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[ CAS No. 280-13-7 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 280-13-7
Chemical Structure| 280-13-7
Chemical Structure| 280-13-7
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Product Details of [ 280-13-7 ]

CAS No. :280-13-7 MDL No. :MFCD09836264
Formula : C6H11NO Boiling Point : -
Linear Structure Formula :- InChI Key :POOPWPIOIMBTOH-UHFFFAOYSA-N
M.W : 113.16 Pubchem ID :12069231
Synonyms :

Calculated chemistry of [ 280-13-7 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 34.53
TPSA : 21.26 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) : -6.96 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.68
Log Po/w (XLOGP3) : 0.04
Log Po/w (WLOGP) : -0.24
Log Po/w (MLOGP) : 0.21
Log Po/w (SILICOS-IT) : 1.2
Consensus Log Po/w : 0.58

Druglikeness

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

Water Solubility

Log S (ESOL) : -0.57
Solubility : 30.7 mg/ml ; 0.271 mol/l
Class : Very soluble
Log S (Ali) : -0.04
Solubility : 103.0 mg/ml ; 0.914 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.81
Solubility : 17.4 mg/ml ; 0.154 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.89

Safety of [ 280-13-7 ]

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

Application In Synthesis of [ 280-13-7 ]

* 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 [ 280-13-7 ]

[ 280-13-7 ] Synthesis Path-Downstream   1~93

  • 1
  • [ 75-21-8 ]
  • [ 280-13-7 ]
  • [ 99969-71-8 ]
  • 2
  • [ 1472-00-0 ]
  • [ 280-13-7 ]
  • 3
  • [ 2144-40-3 ]
  • [ 280-13-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: pyridine 2: methanol. NH3 / 160 °C / Erhitzen des Reaktionsprodukts mit wss. Ba(OH)2
  • 4
  • [ 280-13-7 ]
  • [ 156478-71-6 ]
  • [ 666852-94-4 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 16h; EDC (1.18g, 6.15 mmol) was added to a stirred solution of [N-BOC-PIPERAZINE] acetic acid [(L.] [OOG,] 4.10 mmol), 8-oxa-3-aza-bicyclo [3.2. 1. ] octane (0.556g, 4.92 mmol), 3-hydroxy benzotriazole (0.836g, 6.15 mmol), and diisopropylethylamine (2. 14ml, 12.31 mmol) in DCM (20 ml) at ambient temperature under nitrogen. After stirring for 16h the reaction was quenched by the addition of water [(20ML).] The phases were separated and the organics were washed with sat. brine [(20ML),] dried and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica, eluting with 0-10% MeOH/DCM to give 46 as a white solid (0.780g). MS-ESI: 340 (M++H). [1H NMR (CDC13)] 1.45 (s, 9H), 1.80-2. 00 (m, 4H), 2.30-2. 58 (m, 4H), 2.85-3. 04 (m, [2H),] 3.25 (d, 1H), 3.30-3. 57 (m, 3H), 3.78 (d, 1H), 4.12 (d, 1H), 4.36 (d, 3H).
  • 5
  • [ 280-13-7 ]
  • [ 85-44-9 ]
  • [ 54746-03-1 ]
YieldReaction ConditionsOperation in experiment
In benzene; EXAMPLE 30 3-(o-Carboxybenzoyl)-8-Oxa-3-Azabicyclo(3.2.1)Octane SPC9 A solution of 11.3 grams (0.1 mole) 8-oxa-3-azabicyclo (3.2.1)octane in 20 ml of benzene was added to a suspension of 14.8 grams (0.1 mole) of phthalic anhydride in 50 ml of benzene at 8 C. The reaction mixture was stirred for 1 hour and then left overnight at room temperature. The product, 20.0 grams which separated, was filtered off and recrystallized from benzene ethanol. The product represented by formula (X) had a melting point of 149-150.5 C. Analysis for C14 H15 NO4. Calculated: C, 64.36%; H, 5.79%; N, 5.36%. Found: C, 64.38%; H, 5.85%; N, 5.24%.
  • 6
  • [ 280-13-7 ]
  • [ 5538-51-2 ]
  • 3-(acetylsalicyloyl)-8-oxa-3-azabicyclo(3.2.1)octane [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In benzene; EXAMPLE 29 3-(Acetylsalicyloyl)-8-Oxa-3-Azabicyclo(3.2.1)Octane SPC8 o-Acetoxybenzoyl chloride (0.1 mole, 19.85 grams) was slowly added to a mixture of 8-oxa-3-azabicyclo(3.2.1)octane (0.1 mole, 11.13 grams) and triethylamine (0.1 mole) in 60 ml of benzene at 20 C. The reaction mixture was stirred 2.5 hours at 25 C. The salt was filtered off and washed with benzene. After removal of benzene, the product was obtained as a viscous liquid which was purified by column chromatography (alumina). Impurities were eluted with ether and the product with methanol to yield the product represented by formula (IX). Analysis for C15 H17 NO4. Calculated: C, 65.44%; H, 6.23%; N, 5.09%. Found: C, 65.55%; H, 6.05%; N, 5.05%.
