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[ CAS No. 39267-79-3 ] {[proInfo.proName]}

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Chemical Structure| 39267-79-3
Chemical Structure| 39267-79-3
Structure of 39267-79-3 * Storage: {[proInfo.prStorage]}
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Product Details of [ 39267-79-3 ]

CAS No. :39267-79-3 MDL No. :MFCD08544402
Formula : C3H5BrO Boiling Point : -
Linear Structure Formula :- InChI Key :SZTIZZFKWQWSSP-UHFFFAOYSA-N
M.W :136.98 Pubchem ID :16244493
Synonyms :

Calculated chemistry of [ 39267-79-3 ]

Physicochemical Properties

Num. heavy atoms : 5
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 23.38
TPSA : 9.23 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.65 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.51
Log Po/w (XLOGP3) : 0.68
Log Po/w (WLOGP) : 0.78
Log Po/w (MLOGP) : 0.56
Log Po/w (SILICOS-IT) : 1.8
Consensus Log Po/w : 1.07

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 3.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.12
Solubility : 10.4 mg/ml ; 0.0763 mol/l
Class : Very soluble
Log S (Ali) : -0.45
Solubility : 48.5 mg/ml ; 0.354 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.04
Solubility : 12.4 mg/ml ; 0.0908 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.6

Safety of [ 39267-79-3 ]

Signal Word:Danger Class:3
Precautionary Statements:P261-P305+P351+P338 UN#:1993
Hazard Statements:H225-H302-H315-H319-H335-H412 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 39267-79-3 ]

* 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 [ 39267-79-3 ]

[ 39267-79-3 ] Synthesis Path-Downstream   1~80

  • 1
  • [ 1945-84-2 ]
  • [ 39267-79-3 ]
  • [ 1191128-30-9 ]
  • 2
  • [ 39267-79-3 ]
  • [ 16520-62-0 ]
  • [ 1191128-36-5 ]
  • 3
  • [ 39267-79-3 ]
  • [ 78593-42-7 ]
  • [ 1191128-57-0 ]
  • 4
  • [ 39267-79-3 ]
  • 6-bromo-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester [ No CAS ]
  • [ 1396780-89-4 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In acetonitrile; for 8h;Reflux; [0903] Synthesis of Compound B-15: N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)-l -(oxetan-3-yl)-6-(2,2,6,6-tetramethyl- 1 ,2,3, 6-tetrahy dropyridin-4-yl)- 1H- pyrazolo[3,4-b]pyridine-4-carboxamideCompound B- 15[0904] Step 1 : Synthesis of ethyl 6-bromo-l -(oxetan-3-yl)-lH-pyrazolo[3,4-b]pyridine-4- carboxylate[0905] Ethyl 6-bromo-l H-pyrazoIo[3,4-b]pyridine-4-carboxylate (1 equiv.) was suspended in acetonitrile and K2C03 (1.5 equiv.) and <strong>[39267-79-3]3-bromooxetane</strong> (2 equiv.) was added to it. The reaction mixture was refluxed for 8 h. On completion, acetonitrile was removed under reduced pressure and water was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2S04. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate.
  • 5
  • [ 37622-90-5 ]
  • [ 39267-79-3 ]
  • [ 1401727-18-1 ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h; To a solution of 1H-pyrazole-4-carboxylic acid ethyl ester (1.0 g, 7.13 mmol) in DMF (10 mL) was added Cs2CO3 (6.97 g, 21.40 mmol) and <strong>[39267-79-3]3-bromo-oxetane</strong> (1.07 g, 7.84 mmol) and the mixture was stirred for 16 h at 100 C. The mixture was then quenched with water and extracted with EtOAc (3*20 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness to give 1-oxetan-3-yl-1H-pyrazole-4-carboxylic acid ethyl ester as a colorless oil (1.0 g, 64%) which was used without further purification.
1 g With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h; To a solution of 1 H-pyrazole-4-carboxylic acid ethyl ester (1 .0 g, 7.13 mmol) in DMF (10 mL) was added Cs2C03 (6.97 g, 21.40 mmol) and <strong>[39267-79-3]3-bromo-oxetane</strong> (1 .07 g, 7.84 mmol) and the mixture was stirred for 16 h at 100 C. The mixture was then quenched with water and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2S04 and evaporated to dryness to give 1 -oxetan-3-yl-1 H-pyrazole-4-carboxylic acid ethyl ester as a colorless oil (1 .0 g, 64%) which was used without further purification.
  • 6
  • [ 39267-79-3 ]
  • [ 1429940-08-8 ]
  • [ 1429939-74-1 ]
  • 7
  • [ 39267-79-3 ]
  • [ 1570495-73-6 ]
  • [ 1570495-93-0 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 50℃; for 48h; A mixture of K2C03 (19.8 mg, 0.144 mmol), 3-((5-methyl-3-(3-(4- (trifluoromethoxy)phenyl)- 1 ,2,4-oxadiazol-5-yl)- 1 H- 1 ,2,4-triazol- 1 -yl)methyl)phenol (Example 59; 30.0 mg, 0.072 mmol), sodium iodide (21.6 mg, 0.144 mmol) and <strong>[39267-79-3]3-bromooxetane</strong> (22 uL, 0.288 mmol) in DMF (0.36 mL) was stirred at 50 C for 48 h. The crude mixture was diluted with H20 and extracted with 4: 1 (Zeta(: -RhoGammaOmicronEta. The organic layer was dried over MgS04, concentrated under reduced pressure, and the residue was purified using Prep-HPLC to furnish the title compound; MS (ES+) C22H18F3N5O4 requires: 473, found 474 [M+H]+; *H- NMR (600 MHz, CD3OD) delta ppm 8.28 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.28 (m, 1H), 6.86 (d, / = 7.8 Hz, 1H), 6.64 (m, 2H), 5.42 (s, 2H), 5.18 (m, 1H), 4.95 (m, 2H), 4.74 (m, 2H), 2.54 (s, 3H).
  • 8
  • [ 39267-79-3 ]
  • [ 182344-70-3 ]
  • [ 1612156-13-4 ]
  • 9
  • [ 104-92-7 ]
  • [ 39267-79-3 ]
  • [ 1401878-45-2 ]
  • 10
  • [ 39267-79-3 ]
  • [ 158326-84-2 ]
  • 6-bromo-3,3-dimethyl-1-(oxetan-3-yl)indolin-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 18h;Inert atmosphere; A mixture of 6-bromo-3,3-dimethylindolin-2-one from example la (500 mg), <strong>[39267-79-3]3-bromooxetane</strong> (594 mg) and cesium carbonate (1.36 g) in DMF (17 ml) was flushed with argon for 5 min and heated to 60 C for 18 h. The mixture was partitioned between aqueous HC1 (1 M) and EtOAc, the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, gradient, 0% to 50% EtOAc in n-heptane) to give the title compound (550 mg, 80%) as an orange waxy solid. MS (ESI, m/z): 296.3/298.3 [(M+H)+].
1.49 g With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 21h;Inert atmosphere; a) 6-Bromo-3,3-dimethyl-1-(oxetan-3-yl)indolin-2-one To a solution of 6-bromo-3,3-dimethylindolin-2-one (example 24a, 1.5 g, 6.25 mmol) in DMF(20.0 ml) under argon were added <strong>[39267-79-3]3-bromooxetane</strong> (1.6 g, 895 tl, 11.2 mmol) and cesiumcarbonate (4.07 g, 12.5 mmol) and the reaction mixture heated to 60C for 17.5 hours. Again 3- bromooxetane (250 tl) and cesium carbonate (2 g) were added and stirring at 60C continued for 3.5 hours. The reaction mixture was treated with 50 mL 1 M aqueous HC1 solution and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated invacuo. The crude material purified by silica gel chromatography using heptane/ ethyl acetate aseluent. The title compound was obtained as white solid (1.49 g)MS ESI (m/z): 296.3, 298.3 [(M+H)41.1H NMR (300MHz, CHLOROFORM-d) oe = 7.71 (d, J=1.6 Hz, 1H), 7.30 - 7.23 (m, 1H), 7.12(d, J=7.9 Hz, 1H), 5.63 - 5.50 (m, 1H), 5.16 - 4.98 (m, 4H), 1.36 (s, 6H)
  • 11
  • [ 2075-45-8 ]
  • [ 39267-79-3 ]
  • 4-bromo-1-(oxetan-3-yl)-1H-pyrazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 130℃; for 8h; Step A: 4-Bromo-1-(oxetan-3-yl)-1H-pyrazole 4-Bromo-1H-pyrazole (1.53 g, 10.7 mmol) is dissolved in anhydrous dimethylformamide (15 mL). 3-Bromooxetane (2.0 g, 14.6 mmol) and caesium carbonate (4.7 g, 14 mmol) are successively added thereto. The reaction mixture is heated for 8 hours at 130 C. in a sealed flask. At the end of the reaction, the solvent is evaporated off in vacuo and the residue is purified by chromatography over silica gel using dichloromethane containing diethylamine and methanol as eluants to yield the expected compound.
  • 12
  • [ 39267-79-3 ]
  • [ 3964-56-5 ]
  • 3-(4-bromo-2-chlorophenoxy)oxetane [ No CAS ]
  • 13
  • [ 39267-79-3 ]
  • C21H23FN4O4S [ No CAS ]
  • C24H27FN4O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
General procedure: To a solution of the respective starting material (1 eq.) in DMF cooled to 000 is added sodium hydride (55% in mineral oil, 1 .2 eq.). The mixture is stirred for 30 mm, then the respective alkylating agent (1 eq.) is added. The mixture is stirred over night withoutfurther cooling. Water is added and the mixture is extracted with DCM. The organic layer is separated, dried, and evaporated. The residue is purified by RP-HPLC or FC.
  • 14
  • [ 39267-79-3 ]
  • [ 5334-39-4 ]
  • [ 1374830-15-5 ]
YieldReaction ConditionsOperation in experiment
82% With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 144h; Added <strong>[39267-79-3]3-bromooxetane</strong> (451 ul, 5.901 mmol) to a mixture of 3-methyl-4-nitro-1 H-pyrazole (500 mg, 3.934 mmol) and cesium carbonate (2.564 g, 7.868 mmol) in DMF (5 mL) and stirred at 70 C for 6 d. Added ether (50ml_) and filtered off the residues. Removed the solvent from the filtrate in vacuo and purified the residue by flash chromatography using dichloromethane/ethyl acetate (3/7) to give the titled compound (589 mg, 82%). LCMS (Method 1 ) Rt 1.865 min.
  • 15
  • [ 39267-79-3 ]
  • 6-chloro-3,3-dimethyl-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one [ No CAS ]
  • 6-chloro-3,3-dimethyl-1-oxetan-3-yl-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 16h; A mixture of 6-chloro-3,3-dimethyl-lH-pyrrolo[3,2-c]pyridin-2(3H)-one (2.65 g, prepared according to Woolford et al., WO 2012143726), <strong>[39267-79-3]3-bromooxetane</strong> (1.85 ml) and cesium carbonate (8.78 g) in DMF (20 ml) was heated to 60 C for 16 h. The mixture was partitioned between saturated aqueous ammonium chloride and EtOAc, the organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, gradient, 0% to 30% EtOAc in n-heptane) to give the title compound (2.90 g, 85%) as a white solid. MS (ESI, m/z): 252.8 [(M+H)+].
