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[ CAS No. 138647-49-1 ]

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Chemical Structure| 138647-49-1
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CAS No. :138647-49-1 MDL No. :MFCD09997858
Formula : C11H16F3NO5S Boiling Point : -
Linear Structure Formula :- InChI Key :N/A
M.W :331.31 g/mol Pubchem ID :10991161
Synonyms :

Safety of [ 138647-49-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338-P310 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
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Application In Synthesis of [ 138647-49-1 ]

  • Upstream synthesis route of [ 138647-49-1 ]
  • Downstream synthetic route of [ 138647-49-1 ]

[ 138647-49-1 ] Synthesis Path-Upstream   1~35

  • 1
  • [ 138647-49-1 ]
  • [ 26905-02-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 10, p. 1731 - 1735
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  • [ 138647-49-1 ]
  • [ 58333-75-8 ]
Reference: [1] Patent: WO2014/100501, 2014, A1,
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  • [ 138647-49-1 ]
  • [ 37656-48-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 6, p. 1724 - 1739
[2] Patent: WO2011/139107, 2011, A2,
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  • [ 37595-74-7 ]
  • [ 138647-49-1 ]
YieldReaction ConditionsOperation in experiment
96%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 1.25 h;
Stage #2: at -78 - 20℃;
Di-zso-propylamine (22 ml) was dissolved in dry TηF (125 ml) and cooled to -78°C. 72-Butyllithium (62.5 ml, 2.5M) was added dropwise. The solution was stirred for 15 minutes, then tert-bxxtyl 4-oxopiperidine-l-carboxylate (28.32 g) in TηF (100 ml) was added dropwise. The reaction mixture was stirred for 1 hour at -780C, then N- phenyltrifluoromethanesulfonimide (53.8 g) in TηF (150 ml) was added dropwise. The reaction mixture was stirred at -780C for 2 hours and allowed to warm up to room <n="89"/>temperature and stirred overnight. The reaction mixture was then concentrated in vacuo and the residue dissolved in ether (1000 ml). This was washed with water (500 ml), 2M sodium hydroxide solution (3 x 500 ml), water (500 ml) and brine (500 ml) then dried over magnesium sulfate and concentrated to give the title compound as a pale brown oil (45.38 g, 96percent) which was used without further purification; 1H NMR (CDCl3) δl.48 (9H, s), 2.44 (2H, m), 3.63 (2H, t), 4.00 (2H, q), 5.70 (IH, br m).
83%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexanes at -78℃; for 0.5 h;
Stage #2: for 0.333333 h;
Stage #3: at 20℃;
A 1.6 M solution of n-butyllithium in hexanes (6.9 ml, 11 mmol) was added to a stirred solution of diisopropylamine (1. 5 ml, 11 mmol) in THF at-78°C and the mixture stirred for 30 minutes. A solution of t-butyl 4-oxopiperidine-1-carboxylate (2.0 g, 10 mmol) in THF was added and after 20 minutes a solution of N-phenyl-bis (trifluoromethanesulfonimide) (3. 9 g, 11 mmol) in THF was added. The mixture was stirred at ambient temperature overnight and the solvent evaporated. The resultant residue was partioned between diethyl ether and a 2M solution of aqueous sodium hydroxide, the organic layer separated, washed once with brine and dried over magnesium sulfate, filtered and evaporated to give the title compound (3.01 g, 83percent); NMR Spectrum : (DMSO-d6) 1.48 (s, 9H), 2.44 (m, 2H), 3.63 (t, 2H), 4.04 (d, 2H), 5.76 (s, 1H).
79.5%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78 - 20℃; for 0.666667 h;
Stage #2: at 20℃;
A solution of A/"-boc-piperidin-4-one (10.14 g, 50 mmol) in THF (80 mL) was added to acooled solution (-78 °C) of 2M LDA in THF (30 mL, 60 mmol, 1.2 eq.) and THF (80 mL)over approximately 30 minutes. After stirring a further 10 minutes, a solution of 1,1,1-trifluoro-TV-phenyl-A^t^fluoromethy^sulfonyllmethanesulfonamide (20 g, 56 mmol, 1.1eq.) in THF (80 mL) was added and the mixture was allowed to warm to roomtemperature. The solution was washed with water, the aqueous layer washed with EtOAc(x2), organic phases combined and washed with saturated ammonium chloride solution,brine, dried (sodium sulphate) and evaporated. The residue was filtered through neutralAlumina (200 g) eluting with n-heptane followed by n-heptane/EtOAc 9:1. Afterevaporation the .H-NMR showed some triflating agent still present but the crude productwas used without further purification. Yield (13.17 g, 79.5percent). (Wustrow, D. J., Synthesis,1991, 993-995).*H NMR (CDC13) 5 5.77 (1H, s), 4.05 (2H, q), 3.64 (2H, t), 2.45 (2H, quintet), 1.48 (9H,s).GCMS-MS m/z: 274 [M-57].
52%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 3.41667 h;
Stage #2: at -78 - 20℃; for 18.9167 h;
Example 13B-1. 2-(l-r(2-chlorophenyl")sulfonvπpiperidin-4-vU-3-(trif1uoromethvπpyridine; Step 13BA: 4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-lcarboxylic acid tert-butyl ester; The vinyl triflate was prepared from tert-butyl-4-oxopiperidine-l-carboxylate using the procedure from WO 2004/ 036649. To a -78 0C solution of diisopropylamine {6.0 mL, 42.1 mmol) in THF (59 mL) was added drop wise a solution of n-BuLi (2.5 M in hexanes, 16.8 mL, 42.1 mmol) over 15 min. After 2 h a solution of the piperidone (7.13 g, 35.1 mmol) in THF (59 mL) was added drop wise over 30 min. After 40 min at -78 0C a solution of N- phenyltrifluoroTnethanesulfonirnide (15.2 g, 42.1 mmol) in THF (59 ml) was added over 25 min. After 2.5 hr at -78 0C the mixture was allowed to slowly warm to room temperature. After 16 h the mixture was diluted with a 1 :1 solution of THF and H2O (140 ml). The aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried (MgSO4), and concentrated to give 29.6 g of a brown solid. The crude product was adhered to silica and eluted with 15percent EtO Ac/Hex to give 18.3 g of a yellow oil. Purification by flash chromatography (elution with 0 to 15percent EtOAc-Hex) afforded 13.26 g of a yellow viscous oil, a mixture of the vinyl triflate and phenyl amine. The oil was dissolved in EtOAc washed with 5percent Citric acid, IN NaOH and brine dried (MgSO4), and concentrated to afford the vinyl triflate (6.06 g), a yellow oil, in 52percent yield. IH NMR (400 MHz, CHLOROFORM-D) δ ppm 1.48 (s, 9 H), 2.40 - 2.52 (m, J=2.9, 1.4 Hz, 2 H), 3.63 (t, J=5.6 Hz, 2 H), 4.05 (d, J=2.8 Hz, 2 H), 5.77 (s, 1 H).

Reference: [1] Patent: WO2007/60409, 2007, A1, . Location in patent: Page/Page column 87-88
[2] Patent: WO2003/87057, 2003, A1, . Location in patent: Page/Page column 77-78
[3] Patent: WO2006/4532, 2006, A1, . Location in patent: Page/Page column 25
[4] Patent: WO2007/92435, 2007, A2, . Location in patent: Page/Page column 143-143
[5] Patent: WO2004/35549, 2004, A1, . Location in patent: Page 127
[6] Patent: US2006/172995, 2006, A1, . Location in patent: Page/Page column 61
[7] Patent: WO2006/55752, 2006, A2, . Location in patent: Page/Page column 48-49
[8] Patent: US2007/276002, 2007, A1, . Location in patent: Page/Page column 13-14
[9] Patent: US2008/32998, 2008, A1, . Location in patent: Page/Page column 22
[10] Patent: WO2008/31772, 2008, A1, . Location in patent: Page/Page column 114-115
[11] Patent: WO2008/12622, 2008, A2, . Location in patent: Page/Page column 61
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  • [ 456-64-4 ]
  • [ 138647-49-1 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.333333 h;
Stage #2: at -78 - 0℃; for 3 h;
Part 9; To a solution of tert-butyl-4-oxopiperidine-1-carboxylate (5.21 g, 26.16 mmol) in anhydrous THF (26 mL) was added dropwise LiHMDS (1.0 M in THF, 28.7 mL, 28.7 mmol) at-78°C, under nitrogen. After 20 min, a solution of N-phenyl trifluoromethanesulfonimide (10.0 g, 27.99 mmol) in THF (26 mL) was addedand the reaction was allowed to gradually warm to 0°C and stirred for 3 h. The reaction was quenched with a minimum amount of saturated NaHCO3 and the resultant mixture was concentrated under reduced pressure. Flash chromatography on neutral A1203 afforded the desired enol triflate (8.67 g, 100percent).
