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Chemical Structure| 37595-74-7
Chemical Structure| 37595-74-7
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Product Citations

Product Citations

Henderson, Ian M. ; Zeng, Fanxun ; Bhuiyan, Nazmul H. , et al. DOI: PubMed ID:

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

Purchased from AmBeed: ; ; 103-63-9 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;

Product Details of [ 37595-74-7 ]

CAS No. :37595-74-7 MDL No. :MFCD00000404
Formula : C8H5F6NO4S2 Boiling Point : -
Linear Structure Formula :C6H5N(O2SCF3)2 InChI Key :DIOHEXPTUTVCNX-UHFFFAOYSA-N
M.W : 357.25 Pubchem ID :142176
Synonyms :
N-Phenyltrifluoromethanesulfonimide
Chemical Name :1,1,1-Trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide

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

Physicochemical Properties

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

Pharmacokinetics

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

Lipophilicity

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

Druglikeness

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

Water Solubility

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

Medicinal Chemistry

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

Safety of [ 37595-74-7 ]

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

Application In Synthesis of [ 37595-74-7 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

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

[ 37595-74-7 ] Synthesis Path-Downstream   1~18

  • 1
  • [ 19090-04-1 ]
  • [ 37595-74-7 ]
  • [ 194665-78-6 ]
  • 2
  • [ 37595-74-7 ]
  • [ 703-67-3 ]
  • [ 556107-58-5 ]
  • 3
  • [ 7651-82-3 ]
  • [ 37595-74-7 ]
  • [ 149353-93-5 ]
  • 4
  • [ 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
  • 5
  • [ 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.

  • 6
  • [ 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)+.
  • 7
  • [ 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.
  • 8
  • [ 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).
  • 9
  • [ 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)+.
  • 10
  • [ 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)+.
  • 11
  • [ 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)+.
  • 12
  • [ 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)+.
  • 13
  • [ 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...
  • 14
  • [ 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,
  • 15
  • [ 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.
  • 16
  • [ 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.
  • 17
  • [ 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.
  • 18
  • [ 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.
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