  • 7
  • [ 280-13-7 ]
  • [ 6601-22-5 ]
  • [ 1197160-15-8 ]
YieldReaction ConditionsOperation in experiment
99% With triethylamine; In water; acetone; at 20℃; for 6h; To a stirred acetone/crushed ice suspension of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (1.5 g, 6.5 mmol), 8-oxa-3-azabicyclo[3.2.1]octane (980 mg, 6.5 mmol) and triethylamine (3 ml) was added and stirred at room temperature for 6 h. At the end, the separated solid was filtered and washed with water. The crude product was found to be pure enough for further transformations. Yield: 2.0 g (99%); mp. 118; (M+H) 313.1.
99% With triethylamine; In water; acetone; at 20℃; for 6h; To a stirred acetone/crushed ice suspension of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (1.5 g, 6.5 mmol), 8-oxa-3-azabicyclo[3.2.1]octane (980 mg, 6.5 mmol) and triethylamine (3 ml) was added and stirred at room temperature for 6 hours. At the end, the separated solid was filtered and washed with water. The crude product was found to be pure enough for further transformations. Yield: 2.0 g (99%); mp. 118; (M+H) 313.1
  • 8
  • [ 280-13-7 ]
  • [ 16234-14-3 ]
  • [ 1144081-74-2 ]
  • 10
  • [ 280-13-7 ]
  • [ 1144080-29-4 ]
  • [ 50270-27-4 ]
  • [ 1144080-35-2 ]
  • 11
  • [ 280-13-7 ]
  • methyl [6-chloro-2-(methylsulfanyl)pyrimidin-4-yl](methylsulfonyl)acetate [ No CAS ]
  • [ 1233339-96-2 ]
YieldReaction ConditionsOperation in experiment
44% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 72h; a) 8-oxa-3-azabicyclo[3.2.1]octane (627 mg, 5.54 mmol) was added to 4-chloro-6- (methylsulfonylmethyl)-2-(methylthio)pyrimidine (700 mg, 2.77 mmol) and DIPEA (1.447 mL, 8.31 mmol) in DCM (10 mL). The resulting mixture was stirred at rt for 3 days. The reaction mixture was washed sequentially with IM HCl (2 x 10 mL), water (10 mL) and saturated brine (10 mL). The organic layer was dried over MgSO4, filtered and then evaporated. The residue was purified by chromatography on silica eluting with a gradient of 0 to 10% MeOH in DCM. Pure fractions were combined and evaporated to afford 3-(6- (methylsulfonylmethyl)-2-(methylthio)pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1 Joctane (400 mg, 44%); m/z: (ESI+) MH+, 330.06.
  • 12
  • [ 280-13-7 ]
  • [ 1226854-16-5 ]
  • [ 1198278-01-1 ]
  • 13
  • [ 280-13-7 ]
  • [ 1198278-07-7 ]
  • [ 1226854-18-7 ]
  • 14
  • [ 280-13-7 ]
  • [ 4359-87-9 ]
  • [ 1250867-75-4 ]
YieldReaction ConditionsOperation in experiment
80% With triethylamine; In dichloromethane; at 0 - 20℃; 2,4,6-Trichloro-5-nitropyrimidine (45, 1.43 g, 6.26 mmoles) was dissolved in dichloromethane and cooled to 0 C. A solution of 8-oxa-3-azabicyclo[3.2.1]octane (2, 0.934 g, 6.26 mmoles) in dichloromethane and triethylamine (0.873 ml_, 6.26 mmoles) was slowly added over 1 hour. The solution was allowed to stir at 0 C for 2 hours, then warmed to room temperature and stirred for an additional 16 hours. The reaction mixture was filtered, the filtrate was concentrated, dissolved in ethyl acetate, washed with 1 N hydrochloric acid, saturated sodium bicarbonate, brine, dried, and concentrated to provide 3-(2,6-dichloro-5-nitropyrimidin-4- yl)-8-oxa-3-azabicyclo[3.2.1]octane (46). Yield: 1.53 g (80%). HRMS; [M+H]+ Obs'd = 305.0200, [M+H]+ Calc'd = 305.0203.
  • 15
  • [ 280-13-7 ]
  • 2,4-dichloro-6-[(methylsulfonyl)methyl]pyrimidine [ No CAS ]
  • [ 1250867-57-2 ]
YieldReaction ConditionsOperation in experiment
82% With triethylamine; In dichloromethane; at 0℃;Reflux; A 2,4-dichloro-6-(methylsulfonylmethyl)pyrimidine (42, prepared as reported inWO2008/023159, 1.6O g, 6.64 mmoles) was dissolved in dichloromethane and cooled to 0 0C. A solution of 8-oxa-3-azabicyclo[3.2.1]octane (2, 0.990 g, 6.64 mmoles) in dichloromethane and triethylamine (1.94 ml_, 13.94 mmoles) was slowly added over 15 minutes. The solution was allowed to warm to room temperature over 30 minutes then heated to reflux for 1.5 hours. The reaction mixture was stirred at room temperature for an additional 18 hours, then concentrated and purified by chromatography on silica gel (eluting with 2-3% methanol in dichloromethane) to provide 3-(2-chloro-6-(methylsulfonylmethyl)pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1 ]octane (43) as a white solid. Yield: 1.72 g (82%). HRMS; [M+H]+ Obs'd = 318.0669, [M+H]+ Calc'd = 318.0674
  • 16
  • [ 280-13-7 ]
  • 2-chloro-9-hydroxy-1,9a-dihydropyrido[1,2-a]pyrimidin-4-one [ No CAS ]
  • 9-hydroxy-2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrido[1,2-a]pyrimidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In ethanol; at 120℃; for 2h;Microwave irradiation; 2-chloro-9-hydroxy-1 ,9a-dihydropyrido[1 ,2-a]pyrimidin-4-one (Y2, 383 mg, 1.95 mmol), N- ethyl-N-isopropylpropan-2-amine (0.407 mL, 2.34 mmol) and (8-oxa-3- azabicyclo[3.2.1]octane (350 mg, 2.34 mmol) were dissolved in ethanol (10 mL) and sealed into a microwave tube. The reaction was heated to 1500C for 2 hours in the microwave reactor and cooled to room temperature. The reaction mixture was filtered then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford θ-hydroxy^δ-oxa-S-azabicycloβ^.iloctan-S-yOpyridoϖ ^-alpyrimidin^-one (270 mg, 50.7 %) as a white solid; 1H NMR (400 MHz, DMSO) δ 1.75 (4H, ddd), 3.01 (2H, d), 4.21 (2H, br s), 4.41 (2H, d), 5.49 (1 H, s), 6.93 (1H, t), 7.12 (1 H, dd), 8.29 (1 H, dd), 9.47 (1 H, s); m/z: 274.07 (MH+).