  • 16
  • [ 39267-79-3 ]
  • [ 153747-97-8 ]
  • tert-butyl 4-(5-(oxetan-3-yl)pyridin-2-yl)piperazine-1-carboxylate [ No CAS ]
  • 17
  • [ 39267-79-3 ]
  • [ 281192-93-6 ]
  • 1-benzyl-3-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine [ No CAS ]
  • 18
  • [ 39267-79-3 ]
  • [ 183208-35-7 ]
  • 5-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine [ No CAS ]
  • 19
  • [ 39267-79-3 ]
  • [ 22532-62-3 ]
  • 4-bromo-2-(oxetan-3-yloxy)benzaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;Inert atmosphere; To a solution of 4-bromo-2-hydroxybenzaldehyde (3 g, 14.92 mmol) in DMF (15 mL) stirred under Nitrogen atmosphere were added Cs2CO3 (9.73 g, 29.8 mmol) and then 3- bromooxetane (3.07 g, 22.39 mmol). The reaction mixture was stirred at 100 C for 16 hours, then cooled, and partitioned between water (20m1) and EtOAc (30 mL). The organic phase was separated and the aqueous phase was further extracted with EtOAc (2x30 mL). The combined organic phase was washed with brine solution (30 ml), dried over anhydrous Na2SO4 and then concentrated under reduced pressure to afford the title compound (3 g, 78 % yield) as brown solid.LCMS (e): Rt = 2.48 mi M/z = 255.13 (M+H)
  • 20
  • [ 39267-79-3 ]
  • [ 1363386-50-8 ]
  • C29H34N6O4 [ No CAS ]
  • 21
  • [ 39267-79-3 ]
  • [ 619-42-1 ]
  • [ 1607005-64-0 ]
  • 22
  • [ 39267-79-3 ]
  • [ 1148-11-4 ]
  • benzyl 2-(oxetan-3-yl)pyrrolidine-1-carboxylate [ No CAS ]
  • 23
  • [ 288-32-4 ]
  • [ 39267-79-3 ]
  • 1-(oxetan-3-yl)-1H-imidazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
18% With sodium hydroxide; In acetonitrile; at 90℃; Into a 100-mL round-bottom flask, was placed 1H-imidazole (3 g, 44.07 mmol, 1.00 equiv), ACN (50 mL), sodium hydroxide (3.5 g, 87.50 mmol, 2.00 equiv), and <strong>[39267-79-3]3-bromooxetane</strong> (7.24 g, 52.86 mmol, 1.20 equiv). The resulting solution was stirred overnight at 90 oC, then diluted with 200 mL of H2O and extracted with 3x50 mL of dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was applied onto a silica gel column with dichloromethane/methanol (100/1). The collected fractions were combined and concentrated under vacuum. This resulted in 1 g (18%) of 1-(oxetan-3-yl)-1H-imidazole as a colorless oil.
  • 24
  • [ 25235-85-2 ]
  • [ 39267-79-3 ]
  • 4-chloro-1-(oxetan-3-yl)-1H-indole [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide; In N,N-dimethyl-formamide; at 50℃; Step 1 Preparation of 4-chloro-1-(oxetan-3-yl)-1H-indole To a stirred solution of 4-chloro-1H-indole (0.90 g, 5.93 mmol) and compound <strong>[39267-79-3]3-bromooxetane</strong> (1.22 g, 8.90 mmol) in DMF (10.0 mL) was added potassium hydroxide (1.00 g, 17.81 mmol) at room temperature. The mixture was stirred at 50 C. overnight. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL*3). The combined extracts were collected and washed with water (10 mL) and brine (10 mL), dried over Na2SO4, concentrated in vacuo to give 4-chloro-1-(oxetan-3-yl)-1H-indole (0.70 g, 47%) as a brown oil, which was used in the next step without further purification. [M+H]+ 208.0.
  • 25
  • [ 39267-79-3 ]
  • 4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester [ No CAS ]
  • 4-chloro-1-oxetan-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
53.1% With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 80℃; for 118h; Step 1 Preparation of 4-Chloro-1-oxetan-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester To a solution of 4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (500.00 mg; 2.33 mmol; 1.00 eq.) in dry DMF (15 mL, 30 V), and Cesium carbonate (1531.67 mg, 4.65 mmol, 2.00 eq) was added 3-Bromo-oxetane (487.86 mg, 3.49 mmol, 1.50 eq) drop wise at 0 C. and stirred for 18 h at 80 C. Upon completion, monitored by TLC, the reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The combined organic layer was washed with water, saturated brine solution, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The crude mass was purified by silica gel column chromatography using 25% Ethyl acetate in petroleum ether as eluent to get the compound 4-Chloro-1-oxetan-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (350 mg, 1.23 mmol, 53.1%) as a off-white solid. 1H NMR (400 muMHz, DMSO-d6): delta 8.70 (s, 1H), 8.30 (d, J=5.12 Hz, 1H), 7.41 (d, J=5.12 Hz, 1H), 5.99-5.92 (m, 1H), 5.06-4.97 (m, 4H), 3.81 (s, 3H) ppm.
  • 26
  • [ 39267-79-3 ]
  • [ 74204-00-5 ]
  • 3-(3-bromo-5-methyl phenoxy)oxetane [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 100℃; for 18.0h; <strong>[39267-79-3]3-bromooxetane</strong> (110 mg, 0.802 mmol) was added to a mixture of 3-bromo-5- methylphenol (100 mg, 0.535 mmol), KI (133 mg, 0.802 mmol) and K2CO3 (118 mg, 0.855 mmol) in DMF (0.53 mL). The reaction was stirred at 100 C for 18 hours. Water (5 mL) and ethyl acetate were added (5 mL). The phases were separated. The organic layer was washed with 1 N NaOH (2x5mL), dried with sodium sulfate, filtered and evaporated and afforded the title compound (98 mg, 0.40 mmol, 75%) which was used directly.
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 100℃; for 18.0h; <strong>[39267-79-3]3-bromooxetane</strong> (110 mg, 0.802 mmol) was added to a mixture of 3-bromo-5- methylphenol (100 mg, 0.535 mmol), KI (133 mg, 0.802 mmol) and K2C03 (118 mg, 0.855 mmol) in DMF (0.53 mL). The reaction was stirred at 100 C for 18 hours. Water (5 mL)ethyl acetate were added (5 mL). The phases were separated. The organic layer was washed with 1 N NaOH (2x5mL), dried with sodium sulfate, filtered and evaporated and afforded the title compound (98 mg, 0.40 mmol, 75%) which was used directly.
  • 27
  • [ 39267-79-3 ]
  • ((1S,5S,6S)-3-amino-5-(5-((Z)-2-(5-bromopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)(morpholino)methanone [ No CAS ]
  • ((1S,5S,6S)-3-amino-5-(2-fluoro-5-((Z)-2-fluoro-2-(pyridin-2-yl)vinyl)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)(morpholino)methanone [ No CAS ]
  • ((1S,5S,6S)-3-amino-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(oxetan-3-yl)pyridin-2-yl)vinyl)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)(morpholino)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
24% Preparation of ((l^S^^-S-amino-S-^-f oro-S-^ ^l-fluoro-l-ipyridin-l- yl)vinyl)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-l- yl)(morpholino)methanone (Example 339) and ((l^S^^^-S-amino-S-il-fluoro-S-ii )-- fluoro-2-(5-(oxetan-3-yl)pyridin-2-yl)vinyl)phenyl)-5-methyl-2-thia-4- azabicyclo[4.1.0]hept-3-en-l-yl)(morpholino)methanone (Example 340) A mixture of di-fert-butyl dicarbonate (0.337 ml, 1.466 mmol) and (( Iota^^^,^-Beta- amino-5-(5-((Z)-2-(5-bromopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-methyl-2-thia-4- azabicyclo[4.1.0]hept-3-en-l-yl)(mophiholino)methanone (Example 338) (0.34 g, 0.62 mmol) in the presence of 4-dimethylaminopyridine (0.002 g, 0.02 mmol) in DCM (5 mL) was stirred at 50 C for 2 hours. The solvent was evaporated and the residue was used in the next step assuming quantitative yield. Water was degassed with a stream of N2 for 1 hour prior to use. A mixture of zinc dust (250 mg, 3.82 mmol), sodium caprylate (60 mg, 0.36 mmol), sodium chloride (80 mg, 1.4 mmol), 1-octanol (160 mu, 1.02 mmol), and the Boc-protected intermediate (460 mg, 0.614 mmol) was briefly evacuated and backfilled with N2 (3x). Degassed water (3 mL) was added followed by <strong>[39267-79-3]3-bromooxetane</strong> (100 mu, 1.20 mmol), Nu,Nu,Nu',Nu'-tetra-methyl-ethylenediamine (250 mu, 1.67 mmol) and (2-dicyclohexylphosphino- 2',4',6'-triisopropyl- 1 , 1 '-biphenyl) [2-(2'-amino- 1 , 1 '-biphenyl)]palladium(II) methane sulfonate (50 mg, 0.059 mmol, xPhos-G3, Strem Chemical, Inc.). The mixture was sealed and heated with stirring at 45 C. Occasional sonication was used to help mixing. After 80 hours, the mixture was shaken with EtOAc ( 10 mL) and filtered through a pad of Celite. The residue was washed with HC1 (0.5 N, 5 mL), EtOAc (3x10 mL). The organic layer was washed with brine (5 mL), dried over NaaSO/i, filtered, and concentrated to give the crude product mixture as orange oil. The residue thus obtained was dissolved in DCM (5 mL) and was treated with trifluoroacetic acid (500 mu^, 6.73 mmol). The solution was stirred at room temperature for 20 minutes. Additional trifluoroacetic acid (500 mu^, 6.73 mmol) was added. After another 20 minutes, the mixture was quenched with saturated aq. NaHCC>3 (20 mL) and vigorously stirred for 10 minutes. The aqueous layer was extracted with DCM (3x5 mL). The combined organic phase was dried over NaaSOzi, filtered, and concentrated. The residue was purified by chromatography on silica using NH3-MeOH (2 N) in DCM (5-40%) as eluent. The products were further purified by reverse-phase preparative HPLC (Agilent) using a Kinetex 5 mupiiota Evo C 18 100 column (21.2 x 150 mm) with 0.1% TFA in CH3CN/H20, gradient 5% to 95% over 16 minutes at 35 mL/min. The product fractions were basified with Na2C03 and concentrated to a slurry. The slurry was filtered and the resulting solid was combined with the bulky material from trituration and lyophilized to give: Example 339: ((15',55',65)-3-amino-5-(2-fluoro-5-((Z)-2-fluoro-2-(pyridin-2- yl)vinyl)phenyl)-5 -methyl-2-thia-4-azabicyclo [4.1.0]hept-3 -en- 1 -yl)(morpholino)methanone . LCMS (ESI, pos.): calcd for C24H24F2N402S: 470.2; found: 471.2 (M+1). NMR (400 MHz, CHLOROFORM-d) delta 8.60 (d, J=4.50 Hz, IH), 7.71-7.80 (m, 2H), 7.64-7.70 (m, IH), 7.61 (d, J=8.02 Hz, IH), 7.21-7.25 (m, IH), 6.98-7.12 (m, 2H), 3.59-3.74 (m, 8H), 2.29 (dd, J=7.92, 8.90 Hz, IH), 1.86 (s, 3H), 1.36 (dd, J=5.77, 9.68 Hz, IH), 0.88 (t, J=6.36 Hz, IH). 19F NMR (376 MHz, CHLOROFORM-d) delta -1 10.29 (s, IF), - 124.27 (s, IF). Example 340: (( 15',55',65)-3-amino-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(oxetan-3- yl)pyridin-2-yl)vinyl)phenyl)-5 -methyl -2 -thia-4-azabicyclo [4.1.0]hept-3 -en- 1 - yl)(mophiholino)methanone (76 mg, 24 % yield) as a white sponge. LCMS (ESI, pos.): calcd for C27H28F2N403S: 526.2; found: 527.2 (M+1). NMR (400 MHz, CHLOROFORM-d) delta 8.57 (s, IH), 7.91 (dd, J=2.15, 8.22 Hz, IH), 7.78 (dd, J=1.96, 7.83 Hz, IH), 7.61-7.71 (m, 2H), 7.03-7.13 (m, IH), 6.99 (d, J=36.39 Hz, IH), 5.14 (dd, J=6.26, 8.22 Hz, 2H), 4.76 (t, J=6.36 Hz, 2H), 4.20-4.34 (m, IH), 3.58-3.77 (m, 8H), 2.24-2.36 (m, IH), 1.86 (s, 3H), 1.37 (dd, J=5.67, 9.78 Hz, IH), 0.89 (t, J=6.46 Hz, IH). 19F NMR (376 MHz, CHLOROFORM-d) delta -1 10.22 (s, IF), - 124.07 (s, IF).