96%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h;
Stage #2: at -78 - 25℃;
tert-Butyl 4-{ [(trifluoromethyl)sulfonyl] oxy}-3,6-dihydropyridine-l(2H)-carboxylateDi-wo-propylamine (22 ml) was dissolved in dry THF (125 ml) and cooled to -78°C. "-Butyllithium (62.5 ml, 2.5M) was added dropwise. The solution was stirred for 15 minutes, then tert-bntyl 4-oxopiperidine-l-carboxylate (28.32 g) in THF (100 ml) was added dropwise. The reaction mixture was stirred for 1 hour at -78°C, then N- phenyltrifluoromethanesulfonimide (53.8 g) in THF (150 ml) was added dropwise. The reaction mixture was stirred at -78°C for 2 hours and allowed to warm up to room temperature and stirred overnight. The reaction mixture was then concentrated in vacuo and the residue dissolved in ether (1000 ml). This was washed with water (500 ml), 2M sodium hydroxide solution (3 x 500 ml), water (500 ml) and brine (500 ml) then dried over magnesium sulfate and concentrated to give the title compound as a pale brown oil (45.38 g, 96percent) which was used without further purification; 1H NMR (CDCl3) δl.48 (9H, s), 2.44 (2H, m), 3.63 (2H, t), 4.00 (2H, q), 5.70 (IH, br m).
86%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃; for 0.833333 h;
Stage #2: at -78 - 20℃;
Example 10; 3-(4-Benzo[1,3]dioxol-5-yl-piperidin-1-yl)-propyl]-[4-(4-chloro-phenyl)-quinazolin-2-yl]-amine; Step 1; 4-Methanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester; To a cooled (-10°C) solution of diisopropylamine (2.05ml, 14.63mmol) in dry T.H.F(15ml) was added, under an argon atmosphere, a 1.6M butyllithium solution in n-hexanes (9.15ml, 14.63 mmol). After stirring for 20min. at a temperature of -10 - 0°C,the mixture was cooled to -78°C and a solution of N-Boc-4-oxo-piperidine (2.65g,13.30mmol) in dry T.H.F (15ml) was slowly added. Stirring was continued for afurther 30 min. A solution of N-phenyl trifluoromethylsulfonimide (5g, 14.0mmol) wasthen added dropwise. The reaction mixture was stirred overnight and temperaturewas allowed to reach RT. Solvent was removed in vacua. The crude oil was dilutedwith a EtOAc/Heptane mixture (1/9, 100ml) and purified through a short alumina plug(0: 7cm, H: 5cm). The alumina plug was washed with EtOAc/Heptane (1/9,6x200ml). The filtrates were combined and concentrated in vacua to give the titlecompound Example 10 Step 1 as an orange oil (3.79g, 11.45mmol, 86percent).1H-NMR (300 MHz, CDCI3); .8: 1.49 (s, 9H), 2.46 (m, 2H), 3.65 (t, 2H), 4.06 (d, 2H), 5.78 (s,
75%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexanes at 0℃; for 0.25 h;
Stage #2: for 0.5 h; Cooling with acetone-dry ice
Stage #3: for 4 h; Cooling with acetone-dry ice
[0236] Diisopropylamine (8.4mL, 60.0mmol) was dissolved in anhydrous THF (250mL) and the solution was chilled in an ice bath. To the solution was added dropwise 1.6M nBuLi in hexanes (38mL, 60.0mmol). After fifteen minutes, the ice bath was replaced with a dry ice/acetone bath and a solution of N-Boc-piperidone (9.96g, 50.0mmol) in anhydrous THF (120mL) was added dropwise. After thirty minutes, a solution of N-phenyltrifluoromethanesulfonamide (19.6g, 55.0mmol) in anhydrous THF (60mL) was adde dropwise. After one hour, the chilling bath was removed. After three hours, the reaction was quenched with saturated sodium bicarbonate and diluted with ethyl acetate. The organic phase was washed twice with 1M sodium hydroxide and once with brine. It was dried over magnesium sulfate, filtered and stored overnight in the freezer. The following day, the product was concentrated and purified by column chromatography (5percent EtOAc/Hexanes) on SiC>2 pre-washed with 2percent Et3N/hexanes, using permanganate stain to provide the title compound as a yellow oil (11.86g, 75percent).
74%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 0.166667 h;
Stage #2: at 20℃; for 4 h;
A 2 M solution of lithium diisopropylamide in heptane /tetrahydrofuran/ethylbenzene (20 mL; 0.04 MoI) was stirred under nitrogen atmosphere while cooling -780C, and a solution of l-BOC-4-piperidone (6.79 g; 0.033 MoI) in tetrahydrofuran (50 mL) added (internal temperature < -500C). After 10 min. a solution of N-phenyltrifluoromethanesulfonimide in tetrahydrofuran (50 mL) was added (internal temperature < -6O0C). After 1 hr. the cooling bath was removed, and the mixture allowed to warm to it. After 3 h, the mixture was poured into stirred brine (300 mL) and extracted with hexanes (3 X 100 mL). The combined organic extracts had a lower, orange liquid phase, which was separated and discarded. The resulting organic phase was washed with brine, dried (anhydrous sodium sulfate), filtered and concentrated to afforded 16.45 g of orange brown oil, which was purified by silica gel chromatography (hexanes/dichloromethane gradient). There desired product (8.15 g, 74percent yield) was obtained as an orange-yellow oil. 1H-NMR (CD2Cl2) 65.78 (d, 1 H), 4.03 (q, 2 H), 3.61 (t, 2 H), 2.43 (d, 2 H), 1.45 (s, 9 H).

Reference: [1] Patent: WO2005/37826, 2005, A1, . Location in patent: Page/Page column 90
[2] Patent: WO2007/60408, 2007, A2, . Location in patent: Page/Page column 104
[3] Patent: WO2006/10446, 2006, A2, . Location in patent: Page/Page column 31-32
[4] Patent: WO2006/20879, 2006, A1, . Location in patent: Page/Page column 100
[5] Patent: WO2007/64883, 2007, A2, . Location in patent: Page/Page column 361
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  • [ 37595-74-7 ]
  • [ 79099-07-3 ]
  • [ 138647-49-1 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1 h;
Stage #2: at -78 - 20℃;
A solution of tert-butyl 4-oxopiperidine-1 -carboxylate (1-1 ) (80 g, 0.402 mol) in THF (800 mL) was added to a solution of LiHMDS (1 M in THF, 406 mL) at -78 °C. After the addition, the reaction mixture was stirred at -78 °C for 1 hr. Then a solution of N-phenylbis(trifluoromethanesulfonimide) (156.4 g, 0.438 mol) in THF (400 mL) was added to the mixture at -78 °C. After addition, the reaction was stirred at room temperature overnight. TLC (petroleum ether/EtOAc, V/V = 1 :1) showed the reaction was complete. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether/EtOAc gradient from 1 :0 to 20:1) to give tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1 (2H)-carboxylate (I-2) (120 g, 90percent) as a yellow oil and was used for the next step directly.