  • 17
  • [ 280-13-7 ]
  • [ 1260089-81-3 ]
  • [ 1260089-85-7 ]
  • 18
  • [ 280-13-7 ]
  • [ 1313026-83-3 ]
  • [ 1313026-63-9 ]
YieldReaction ConditionsOperation in experiment
51% With triethylamine; In ISOPROPYLAMIDE; for 0.5h;microwave irradiation; To a solution of 5-(2-chloro-9-/sopropyl-9H-purin-6-yl)-pyrazin-2-ylamine (0.46 g, 1.60 mmol) dissolved in 15 ml. of DMA was added 8-oxa-3-aza- bicyclo[3.2.1]octane (0.81 g, 7.19 mmol) and 7 mL of triethyamine. The brown solution was heated using microwave irradiation for 30 minutes. The reaction mixture was dissolved in H2O and ethyl acetate and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. Purification by flush column chromatography (silica gel, 2% of methanol in DCM) afforded 5-[9-/sopropyl-2-(8-oxa- 3-aza-bicyclo[3.2.1]oct-3-yl)-9H-purin-6-yl]-pyrazin-2-ylamine (51% yield) as a brown solid. 1H NMR CDCI3 (ppm): 9.21 (d, 1H), 8.25 (d, 1H), 7.88 (s, 1H), 4.84 (s, 2H), 4.74-4.82 (septet, 1H), 4.51 (m, 2H), 3.26-3.30 (dd, 4H), 1.87-1.97 (m, 4H), 1.59-1.60 (d, 6H). m/z: 367.22 [MH+]
  • 19
  • [ 280-13-7 ]
  • [ 1339891-28-9 ]
  • [ 1339891-88-1 ]
YieldReaction ConditionsOperation in experiment
49% With potassium tert-butylate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In tetrahydrofuran; at 40℃; for 11h;Inert atmosphere; Example 583-(4-(7-(4-(8-Oxa-3-azabicvclo[3.2.11octan-3-yl)phenyl)imidazori,2-c1pyrimidin-5-yl)-lH- pyrazol- -yl)-3 -cyclopropylpropanenitrile[00700] Preparation of 3 -(4-(5 -(1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-Pyrazol-4-yl)imidazo[l ,2-c1pyrimidin-7-yl)phenyl)-8-oxa-3-azabicvclo[3.2.11octane: To a flask charged with 7-(4-bromophenyl)-5-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4- yl)imidazo[l,2-c]pyrimidine (Preparation L; 0.250 g, 0.531 mmol), 8-oxa-3- azabicyclo[3.2.1]octane (0.430 g, 3.80 mmol), and potassium 2-methylpropan-2-olate (0.1 19 g, 1.06 mmol) was added 6 mL of THF at ambient temperature with stirring. Argon was bubbled through the reaction for 10 minutes before dicyclohexyl(2',6'-dimethoxybiphenyl-2- yl)phosphine (0.0436 g, 0.106 mmol) and tris(dibenzylideneacetone)dipalladium (0.0487 g, 0.0531 mmol) were added. Argon was bubbled through the reaction for 15 minutes before the reaction was sealed and allowed to proceed at 40 C for 4 hours. The reaction was charged with more tris(dibenzylideneacetone)dipalladium (0.0487 g, 0.0531 mmol) and purged with argon for 5 minutes before it was sealed and allowed to proceed at 40 C for 7 hours. The reaction mixture was diluted with DCM and aqueous saturated sodium bicarbonate (2 mL) and stirred for 30 minutes. The layers were separated and the organic layer was dried over MgSO i, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 1% methanol in DCM to afford 3 -(4-(5 -( 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-pyrazol-4-yl)imidazo [ 1 ,2- c]pyrimidin-7-yl)phenyl)-8-oxa-3-azabicyclo[3.2.1]octane (0.133 g, 0.265 mmol, 49.0% yield). MS (apci) m/z = 503.2 (M+H).