  • 28
  • [ 39267-79-3 ]
  • ((1S,5S,6S)-3-amino-5-(5-((Z)-2-(5-bromopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)(morpholino)methanone [ No CAS ]
  • C32H36F2N4O5S [ No CAS ]
  • C29H32F2N4O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With octanol; N,N,N,N,-tetramethylethylenediamine; methanesulfonic acid(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II); sodium caprylate; sodium chloride; zinc; In water; at 45℃; for 80h;Inert atmosphere; Sealed tube; Preparation of ((l^S^^-S-amino-S-^-f oro-S-^ ^l-fluoro-l-ipyridin-l- yl)vinyl)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-l- yl)(morpholino)methanone (Example 339) and ((l^S^^^-S-amino-S-il-fluoro-S-ii )-- fluoro-2-(5-(oxetan-3-yl)pyridin-2-yl)vinyl)phenyl)-5-methyl-2-thia-4- azabicyclo[4.1.0]hept-3-en-l-yl)(morpholino)methanone (Example 340) A mixture of di-fert-butyl dicarbonate (0.337 ml, 1.466 mmol) and (( Iota^^^,^-Beta- amino-5-(5-((Z)-2-(5-bromopyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-methyl-2-thia-4- azabicyclo[4.1.0]hept-3-en-l-yl)(mophiholino)methanone (Example 338) (0.34 g, 0.62 mmol) in the presence of 4-dimethylaminopyridine (0.002 g, 0.02 mmol) in DCM (5 mL) was stirred at 50 C for 2 hours. The solvent was evaporated and the residue was used in the next step assuming quantitative yield. Water was degassed with a stream of N2 for 1 hour prior to use. A mixture of zinc dust (250 mg, 3.82 mmol), sodium caprylate (60 mg, 0.36 mmol), sodium chloride (80 mg, 1.4 mmol), 1-octanol (160 mu, 1.02 mmol), and the Boc-protected intermediate (460 mg, 0.614 mmol) was briefly evacuated and backfilled with N2 (3x). Degassed water (3 mL) was added followed by <strong>[39267-79-3]3-bromooxetane</strong> (100 mu, 1.20 mmol), Nu,Nu,Nu',Nu'-tetra-methyl-ethylenediamine (250 mu, 1.67 mmol) and (2-dicyclohexylphosphino- 2',4',6'-triisopropyl- 1 , 1 '-biphenyl) [2-(2'-amino- 1 , 1 '-biphenyl)]palladium(II) methane sulfonate (50 mg, 0.059 mmol, xPhos-G3, Strem Chemical, Inc.). The mixture was sealed and heated with stirring at 45 C. Occasional sonication was used to help mixing. After 80 hours, the mixture was shaken with EtOAc ( 10 mL) and filtered through a pad of Celite. The residue was washed with HC1 (0.5 N, 5 mL), EtOAc (3x10 mL). The organic layer was washed with brine (5 mL), dried over NaaSO/i, filtered, and concentrated to give the crude product mixture as orange oil. The residue thus obtained was dissolved in DCM (5 mL) and was treated with trifluoroacetic acid (500 mu^, 6.73 mmol). The solution was stirred at room temperature for 20 minutes. Additional trifluoroacetic acid (500 mu^, 6.73 mmol) was added. After another 20 minutes, the mixture was quenched with saturated aq. NaHCC>3 (20 mL) and vigorously stirred for 10 minutes. The aqueous layer was extracted with DCM (3x5 mL). The combined organic phase was dried over NaaSOzi, filtered, and concentrated. The residue was purified by chromatography on silica using NH3-MeOH (2 N) in DCM (5-40%) as eluent. The products were further purified by reverse-phase preparative HPLC (Agilent) using a Kinetex 5 mupiiota Evo C 18 100 column (21.2 x 150 mm) with 0.1% TFA in CH3CN/H20, gradient 5% to 95% over 16 minutes at 35 mL/min. The product fractions were basified with Na2C03 and concentrated to a slurry. The slurry was filtered and the resulting solid was combined with the bulky material from trituration and lyophilized to give: Example 339: ((15',55',65)-3-amino-5-(2-fluoro-5-((Z)-2-fluoro-2-(pyridin-2- yl)vinyl)phenyl)-5 -methyl-2-thia-4-azabicyclo [4.1.0]hept-3 -en- 1 -yl)(morpholino)methanone . LCMS (ESI, pos.): calcd for C24H24F2N402S: 470.2; found: 471.2 (M+1). NMR (400 MHz, CHLOROFORM-d) delta 8.60 (d, J=4.50 Hz, IH), 7.71-7.80 (m, 2H), 7.64-7.70 (m, IH), 7.61 (d, J=8.02 Hz, IH), 7.21-7.25 (m, IH), 6.98-7.12 (m, 2H), 3.59-3.74 (m, 8H), 2.29 (dd, J=7.92, 8.90 Hz, IH), 1.86 (s, 3H), 1.36 (dd, J=5.77, 9.68 Hz, IH), 0.88 (t, J=6.36 Hz, IH). 19F NMR (376 MHz, CHLOROFORM-d) delta -1 10.29 (s, IF), - 124.27 (s, IF). Example 340: (( 15',55',65)-3-amino-5-(2-fluoro-5-((Z)-2-fluoro-2-(5-(oxetan-3- yl)pyridin-2-yl)vinyl)phenyl)-5 -methyl -2 -thia-4-azabicyclo [4.1.0]hept-3 -en- 1 - yl)(mophiholino)methanone (76 mg, 24 % yield) as a white sponge. LCMS (ESI, pos.): calcd for C27H28F2N403S: 526.2; found: 527.2 (M+1). NMR (400 MHz, CHLOROFORM-d) delta 8.57 (s, IH), 7.91 (dd, J=2.15, 8.22 Hz, IH), 7.78 (dd, J=1.96, 7.83 Hz, IH), 7.61-7.71 (m, 2H), 7.03-7.13 (m, IH), 6.99 (d, J=36.39 Hz, IH), 5.14 (dd, J=6.26, 8.22 Hz, 2H), 4.76 (t, J=6.36 Hz, 2H), 4.20-4.34 (m, IH), 3.58-3.77 (m, 8H), 2.24-2.36 (m, IH), 1.86 (s, 3H), 1.37 (dd, J=5.67, 9.78 Hz, IH), 0.89 (t, J=6.46 Hz, IH). 19F NMR (376 MHz, CHLOROFORM-d) delta -1 10.22 (s, IF), - 124.07 (s, IF).
  • 29
  • [ 39267-79-3 ]
  • C12H13N7OS [ No CAS ]
  • C15H17N7O2S [ No CAS ]
  • 30
  • [ 39267-79-3 ]
  • 3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one [ No CAS ]
  • 3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(oxetan-3-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
16% Example 265: Preparation of 3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(oxetan-3-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one: (0460) (0461) [00200] To a stirred suspension of sodium hydride (0.04 g, 1.16 mmol) in N,N-dimethyl formamide was added 3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2- oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.15 g, 0.35mmol) at 0 C and the reaction mixture was stirred at room temperature for 20 min. Then <strong>[39267-79-3]3-bromooxetane</strong> (0.03 mL, 0.70 mmol) was added and the reaction mixture was heated at 130 C for 16 h. The reaction mixture was quenched with ice cold water (10 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layer was concentrated under vacuum to afford crude product, which was purified by silica gel column chromatography using 4% methanol in dichloromethane to afford title compound 3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin-1-yl)-2- oxoethyl)-1-(oxetan-3-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.027 g, 16% yield) as white solid. 1H-NMR (DMSO-d6, 400 MHz) delta (ppm): 8.35-8.33 (m, 1H), 8.24-8.18 (m, 1H), 8.02 (s, 1H), 7.45 (t, J = 10 Hz, 1H), 7.34(d, J = 7.6 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 5.74-5.67 (m, 1H), 5.37 (t, J = 48.8 Hz, 1H), 5.02-4.94 (m, 4H), 4.87-4.69 (m, 2H), 3.89-3.3 (m, 4H), 2.40- 1.90 (m, 2H). Calculated (M+H): 482.14, found (M+H): 482.1. HPLC purity: 99.41%
  • 31
  • [ 22282-99-1 ]
  • [ 39267-79-3 ]
  • 2-methyl-4-(oxetan-3-yl)pyridine [ No CAS ]
  • 32
  • [ 39267-79-3 ]
  • [ 766-11-0 ]
  • 2-fluoro-5-(oxetan-3-yl)pyridine [ No CAS ]
  • 33
  • [ 39267-79-3 ]
  • [ 41404-58-4 ]
  • 5-fuoro-2-(oxetan-3-yl)pyridine [ No CAS ]
  • 34
  • [ 4926-28-7 ]
  • [ 39267-79-3 ]
  • 4-methyl-2-(oxetan-3-yl)pyridine [ No CAS ]
  • 35
  • [ 39267-79-3 ]
  • [ 2987-16-8 ]
  • 3,3-dimethyl-1-(oxetan-3-yl)butan-1-one [ No CAS ]
  • 36
  • [ 39267-79-3 ]
  • 1-(5-chloro-9H-xanthen-3-yl)pyrrolidine [ No CAS ]
  • 1-[5-chloro-9-(oxetan-3-yl)-9H-xanthen-3-yl]pyrrolidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
9.3% With sodium hydride; In tetrahydrofuran; dimethyl sulfoxide; mineral oil; at 65℃; for 48h; To a solution of 1-(5-chloro-9H-xanthen-3-yl)pyrrolidine (70 mg, 245 muiotamomicron) and NaH (60% in mineral oil) (100 mg, 2.5 mmol) in a mixed solvent of THF (2 mL) and DMSO (2 mL) was added <strong>[39267-79-3]3-bromooxetane</strong> (268 mg, 1.96 mmol), the mixture was then stirred at 65 C for 48 hours. The reaction was quenched with a saturated aqueous NaCl solution (20 mL) and the resulting mixture was extracted by EtOAc (30 mL) three times. The combined organic layer was concentrated under reduced pressure and the residue was purified by preparative HPLC to give l-[5-chloro-9-(oxetan-3-yl)-9H-xanthen-3-yl]pyrrolidine (8.4 mg, 9.3%) as a white solid. 1H NMR(400 MHz, CDC13): delta ppm 7.32 (d, 7=8.03 Hz, IH), 7.12 (d, 7=7.53 Hz, IH), 7.06 (d, 7=8.28 Hz, IH), 6.99 (s, IH), 6.45 (s, IH), 6.33-6.39 (m, IH), 4.63-4.71 (m, 2H), 4.54 (q, 7=7.53 Hz, 2H), 4.10 (d, 7=9.03 Hz, IH), 3.27-3.36 (m, 4H), 3.17 (dd, 7=7.53, 15.81 Hz, IH), 2.00-2.08 (m, 4H). MS obsd. (ESI+) [(M+H)+] : 342.1.