90%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -75℃; for 0.5 h;
Stage #2: at -75 - 0℃;
Stage #3: With water In tetrahydrofuran; ethyl acetate for 0.166667 h; Cooling
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, (5.00 g, 25.13 mmol) in tetrahydrofuran (50 mL) is added 20percent lithium bis(trimethylsilyl)amide solution in tetrahydrofuran (50 mL) at -75 °C and the mixture is stirred for 30 minutes. A solution of N-phenyl trifluoromethanesulfonimide (9.85 g, 27.64 mmol) in tetrahydrofuran (100 mL) is added slowly at -75 °C to the reaction mixture and the temperature is raised to 0 °C. The mixture is stirred at this temperature for 3 hours. To the reaction mixture ice cold water (100 mL) and ethyl acetate (100 mL) are added and the mixture is stirred for 10 minutes. The organic phase is separated and the aqueous layer is extracted with ethyl acetate (100 mL). The combined organic phase is dried and distilled. The crude material is purified via silica gel chromatography using a gradient elution of 10percent ethyl acetate/petroleum ether to afford the desired product (5.30 g, 90percent).
82%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.333333 h;
Stage #2: at 0℃; for 3 h;
To a solution of diisopropylamine (0.8mL, 5.52mmol) in THF (7mL) was dropwised n-butyllithium solution in hexane (3.5mL, 2.5M in hexane, 5.52mmol) at−78°C. After 15min, 1-Boc-4-piperidone (1.0g, 5.02mmol) in THF (7mL) was slowly added to the reaction mixture at−78°C. After 20min, a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (2.0g, 5.52mmol) was slowly added to the mixture. The reaction mixture was stirred at 0°C for 3h. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography with hexane/ethyl acetate (20/1, v/v) to obtain the title compound (1.4g, 82percent yield): 1H NMR (300MHz, CDCl3) δ 5.77 (bs, 1H), 4.05 (d, J=2.9Hz, 2H), 3.64 (t, J=5.7Hz, 2H), 2.47–2.44 (m, 2H), 1.48 (s, 9H).
79.5%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78 - 20℃; for 0.666667 h;
Stage #2: at 20℃;
A solution of N-boc-piperidin-4-one (10.14 g, 50 mmol) in THF (80 mL) was addeddropwise to a cooled solution (-78 °C) of 2M LDA in THF (30 mL, 60 mmol, 1.2 eq.) andTHF (80 mL) over approximately 30 minutes. After stirring a further 10 minutes, asolution of 1,1,l-trifluoro-A^-phenyl-JV-f^ifluoromethy^sulfonyljmethanesulfonamide(20 g, 56 mmol, 1.1 eq.) in THF (80 mL) was added and the mixture was allowed towarm to room temperature. The solution was washed with water, the aqueous layerwashed with EtOAc (x 2), and the organic phases combined and washed with saturatedammonium chloride solution, brine, dried (sodium sulphate) and evaporated. The residuewas filtered through neutral alumina (200 g) eluting with n-heptane followed byn-heptane/EtOAc 9:1. After evaporation, the ^-NMR spectrum showed some triflatingagent still present but the product was used without further purification. Yield 13.17 g(79.5 percent). (Wustrow, D: J., Synthesis, 1991, 993-995)..H NMR (CDC13): 5 5.77 (1H, s), 4.05 (2H, q), 3.64 (2H, t), 2.45 (2H, quintet), 1.48 (9H,s).GCMS-MS m/z: 274 [M-57].
74%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h;
Stage #2: at -78 - 20℃;
LDA (2M, 65 mL) was added to a solution of 4-oxo-piperidine-l-carboxylic acid tert-butyl ester (20 g, 100 mmol) in 300 mL of dry THF at -78 °C and the mixture was stirred for 30 min. A solution of N,N-bis-(trifluoromethanesulfonyl)aniline in dry THF (100 mL) was added slowly at -78 °C and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with sat. NH4C1 solution (50 mL) and water (400 mL). The mixture was extracted with EtOAc (200 mL). The organic layer was washed with water (50 mL) and brine (50 mL), and dried over Na2S04. The solution was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EA = 50/1) to give compound (298) (24.5 g, yield: 74percent) as a yellow oil. [00726] lH NMR (300 MHz, CDC13): δ = 5.76 (s, 1H), 4.04 (d, J= 1.8 Hz, 2H), 3.62 (t, J= 5.6 Hz, 2H), 2.43 (s, 2H), 1.47 (s, 9H).
74%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 30 h; Inert atmosphere
Stage #2: at -78 - 20℃; Inert atmosphere
[00296] LDA (2M, 65 mL) was added to a solution of 4-oxo-piperidine-l -carboxylic acid tert-butyl ester (20 g, 100 mmol) in 300 mL of dry THF at -78 °C and the mixture was stirred for 30 min. A solution of N,N-bis-(trifluoromethanesulfonyl)aniline in dry THF (100 mL) was added slowly at -78 °C and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with sat. NH4C1 solution (50 mL) and water (400 mL). The mixture was extracted with EtOAc (200 mL). The organic layer was washed with water (50 mL) and brine (50 mL), and dried over Na2S04. The solution was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EA = 50/1) to give compound 4-trifluoromethanesulfonyloxy-3,6 -dihydro-2H-pyridine-l -carboxylic acid tert- butyl ester (24.5 g, yield: 74percent) as a yellow oil. lH NMR (300 MHz, CDC13): δ = 5.76 (s, 1H), 4.04 (d, J = 1.8 Hz, 2H), 3.62 (t, J= 5.6 Hz, 2H), 2.43 (s, 2H), 1.47 (s, 9H).
72%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -60℃; for 0.166667 h; Inert atmosphere
Stage #2: at -60 - 20℃; for 2.5 h;
To a solution of diisopropylamine (0.847 mL, 6.00 mmol) in dry tetrahydrofuran (15 mL) at -60 °C was added n-butyllithium (1.6M in hexane; 3.75mL, 6.00 mmol) under nitrogen atmosphere. The reaction mixture was stirred for 5 min at -60 °C. A solution of tert-butyl 4-oxopiperidine-l-carboxylate (1.0 g, 5.00 mmol) in dry tetrahydrofuran (20 mL) was added, and the reaction mixture was stirred for 10 min. Then a solution of N- phenyltrifluoromethanesulfonamide (1.96 g, 5.50 mmol) was added. The reaction mixture was stirred at -60 °C for 30min and the mixture was allowed to warm to room temperature and was stirred for 2 h. The reaction was quenched with saturated sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed sequentially with 5percent citric acid solution, IN aqueous sodium hydroxide, water and brine, was dried over magnesium sulfate, was filtered and was concentrated. The residue was purified by column chromatography (eluted with ethyl acetate:hexanes = 1 : 10) to give tert-butyl 4- [(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-l(2H)-carboxylate (1.2 g, 72percent yield) as a colorless oil. XH NMR (400 MHz, CDC13): δ 5.73 (s, 1H), 4.01 (s, 2H), 3.59 (t, 2H), 2.40 (s, 2H), 1.43 (s, 9H).
68%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃;
Stage #2: at -78 - 20℃;
A solution of t-butoxycarbonyl-4-piperidone (3 g, 15.1 mmol) in THF (10 mL) was slowly added to a stirring 2M solution of LDA (9.0 mL, 18.1 mmol) in THF (10 mL) at -78° C. After 10 min, a solution of N-phenyl bis(trifluoromethanesulfonamide) (5.9 g, 16.6 mmol) in THF (10 mL) was slowly added. After 30 min, the cooling bath was removed and reaction mixture was allowed to warm to room temperature over the course of 1.5 hours. The mixture was cooled to 0° C., quenched with sat. NaHCO3 (30 mL), and extracted with ether (200 mL). The organic layer was washed with 5percent citric acid (40 mL), 1M NaOH (4.x.40 mL), H2O (2.x.40 mL), brine (40 mL), dried (MgSO4), concentrated on silica and flash column chromatography (15-50percent EtOAc/hexane gradient) afforded 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as brown oil (3.4 g, 68percent). 1H NMR (CDCl3, 300 MHz) δ 1.48 (s, 9H), 2.48 (m, 2H), 3.63 (t, 2H, J=5.70 Hz), 4.07 (m, 2H), 6.10 (t, 1H, J=3.30 Hz); MS (ESI) m/z=276.0 (MH+-t-Bu).