  • 20
  • [ 280-13-7 ]
  • [ 1352076-83-5 ]
  • [ 1352065-32-7 ]
YieldReaction ConditionsOperation in experiment
With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo- l-((S)-l-oxobutan-2-yl)piperidin-3-yl)acetic acid (99 mg, 0.215 mmol; Example 210, Step A) in DCE (3 mL) was added 48.7 mg (0.43 mmol) of 8-oxa-3-azabicyclo[3.2.1]octane(Connolly, T.; Considine, J.; Ding, Z.; Forsatz, B.; Jennings, M.; MacEwan, M.; McCoy, K.; Place, D.; Sharma, A.; Sutherland, K. Organic Process Research & Development. 2010,14(2), 459-465. Note: reference is for the HC1 Salt). Sodium triacetoxyborohydride (91 mg, 0.430 mmol) was added followed by acetic acid (1.2 μΕ, 0.022 mmol). After stirring overnight, the mixture was partitioned between 5% aq. HC1 and ethyl acetate. The organic layer was washed with sat. aq. NaCl solution, dried over Na2S04, and concentrated. The residue was purified by reversed phase preparatory HPLC (eluent: 0-100% MeCN +0.1% TFA in water + 0.1% TFA, over 20 minutes). Fractions containing the product were transferred to a separatory funnel and sat. aq. NaHCOs and dichloromethane were added. The aqueous layer was back extracted with dichloromethane. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2S04, filtered and the filtrate was concentrated to afford the title compound. 1H NMR (400 MHz, CHLOROFORM-;/) δ ppm 0.37 - 0.53 (m, 3 H) 1.48 - 1.58 (m, 4 H) 1.83 - 2.15 (m, 7 H) 2.18 - 2.31 (m, 2 H) 2.50 (s, 2 H) 2.60 (d, J=10.76 Hz, 1 H) 2.70 (d, J=15.65 Hz, 1 H) 2.96 - 3.17 (m, 4 H) 4.29 - 4.42 (m, 2 H) 4.55 (d, J=10.56 Hz, 1 H) 6.65 (dt, J=7.68, 1.44 Hz, 1 H) 6.94 - 7.02 (m, 1 H) 7.06 - 7.13 (m, 1 H) 7.14 - 7.21 (m, 1 H) 7.21 - 7.33 (m, 4 H). Mass Spectrum (ESI) m/z = 559.2 (M+l).
  • 21
  • [ 280-13-7 ]
  • [ 1374986-81-8 ]
  • 22
  • [ 280-13-7 ]
  • [ 1374986-57-8 ]
  • 23
  • [ 280-13-7 ]
  • [ 1374986-58-9 ]
  • 24
  • [ 280-13-7 ]
  • [ 1393120-63-2 ]
  • 25
  • [ 280-13-7 ]
  • [ 1374986-73-8 ]
  • 26
  • [ 280-13-7 ]
  • [ 1374986-74-9 ]
  • 27
  • [ 280-13-7 ]
  • C24H26ClNO6S [ No CAS ]
  • 28
  • [ 280-13-7 ]
  • [ 108-36-1 ]
  • [ 1416776-17-4 ]
YieldReaction ConditionsOperation in experiment
67.3% With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 80℃; for 13h;Inert atmosphere; Example 42Synthesis of 3-{3-[4-(1-Aminocyclobutyl)phenyl]-5-[3-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine trihydrochloride Step 13-(3-Bromophenyl)-8-oxa-3-azabicyclo[3.2.1]octaneA mixture of 1,3-dibromobenzene (242 μL, 2.00 mmol), 8-oxa-3-azabicyclo[3.2.1]octane (226 mg, 2.00 mmol), Pd2(dba)3 (45.8 mg, 0.0500 mmol), rac-BINAP (96.3 mg, 0.150 mmol) and NaOtBu (231 mg, 2.40 mmol) in toluene was heated at 80 C. for 13 hours under nitrogen. After cooling to room temperature, the mixture was diluted with DCM and filtered through a Celite pad. The combined filtrate and washings were concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=9:1) to afford desired product (361 mg, 67.3%) as colorless oil.400 MHz 1H-NMR (CDCl3) δ: 7.09 (t, J=8.2 Hz, 1H), 6.95-6.90 (m, 2H), 6.74-6.68 (m, 1H), 4.53-4.43 (m, 2H), 3.31-3.26 (m, 2H), 3.01 (dd, J=11.7 Hz and 2.5 Hz, 2H), 2.03-1.86 (m, 4H); LCMS [M+H]: 268.
  • 29
  • [ 280-13-7 ]
  • [ 1416776-19-6 ]
  • 30
  • [ 280-13-7 ]
  • [ 1416776-20-9 ]
  • 31
  • [ 280-13-7 ]
  • [ 1233339-48-4 ]
  • 32
  • [ 280-13-7 ]
  • [ 1233339-95-1 ]
  • 33
  • [ 280-13-7 ]
  • [ 170235-26-4 ]
  • methyl 2-(8-oxa-3-azabicyclo[3.2.1 ]octan-3-yl)thiazole-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
62% With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 18h;Reflux; A solution of bicyclomorpholine (0.52 mL, 4.75 mmol) in THF (10 mL) was treated with <strong>[170235-26-4]methyl 2-bromothiazole-4-carboxylate</strong> (1.0 g, 4.24 mmol) and DIEA (1.66 mL, 9.50 mmol) and the resulting mixture was refluxed for 18 h under N2. The reaction mixture was then concentrated under reduced pressure and the residue was purified on the ISCO using a REDISEP 24 g column (0 to 40% EtOAc-DCM) to give the desired product as a yellow gum (0.740 g, 62%). LCMS (APCI): calcd for C11H15N2O3S [M+H]+ m/z 255.07, found 255.1. 1H NMR (CDCl3, 400 MHz) delta ppm: 7.48 (s, 1H), 4.48 (d, J = 2.7 Hz, 2H), 3.89 (s, 3H), 3.58 (d, J= 12.1 Hz, 2H), 3.37 (dd, J= 11.9, 2.5 Hz, 2H), 1.98 - 2.07 (m, 2H), 1.86 - 1.94 (m, 2H).
