trifluoromethylsulfonyl)aniline

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P264-P280-P302+P352-P305+P351+P338-P332+P313-P337+P313-P362+P364

Application In Synthesis of N,N-Bis(trifluoromethylsulfonyl)aniline

* 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   1~35

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  • [ 23432-43-1 ]
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  • Trifluoro-methanesulfonic acid 6-chloro-quinolin-4-yl ester [ No CAS ]
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  • [ 67342-99-8 ]
  • (Z)-3-Trifluoromethanesulfonyloxy-dodec-2-enoic acid ethyl ester [ No CAS ]
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  • [ 19090-04-1 ]
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  • [ 194665-78-6 ]
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  • [ 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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  • [ 21906-39-8 ]
  • [ 625382-97-0 ]
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  • [ 703-67-3 ]
  • [ 556107-58-5 ]
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  • [ 19832-98-5 ]
  • [ 851485-48-8 ]
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  • [ 7651-82-3 ]
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  • [ 149353-93-5 ]
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  • [ 516-09-6 ]
  • [ 157123-02-9 ]
  • 10
  • [ 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).
  • 11
  • [ 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
  • 12
  • [ 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).
  • 13
  • [ 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.

  • 14
  • [ 37595-74-7 ]
  • [ 52927-22-7 ]
  • [ 145369-29-5 ]
  • 15
  • [ 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)+.
  • 16
  • [ 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.
  • 17
  • [ 37595-74-7 ]
  • [ 53400-41-2 ]
  • [ 890028-85-0 ]
  • 18
  • [ 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.

  • 19
  • [ 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).
  • 20
  • [ 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.
  • 21
  • [ 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)+.
  • 22
  • [ 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)+.
  • 23
  • [ 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)+.
  • 24
  • [ 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)+.
  • 25
  • [ 37595-74-7 ]
  • [ 15777-70-5 ]
  • 4-cyano-2-methylphenyl trifluoromethanesulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% With triethylamine; In dichloromethane; at 20℃; To a stirred solution of <strong>[15777-70-5]4-hydroxy-3-methylbenzonitrile</strong> (commercial source, 0.45 g, 3.38 mmol) and triethylamine (0.708 ml, 5.08 mmol) in dry DCM (8 ml) was added aniline triflate (1 .44 g, 4.03 mmol) and the mixture was stirred overnight at RT. The reaction mixture was diluted with diethylether (50 ml), washed with water, brine, dried over sodium sulfate, concentrated and purified by flash column chromatography to obtain the title compound (0.43 g) as colorless semi solid. Yield: 48%; 1 H NMR (CDCI3, 300 MHz): δ 7.655 (s, 1 H), 7.62 (d, J=8.7 Hz, 1 H), 7.408 (d, J=8.7 Hz, 1 H), 2.445 (s, 3H); MS: (m/z) 265.9 (M+H).
  • 26
  • [ 37595-74-7 ]
  • [ 18938-60-8 ]
  • [ 174003-17-9 ]
YieldReaction ConditionsOperation in experiment
99.6% With triethylamine; In dichloromethane; at 5 - 25℃; for 20h;Large scale; To a 100L stirred reactor was charged with dichloromethane (94.3 kg). The contents was cooled to 5±3C. N-tert-butoxycarbonyl-L-tyrosine-t-butyl ester (12.5 kg, 37.0 moles) (2) and N-phenyl-bis(trifluoromethane sulfonimide(13.5 kg, 37.8 moles) were charged to the reactor. Triethylamine (5.5 kg, 54.5 moles) was slowly added to the reactor while keeping the temperature below 10C. The mixture was heated to 25±5C and the mixture stirred at this temperature for 20h. The mixture was sampled for completion of reaction by HPLC analysis. The mixture was concentrated by distillation to minimum stir volume at 40±5C. Petroleum ether (65 kg) and water (37 kg) were charged to the reactor, consecutively and the mixture stirred. Saturated sodium carbonate solution (15 kg) was charged to the reactor. Methanol (8.1 kg) was charged to the reactor. Themixture was stirred for 10-15 minutes then the stirring was stopped to allow for the phases to separate. The phases were separated and the aqueous phase returned to the reactor. Petroleum ether (22 kg) was added to the reactor and the mixture stirred for 10-15 mins. The stirring was stopped to allow the phases to separate. The aqueous phase was drained from the reactor and the first organic extract wascombined with the organic phase in the reactor. Brine (50 kg) was charged to the reactor and the mixture stirred for 10-15 minutes. Stirring was stopped to allow the phases to separate. The aqueous phase was drained and discarded. The organic phase was drained to a drum. To this drum was added sodium sulfate (5kg) and the mixture stirred. The mixture was transferred to a rotary evaporator vessel througha filter remove the solid sodium sulfate. The solution was concentrated by rotary evaporation to dryness to afford tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-3 -(4- (((trifluoromethyl)sulfonyl)oxy) phenyl)propanoate (3) (17.3 kg, 36.8 moles, 99.6 % yield, purity: 98.8%).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 39h; To a stirred solution of tert-butyl (tert-butoxycarbonyl)-Z-tyrosinate (145 g, 429 mmol) in DCM (1.5 L) was added DIEA (95 mL, 514 mmol) then 1,1,1- trifluoro-iV-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (7.66 g, 21.5 mmol). After 16 h, additional 1,1,1-trifluoro-JV-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (7.66 g, 21.5 mmol) was added. After a further 3 h, additional 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (153.11 g, 429 mmol) was added. After a further 20 h, the mixture was washed successively with a solution of citric acid monohydrate (105 g, 500 mmol) in water (1.5 L) then saturated aqueous sodium bicarbonate (1 L). The organics were dried over Na2SO4 and solvents evaporated to afford tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4- (((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate, overweight with phenyltriflimide and used crude for the next step. LCMS-ESI (m/z) calculated for Ci9H26F3NO7S: 469.1 ; found 492.2 [M+Na]+, tR = 2.87 min (Method 11).
  • 27
  • [ 37595-74-7 ]
  • [ 24985-85-1 ]
  • 2-formyl-1H-indol-5-yl trifluoromethanesulfonate [ No CAS ]
  • 28
  • [ 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%)
  • 29
  • [ 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...
  • 30
  • [ 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,
  • 31
  • [ 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.
  • 32
  • [ 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.
  • 33
  • [ 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.
  • 34
  • [ 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.
  • 35
  • [ 37595-74-7 ]
  • [ 127685-76-1 ]
  • trifluoromethanesulfonic acid 2-fluoro-6-methoxy-4-methylphenyl ester [ No CAS ]
 

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