68.2%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃;
Stage #2: at 20℃; Cooling with ice
A solution of t-butoxycarbonyl-4-piperidone (3 g, 15.06 mmol) in THF (10 mL) was slowly added to a stirring 2M solution of LDA (9.03 mL, 18.07 mmol) in THF (10 mL) at -78° C. After 10 min, a solution of N-phenyl bis(trifluoromethanesulfonimide) (5.92 g, 16.56 mmol) in THF (10 mL) was slowly added. After 30 min, the cooling bath was removed and the mixture was allowed to warm to room temperature over the course of 1.5 hours. The mixture was cooled to 0° C., quenched with saturated aqueous NaHCO3 (30 mL), and extracted with ether (200 mL). The organic layer was washed with 5percent citric acid (40 mL), aqueous NaOH (1M, 4.x.40 mL), H2O (2.x.40 mL), brine (40 mL), dried (MgSO4), the filtrate was concentrated on silica and subjected to flash column chromatography (15-50percent EtOAc/hexane gradient) to afford 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.40 g, 68.2percent) as a brown oil. 1H NMR (CDCl3, 300 MHz) δ 6.10 (t, J=3.30 Hz, 1H), 4.07 (m, 2H), 3.63 (t, J=5.70 Hz, 2H), 2.48 (m, 2H), 1.48 (s, 9H); MS (ESI) m/z=276 (MH+-tBu).
67.4%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 1 h;
Stage #2: at 20℃;
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 25.09 mmol) in THF (40 mL) was added LDA (25.09 mL, 50.2 mmol, 2M in THF/hepatane/ethylbenzene) at -78. After stirring at -78 for 1h, N, N-bis (trifluoromethylsulfonyl) aniline (10.76 g, 30.1 mmol) was added to the mixture. The resulting mixture was stirred at rt overnight, quenched with aq NH4Cl (30 mL) and extracted with EtOAc (30 mL× 3) . The combined organic layer was washed with brine (15 mL) , dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel chromatography (PE/EtOAc20/1 to 10/1) to afford the tert-butyl 4- ( ( (trifluoromethyl) sulfonyl) oxy) -5, 6-dihydropyridine-1 (2H) -carboxylate (5.6 g, 16.90 mmol, 67.4) . LRMS m/z (M-55) 276.0 found, 276.1 required.
65% With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene Step 1:
Synthesis of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate
To a cooled (-78° C.) solution of 1-Boc-4-piperidone (1.98 g, 9.94 mmol, Lancaster) in THF (25 mL) was added lithium diisopropylamide, 2.0M solution in THF/heptane/ethylbenzene (8 mL, 16.00 mmol) dropwise via syringe.
After 30 min a solution of N-phenyl-bis(trifluoromethanesulfonimide) (4.02 g, 11.25 mmol) in THF (10 mL) was added via syringe and the reaction was allowed to warm to room temperature overnight.
The reaction was partitioned between EtOAc/water and the aqueous layer was extracted with EtOAc (3*).
The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco (80 gram)) eluting with (EtOAc):hexanes (0:1→1:4) to give tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate as a light-yellow oil (2.14 g, 65percent yield).
63.74%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -70℃; for 1.16667 h;
Stage #2: for 18 h;
Step 2: Lithium diisopropylamide solution was prepared by adding n-butyllithium (1.1 eq) to the -70 °C cold solution of diisopropylamine (1.3 eq) dissolved in THF (15 mL) under nitrogen atmosphere and by stirring the resultant pale yellow solution at -20 °C for one hour. To a solution of lithium diisopropylamide at -70 °C, tert-butyl 4-hydroxypiperidine-l- carboxylate(1.5 g, 1.0 eq) dissolved in THF (10 mL) was added drop wise over lOminutes. The resultant yellow solution was stirred for one hour at the same temperature. 1,1,1-trifluoro-N- phenyl-N-(trifluoromethylsulfonyl) methanesulfonamide (2.82 g, 1.05 eq) dissolved in THF (10 mL) was added drop wise over 5 minutes. Finally the resultant brown solution was allowed to stir for 18 hours. TLC showed the complete consumption of starting material. The reaction mixture was cooled to -20 °C and then added saturated ammonium chloride solution drop wise. The resultant biphasic layer was allowed to stir at room temperature for 10 minutes then the organic layer was separated and the aqueous layer extracted with ethyl acetate (3 x 20 mL). The pooled organic layers were washed with brine, dried and concentrated to get 2.5 g of pale yellow oil. The crude material was purified on basic alumina column, using ethyl acetate and petroleum ether as eluents. Pure desired fractions were collected and concentrated to get 1.6 g (yield: 63.74percent) of tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-l(2H)- carboxylate as pale yellow oil.
60%
Stage #1: With diisopropylamine In tetrahydrofuran; hexane at -78℃; for 3.5 h;
Stage #2: at 20℃;
N-Boc-4-(Trifluoromethanesulfonyloxy)tetrahydro-1,2,3,6-pyridine A solution of 13.2 g (0.13 mol) of diisopropylamine in 200 ml of THF was deprotonated at -78° C. with 100 ml nBuLi (1.6M in hexane) and, after 30 minutes at this temperature, 20.0 g (0.1 mol) of N-Boc-piperidone dissolved in 50 ml of THF were added dropwise. After a further three hours at -78° C., a solution of 39.3 g (0.11 mol) of N,N,-bistrifluoromethanesulfonylaniline in 50 ml of THF was added, and the mixture was allowed to reach room temperature overnight. For workup, water was added, the mixture was extracted with ether, the organic phases were washed with NaHCO3 solution and water and dried over sodium sulfate, and the solvent was evaporated off. The crude product was purified by flash chromatography (silica gel, mobile phase heptane/ethyl acetate=3/1). Yield: 20.2 g (60percent of theory) 1H-NMR:(270 MHz,CDCl3 [sic]) δ=1.4 (s, 9H); 2.4(m, 2H); 3.6 (t, 2H); 4.1 (m, 2H); 5.8 (m, 1H) ppm.
59%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 2 h;
The 1 ,1-dimethylethyl 4-{4-[([2-chloro-3-(trifluoromethyl)phenyl]methyl}amino)carbonyl]-3-methyl-2-oxo-1-imidazolidinyl}-1- piperidinecarboxylate used in the method described above was prepared as follows: (i) A solution of 1 ,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (3.0 g, 15 mmol) inTHF (45 ml) was stirred at -780C under argon. Lithium hexamethyldisilazide (15 ml, 15 mmol, 1 M solution in THF) was added dropwise and the reaction was stirred at -780C for 1 hour. A solution of 1 ,1 ,1-trifluoro-λ/-phenyl-/V-[(trifluoromethyl)sulfonyl]methanesulfonamide (6.43 g, 18 mmol) in THF (12 ml) was <n="47"/>added dropwise. The reaction was allowed to warm to room temperature over 2 hours. The reaction was quenched by the addition of water and the THF was evaporated. The residue was extracted with ether. The ether layer was separated and washed with water, 2N sodium hydroxide solution, water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 5- 25percent ethyl acetate in hexanes to give 1 ,1-dimethylethyl 4-[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1 (2H)-pyridinecarboxylate (2.91 g, 59percent).
58%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5 h;
Stage #2: at -78 - 0℃; for 3 h;
To the solution of 37a (1Og, 50mmol) in THF (5OmL) was added a solution of LiHMDSA (55mmol) in THF (5OmL) at -780C. After being stirred at that temperature for 30min, the mixture was added a solution of N-phenyltrifluoromethanesulfonimide (18.2g, 51mmol) in 5OmL of THF. The resulting mixture was warmed to O0C, stirred for 3h and evaporated. The residue was purified by neutral alumina column chromatography (PE:EA=10:l) to provide compound 37b (9.3g, 58percentyield) as an oil. 1H NMR (300MHz, CDCl3): δ=1.45 (s, 9H), 2.43-2.45 (m, 2H), 3.60-3.64 (m, 2H), 4.03-4.04 (m, 2H), 5.76 (m, IH).