  • 37
  • [ 39267-79-3 ]
  • tert-butyl 3-[hydroxy(methyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate [ No CAS ]
  • tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
45.88% With tetra-(n-butyl)ammonium iodide; caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 3h;Inert atmosphere; A mixture of tert-butyl 3- [hydroxy(methyl)carbamoyl]-l,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxylate (8.00 g, 27.00 mmol, 1.00 eq), <strong>[39267-79-3]3-bromooxetane</strong> (4.07 g, 29.70 mmol, 1.10 eq), TBAI (997.22 mg, 2.70 mmol, 0.10 eq) and CS2CO3 (13.19 g, 40.50 mmol, 1.50 eq) in DMF (80.00 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 C for 3 hr under N2 atmosphere. TLC (DCM/MeOH=10/l) showed the starting material was consumed completely and the title compound was major. The mixture was poured into water (200 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (300 mL x 2), dried with anhydrous Na2S04, filtered and concentrated in vacuum. The residue was purified by column chromatography (S1O2, PE/EA = 100/1 to 1/2) to afford the title compound (4.50 g, 12.39 mmol, 45.88% yield, 97% purity) as a yellow solid. LCMS: 353 [M+l]. NMR (400 MHz, CDCI3CDCI3) delta = 4.62 (brs, 2 H) 4.53 (brs, 2 H) 4.32 - 4.42 (m, 1 H) 3.57 - 3.88 (m, 4 H) 3.29 (br. s., 3 H) 2.68 - 2.79 (m, 2 H) 1.41 - 1.53 (m, 9 H).
  • 38
  • [ 39267-79-3 ]
  • 4-bromo-1-(1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene [ No CAS ]
  • 4-Bromo-1-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With caesium carbonate; Step 2: 4-Bromo-1-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene To a solution of 4-bromo-1-(1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (270 mg, 0.85 mmol) in DMF (11 mL) was added cesium carbonate (414 mg, 1.27 mmol) then <strong>[39267-79-3]3-bromooxetane</strong> (105 muL, 1.27 mmol) and the reaction mixture was stirred at 90 C. for 3 h. The resultant mixture was allowed to cool to room temperature and filtered. The solid was collected, washed with water and dried to yield 190 mg (60%) of the title compound. LCMS (ESI): [M+H]+=375/377.
  • 39
  • [ 39267-79-3 ]
  • tert-butyl 3-[hydroxy(trideuteriomethyl)carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate [ No CAS ]
  • tert-butyl 4-(hydroxymethyl)-2-(methyl-d3)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4’,3’:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tetra-(n-butyl)ammonium iodide; caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 3h;Inert atmosphere; . A mixture of tert-butyl 3 -[hydroxy(trideuteriomethyl)carbamoyl] -2,4,6,7- tetrahydropyrazolo[4, 3 -c]pyridine5-carboxylate (75.0 mg, 250.55 jimol, 1.0 eq), <strong>[39267-79-3]3-bromooxetane</strong> (41.18 mg, 30.66 jimol,1.20 eq), TBAI (9.25 mg, 25.06 jimol, 0.10 eq) and Cs2CO3 (122.45 mg, 375.83 jimol, 1.50eq) in DMF (3.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 C for 3 hour under N2 atmosphere. TLC showed the starting material was consumed completely and two new spots appeared. The mixture was poured into water (10 mL) and stirred at 5 mm. The aqueous phase was extracted with ethyl acetate (5 mL *3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2504, filteredand concentrated in vacuum. The residue was purified by Prep-TLC (DCMIMeOH = 10/1) to give the title 0 (41.0 mg, 98.06 jimol, 39.14% yield, 85% purity) as a white solid. ?H NMR (400 MHz, CHLOROFORM-cl) 4.47 -4.72 (m, 4H) 4.31 -4.43 (m, 1)3.59- 3.95 (m, 4H) 2.77 (br. s., 2H) 1.49 (s, 9H). LCMS: 356 [M+l].
  • 40
  • [ 39267-79-3 ]
  • tert-butyl 6-ethyl-3-[hydroxy(methyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate [ No CAS ]
  • tert-butyl 9-ethyl-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4’,3’:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
430 mg With tetra-(n-butyl)ammonium iodide; caesium carbonate; In N,N-dimethyl-formamide; at 55℃; for 4h; . To a mixture of tert-butyl 6-ethyl-3 -[hydroxy(methyl)carbamoyl] - 1,4,6,7- tetrahydropyrazolo[4, 3 -c]pyridine5-carboxylate (50.0 mg, 1.54 mmol, 1.0 eq) and <strong>[39267-79-3]3-bromooxetane</strong> (253.14 mg, 1.85 mmol,1.20 eq) in DMF (3.0 mL) was added Cs2CO3 (752.64 mg, 2.31 mmol, 1.50 eq) and TBAI(56.88 mg, 154.0 jimol, 0.10 eq), the reaction mixture was stirred at 55 C for 4 hours. LCMS showed one main peak with desired MS was detected. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (50 mL*3). The organic phase was dried with anhydrous Na2504, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give the title 0 (430.0 mg, 1.13 mmol, 73.39% yield) as whitesolid. LCMS: 381 [M+l].
  • 41
  • [ 39267-79-3 ]
  • (R)-5-(tert-butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid [ No CAS ]
  • (R)-tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4’,3’:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate [ No CAS ]
  • (S)-tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4’,3’:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tetra-(n-butyl)ammonium iodide; caesium carbonate; In N,N-dimethyl-formamide; at 75℃; for 4h; To a solution of (R)-5 -(tert-butoxycarbonyl)-6-methyl-4, 5, 6,7-tetrahydro- 1 Hpyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 13, 2.30 g, 7.41 mmol, 1.0 eq) in DMF (20.0 mL) was added C52CO3 (7.24 g, 22.23 mmol, 3.0 eq) followed by <strong>[39267-79-3]3-bromooxetane</strong> (1.32 g, 9.63 mmol, 1.30 eq) and TBAI (273.74 mg, 741.0 jimol, 0.10 eq). The mixture was stirredat 75 C for 4 hr. LCMS showed 70% desired product. The mixture was extracted with ethyl acetate (20 mL*2) and H20 (20 mL). The combined organic layer was washed with H20 (20 mL*2), dried with Na2SO4, filtrated. The filtrate was concentrated in vacuum. The residue was purified by colunm chromatography (Petroleum ether: ethyl acetate = 50%l0%) to get 1.8 g desired prouct with 85% purity. 1.5 g was re-purified by prep-HPLC (FA)to get 1.1 g of puredesired product, which was seperated by SFC to afford both diastereomers (420 mg) and (470 mg).SFC separation condition: Instrument: SFC Thar 80 Q; Column: OD-10tm; Mobilephase: A for C02 and B for Isopropanol (0.1% Ammonia); Isocratic: B 20%; Flow rate: 50 mL 1mm; Back pressure: 10 bar; Column temperature: 3 5C; Wavelength: 220 nm.
  • 42
  • [ 39267-79-3 ]
  • tert-butyl 3-[hydroxy(methyl)carbamoyl]-7,7-dimethyl-4,6-dihydro-1H-pyrazolo[4,3-c]pyridine-5-carboxylate [ No CAS ]
  • tert-butyl 4-(hydroxymethyl)-2,8,8-trimethyl-1-oxo-1,2,4,5,8,9-hexahydropyrido[4’,3‘:3,4]pyrazolo[5,1-d][1,2,5]-oxadiazepine-10(11H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tetra-(n-butyl)ammonium iodide; caesium carbonate; In N,N-dimethyl-formamide; at 75℃; for 6h; To a mixture of tert15 butyl 3 -[hydroxy(methyl)carbamoyl]-7,7-dimethyl-4,6-dihydro- 1H-pyrazolo[4,3 -c]pyridine-5-carboxylate (70.0 mg, 215.80 jimol, 1.0 eq) and <strong>[39267-79-3]3-bromooxetane</strong> (35.47 mg, 258.96 jimol, 1.20 eq) in DMF (2.0 mL) was added Cs2CO3 (105.47 mg, 323.70 jimol, 1.50 eq) and TBAI (7.97 mg, 21.58 jimol, 0.10 eq), the reaction mixture was warmed to 75 C and stirred at 75 C for 3 hours. LCMS showed 50% of the starting material was remained. The reaction mixturewas stirred at 75 C for another 3 hours. LCMS showed the starting material was consumed completely and one main peak with desired MS was detected. The reaction mixture was diluted with EtOAc (10 mL) and washed with water (50 mL*3), the organic phase was dried with anhydrous Na2 SO4, filtered and concentrated in vacuum to afford the title 0 (53.0 mg, crude) as yellow oil. The product was used in the next step directly without further purification.LCMS: 381 [M+l].
  • 43
  • [ 39267-79-3 ]
  • tert-butyl 3-[hydroxy(methyl)carbamoyl]-7-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate [ No CAS ]
  • tert-butyl 4-(hydroxymethyl)-2,8-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4’,3’:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 75℃; for 4h; To asolution of tert-butyl 3 -[hydroxy(methyl)carbamoyl]-7-methyl- 1,4, 6,7-tetra hydropyrazolo[4,3 - c]pyridine-5-carboxylate (60.0 mg, 193.33 jimol, 1.0 eq) in DMF (2.0 mL) was addedCs2CO3 (188.97 mg, 579.99 jimol, 3.0 eq) followed by <strong>[39267-79-3]3-bromooxetane</strong> (31.78 mg, 232.0 jimol, 1.20 eq). The mixture was stirred at 75 C for 4 hr. LCMS showed the reaction wascompleted, major desired product was detected. The mixture was diluted with EtOAc (60 mL) and H20 (30 mL). Seperated the organic layer and washed with H20 (30 mL*3), dried over Na2SO4, filtrated. The filtrate was concentrated in vacuum to afford the title 0 (60.0 mg, crude) as yellow oil. LCMS: 367 [M+l].