  • 34
  • [ 280-13-7 ]
  • (2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)thiazole-4-yl)methanol [ No CAS ]
  • 35
  • [ 280-13-7 ]
  • 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane [ No CAS ]
  • 36
  • [ 280-13-7 ]
  • 3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylthiazol-2-yl)-8-oxa-3azabicyclo[3.2.1]octane [ No CAS ]
  • 37
  • [ 280-13-7 ]
  • (2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-methylthiazol-4-yl)methanol [ No CAS ]
  • 38
  • [ 280-13-7 ]
  • [ 460081-20-3 ]
  • ethyl 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)oxazole-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 18h;Reflux; Inert atmosphere; To a solution of 8-oxa-3-azabicyclo[3.2.1 Joctane (0.292 mL, 2.65 mmol) in THF (10 mL) was added <strong>[460081-20-3]ethyl 2-bromooxazole-4-carboxylate</strong> (0.583 g, 2.65 mmol) followed by DIEA (0.926 mL, 5.30 mmol). The mixture was heated to reflux for 18 h under N2. The cooled reaction mixture was then concentrated under reduced pressure and the crude residue was purified on the ISCO using a REDISEP 24 g column (0 to 45% EtOAc-DCM) to give the desired product as a pale yellow solid (0.592 g, 89%). LCMS (APCI): calcd for C12H17N2O4 [M+H]+ m/z 253.11, found 253.1. 1H NMR (CDCl3, 400 MHz) delta ppm: 7.78 (s, 1H), 4.43 (d, J= 2.2 Hz, 2H), 4.35 (q, J= 7.2 Hz, 2H), 3.66 (d, J = 12.4 Hz, 2H), 3.34 (dd, J= 12.3, 2.2 Hz, 2H), 1.92-2.04 (m, 2H), 1.84-1.92 (m, 2H), 1.36 (t, J= 7.0 Hz, 3H
  • 39
  • [ 280-13-7 ]
  • [ 1258444-28-8 ]
  • (1R,2R,4R)-4-(benzenesulfonyl)-N-(1-cyanocyclopropyl)-2-({8-oxa-3-azabicyclo[3.2.1]octan-3-yl}carbonyl)cyclopentane-1-carboxamide [ No CAS ]
  • 40
  • [ 280-13-7 ]
  • (S)-2-chloro-9-(2-oxo-2-pyridin-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one [ No CAS ]
  • [ 1523192-21-3 ]
  • 41
  • [ 280-13-7 ]
  • [ 49584-26-1 ]
  • [ 1529785-88-3 ]
  • 43
  • [ 280-13-7 ]
  • [ 1407972-38-6 ]
  • 45
  • [ 280-13-7 ]
  • [ 124-38-9 ]
  • [ 1505455-71-9 ]
  • 46
  • [ 280-13-7 ]
  • trans-N-(4-[8-oxa-3-azabicyclo[3.2.1]octane-3-sulfonyl]phenyl)-2-(pyridin-3-yl)cyclopropane-1-carboxamide [ No CAS ]
  • 47
  • [ 280-13-7 ]
  • [ 1443137-46-9 ]
  • 48
  • [ 280-13-7 ]
  • [ 98-74-8 ]
  • [ 1609560-76-0 ]
YieldReaction ConditionsOperation in experiment
300 mg With triethylamine; In dichloromethane; at 20℃; for 1h;Inert atmosphere; A mixture of 8-oxa-3-azabicyclo[3.2.1]octane (1 g, 8.84 mmol, 1.00 equiv), 4-nitrobenzene-l-sulfonyl chloride (2 g, 9.02 mmol, 1.00 equiv) and Et3N (2 mL) in DCM (30 mL) was stirred under nitrogen at rt for 1 h. The reaction was quenched by the addition of 5 mL of water. The resulting mixture was extracted with 3x30 mL of DCM. The organic combined layers were concentrated under vacuum. The residue was purified on a silica gel column eluted with EtO Ac/petroleum ether (1 :3) to yield 300 mg of the title compound as a yellow solid. TLC: Rf= 0.5, EtO Ac/petroleum ether = 1 : 1.
  • 49
  • [ 280-13-7 ]
  • [ 1612164-44-9 ]
  • 50
  • [ 280-13-7 ]
  • [ 7461-50-9 ]
  • [ 1041054-15-2 ]
YieldReaction ConditionsOperation in experiment
43% With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 1h;Sealed tube; Microwave irradiation; Into a 30 mL sealed tube was added a solution of 2-chloropyrimidin-4-amine (589 mg, 4.55 mmol) in N,N-dimethylformamide (10 mL), 8-oxa-3-azabicyclo[3.2.1]octane (745 mg, 6.58 mmol) and potassium carbonate (1.59 g, 11.5 mmol). The reaction mixture was irradiated with microwave radiation for 1 h at 120 C. The resulting solution was diluted with H20 (20 mL). The resulting solution was extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography with dichloromethane/methanol (100:9.8) to afford 2-[8-oxa-3-azabicyclo[3.2.1]octan-3-yl]pyrimidin-4-amine (400 mg, 43%) as a white solid. LCMS (ESI): RT (min) = 1.00, [M+H]+ = 207, method = J.