50%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 0.5 h;
Stage #2: at -78 - 20℃; for 24.5 h;
Lithium diisopropylamide (2 M in heptane/THF/ethylbenzene; 15.1 mL, 30.1 mmol) was added dropwise to a solution of ferf-butyl 4-oxopiperidine-1-carboxylate (3.00 g, 15.1 mmol) in THF (50 mL) at -78 °C and the mixture left to stir for 30 minutes. A solution of /V-phenyl-bis(trifluoromethanesulfonimide) (6.46 g, 18.1 mmol) in THF (60 mL) was then added dropwise over 30 minutes to the reaction and mixture left to stir for 30 minutes-78 °C Trie resuming mixture was then allowed to warm to room temperature and was stirred for 24 hours. The solvent was partially removed (ca 80 mL) and the reaction mixture quenched with saturated NaHC03 solution (50 mL). DCM (50 mL) was added to the solution and the layers separated. The aqueous layer was then extracted with DCM (2 x 50 mL). The organic layers were combined and washed with 0.2 M citric acid solution (50 mL), 1 M NaOH (50 mL), brine (50 mL) and dried over Na2S0 . The solvent was removed under reduced pressure to give a brown oil which was purified by column chromatography on silica gel (0-10percent diethyl ether in petroleum benzine 40-60 °C) to afford the title compound (142) (2.48 g, 50percent) as an orange oil which crystallized on cooling to -18 °C; 1H NMR (400 MHz, CDCI3) δ 5.76 (s, 1 H), 4.05 - 4.04 (m, 2H), 3.63 (t, J = 5.6 Hz, 2H), 2.46 - 2.43 (m, 2H), 1 .47 (s, 9H).
50%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h;
Stage #2: at -78 - 20℃; for 24.5 h;
Lithium diisopropylamide (2 M in heptane/THF/ethyibenzene; 15.1 mL, 30.1 mmol) was added dropwise to a solution of ferf-butyl 4-oxopiperidine-1-carboxylate (3.00 g, 15.1 mmol) in THF (50 mL) at -78 °C and the mixture left to stir for 30 minutes. A solution of A-phenyl-bis(trifiuoromethanesuifonimide) (6.46 g, 18.1 mmol) in THF (60 mL) was then added dropwise over 30 minutes to the reaction and mixture left to stir for 30 minutes-78 °C. The resulting mixture was then allowed to warm to room temperature and was stirred for 24 hours. The solvent was partially removed (ca 80 mL) and the reaction mixture quenched with saturated NaHC03 solution (50 mL). DCM (50 mL) was added to the solution and the layers separated. The aqueous layer was then extracted with DCM (2 x 50 mL). The organic layers were combined and washed with 0.2 M citric acid solution (50 mL), 1 M NaOH (50 mL), brine (50 mL) and dried over Na2S04, The solvent was removed under reduced pressure to give a brown oil which was purified by column chromatography on silica gel (0-10percent diethyl ether in petroleum benzine 40-80 °C) to afford the title compound (142) (2.48 g, 50percent) as an orange oil which crystallized on cooling to - 8 °C; 1 H NMR (400 MHz, CDCi3) δ 5.76 (s, 1 H), 4,05 - 4.04 (m, 2H), 3.83 (t, J = 5.6 Hz, 2H), 2.46 - 2.43 (m, 2H), .47 (s, 9H).
48%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -75℃; for 1 h; Inert atmosphere
Stage #2: at -75 - 20℃;
4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester
n-Butyllithium (1.9 M; 30.6 mL, 58 mmol) was added dropwise to a stirred solution of diisopropylamine (4.6 mL, 32.6 mmol) in THF (60 mL) at about -75° C. under nitrogen.
The reaction temperature was brought to about 0° C. and the mixture was stirred for 1 h at this temperature.
The reaction mixture was cooled to -75° C. and a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (10.0 g, 50.2 mmol) in THF was added.
The mixture was stirred for 1 h at -75° C., and then N-phenylbis(trifluoromethanesulfonimide) (19.7 g, 55.1 mmol) was added.
The mixture was allowed to warm to room temperature and stir overnight.
The reaction mixture was extracted with ethyl acetate and the extracts were washed with water.
The organic extracts were dried over Na2SO4, filtered, evaporated, and purified by chromatography on an alumina column to give 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (8 g, 48percent).
1H NMR (300 MHz, CDCl3) δ ppm: 5.75 (s, 1H), 4.03 (s, 2H), 3.60-3.63 (m, 2H), 1.46 (s, 9H); MS cald. for C11H17F3NO5S [(M+H)+] 332, obsd. 332.5.
11 g
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 2 h;
Stage #2: at -78 - -70℃; for 5 h;
To a solution of N-isopropylpropan-2-amine (16.9 mL, 0.12 mol) in tetrahydrofuran (240 mL)added n-butyllithium (7.45 g, 0.12 mol) (2M Solution in tetrahydrofuran) at -10°C, stirred for30 min. The resulted lithium diisopropylamine solution was added drop wise to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (20.0 g, 0.10 mol) in tetrahydrofuran (100 mL) at -78°C. After stirring for 2 h at the same temperature, a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (39.4 g, 0.11 mol) in tetrahydrofuran (780 ml)was added to the reaction mixture and stirred for 5 h at -70°C Reaction mixture was concentrated under reduced pressure. The obtained crude product was purified by combi flash (eluting with 3percent ethylacetate:n-hexane) to get 11 g of tert-butyl 4- (trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylate. MS: m/z = 332 (M+1).
11 g
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 2 h;
Stage #2: at -70℃; for 5 h;
To a solution of N-isopropylpropan-2-amine (16.9 mL, 0.12 mol) in tetrahydrofuran (240 mL) added n-butyllithium (7.45 g, 0.12 mol) (2M Solution in tetrahydrofuran) at −10° C., stirred for 30 min. The resulted lithium di-isopropylamine solution was added drop wise to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (20.0 g, 0.10 mol) in tetrahydrofuran (100 mL) at −78° C. After stirring for 2 h at the same temperature, a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (39.4 g, 0.11 mol) in tetrahydrofuran (780 mL) was added to the reaction mixture and stirred for 5 h at −70° C. Reaction mixture was concentrated under reduced pressure. The obtained crude product was purified by combi flash (eluting with 3percent ethylacetate:n-hexane) to get 11 g of tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylate. MS: m/z=332 (M+1).

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  • 7
  • [ 456-64-4 ]
  • [ 79099-07-3 ]
  • [ 138647-49-1 ]
YieldReaction ConditionsOperation in experiment
83%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 5 h;
For synthesis of the ester, LiHMDS (20percent in THF, 20 ml, 21 mmol) is added to a solution of l-Boc-4-piperidone (2.79 g, 14 mmol) in dry THF (20 ml) at -780C under nitrogen. The mixture is stirred at -780C for Ih. N-phenyltrifluoromethanesulfonimide (5.0 g, 14 mmol) is added as solid in one portion. The reaction mixture is stirred at -780C for Ih. Then the mixture is wanned up to room temperature over a period of 4 h. Saturated NaHCO3 is added, and the aqueous solution is EPO <DP n="68"/>extracted with ethyl acetate two times (10 ml). The combined organic extracts are dried with Na2SO4, evaporated to dryness and the residue is purified by flash chromatography 0-15percent ethyl acetate/hexane to afford product 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-l- carboxylic acid tert-butyl ester as a yellow oil (3.86 g, 83percent). The compound is carried onto the next step without purification.
60%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 0.5 h;
Stage #2: at -78 - 20℃; for 3 h;
A. To a stirred solution of n-butyllithium (18.8 mL, 30.113 mmol) in THF(40.0 mL) was added diisopropylamine (4.2 mL, 30.113 mmol) at -780C. The resulting mixture was stirred at -78°C for 10 minutes. 4-Oxo-piperidine-1-carboxylic acid tert- butyl ester (4.000 g, 20.075 mmol), dissolved in THF (40 mL), was added to the EPO <DP n="36"/>mixture and the whole was left stirring at -78°C for another 30 minutes. N- Phenyltrifluoromethanesulfonimide was added to the mixture at -78°C and the solution was warmed up to room temperature over 3 hours. Ethyl acetate (200 ml_) was added to the mixture and the organic phase was washed with water (100 ml_), brine (100 ml_), dried over MgSO4 and then concentrated in vacuo. The crude product was purified by column chromatography, eluting with a solvent gradient of 20percent ethyl acetate and 80percent hexane to yield the desired product, 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H- pyridine-1-carboxylic acid terf-butyl ester (4.000 g, 60percent).