  • 44
  • [ 39267-79-3 ]
  • tert-butyl 3-[ethyl(hydroxy)carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate [ No CAS ]
  • tert-butyl 2-ethyl-4-(hydroxymethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4’,3’:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
58.82% With tetra-(n-butyl)ammonium iodide; caesium carbonate; In N,N-dimethyl-formamide; at 75℃; for 6h; To a solution of tert-butyl 3 -[ethyl(hydroxy)carbamoyl] -2,4,6, 7-tetrahydropyrazolo [4,3 -c]pyridine-5 - carboxylate (36.0 mg, 116.0 jimol, 1.0 eq) and <strong>[39267-79-3]3-bromooxetane</strong> (19.07 mg, 139.20 jimol, 1.20 eq) in DMF (2.0 mL) was added Cs2CO3 (45.35 mg, 139.20 jimol, 1.20 eq) and TBAI(4.28 mg, 11.60 jimol, 0.10 eq). The mixture was stirred at 75C for 3 hr. LCMS showed about 400% starting material 2 was remained. The mixture was stirred at 75C for another 3hr. The mixture was diluted with ethyl acetate (400 mL), washed with brine (30 mL*3). The organic layer was dried over anhydrous Na2SO4, concentrated in vacuum. The crude was purified by prep-TLC (10 % Ethyl acetate). The title 0 (25.0 mg, 68.23 jimol, 58.82% yield) was obtained as the colorless oil.
  • 45
  • [ 39267-79-3 ]
  • N5-(3-chloro-4-fluorophenyl)-N3-hydroxy-N3-methyl-4,5,6,7-tetrahydro-2H-indazole-3,5-dicarboxamide [ No CAS ]
  • N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-4,5,8,9,10,11-hexahydro[1,2,5]oxadiazepino[5,4-b]indazole-10-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
74.16% With tetra-(n-butyl)ammonium iodide; caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 7.5h; To a solution of N5-(3 -chloro4-fluoro-phenyl)-N3-hydroxy-N3 -methyl -4,5,6, 7-tetrahydro-2H-indazole-3 , 5 -dicarboxamide(50.00 mg, 136.33 jimol, 1.00 eq) and <strong>[39267-79-3]3-bromooxetane</strong> (37.35 mg, 272.65 jimol, 2.00 eq) inDMF (2.00 mL) was added Cs2CO3 (66.63 mg, 204.49 jimol, 1.50 eq) and TBAI (5.04 mg,13.63 jimol, 0.10 eq). The mixture was stirred at 80 C for 7.5 hr. LCMS showed the reactantconsumed and the major desired product detected. The mixture was poured into water (20 mL), extracted with ethyl acetate(10 mL*3), the organic layer was washed with brine (20 mL), dried over anhydrous Na2504 and concentrated in vacuum. The crude was purified by prep-HPLC to afford N-(3 -chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2-methyl- 1 -oxo-4, 5,8,9,10,11 - hexahydro-[ 1 ,2,5]oxadiazepino[5,4-b]indazole- 1 0-carboxamide (45.00 mg, 101.10 jimol,74.16% yield, 95% purity) as white solid. LCMS: 423/425 [M+1]. 1HNMR (4000 IVIHz, CHLOROFORM-d) 7.74 (dd, J= 2.26, 6.53 Hz, 1 H), 7.56 (br d, J= 10.04 Hz, 1 H), 7.34 (td, J= 2.13, 4.77 Hz, 1 H), 7.08 (dt, J= 1.19, 8.75 Hz, 1 H), 4.45 -4.63 (m, 2 H), 4.34 -4.43 (m, 1
  • 46
  • [ 39267-79-3 ]
  • tert-butyl 3-[hydroxy(methyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate [ No CAS ]
  • tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4’,3’:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
45.88% With tetra-(n-butyl)ammonium iodide; caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 3h;Inert atmosphere; A mixture of tert-butyl 3 -[hydroxy(methyl)carbamoyl]- 1,4, 6,7-tetrahydroPyrazolo [4,3 -c]pyridine-5 - carboxylate (8.0 g, 27.0 mmol, 1.0 eq), <strong>[39267-79-3]3-bromooxetane</strong> (4.07 g, 29.70 mmol, 1.10 eq), TBAI(997.22 mg, 2.70 mmol, 0.10 eq) and Cs2CO3 (13.19 g, 400.50 mmol, 1.50 eq) in DMF (80.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 C for 3 hr under N2 atmosphere. TLC showed the starting material was consumed completely, desired product was major. The mixture was poured into water (20 mL) and stirred for 5 mm. Theaqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (30 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate = 10/1 to 1/2) to give the title 0 (4.50 g, 12.39 mmol, 45.88% yield, 97% purity) as a yellow solid. ?H NMR (400 MHz, CHLOROFORM-cl) = 4.62 (brs, 2 H) 4.53 (brs,2H)4.32-4.42(m, 1H)3.57-3.88(m,4H)3.29(br.s.,3H)2.68-2.79(m,2H)1.41-1.53 (m, 9 H). LCMS: 353 [M+1].
  • 47
  • [ 39267-79-3 ]
  • [ 124-38-9 ]
  • [ 123974-18-5 ]
  • 3-benzyl-5-(oxetan-3-ylmethyl)-5-phenyloxazolidin-2-one [ No CAS ]
  • 48
  • [ 39267-79-3 ]
  • 4-chloro-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide [ No CAS ]
  • N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-(oxetan-3-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
10% In a 100 mL round bottom flask, a mixture of 4-chloro-N-[(4S)-3,4-dihydro-2H-chromen-4-yI]-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide (500 mg, 1.066 mmol), anhydrous lithium hydroxide (51 mg, 2.133 mmol), <strong>[39267-79-3]3-bromooxetane</strong> (0.133 mL, 1.600 mmol), [4,4?-bis(l,l- dimethylethyl)-2,2?-bipyridine-N 1 ,N 1 ?]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C] iridium(lll) hexafluorophosphate (24 mg, 0.021 mmol) and tris(trimethylsilyl)silane (0.329 mL, 1.066 mmol) in 1,2-dimethoxyethane (20 mL) was degassed by purging with argon. In a50 mL round bottom flask, a mixture of nickel(ll) chloride ethylene glycol dimethyl ether complex (14 mg, 0.064 mmol) and 4,4?-di-tert-butyl-2,2?-bipyridine (17 mg, 0.064 mmol) in 1,2- dimethoxyethane (10 mL) was gently warmed with a heatgun, purged with argon and stirred for five minutes. By syringe half of this nickel-catalyst mixture (5 mL) was added to the reaction mixture. The resulting suspension was purged with argon for five minutes and wassubsequently stirred under irradiation with blue LED light for 18 h while cooling with a fan. The reaction mixture was diluted with dichloromethane (30 mL). Water (10 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (2x10 mL). Combined organic layers were dried with sodium sulfate and solvents were removed in vacuo. Purification by flash column chromatography (80 g; heptane, 10%-60% ethyl acetate) andpreparative HPLC (Method 11) afforded 0.054 g (0.110 mmol; 10% of theory) of the title compound. LC-MS (Method 2): R1 = 3.65 mm; mlz = 491 (M--H)1H-NMR (400 MHz, DMSO-d6) 6 9.26 (d, J = 8.1 Hz, 1H), 8.87 (s, 1H), 7.91 - 7.87 (m, 1H),7.84-7.73 (m, 2H), 7.70-7.57 (m, 1H), 7.35(d, J= 7.8 Hz, 1H), 7.30-7.23 (m, 1H), 7.19 (t,J = 7.8 Hz, 1 H), 6.93 (t, J = 7.5 Hz, 1 H), 6.81 (d, J = 8.2 Hz, 1 H), 5.31 - 5.11 (m, 4H), 4.84 -4.70 (m, 2H), 4.34-4.21 (m, 2H), 2.25-2.15 (m, 1 H), 2.08-2.01 (m, 1 H).
  • 49
  • [ 39267-79-3 ]
  • [ 121-71-1 ]
  • 1-[3-(oxetan-3-yloxy)phenyl]ethan-1-one [ No CAS ]
  • 50
  • [ 39267-79-3 ]
  • [ 1611-83-2 ]
  • C13H17NO2 [ No CAS ]
  • 51
  • [ 536-75-4 ]
  • [ 39267-79-3 ]
  • (S)-3-(2-benzyl-3-chloro-7-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]pyridin-6(7H)-yl)-8-bromo-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one [ No CAS ]
  • (3S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(oxetan-3-yl)-2,3-dihydro-1,5-benzoxazepin-4(5H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
5 mg With manganese; sodium tetrafluoroborate; 1,10-Phenanthroline; nickel dichloride; In methanol; at 60℃; for 5h;Inert atmosphere; Example 59 (3S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(oxetan-3-yl)-2,3-dihydro-1,5-benzoxazepin-4(5H)-one To a mixture of (3S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-8-bromo-5-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (80 mg), 1,10-phenanthroline (5.6 mg), 4-ethylpyridine (8.3 mg), sodium tetrafluoride (8.5 mg), manganese powder (325 mesh, 99.9%) (17 mg), <strong>[39267-79-3]3-bromooxetane</strong> (21 mg) and methanol (5 mL) was added nickel(II) chloride (dimethoxyethane additive) (6.8 mg) at room temperature, and the mixture was stirred under argon atmosphere at 60C for 4 hr. To the reaction mixture were added <strong>[39267-79-3]3-bromooxetane</strong> (42.5 mg), nickel(II) chloride (dimethoxyethane additive) (13.6 mg), 4-ethylpyridine (16.6 mg), 1,10-phenanthroline (11.2 mg), sodium tetrafluoride (17 mg) and manganese powder (325 mesh, 99.9%) (34 mg) at room temperature, and the mixture was stirred under argon atmosphere at 60C for 1 hr. The insoluble substance was removed by filtration, the filtrate was poured into water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and then silica gel column chromatography (NH, ethyl acetate/hexane). To the obtained residue were added diisopropyl ether, hexane and ethyl acetate, and the solid was collected by filtration to give the title compound (5 mg). 1H NMR (300 MHz, CDCl3) delta 2.67 (1H, dt, J = 15.7, 4.6 Hz), 3.06 (1H, ddd, J = 15.6, 10.5, 5.3 Hz), 3.37 (3H, s), 3.49-3.63 (1H, m), 4.16-4.31 (2H, m), 4.42 (1H, dd, J = 10.0, 8.1 Hz), 4.64 (1H, dd, J = 11.5, 10.0 Hz), 4.73-4.84 (2H, m), 5.04-5.16 (2H, m), 5.40 (2H, s), 5.92 (1H, dd, J = 11.7, 8.3 Hz), 7.19-7.37 (8H, m).
  • 52
  • [ 79762-54-2 ]
  • [ 39267-79-3 ]
  • 6-bromo-1-(oxetan-3-yl)indazole [ No CAS ]
  • 6-bromo-2-(oxetan-3-yl)indazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.6 g; 0.6 g With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 16h; Step-1: A solution of6-bromo-lH-indazole (2 g, 10.2 mmol), <strong>[39267-79-3]3-bromooxetane</strong> (2.7 g, 20.4 mmol) and anhydrous K2CO3 (2.8 g, 20.4 mmol) in DMF (15 mL) was stirred at 85 C for 16 h. It was then cooled to room temperature and diluted using water (50 mL). Extraction was carried out using EtOAc (30 mL x 3); the combined organic layers were washed with water (50 mL x 2); brine (50 mL); dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue obtained was purified using silica gel column chromatography (0-30% EtOAc in hexane) to provide desired intermediates III-B-4 (non-polar spot) (0.6 g) and III-B- 5 (polar spot) (0.6 g). III-B-4:LCMS: m/z; 253 (M+1)+. 1H NMR (CDCI3; 400 MHz) 5.11-5.15 (m, 2H); 5.25-5.29 (m, 2H); 5.69-5.76 (m, 1H); 7.26-7.30 (aromatics, 1H); 7.61 (d, J = 8.8 Hz, 1H); 7.71 (s, 1H); 8.06 (s, 1H). III-B-5:LCMS: m/z; 253 (M+1)+. 1H NMR (CDCI3; 400 MHz) 5.14-5.21 (m, 4H); 5.66-5.73 (m, 1H); 7.19 (dd, Jl= 1.5 Hz, J2 = 8.9 Hz, 1H); 7.54 (d, J = 8.8 Hz, 1H); 7.93 (s, 1H); 8.09 (s, 1H).