  • 51
  • [ 280-13-7 ]
  • 5-bromo-7-fluoroquinoxaline [ No CAS ]
  • 3-(8-bromoquinoxalin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane [ No CAS ]
YieldReaction ConditionsOperation in experiment
41% In 1-methyl-pyrrolidin-2-one; at 180℃; for 0.333333h;Sealed tube; As shown in step 4-i of Scheme 4, to a solution of 5-bromo-7- fluoroquinoxaline (compound 1002, 150 mg, 0.66 mmol) in NMP (2.3 mL) was added 8-oxa-3-azabicyclo[3.2. l]octane (178 mg, 1.2 mmol) at RT. The reaction mixture was sealed in a microwave vial and heated at l80C for 20 minutes. Afte cooling to RT and pouring into water, the aqueous phase was extracted with EtOAc (3x). The combined extracts were dried over MgS04, filtered, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0 to 100% EtO Ac/hexanes gradient) to provide 3-(8-bromoquinoxalin-6-yl)-8-oxa-3- azabicyclo[3.2.l]octane (compound 1006, 87 mg, 41% yield) as a dark orange oil: ESMS (M+H+) = 320.07.
  • 52
  • [ 280-13-7 ]
  • C35H28ClN3O [ No CAS ]
  • C22H24N4O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
The chloro-pyridine (150 mg), 8-oxa-3-azabicyclo[3.2.1 ]octane (41 mg), 1,3- bis(2,6-diisopropylphenyl)-4,5-dihydro-lH-imidazol-3-ium chloride (36 mg), Pd2(dba)3 (50 mg), and NaOTiu (53 mg) were taken up in 2 ml of dioxane in a sealed tube. The solution was heated at 100 C for 24 h. The solution was filtered and concentrated. The residue was treated with 2 ml of TFA and 0.5 ml of Et3SiH. After stirring at RT for 2 h, the solution was concentrated. The residue was treated with 5 ml of 7 NH3 in MeOH, and the resulting solution was concentrated. The residue was purified via thin-layer preparative chromatography (40% EtOAc in hexanes, Si02) which provided Example 4 as a yellow solid.
  • 53
  • [ 280-13-7 ]
  • C64H111N11O14 [ No CAS ]
  • C70H122N12O14 [ No CAS ]
  • 54
  • [ 280-13-7 ]
  • 2-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino) pyrimidin-2-yl)amino)thiazole-4-carboxylic acid [ No CAS ]
  • 8-oxa-3-azabicyclo[3.2.1]octan-3-yl(2-((5-chloro-4-((2(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)thiazol-4-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
98% With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 3h; General procedure: To a solution of 7b or 27 (0.17 mmol) in DMF (4 mL), DIPEA (130uL, 0.72 mmol), amino (0.2 mmol), HATU (0.42 mmol) and HOAT (0.05 mmol) were added, and the reaction was stirred at RT for 3 h. The mixture was diluted with water (8 mL), extracted with CHCl3, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CHCl3/MeOH:25/1) to give corresponding products 8-17.
  • 55
  • [ 280-13-7 ]
  • 6-chloro-3-iodo-1-isopropyl-1H-pyrazolo[4,3-c]pyridine [ No CAS ]
  • 3-(6-chloro-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane [ No CAS ]
YieldReaction ConditionsOperation in experiment
31% With copper(l) iodide; potassium carbonate; L-proline; In N,N-dimethyl-formamide; at 80℃; for 16h; A mixture of 6-chloro-3-iodo-l-isopropyl-lH-pyrazolo[4,3-c]pyridine (400 mg, 1.24 mmol)(Example 1, step 8), copper (I) iodide (71.1 mg, 0.370 mmol), potassium carbonate (344 mg, 2.49 mmol), 8-oxa-3-azabicyclo [3.2.1]octane(563 mg, 4.98 mmol) and (S)-pyrrolidine-2- carboxylic acid (28.6 mg, 0.250 mmol) in NN-dimethylformamide (8 mL) was stirred for 16 h at 80 C. The reaction mixture was cooled to room temperature and diluted with water (20 mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (solvent gradient: 0-10% ethyl acetate in petroleum) to afford the title compound (120 mg, 31%) as a yellow solid. LCMS (ESI): [M+H]+ = 307.
  • 56
  • [ 280-13-7 ]
  • [ 61072-56-8 ]
  • 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-chlorobenzaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
43% With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 4h; A round bottom flask was charged with 8-oxa-3-azabicyclo[3.2.1]octane (495 mg,3.32 mmol), K2 C03 (436 mg, 3.16 mmol) and <strong>[61072-56-8]4-chloro-2-fluorobenzaldehyde</strong> (500 mg, 3.15 mmol), and the contents were dissolved in DMSO (10 mL) and heated to 120 C. After 4 h, the reaction mixture was diluted in DCM (200 mL) and washed 3X with brine. The organics were dried over anhydrous Na2 S04 and concentrated. The resulting orange oil was chromatographed on a silica column with a gradient (100% hexanes to 80% Hexanes/20% EtOAc) to provide 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-chlorobenzaldehyde as a yellow solid (336 mg, 43 %). 1H NMR(400 MHz, Chloroform-d) 810.32 (s, lH), 7.72 (s, lH), 7.46 (ddd,J= 8.7, 3.3, 1.7 Hz, 1H), 7.08 (dd, J= 8.7, 1.3 Hz, 1H), 4.47-4.41 (m, 2H), 3.21 (d, J= 11.5 Hz, 2H), 2.91 (d, J= 11.7 Hz, 2H),2.19-2.06 (m, 2H), 2.06-1.96 (m, 2H). LCMS (ESI, m/z): 252.1 [M+Ht.