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[2] Patent: WO2007/38459, 2007, A2, . Location in patent: Page/Page column 66-67
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  • 8
  • [ 79099-07-3 ]
  • [ 138647-49-1 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1.5 h;
Stage #2: at 0℃; for 3 h;
A solution of tert-butyl 4-oxopiperidine-l-carboxylate (1, 1.0 g, 5.02 mmol) in THF (30 mL) was cooled to -78 °C. LiHMDS (1.0 M solution in THF, 6.52 mL) was added dropwise over 30 min. The reaction was stirred at -78 °C for 1 h, then a solution of W-phenyl- bis (trifluoromethanesulfonimide) (2.52 g, 7.05 mmol) in THF (5.0 mL) was added dropwise over 30 min. The mixture stirred at 0 °C for 3 h, and was then concentrated under reduced pressure. The residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 24 g Redisep column, 0percent to 100percent EtOAc in hexanes) to provide tert-butyl 4- ( ( (trifluoromethyl ) sulfonyl) oxy) -5, 6-dihydropyridine-l (2ff) - carboxylate (2) as a light yellow oil (1.50 g, 90percent) : XH NMR (300 MHz, CDC13) δ 5.75 (br s, 1H) , 4.05-4.02 (m, 2H) , 3.64-3.60 (m, 2H) , 2.44- 2.42 (m, 2H) , 1.46 (s, 9H) .
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  • 9
  • [ 40906-82-9 ]
  • [ 79099-07-3 ]
  • [ 138647-49-1 ]
YieldReaction ConditionsOperation in experiment
85% With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃; for 6 h; Inert atmosphere Example 9A1 tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine- 1 (2H)-carboxylate Lithium bis(trimethylsilyl)amide (1 M, 40 mL) was added to a solution of tert- butyl-4-oxopiperidine- 1 -carboxylate (28 mmol) in dry THF (50 mL) at -78 °C under N2. The mixture was stirred at -78 °C for 1 hour. N-pheny-lbis(trifluoromethanesulfonimide) (28 mmol) was added as solid in one portion. The mixture was stirred at -78 °C for 1 hour. The solution was warmed up to room temperature over a period of 4 hours. Saturated NaHC(¾ was added and the aqueous layer was extracted by dichloromethane (5 x 100 mL) and dried over Na2S04, filtered, and dried. The residue was purified by column chromatography on silica gel (petroleum ether: EtOAc =80: 1) to give Example 9A1 in 85percent yield as yellow liquid.
Reference: [1] Patent: WO2013/10453, 2013, A1, . Location in patent: Page/Page column 101
  • 10
  • [ 79099-07-3 ]
  • [ 145100-51-2 ]
  • [ 138647-49-1 ]
YieldReaction ConditionsOperation in experiment
2.9 g
Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5 h; Inert atmosphere
Stage #2: at -78 - 20℃; Inert atmosphere
Reaction under N2. BuLi (1.6 M in hexane) (8.28 ml, 13.2 mmol) was added dropwise at -20°C to a solution of DIP A (1.86 ml, 13.2 mmol) in THF (20 ml) then the mixture was stirred at -20°C for 20 minutes. A solution of l-tert-butyloxycarbonyl-4-piperidone (2.2 g, 11.0 mmol) in THF (20ml) was then added at -78°C and the resulting mixture was stirred for 30 minutes at -78°C. A solution of 2-[N,N-bis(trifluoromethylsulfonyl)- amino]-5-chloropyridine (4.97 g, 12.1 mmol) in THF (10ml) was added at -78°C then the mixture was allowed to reach room temperature and was stirred overnight. The mixture was concentrated and the purification of the residue was carried out by flash chromatography over silica gel (silicagel 30μιη, 80g, heptane/EtOAc 75/25. The desired product was collected and the solvent was evaporated, yielding 2.9 g of intermediate (4).
2.9 g
Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5 h; Inert atmosphere
Stage #2: at -78 - 20℃;
Reaction under N2. BuLi (1.6 M in hexane) (8.28 ml, 13.2 mmol) was added dropwiseat -20°C to a solution of DIPA (1.86 ml, 13.2 mmol) in THF (20 ml) then the mixturewas stirred at -20°C for 20 minutes. A solution of l-tert-butyloxycarbonyl-4-piperidone (2.2 g, 11.0 mmol) in THF (20m1) was then added at -78°C and the resulting mixture was stirred for 30 minutes at -78°C. A solution of 2-[N,N-bis(trifluoromethylsulfonyl)- amino]-5-chloropyridine (4.97 g, 12.1 mmol) in THF (lOml) was added at -78°C thenthe mixture was allowed to reach room temperature and was stirred overnight. The mixture was concentrated and the purification of the residue was carried out by flash chromatography over silica gel (silicagel 30jim, 80g, heptane/EtOAc 75/25. The desired product was collected and the solvent was evaporated, yielding 2.9 g of intermediate (A4).
Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 15, p. 4544 - 4567
[2] Patent: US2010/216764, 2010, A1, . Location in patent: Page/Page column 17
[3] Patent: US2004/2504, 2004, A1, . Location in patent: Page/Page column 20
[4] Patent: US2004/2504, 2004, A1, . Location in patent: Page/Page column 21
[5] Patent: WO2013/21052, 2013, A1, . Location in patent: Page/Page column 20
[6] Patent: WO2014/23815, 2014, A1, . Location in patent: Page/Page column 38
  • 11
  • [ 79099-07-3 ]
  • [ 138647-49-1 ]
YieldReaction ConditionsOperation in experiment
61%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h;
Stage #2: at 20℃;
Step 1:
4-(trifluoromethanesulfonyloxy)-1-(tert-butoxycarbonyl)-1,2,5,6-tetrahydropyridine
Tert-butyl 4-oxopiperidine-1-carboxylate (22.8 g, 115 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL), the resultant was cooled to -78°C, and then a solution of lithium diisopropylamide (126 mmol) in tetrahydrofuran (100 mL) was added dropwise.
Upon completion of the addition, the solution was stirred for 30 minutes, and a solution of bis(trifluoromethanesulfonyloxy)aniline (45.0 g) in tetrahydrofuran (126 mmol) was added dropwise.
The resultant was warmed up to room temperature and stirred overnight.
Tthe solvent was evaporated, and the residue was dissolved by adding ether.
The solution was washed by 2 M NaOH solution, dried, concentrated, and purified by silica gel column chromatography to give 4-(trifluoromethanesulfonyloxy)-1-(tert-butoxycarbonyl)-1,2,5,6-tetrahydropyridine (23.4 g, 61percent yield).