  • 53
  • [ 39267-79-3 ]
  • [ 28279-49-4 ]
  • 6-bromo-1-(oxetan-3-yl)imidazo[4,5-b]pyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 16h; Step-1: A solution of6-bromo-lH-indazole (2 g, 10.2 mmol), <strong>[39267-79-3]3-bromooxetane</strong> (2.7 g, 20.4 mmol) and anhydrous K2CO3 (2.8 g, 20.4 mmol) in DMF (15 mL) was stirred at 85 C for 16 h. It was then cooled to room temperature and diluted using water (50 mL). Extraction was carried out using EtOAc (30 mL x 3); the combined organic layers were washed with water (50 mL x 2); brine (50 mL); dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue obtained was purified using silica gel column chromatography (0-30% EtOAc in hexane) to provide desired intermediates III-B-4 (non-polar spot) (0.6 g) and III-B- 5 (polar spot) (0.6 g). III-B-4:LCMS: m/z; 253 (M+1)+. 1H NMR (CDCI3; 400 MHz) 5.11-5.15 (m, 2H); 5.25-5.29 (m, 2H); 5.69-5.76 (m, 1H); 7.26-7.30 (aromatics, 1H); 7.61 (d, J = 8.8 Hz, 1H); 7.71 (s, 1H); 8.06 (s, 1H). III-B-5:LCMS: m/z; 253 (M+1)+. 1H NMR (CDCI3; 400 MHz) 5.14-5.21 (m, 4H); 5.66-5.73 (m, 1H); 7.19 (dd, Jl= 1.5 Hz, J2 = 8.9 Hz, 1H); 7.54 (d, J = 8.8 Hz, 1H); 7.93 (s, 1H); 8.09 (s, 1H).
  • 54
  • [ 39267-79-3 ]
  • 6-((3-fluorobenzyl)thio)-5-(o-tolyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one [ No CAS ]
  • 6-((3-fluorobenzyl)thio)-1-(oxetan-3-yl)-5-(o-tolyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one [ No CAS ]
  • 6-((3-fluorobenzyl)thio)-2-(oxetan-3-yl)-5-(o-tolyl)-2H-pyrazolo[3.4-d]pyrimidin-4(5H)-one [ No CAS ]
  • 55
  • [ 39267-79-3 ]
  • 6-((3-fluorobenzyl)thio)-5-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one [ No CAS ]
  • 6-((3-fluorobenzyl)thio)-1-(oxetan-3-yl)-5-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one [ No CAS ]
  • 6-((3-fluorobenzyl)thio)-2-(oxetan-3-yl)-5-phenyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one [ No CAS ]
  • 56
  • [ 39267-79-3 ]
  • [ 829-85-6 ]
  • (oxetan-3-yl)diphenylphosphine [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.14 g A stirred solution of diphenylphosphine (2.3 mL, 13.22 mmol) in dry THF (5 mL) at 0 00was treated with n-butyllithium (2.5 M in hexanes) (8.4 mL, 13.4 mmol). After 5 mm asolution of <strong>[39267-79-3]3-bromooxetane</strong> (1 .7 mL, 20.49 mmol) in dry THF (1 mL) was added dropwise.The reaction mixture was allowed to warm to room temperature. After 16 h the reactionmixture was partitioned between EtOAc (20 mL) and H20 (20 mL). The aqueous phase was separated and further extracted with EtOAc (20 mL). The combined organic extracts were washed with brine (20 mL) and dried over MgSO4.The solvent was removed under reduced pressure and the resulting residue was purified by silica column chromatographyeluting with 0-10% EtOAc in isohexaneto give (oxetan-3-yl)diphenylphosphine (1.14 g) asa white solid, which was used in the next step.LC-MS (Method J) 243 [M+H] RT 1.53 mm
  • 57
  • [ 39267-79-3 ]
  • ethyl 6-(tert-butyl)-10-hydroxy-2-oxo-6,7-dihydro-2H-pyrido[2’,1‘:3,4]pyrazino[1,2-b]indazole-3-carboxylate [ No CAS ]
  • ethyl 6-(tert-butyl)-10-(oxetan-3-yloxy)-2-oxo-6,7-dihydro-2H-pyrido[2’,1’:3,4]pyrazino[1,2-b]indazole-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
10501] To 2.lh (18 mg, 0.047 mmol) was added DMF (Volume: 0.5 mE) and cesium carbonate (53.8 mg, 0.165 mmol). The reaction was stirred at room temperature for 5 minutes then <strong>[39267-79-3]3-bromooxetane</strong> (16.16 mg, 0.118 mmol) was added. The reaction was heated to 700 C. and stirred for 3 hours or until done by LCMS. The reaction was cooled, 0.5 ml of DMF was added, then filtered through a 0.45 nM in line filter. The DMF solution with the desired product 2.26a was used as is for the next step, assume quantitative yield. LC-MS (mlz): 438.5 [M+H], 0.81 mm.
  • 58
  • [ 39267-79-3 ]
  • N-(4-((7-hydroxy-6-methoxyquinazolin-4-yl)oxy )phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide [ No CAS ]
  • 2-(4-isopropyl-1H-1,2,3-triazol-1-yl)-N-(4-((6-methoxy-7-(oxetan-3-yloxy)quinazolin-4-yl)oxy)phenyl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
25% With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4h;Inert atmosphere; Cesium carbonate (450 mg, 1.4 mmol) was added to a solution of N-(4-((7-hydroxy-6-methoxyquinazolin-4-yl)oxy)phenyl)-2-( 4-isopropyl-1H-1 ,2,3-triazol-1-yl)acetamide (20025 mg, 0.5 mmol) and <strong>[39267-79-3]3-bromooxetane</strong> (315 mg, 2.3 mmol) in DMF (3 mL) under nitrogen. Theresulting mixture was stirred at 100C for 4 hours. The crude product was purified by preparative HPLC. Fractions containing the desired product were combined and concentratedunder vacuum to afford the title compound as a white solid (56 mg, 25%). 1H NMR (400 MHz,DMSO-d6) 8 1.26 (6H, d), 3.01 (lH, p), 4.01 (3H, s), 4.60- 4.68 (2H, m), 5.05 (2H, t), 5.29(2H, s), 5.56-5.58 (lH, m), 7.03 (lH, s), 7.29 (2H, d), 7.62 (lH, s), 7.69 (2H, d), 7.89 (lH, s),5 8.54 (lH, s), 10.58 (lH, s); m/z: ES+ [M+H]+ 491.
  • 59
  • [ 116209-30-4 ]
  • [ 39267-79-3 ]
  • oxetan-3-yl 4-bromo-2-(oxetan-3-ylthio)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
33% To a cooled (0C) mixture of 4-bromo-2-mercaptobenzoic acid (500 mg, 2.04 mmol) in anh. DMF (20 mL) is added cesium carbonate (1.394 g, 4.28 mmol) and the mixture is stirred at RT for 15 min. The cooled (0C) mixture is then treated with <strong>[39267-79-3]3-bromooxetane</strong> (855 mg, 6.1 1 mmol) and the RM is heated to 85C for 16h. The RM is allowed to cool to RT, water and EtOAc are then added, and the layers are separated. The aqueous layer is extracted twice with EtOAc and the combined organic layers are washed with brine, dried over anh. MgSC>4, filtered and concentrated to dryness under reduced pressure. Purification by FC (from heptane to tert-butyl methyl ether) affords oxetan-3-yl 4-bromo-2-(oxetan-3-ylthio)benzoate as a pale orange solid (229 mg, 33%). LC-MS A: tR = 0.83 min; [M+H]+ = 344.98.
  • 60
  • [ 39267-79-3 ]
  • [ 123-08-0 ]
  • 4-(oxetan-3-yloxy)benzaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.51 g With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; p-Hydroxybenzaldehyde 0.5g (4mmol), cesium carbonate 0.5g (6mmol), <strong>[39267-79-3]3-bromo oxetane</strong> 0.5g (3.6 mmol), 5 ml of N,N-dimethylformamide was added to the reaction flask, and the reaction was carried out at 80 C overnight. Add water, extract, wash, dry and concentrate Column chromatography gave 0.51 g.
  • 61
  • [ 39267-79-3 ]
  • [ 4268-35-3 ]
  • dimethyl(oxetan-3-yl)phosphine borane [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% Dimethylphosphine borane I-2 (55% wt. in THF, 1.3 g, 9.2 mmol) was dissolved in THF (60 mL) and the colourless solution cooled to 0C. NaH (60% in mineral oil, 1.6 g, 40.5 mmol) was added in one portion, whereupon effervescence was observed. The opaque reaction was stirred at rt for 20 min whereupon <strong>[39267-79-3]3-bromooxetane</strong> (1.52 mL, 18.4 mmol) was added in one portion. When TLC had indicated completion of the reaction, the reaction was cooled to 0C and MeOH added until effervescence has ceased. The solvent was removed in vacuo and the crude residue taken up in DCM (100 mL) and passed through a phase separator cartridge (Biotage). Concentration in vacuo gave the crude material which was purified by column chromatography (Biotage Isolera Four, 50 g KP-Sil column eluting with isohexane to 50% EtOAc / isohexane) to provide the title compound as a colourless oil (630 mg, 4.7 mmol, 51 %).
  • 62
  • [ 39267-79-3 ]
  • [ 344791-87-3 ]
  • (±) 3-(4-(4-methoxyphenyl)butan-2-yl)oxetane [ No CAS ]
  • 63
  • [ 39267-79-3 ]
  • (4-bromopiperidin-1-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone [ No CAS ]
  • (4-(oxetan-3-yl)piperidin-1-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone [ No CAS ]
  • 64
  • [ 39267-79-3 ]
  • 2-(2H-tetrazol-5-yl)-N-[4-(trifluoromethyl)phenyl]aniline [ No CAS ]
  • 2-[2-(oxetan-3-yl)tetrazol-5-yl]-N-[4-(trifluoromethyl)phenyl]aniline hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
3.94% [00498] 123-1 (50.0 mg, 0.16 mmol, 1.0 eq), 123-2 (26.9 mg, 0.20 mmol, 1.2 eq) and K2C03 (45.3 mg, 0.33 mmol, 2.0 eq) were taken up into a microwave tube in DMF (2.0 mL). The sealed tube was heated at 150 C for 3Hours under microwave conditions. LCMS showed the desired compound was formed. The reaction was filtered to give a crude product. The crude product was purified by prep-HPLC to give the title compound (2.57 mg, 6.46 umol, 3.94% yield, HC1). LCMS (ESI): RT = 0.890 min, mass calc. for C17H14F3N5O 361.12, m/z found 362.0[M+H]+; 1HNMR (400 MHz, COC -d) 9.01 (s, 1H), 8.25 (dd, J= 1.5, 7.9 Hz, 1H), 7.55 (d, J= 8.4 Hz, 3H), 7.41 (dt, J = 1.5, 7.8 Hz, 1H), 7.31 (d, J= 8.6 Hz, 2H), 7.10 - 7.05 (m, 1H), 6.15- 6.07 (m, 1H), 5.31- 5.25 (m, 2H), 5.24- 5.19 (m, 2H).