  • 57
  • [ 280-13-7 ]
  • 2-chloro-N-(3-((5-chloro-4-((2-(isopropylsulfonyl)-phenyl)amino)pyrimidin-2-yl)amino)phenyl)acetamide [ No CAS ]
  • 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)acetamide [ No CAS ]
  • 58
  • [ 280-13-7 ]
  • [ 1260585-11-2 ]
  • (2S)-8-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-(trifluoromethyl)-1,2,3,4-tetrahydropyrimido[1,2-a]pyrimidin-6-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
600 mg With triethylamine; at 150℃; for 0.166667h;Microwave irradiation; 500 mg (1.97 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 884 mg (5.91 mmol) of 8-oxa-3-azabicyclo[3.2.1]octane and 820 μl (5.91 mmol) of triethylamine are placed in a microwave tube. The mixture is irradiated for 10 minutes at 150 C. The reaction medium is purified directly by passing through an RP18 reverse-phase column (eluent: H2O: 100% to CH3CN: 100%) to give 600 mg of (8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows: LC/MS (method A): ESI+ [M+H]+: m/z 331 tr (min)=0.53 1H NMR (600 MHz, δ in ppm, DMSO-d6): 1.66 (m, 2H), 1.81 (m, 2H), 2.09 (m, 1H), 2.2 (m, 1H), 2.89 (d, 2H), 3.34 (m, 1H), 3.75 (m, 2H), 4.14 (m, 1H), 4.26 (s, 1H), 4.37 (s, 2H), 4.84 (s, 1H), 8.17 (s, 1H).
  • 59
  • tetrahydrofuran-2,5-dimethanol [ No CAS ]
  • [ 280-13-7 ]
YieldReaction ConditionsOperation in experiment
63%Chromat. With ammonia; hydrogen; In toluene; at 200℃; under 3000.3 Torr; for 11h;Autoclave;Mechanism; General procedure: All the reactions were performed in an 80 mL autoclave containing aglass tube inside and equipped with a magnetic stirrer. In each catalytictest, 1.0 mmol of 2,5-THFDM, 30-100 mg of catalyst and 2 mL of the target solvent were added. The autoclave was sealed and pressurized/depressurized with either nitrogen or hydrogen (0.1-1.0 MPa) for 3times. Then, ammonia (0.4 MPa) was introduced and the reaction wasconducted at 200 C for 6-16 h. After the reaction, the autoclave wascooled down to room temperature and 40 mg biphenyl and 10 mLethanol were added for quantitative analysis (GC-FID, Agilent 6890A).Specic analyses were performed on an HP 6890/5973 GC-MS to assistthe identication of reaction intermediates.
  • 60
  • [ 280-13-7 ]
  • [ 113898-56-9 ]
  • methyl 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)nicotinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
42% With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 100℃; for 1h;Microwave irradiation; Step 1a. To a solution of ethyl 2-fluoronicotinate (0.15 g, 0.97 mmol) in NMP (0.5 mL) was added diisopropylethyl amine (0.50 mL, 2.9 mmol), and 8-oxa-3-azabicyclo[3.2.1]octane (0.17 g, 0.72 mmol). The resulting mixture was irradiated with microwaves (100 C.) for 1 h and loaded directly onto a silica column. Eluting the column with EtOAc/hexanes (0-100%) provided methyl 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)nicotinate as a clear oil (0.100 g, 42% yield). MS (ES) for C13H16N2O3: 249 (MH+).
  • 61
  • [ 280-13-7 ]
  • [ 446-26-4 ]
  • methyl 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)nicotinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
42% With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 100℃; for 1h;Microwave irradiation; 101111 Step la. To a solution of ethyl 2-fluoronicotinate (0.15 g, 0.97 mmol) in NMP (0.5 ml..) was added diisopropylethyl amine (0.50 mL, 2.9 mmol), and 8-oxa-3- azabicyclo[3.2.Iioctanc (0.17 g, 0.72 mmol). Thc resulting mixture was irradiated with microwaves (100C) for lh and loaded directly onto a silica column. Eluting the column with EtOAc/hexanes (0-100%) provided methyl 2-(8-oxa-3-azabicyclo[3.2.l]octan-3- yl)nicotinate as a clear oil (0.100 g, 42% yield). MS (ES) for C13H1(,N203: 249 (MW).
  • 62
  • [ 280-13-7 ]
  • [ 1017802-88-8 ]
  • ethyl 5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-bromo-1-methyl-1H-pyrazole-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
155mg With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 150℃; for 3h;Microwave irradiation; obtained in Reference Example 1, Step B ethyl 3,5-dibromo-1-methyl -1H- pyrazole-4-carboxylate (410 mg), 8- oxo-3-azabicyclo [3.2.1] octane (205 mg), and potassium carbonate (369 mg) of 1-methylpyrrolidone (4 mL) and the mixture was stirred for 3 hours at 150 C. using a micro web reactor.The reaction mixture was purified by column chromatography (hexane / ethyl acetate) to give the title compound (155 mg).