Reference: [1] Patent: EP2952510, 2015, A1, . Location in patent: Paragraph 0141
  • 12
  • [ 79099-07-3 ]
  • [ 138647-49-1 ]
Reference: [1] Patent: US5665719, 1997, A,
[2] Patent: WO2008/30520, 2008, A1, . Location in patent: Page/Page column 145
[3] Journal of Organic Chemistry, 2014, vol. 79, # 6, p. 2781 - 2791
[4] Molecules, 2013, vol. 18, # 10, p. 12119 - 12143
[5] Patent: US2017/174641, 2017, A1,
  • 13
  • [ 27607-77-8 ]
  • [ 79099-07-3 ]
  • [ 138647-49-1 ]
Reference: [1] Patent: WO2004/5256, 2004, A2, . Location in patent: Page 28
[2] Patent: WO2004/5256, 2004, A2, . Location in patent: Page 43-44
  • 14
  • [ 79099-07-3 ]
  • [ 138647-49-1 ]
Reference: [1] Patent: WO2004/58727, 2004, A1, . Location in patent: Page 52
  • 15
  • [ 79099-07-3 ]
  • [ 138647-49-1 ]
Reference: [1] Heterocycles, 1996, vol. 43, # 10, p. 2131 - 2138
  • 16
  • [ 79099-07-3 ]
  • [ 138647-49-1 ]
Reference: [1] Patent: US6051712, 2000, A,
  • 17
  • [ 79099-07-3 ]
  • [ 138647-49-1 ]
Reference: [1] Patent: US6235759, 2001, B1,
  • 18
  • [ 109-72-8 ]
  • [ 79099-07-3 ]
  • [ 108-18-9 ]
  • [ 138647-49-1 ]
Reference: [1] Patent: US2003/69261, 2003, A1,
[2] Patent: US2003/82623, 2003, A1,
[3] Patent: US2004/38855, 2004, A1,
  • 19
  • [ 79099-07-3 ]
  • [ 4111-54-0 ]
  • [ 138647-49-1 ]
Reference: [1] Patent: US2003/195221, 2003, A1,
  • 20
  • [ 37595-74-7 ]
  • [ 159503-90-9 ]
  • [ 138647-49-1 ]
Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 6, p. 2781 - 2791
[2] Molecules, 2013, vol. 18, # 10, p. 12119 - 12143
  • 21
  • [ 41979-39-9 ]
  • [ 138647-49-1 ]
Reference: [1] Patent: US2013/150407, 2013, A1,
  • 22
  • [ 24424-99-5 ]
  • [ 138647-49-1 ]
Reference: [1] Patent: US2013/150407, 2013, A1,
  • 23
  • [ 138647-49-1 ]
  • [ 99329-53-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 10, p. 1731 - 1735
  • 24
  • [ 138647-49-1 ]
  • [ 143924-45-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 25, p. 7450 - 7465
  • 25
  • [ 67-56-1 ]
  • [ 201230-82-2 ]
  • [ 138647-49-1 ]
  • [ 184368-74-9 ]
YieldReaction ConditionsOperation in experiment
2 g With palladium diacetate; triethylamine; triphenylphosphine In N,N-dimethyl-formamide at 20℃; for 12 h; To a mixture of tert-butyl4-(((trifluoromethyl)sulfonyl)oxy)-3 ,6-dihydropyridine-1(2H)-carboxylate (5.6 g, 16.8 mmol), Et3N (4.7 ml, 33.0 mmol) in DMF (69 ml) andMeOH (52 ml) was added PPh3 (0.2 g, 1.0 mmol) and Pd(OAc)2 (0.1 g, 0.5 mmol) at RT under nitrogen followed by stirring under CO atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography to give 2.0 g of the title compound as a greenish liquid. 1H-NMR (400MHz; DMSO-d6): ö 6.85 (d, 1H), 4.00 (t, 2H), 3.67 (s, 3H), 3.42 (d, 2H), 2.25 (t, 2H),1.41 (s, 9H).
Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 15, p. 4544 - 4567
[2] Heterocycles, 1996, vol. 43, # 10, p. 2131 - 2138
[3] Patent: WO2018/115591, 2018, A1, . Location in patent: Page/Page column 84; 85
  • 26
  • [ 138647-49-1 ]
  • [ 184368-74-9 ]
YieldReaction ConditionsOperation in experiment
65% With triethylamine; triphenylphosphine In methanol; hexane; N,N-dimethyl-formamide B.
Methyl 1-boc-1,2,3,6-Tetrahydro-4-pyridinecarboxylate
To a stirred solution of 1-Boc-1,2,3,6-tetrahydro-4-[(trifluoromethyl)sulfonyloxy]pyridine (74.84 g, 226 mmol) in N,N-dimethylformamide (60 mL) was added triethylamine (4.2 mL, 30.2 mmol), palladium acetate (0.100 g, 0.45 mmol), triphenylphosphine (0. 235 g, 0.9 mmol), and methanol (24.5 mL) and the solution was placed under an atmosphere of carbon monoxide.
After stirring for 48 h, the solvent was removed in vacuo.
The residue was chromatographed over silica gel, eluding with 5-10percent ethyl acetate in hexane.
The product containing fractions were combined and concentrated in vacuo to give 2.35 g (65percent) of the title compound as a clear oil.
1H-NMR;
FD-MS, m/e 240.2 (m); Analysis for C12H19NO4: Calcd: C, 59.74; H, 7.94; N, 5.81; Found: C, 59.60; H, 8.07; N, 5.85.
Reference: [1] Patent: US6635657, 2003, B1,
  • 27
  • [ 138647-49-1 ]
  • [ 211108-50-8 ]
Reference: [1] Patent: WO2004/5256, 2004, A2, . Location in patent: Page 28
[2] Patent: WO2004/5256, 2004, A2, . Location in patent: Page 43-44
  • 28
  • [ 1579291-74-9 ]
  • [ 138647-49-1 ]
  • [ 168824-94-0 ]
Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 6, p. 2781 - 2791
  • 29
  • [ 138647-49-1 ]
  • [ 170011-57-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 22, p. 7860 - 7883
[2] Patent: WO2012/110773, 2012, A1,
[3] Patent: WO2013/43232, 2013, A2,
[4] Patent: WO2014/27199, 2014, A1,
[5] Patent: WO2018/68297, 2018, A1,
  • 30
  • [ 138647-49-1 ]
  • [ 387827-18-1 ]
YieldReaction ConditionsOperation in experiment
81% With sodium carbonate; lithium chloride In 1,2-dimethoxyethane; water for 3 h; Heating / reflux A degassed mixture of 2.0 M aqueous [NA2CO3] solution (4.20 mL), tert-butyl [4-[(TRIFLUOROMETHYL)] sulfonyl] [OXY}-3,] 6-dihydro-1 (2H) -pyridine carboxylate (0.500 g, 1. 51 mmol), 3-aminophenylboronic acid [HEMISULFATE] (0.393 g, 2.11 mmol), lithium chloride (0.191 g, 4.50 mmol) and tetrakis-triphenylphosphine palladium (0.080 g, 0.075 mmol) in dimethoxyethane (5.00 mL) was heated at reflux temperature for 3 hours under Argon. The organic layer of the cooled reaction mixture was separated and the aqueous layer was washed with ethyl acetate (3 x 50 [ML).] The combined organic solutions were dried and concentrated in vacuo. The crude product was chromatographed (silica, hexanes: EtOAc: dichloromethane 6: 1: 1 with [1percent] isopropylamine) to give the desired product (0.330 g, [81percent). 1H] NMR (400 MHz, [CDC13)] 8 7.12 (t, [1H,] J = 7. [60] Hz), 6. [78] (d, 1H, J = 8.4 Hz), 6. [69] (t, 1H, J =. [2.] 0 Hz), 6.59 (dd, 1H, J = 2.2, 8.0 Hz), 6.01 (br, 1H), 4.10- 4.01 (d, 2H, J = 2.4 Hz), 3.61 (t, 2H, J [= 5.] 6 Hz), 2.52- 2.46 (m, 2H), 1.49 (s, 9H); ESMS m/e : 275.2 (M + H) +. Anal. Calc. for [C16H24N202] : C, 70.04 ; H, 8. [08 ;] N, 10. [21.] Found: C, 69.78 ; H, 7.80 ; N, 9.92.
81% With sodium carbonate In 1,2-dimethoxyethane; water for 3 h; Heating / reflux A degassed mixture of 2.0 M aqueous Na2CO3 solution (4.20 mL), tert-butyl 4-[(trifluoromethyl) sulfonyl]oxy}-3,6-dihydro-1 (2H)-pyridine carboxylate (0.500 g, 1.51 mmol), 3-aminophenylboronic acid hemisulfate (0.393 g, 2.11 mmol), lithium chloride (0.191 g, 4.50 mmol) and tetrakis-triphenylphosphine palladium (0.080 g, 0.075 mmol) in dimethoxyethane (5.00 mL) was heated at reflux temperature for 3 hours under Argon. The organic layer of the cooled reaction mixture was separated and the aqueous layer was washed with ethyl acetate (3?50 mL). The combined organic solutions were dried and concentrated in vacuo. The crude product was chromatographed (silica, hexanes:EtOAc: dichloromethane 6:1:1 with 1percent isopropylamine) to give the desired product (0.330 g, 81percent). 1H NMR (400 MHz, CDCl3) ? 7.12 (t, 1H, J=7.60 Hz), 6.78 (d, 1H, J=8.4 Hz), 6.69 (t, 1H, J=2.0 Hz), 6.59 (dd, 1H, J=2.2, 8.0 Hz), 6.01 (br, 1H), 4.10-4.01 (d, 2H, J=2.4 Hz), 3.61 (t, 2H, J=5.6 Hz), 2.52-2.46 (m, 2H), 1.49 (s, 9H); ESMS m/e: 275.2 (M+H)+. Anal. Calc. for C16H24N2O2: C, 70.04; H, 8.08; N, 10.21. Found: C, 69.78; H, 7.80; N, 9.92.