  • 65
  • [ 39267-79-3 ]
  • 5-amino-6-bromo-2-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]isoindolin-1-one [ No CAS ]
  • 5-amino-2-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]-6-(oxetan-3-yl)isoindolin-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
21.5% With (1,2-dimethoxyethane)dichloronickel(II); tris-(trimethylsilyl)silane; [4,4?-bis(1,1-dimethylethyl)-2,2?-bipyridine-N1,N1?]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate; sodium carbonate; 4,4'-di-tert-butyl-2,2'-bipyridine; In 1,2-dimethoxyethane; at 15℃; for 16h;Molecular sieve; Inert atmosphere; Microbiological reaction; A vial was charged with 5 -amino-6-bromo-2- [(2R)-2-fluoro-3 -hydroxy-3 -methylbutyl]isoindolin- 1-one (150 mg, 0.45 mmol), [4,4? -bis( 1,1 -dimethylethyl)-2,2 ? -bipyridineNi ,N1 ?]bis [3,5 -difluoro-2- [5-(trifluoromethyl)-2-pyridinyl-JV]phenyl-C]iridium(III) hexafluorophosphate (50.8 mg, 0.05 mmol), dry molecular sieves (100 mg) and anhydrous sodium carbonate (48.0 mg, 0.45 mmol) and purged with nitrogen for 5 mm. A solution of <strong>[39267-79-3]3-bromooxetane</strong> (186 mg, 1.36 mmol) in anhydrous 1,2-dimethoxyethane (2 mL) was added, followed by tris(trimethylsilyl)silane (338 mg, 1.36 mmol). The resulting mixture was purged with nitrogen for 5 mm. A second vial was charged with nickel(ii) chloride diglyme complex (16.7 mg, 0.09 mmol), 4,4?-di-tert-butyl-2,2?-dipyridyl (24.31 mg, 0.09 mmol) and 1,2- dimethoxyethane (2 mL) and purged with nitrogen for 5 mm. This resulted in the formation of a green active Ni catalyst solution. The catalyst solution was transferred by syringe to the first vial. The resulting mixture was further purged with nitrogen for 2 mi stirred at 15 C under nitrogen and a cooling fan, and irradiated with a 34W blue LED for 16 h. The reactionwas filtered and concentrated. The residue was purified by preparatory thin layer chromatography (eluting with ethyl acetate) to give 5 -amino-2-[(2R)-2-fluoro-3 -hydroxy-3 - methyl-butyl]-6-(oxetan-3-yl)isoindolin-1-one (30 mg, 2 1.5%) as a white solid. LCMS (ESI):m/z 309.1 [M+H].
  • 66
  • [ 39267-79-3 ]
  • 5-bromo-2-chloro-N-(3-((5-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propyl)pyrimidin-4-amine [ No CAS ]
  • 5-bromo-2-chloro-N-(3-((5-methyl-4-nitro-1-(oxetan-3-yl)-1H-pyrazol-3-yl)oxy)propyl)pyrimidin-4-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% With potassium carbonate; In dimethyl sulfoxide; at 100℃; To a solution of <strong>[39267-79-3]3-bromooxetane</strong> (1 .245 g, 9.09 mmol) in DMSO (15.0 mL) was added D107 (890 mg, 2.27 mmol) and K2CO3 (942 mg, 6.82 mmol). The reaction was stirred overnight at 100 C. The cooled mixture was diluted with water (150mL) and extracted with EtOAc (3X80 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04and filtered. The filtrate was concentrated and the crude was purified by columnchromatography on silica gel (PE: EtOAc= 4:1 ) to give the title compound as a yellow solid (537 mg, yield 52%). LC-MS: 449.1 [M+H]+.
  • 67
  • [ 39267-79-3 ]
  • (R)-2,5-dichloro-N-(4-((3-methyl-4-nitro-1H-pyrazol-5-yl)oxy)butan-2-yl)pyrimidin-4-amine [ No CAS ]
  • (R)-2,5-dichloro-N-(4-((5-methyl-4-nitro-1-(oxetan-3-yl)-1H-pyrazol-3-yl)oxy)butan-2-yl)pyrimidin-4-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 16h; A solution of D79 (10.0 g, 27.66 mmol), <strong>[39267-79-3]3-bromooxetane</strong> (13.7 g, 99.67 mmol) and K2003 (11.5 g, 82.98 mmol) in DMSO (100 mL) was heated to 80 00 and stirred for 16 hrs. Themixture was poured into ice water (300 mL) and extracted with EtOAc (5x200 mL). The organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude was purified by chromatography on silica gel (PE: EtOAc= 1:3) to give the title compound (6.5 g, crude). LC-MS: 417.2 [M+H].
  • 68
  • [ 39267-79-3 ]
  • (S)-8-bromo-N-(chroman-4-yl)-4-(dimethylamino)quinoline-3-carboxamide [ No CAS ]
  • (S)-N-(chroman-4-yl)-4-(dimethylamino)-8-(oxetan-3-yl)quinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
31% With (1,2-dimethoxyethane)dichloronickel(II); tris-(trimethylsilyl)silane; [4,4?-bis(1,1-dimethylethyl)-2,2?-bipyridine-N1,N1?]bis [3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate; 4,4'-di-tert-butyl-2,2'-bipyridine; lithium hydroxide; In 1,2-dimethoxyethane; for 18.0833h;Inert atmosphere; Irradiation; Cooling; In an 8 ml screw capped vial anhydrous lithium hydroxide (11 mg, 0.469 mmol) was dried with a heat gun under argon flow. Under argon the vial was allowed to cool to room temperature and (S)-8-bromo-N-(chroman-4-yl)-4-(dimethylamino)quinoline-3 -carboxamide (100 mg, 0.235 mmol), 3- bromooxetane (0.03 mL, 0.352 mmol), [4,4?-bis( 1,1 -dimethylethyl)-2,2?-bipyridine-Nl ,N1 ?]bis [3,5- difluoro-2- [5 -(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate (3 mg, 0.002 mmol) and tris(trimethylsilyl)silane (0.07 mL, 0.235 mmol) were added. The mixture was degassed by purging with argon. 1 ,2-Dimethoxyethane (4.0 mL) (degassed by purging with nitrogen) was added. Inanother 8 ml screw capped vial a mixture of nickel(II) chloride ethylene glycol dimethyl ether complex(2 mg, 0.009 mmol) and 4,4?-di-tert-butyl-2,2?-dipyridyl (3 mg, 0.009 mmol) was degassed by purgingwith argon. 1,2-Dimethoxyethane (2.0 mL) (degassed by purging with nitrogen) was added. Thismixture was gently warmed with a heat gun and was allow to cool to room temperature while stirring for5 mm. By syringe 0.9 mL of this nickel-catalyst containing solution was added to the reaction mixture.The resulting solution was purged with argon for 1 mm and was subsequently stirred under irradiation with blue LED light for 18 h while cooling with a fan. The reaction mixture was partitioned between water (5 mL) and dichloromethane (10 mL). Layers were separated using a phase separator. Aqueous layer was extracted with ethyl acetate (3x5 mL). All organic layers were combined, dried with sodium sulfate and concentrated in vacuo. Purification by preparative HPLC (Method 11) afforded 30 mg (0.074mmol; 31% of theory) of the title compound.LC-MS (Method 4): R = 3.52 mm; mlz = 404 (M+H)1H NMR (400 MHz, DMSO-d6) 9.08 (d, J= 8.2 Hz, 1H), 8.56 (s, 1H), 8.07 (d, J= 8.5 Hz, 1H), 7.68(d, J= 7.0 Hz, 1H), 7.62 - 7.54 (m, 1H), 7.36 (d, J= 7.0 Hz, 1H), 7.21 - 7.15 (m, 1H), 6.96 - 6.91 (m, 1H), 6.80 (d, J= 8.2 Hz, 1H), 5.28 - 5.21 (m, 1H), 5.06 (t, J= 2.8 Hz, 3H), 4.85 - 4.71 (m, 2H), 4.32 -4.21 (m, 2H), 3.03 (s, 6H), 2.25 -2.16 (m, 1H), 2.09 -2.00 (m, 1H).
  • 69
  • [ 39267-79-3 ]
  • di-tert-butyl (5-(4-(3-bromophenyl)piperazin-1-yl)pyrimidine-2,4-diyl)bis((tert-butoxycarbonyl)carbamate) [ No CAS ]
  • di-tert-butyl (5-(4-(3-(oxetan-3-yl)phenyl)piperazin-1-yl)pyrimidine-2,4-diyl)bis((tert-butoxycarbonyl)carbamate) [ No CAS ]
YieldReaction ConditionsOperation in experiment
12.4% To an 8 mL vial equipped with a stir bar and containing di-tert-butyl (5-(4-(3- bromophenyl)piperazin- 1 -yl)pyrimidine-2,4-diyl)bis((tert-butoxycarbonyl)carbamate) (100 mg,133 iimol, 1 eq) was added photo-catalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1.50 mg, 1.33 iimol,0.01 eq), <strong>[39267-79-3]3-bromooxetane</strong> (54.81 mg, 400 iimol, 3 eq), tris(trimethylsilyl)silane (66.3 mg, 267iimol, 82.3 pL, 2 eq) and placed under N2 atomosphere before DME (4 mL) was added. To a separate vial was added NiC12glyme (2.93 mg, 13.3 iimol, 0.1 eq) and 4,4?-di-tert-butyl-2,2?- bipyridine (3.58 mg, 13.3 iimol, 0.1 eq). The catayst vial was sealed, purged with N2 then to itwas added DME (1 mL). The precatalyst solution was sonicated for 5 mm, and then added to thereaction vessel by syringe. The reaction was stirred and irradiated with 34 W blue LED lamp for16 h. The mxiture was diluted by MeCN (10 mL), filtered and the filtrate was concentrated togive a residue, which was purified by prep-HPLC (neutral condition) to give di-tert-butyl (5-(4-(3 -(oxetan-3 -yl)phenyl)piperazin- 1 -yl)pyrimidine-2,4-diyl)bis((tert-butoxycarbonyl)carbamate)(12 mg, 16.51 iimol, 12.4% yield) as a yellow solid. 1H NMR: (400IVIHz, CDC13) oe = 8.32 (s,1H), 7.15 (s, 1H), 6.90 - 6.78 (m, 2H), 6.73 (d, J= 6.8 Hz, 1H), 4.93 (s, 2H), 4.65 (s, 2H), 4.07 (d, J 6.8 Hz, 1H), 3.26 - 3.06 (m, 8H), 1.31 (d, J= 7.2 Hz, 36H).