81% With sodium carbonate; lithium chloride In 1,2-dimethoxyethane; water for 3 h; Heating / reflux TERT-BUTYL 4-(3-AMINOPHENYL)-3,6-DIHYDRO-1(2H)-PYRIDINE CARBOXYLATE:
A degassed mixture of 2.0 M aqueous Na2CO3 solution (4.20 mL), tert-butyl 4-[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)-pyridine carboxylate (0.500 g, 1.51 mmol), 3-aminophenylboronic acid hemisulfate (0.393 g, 2.11 mmol), lithium chloride (0.191 g, 4.50 mmol) and tetrakis-triphenylphosphine palladium (0.080 g, 0.075 mmol) in dimethoxyethane (5.00 mL) was heated at reflux temperature for 3 hours under Argon.
The organic layer of the cooled reaction mixture was separated and the aqueous layer was washed with ethyl acetate (3*50 mL).
The combined organic solutions were dried and concentrated in vacuo.
The crude product was chromatographed (silica, hexanes:EtOAc:dichloromethane 6:1:1 with 1percent isopropylamine) to give the desired product (0.330 g, 81percent).
1H NMR (400 MHz, CDCl3) δ 7.12 (t, 1H, J=7.60 Hz), 6.78 (d, 1H, J=8.4 Hz), 6.69 (t, 1H, J=2.0 Hz), 6.59 (dd, 1H, J=2.2, 8.0 Hz), 6.01 (br, 1H), 4.10-4.01 (d, 2H, J=2.4 Hz) 3.61 (t, 2H, J=5.6 Hz), 2.52-2.46 (m, 2H), 1.49 (s, 9H); ESMS m/e: 275.2 (M+H)+. Anal. Calc. for C16H24N2O2: C, 70.04; H, 8.08; N, 10.21. Found: C, 69.78; H, 7.80; N, 9.92.
Reference: [1] Patent: WO2004/5257, 2004, A1, . Location in patent: Page 53
[2] Patent: US2005/154020, 2005, A1, . Location in patent: Page/Page column 8
[3] Patent: US2005/154022, 2005, A1, . Location in patent: Page/Page column 4; 8-9
  • 31
  • [ 138647-49-1 ]
  • [ 387827-18-1 ]
YieldReaction ConditionsOperation in experiment
60% With sodium carbonate; lithium chloride In 1,2-dimethoxyethane; water at 100℃; A mixture of 2 M AQ NA2C03 solution (42 mL), triflate from Step 1 (50.0 g, 15.1 mmol), 3- aminophenylboronic acid hemisulfate (3.93 g, 2.11 MMOL), lithium chloride (1.91 g, 45.0 mmol), and tetrakis-triphenyl phosphine palladium (0.80 g, 0.75 mmol) in dimethoxyethane (50 mL) was purged with argon and heated at 100°C under an inert atmosphere overnight. The organic layer of the cooled reaction mixture was separated, and the aqueous layer was washed with EtOAc (3x). The combined organic extracts were dried and concentrated in vacuo. The crude product was separated by flash chromatography (silica, EtOAc: Hexane 3: 7) to give the product as a yellow oil (2.5 g, 60 percent). 1H NMR (CDC13) 6 7.25 (s, 1 H), 7.22 (m, 1H), 6.92 (m, 2 H), 6.84 (m, 1H), 6.02 (s, 1H), 4.1 (m, 2H), 3.62 (2 H), 2.49 (s, 2H), 1.49 (s, 9H), 1.26 (t, 2H).
Reference: [1] Patent: WO2004/58727, 2004, A1, . Location in patent: Page 52-53
  • 32
  • [ 138647-49-1 ]
  • [ 387827-18-1 ]
YieldReaction ConditionsOperation in experiment
81% With sodium carbonate; lithium chloride In 1,2-dimethoxyethane; water for 3 h; Heating / reflux A mixture of 2 M aqueous Na2CO3 solution (4.2 mL), tert-butyl 4-[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydro-1-pyridine-carboxylate (0.500 g, 1.51 mmol), 3-aminophenylboronic acid hemisulfate (0.393 g, 2.11 mmol), lithium chloride (0.191 g, 4.50 mmol) and tetrakis-triphenylphosphine palladium(0) (0.080 g, 0.075 mmol) in dimethoxyethane (5 mL) was heated at reflux temperature for 3 hours, under an inert atmosphere (an initial degassing of the mixture is recommended to prevent the formation of triphenylphosphine oxide). The organic layer of the cooled reaction mixture was separated and the aqueous layer was washed with ethyl acetate (3.x.). The combined organic extracts were dried and concentrated in vacuo. The crude product was chromatographed (silica, hexanes:EtOAc:dichloromethane (6:1:1) with 1percent added isopropylamine to protect the BOC group from hydrolysis) to give 0.330 g of the desired product in 81percent yield. 1H NMR (400 MHz, CDCl3) δ 7.12 (t, 1H, J=7.60 Hz), 6.78 (d, 1H, J=8.4 Hz), 6.69 (t, 1H, J=2.0 Hz), 6.59 (dd, 1H, J=2.2, 8.0 Hz), 6.01 (m, 1H), 4.10-4.01 (d, 2H, J=2.4 Hz), 3.61 (t, 2H, J=5.6 Hz), 2.52-2.46 (m, 2H), 1.49 (s, 9H); ESMS m/e: 275.2 (M+H)+. Anal. Calc. for C16H24N2O2: C, 70.04; H, 8.08; N, 10.21. Found: C, 69.78; H, 7.80; N, 9.92.
Reference: [1] Patent: US6727264, 2004, B1, . Location in patent: Page column 56; 91
  • 33
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  • [ 138647-49-1 ]
  • [ 387827-18-1 ]
Reference: [1] Molecules, 2013, vol. 18, # 10, p. 12119 - 12143
  • 34
  • [ 557-21-1 ]
  • [ 138647-49-1 ]
  • [ 873551-20-3 ]
YieldReaction ConditionsOperation in experiment
3.5 g With tetrakis(triphenylphosphine) palladium(0) In dimethyl sulfoxide at 100℃; for 2 h; To a solution of tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylate(6.0 g, 0.018 mol) in dimethyl sulphoxide (60 ml), palladium(0) tetrakis(triphenylphosphine)(0.84 g, 0.007 mmol) and zinc cyanide (3.81 g, 0.032 mol) was added. The reaction mixture was heated to 100°C for 2 hr. The reaction mixture was diluted with water extracted with ethyl acetate. The organic layer was washed with water, followed by brine further dried over sodium sulphate and evaporated. The residue is purified by combi flash (eluting with 5percent ethylacetate:n-hexane) to get 3.5 g of tert-butyl 4-cyano-3,6-dihydro-2H-pyridine-1-carboxylate. MS: m/z = 209 (M+1).
3.5 g With tetrakis(triphenylphosphine) palladium(0) In dimethyl sulfoxide at 100℃; for 2 h; To a solution of tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylate (6.0 g, 0.018 mol) in dimethyl sulphoxide (60 mL), palladium(0) tetrakis(triphenylphosphine) (0.84 g, 0.007 mmol) and zinc cyanide (3.81 g, 0.032 mol) was added. The reaction mixture was heated to 100° C. for 2 hr. The reaction mixture was diluted with water extracted with ethyl acetate. The organic layer was washed with water, followed by brine further dried over sodium sulphate and evaporated. The residue is purified by combi flash (eluting with 5percent ethylacetate:n-hexane) to get 3.5 g of tert-butyl 4-cyano-3,6-dihydro-2H-pyridine-1-carboxylate. MS: m/z=209 (M+1).
Reference: [1] Patent: WO2013/127808, 2013, A1, . Location in patent: Page/Page column 31
[2] Patent: US2015/31541, 2015, A1, . Location in patent: Paragraph 0146
  • 35
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  • [ 159503-91-0 ]
Reference: [1] Chemical Communications, 2009, # 34, p. 5088 - 5090
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