  • 70
  • [ 39267-79-3 ]
  • [ 14755-02-3 ]
  • (E)-3-(2-(oxetan-3-yl)vinyl)phenol [ No CAS ]
  • 71
  • [ 39267-79-3 ]
  • C17H17N5O2*ClH [ No CAS ]
  • (S)-5-(benzo[d][1,3]dioxol-5-yl)-7-(1-(oxetan-3-yl)pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 25℃; General procedure: A DMF solution of 2-bromoacetamide (1.3 eq), DIEA (5.0 eq) and 16a (1.0 eq) atrt. overnight. Then reaction was subsequently diluted with H2O. The aqueous layer was extracted with CH2Cl2 (20 mL 3), the organic layers were combined, washed with brine (20 mL 1) and dried over Na2SO4. The organic solvent was removed under reduced pressure, the crude product was purified by column chromatography (DCM/MeOH =20/1) to afford 17h as white solid in 60% yield.
  • 72
  • [ 39267-79-3 ]
  • C18H19N5O2*ClH [ No CAS ]
  • 5-(benzo[d][1,3]dioxol-5-yl)-7-(1-(oxetan-3-yl)piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With potassium carbonate; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20 - 25℃; General procedure: The title compound was obtained by 16a (1.0eq), (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (1.0eq) and K2CO3 (1.3eq) stirred at rt overnight in CH3CN/DIEA(2mL/500 mL) to afford compound 17k (55% yield).
  • 73
  • [ 39267-79-3 ]
  • [ 6627-55-0 ]
  • 3-(2-bromo-4-methylphenoxy)oxetane [ No CAS ]
YieldReaction ConditionsOperation in experiment
To 2-bromo-4-methylphenol (1.3 mL, 10.63 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (2.94 g, 21.25 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 10 minutes before adding <strong>[39267-79-3]3-bromooxetane</strong> (2.91 g, 21.25 mmol) dropwise. The reaction was heated at 50 C. for 72 hours with stirring. Ethyl acetate (100 mL) was added and the reaction was filtered. The material was washed with ethyl acetate (50 mL) two times. The combined organics were washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified via chromatography on a 80 g silica gel cartridge, eluting with ethyl acetate in heptane at 0-40% gradient to provide the title compound. 1H NMR (400 MHz, chloroform-d) delta ppm 7.40 (d, J=2.1 Hz, 1H), 7.01 (dd, J=8.3, 2.1 Hz, 1H), 6.37 (d, J=8.2 Hz, 1H), 5.21 (p, J=5.7 Hz, 1H), 4.97 (dd, J=7.4, 6.2 Hz, 2H), 4.87-4.81 (m, 2H), 2.28 (s, 3H)+
  • 74
  • [ 39267-79-3 ]
  • N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-1-(4-methylpiperazin-1-yl)cyclopropanecarboxamide [ No CAS ]
  • 1-(4-methylpiperazin-1-yl)-N-{5-[7-(oxetan-3-yl)-4-oxoquinazolin-3(4H)-yl]-2-(trifluoromethoxy)phenyl}cyclopropanecarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
32% In a 2 mL vial, Iridium( 1+), [4,4?-bis( 1,1 -dimethylethyl)-2,2?-bipyridine-icNl ,icNl ?]bis [3 ,5-difluoro-2- [5-(trifluoromethyl)-2-pyridinyl-icN]phenyl-icC] -, (OC-6-3 3)-, hexafluorophosphate( 1-) (1:1) (CAS870987-63-6) (5.61 mg, 5.00 jimol) and N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl] -1 -(4-methylpiperazin- 1 -yl)cyclopropanecarboxamide (56.6 mg, 100 jimol)were loaded. The nickel pre-catalyst was then prepared in a second microwave vial. To this vial, nickel(II) chloride dimethoxyethane adduct (5.49 mg, 0.025 mmol, 0.25 equiv.) and 4,4?-di-tert-butyl-2,2?-bipyridine (8.05 mg, 0.03 mmol, 0.3 equiv.) were loaded and dissolved in 5.0 mL of 1,2-dimethoxyethane, placed under argon, sealed and sonicated for 5 minutes. 1 mL of the nickel precatalyst solution was syringed into the vial containing the reaction mixture. The solution was degassed asecond time by sparging with argon while stirring for 10 minutes. Under a constant flow of argon, <strong>[39267-79-3]3-bromooxetane</strong> (12 jil, 150 jimol), 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (31 jil, 100 jimol)and 2,6-dimethylpyridine (58 jil, 500 jimol) were added to the reaction mixture using a Hamiltonsyringe. The cap of the microwave vial was removed and replaced with a new cap. The reactionmixture was iffadiated with one 34 W blue LED lamp in the EvoluChemTM PhotoChemistry Deviceusing the 8 x 2 mL vial rack which contains an incorportated fan for cooling to maintain experiment atroom temperature. The reaction mixture was allowed to stir in the device for 15 hours. The reactionmixture was then filtered through a silica column eluting with a gradient of dichloromethane/methanolfrom 100:0 to 85:15. The material obtained was purified by preparative RP-HPLC 125x30mm withacetonitrile/water (0.2% ammonia) to deliver 18.0 mg (97 % purity, 32 % yield) of the title compound.LC-MS (Method 6): R = 1.01 mm; MS (ESIpos): m/z = 544 [M+H]1HNMR (400 MHz, DMSO-d6) [ppm]: -0.008 (1.15), 0.008 (1.30), 1.102 (1.34), 1.115 (3.58), 1.123(4.22), 1.133 (2.02), 1.237 (1.87), 1.246 (4.14), 1.254 (3.32), 1.267 (1.46), 2.194 (16.00), 2.328 (0.61),2.367 (0.66), 2.670 (0.52), 4.448 (0.87), 4.465 (1.69), 4.482 (1.13), 4.502 (0.49), 4.679 (4.52), 4.695(7.64), 4.711 (4.38), 5.006 (4.88), 5.021 (4.92), 5.027 (4.95), 5.042 (3.95), 7.385 (2.23), 7.392 (2.27),7.407 (2.53), 7.414 (2.64), 7.659 (2.01), 7.663 (2.28), 7.684 (4.17), 7.703 (1.67), 7.726 (4.20), 8.192(4.15), 8.213 (3.79), 8.376 (9.40), 8.594 (4.52), 8.600 (4.40), 10.655 (3.69).
  • 75
  • [ 39267-79-3 ]
  • [ 22918-01-0 ]
  • 4-chloro-2-(oxetan-3-yl)pyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
19% With hexanedioic acid dimethyl ester; 2,6-pyridinedicarboxamidine; trifluoroacetic acid; sodium iodide; nickel dichloride; zinc; at 60℃;Sealed tube; Microwave irradiation; The indicated ligand was prepared as described in J. Org. Chem.82:7085, 2017. In a flame dried 5 mL microwave vial was successively added dimethyl adipate (DMA; 5 mL), ligand (15.3 mg, 65.0 mumol), nickel chloride, dimethoxyethane adduct (14.7 mg, 65.0 mumol), sodium iodide (48.7 mg, 325 mumol) 2-Bromo-4-chloropyridine (286 muL, 1.30 mmol), <strong>[39267-79-3]3-bromooxetane</strong> (162 muL, 1.95 mmol) zinc (173 mg, 2.60 mmol), trifluoroacetic acid (10.0 muL, 130 mumol). The vial was capped and argon was bubbled into the solution for 8 minutes in the sonic bath. The reaction mixture was heated to 60 C with stirring overnight then filtered through a Celite padsubsequently washed with EtOAc. The filtrate was then washed with 5% aq NH4OH. The organic layer was washed with brine, dried over MgSO4, and filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel and eluting with 10 to 100% EtOAc in heptane). We obtained a pale yellow oil (41.0 mg, 19 %). LCMS m/z = 350.1 (M+H)+.
  • 76
  • [ 39267-79-3 ]
  • [ 104253-44-3 ]
  • methyl 2-chloro-4-(oxetan-3-yloxy)benzoate [ No CAS ]
  • 77
  • [ 39267-79-3 ]
  • ethyl 9-hydroxy-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylate [ No CAS ]
  • C23H27NO6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
42.9% With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 40h; Compound 10-rac (100 mg, 0.28 mmol) and 41 <strong>[39267-79-3]3-bromo-oxetane</strong> (75 mg, 0.56 mmol) were dissolved in 31 DMF (5mL), and then the solution was added with 25 K2CO3 (78 mg, 0.56 mmol) and stirred at 90 C for 40 h. After the reaction finished, the mixture was poured into water and extracted with EtOAc (40 mL×3). The ethyl acetate layers were combined and washed with water and saturated salt solution, then dried over anhydrous sodium sulfate, filtered and spin-dried to give a crude product, which was purified by a preparation plate to give Compound 4a-rac (51 mg, 42.9 % yield).
  • 78
  • [ 39267-79-3 ]
  • 3-[1-(2-fluoro-6-methylphenyl)piperidin-4-yl]-1-(2-hydroxybenzyl)-3,4-dihydro-1H-quinazolin-2-one [ No CAS ]
  • 3-[1-(2-fluoro-6-methylphenyl)piperidin-4-yl]-1-[2-(oxetan-3-yloxy)benzyl]-3,4-dihydro-1H-quinazolin-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 96h; General procedure: To a stirred soln. of compounds of formula la (1 eq) in DMF (6 mL/mmol) was added K2CO3 (2 eq) followed by the appropriate halide (1.5 eq). The rxn mixture was stirred at a given temperature for a given time (see Table 26). It was partitioned between EtOAc and H2O. The org. phase was washed with water (2x) and brine (1x), dried over MgS04 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc and/or DCM/MeOH.
  • 79
  • [ 39267-79-3 ]
  • 1-[(R)-1-(2-fluoro-6-methylphenyl)pyrrolidin-3-yl]-4-hydroxy-3-(2-trifluoromethylbenzyl)-1,3-dihydrobenzoimidazol-2-one [ No CAS ]
  • 1-[(R)-1-(2-fluoro-6-methylphenyl)pyrrolidin-3-yl]-4-(oxetan-3-yloxy)-3-(2-trifluoromethylbenzyl)-1,3-dihydrobenzoimidazol-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In dimethyl sulfoxide; at 60 - 105℃; for 72h; General procedure: To a stirred soln. of Ij (1 eq) in DMSO (10 mL/mmol) was added K2CO3 (2 eq) followed by the corresponding halide (1.1 eq). The rxn mixture was stirred at a given temperature for a given time (see Table 34). It was partitioned between EtOAc and H2O. The org. phase was washed with water (3x) and brine, dried over MgSC>4 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc or by prep. LC-MS using method 3.
  • 80
  • [ 39267-79-3 ]
  • 1-[1-(2-fluoro-6-methylphenyl)piperidin-4-yl]-3-(2-hydroxybenzyl)-4-methoxy-1,3-dihydrobenzoimidazol-2-one [ No CAS ]
  • 1-[1-(2-fluoro-6-methylphenyl)piperidin-4-yl]-4-methoxy-3-[2-(oxetan-3-yloxy)benzyl]-1,3-dihydrobenzoimidazol-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 120h; Method B /K?CC /DMF) To a stirred soln. of phenol E-2 (1 eq) in anh. DMF (8 mL/mmol) was added K2CO3 (2 eq) and the corresponding halide (2 eq). The rxn mixture was stirred for a given time and a given temperature (see Table 64). Additional amount of halide (3 x 2 eq) were added to bring the rxn to completion. It was partitioned between EtOAc and H2O and the org. phase was washed with brine, dried over MgS04 and concentrated in vacuo. The crude was purified by CC using Hept/EtOAc.
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