  • 63
  • [ 280-13-7 ]
  • (5-(2-chloro(morpholine-4-yl)pyrido[2,3-d]pyrimidine-7-yl)-2-methoxyphenyl)methanol [ No CAS ]
  • (5-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-morpholino-pyrido[2,3-d]pyrimidin-7 yl)-2-methoxyphenyl)methanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
33.2% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 130℃; for 6h;Inert atmosphere; The (5- (2-chloro-4-morpholino-pyrido [2,3-d] pyrimidin-7-yl) -2-methoxyphenyl) methanol (300mg, 0.78mmol), and 8-oxa--3 - azabicyclo [3.2.1] octane (105mg, 0.93mmol) was dissolved in DMA (20mL) and then added diisopropylethyl amine (290mg, 2.23mmol), N2Under the protection of the reaction 6h and 130 , reaction mixture was diluted with water, CH2Cl2Was extracted 3 times, the organic phase was dried and concentrated, the residue by column chromatography to give the product (120mg, 33.2%).
  • 64
  • [ 280-13-7 ]
  • [ 1005-37-4 ]
  • N4-methyl-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidine-2,4-diamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
3.5 mg With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 150℃; for 2h;Sealed tube; 6-Chloro-N -methyl-pyrimidine-2,4-diamine (20,00 mg; 0,13 mmol) is dissolved in dimethyl sulfoxide (5,00 ml) and N-ethyldiisopropylamine (70,00 muIota). 8-Oxa-3-aza-bicyclo[3.2.1]octane (21 ,00 mg; 0,14 mmol) is added and the mixture is heated for 2h at 150C in a closed vial. For work up the mixture is lyophilized and pyrified by HPLC giving 3,5 mg of the product as yellowish foam.
  • 65
  • [ 280-13-7 ]
  • tert-butyl 4-(3-bromo-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate [ No CAS ]
  • tert-butyl 4-(3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
43% With palladium diacetate; sodium pivalate; ruphos; In tetrahydrofuran; at 83℃; for 18h;Inert atmosphere; [00162] A vial was charged with tert-butyl 4-(3-bromo-4-(trifluoromethyl)benzyl)piperazine-1- carboxylate (296 mg, 0.699 mmol). To this vial was added Pd(OAc)2 (9.4 mg, 0.042 mmol), RuPhos (78.4 mg, 0.168 mmol), and sodium tert-butoxide (201 mg, 2.098 mmol). The vial was flushed with nitrogen and evacuated 3 times. 8-Oxa-3-azabicyclo[3.2.1]octane (271 mg, 2.098 mmol) was added to the vial, followed by anhydrous THF (3 mL). The resulting stirred mixture was heated at 83 C for 18 h. The reaction was cooled to rt whereupon 5 mL H2O was added. The reaction mixture was extracted with EtOAc (3 x 10 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated to yield an oil. The oil was purified on silica gel by flash column chromatography to afford tert-butyl 4-(3-(8-oxa-3-azabicyclo[3.2.1]octan-3- yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate as a clear oil (140 mg, 43% yield). 1H NMR (400 MHz, Chloroform-d4.44- 4.36 (m, 2H), 3.56- 3.50 (m, 2H), 3.50- 3.40 (m, 4H), 3.17- 3.11 (m, 2H), 2.75- 2.69 (m, 2H), 2.44- 2.34 (m, 4H), 2.25- 2.16 (m, 2H), 1.98- 1.88 (m, 2H), 1.47 (s, 9H). LCMS (ESI, m/z): 456.2 [M + H]+.
  • 66
  • [ 280-13-7 ]
  • 4-((2-(2,6-difluorophenyl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)amino)benzoic acid [ No CAS ]
  • 4-((4-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)phenyl)-amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
52.1% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; Example 5 Synthesis of 4-((4-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)phenyl)-amino)-2-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one, I-5 To a solution of 5.1 (0.1 g 0.26 mmol, 1.0 eq) in dry THF (5.0 mL) was added EDCl-HCl (0.1 g, 0.52 mmol, 2.0 eq) followed by HOBt (0.069 g, 0.39 mmol, 1.5 eq) at 0 C. Solution was allowed to stir at 0 C. for 1 hour. 8-oxa-3-azabicyclo[3.2.1]octane (0.035 g, 0.312 mmol, 1.2 e q) was added followed by DIPEA (0.1 g, 0.78 mmol, 3.0 eq). Reaction mixture was allowed to warm to room temperature and was stirred overnight. After completion of the reaction, mixture was poured into water and extracted using ethyl acetate (50 mL*2). Organic layer was washed with by brine solution, dried over sodium sulfate and concentrated under reduced pressure. Crude was purified by column chromatography to afford pure compound I-5 (65 mg, 52.1%). MS (ES): M/z 478.53 [M+H]+, 1H NMR (400 MHz, DMSO-d6): δ 9.226 (s, 1H), 8.963 (s, 1H), 7.828-7.849 (d, 2H), 7.568-7.641 (m, 1H), 7.373-7.394 (d, 2H), 7.249-7.343 (m, 2H), 4.505 (2H), 4.358 (m, 2H), 7.193 (m, 1H), 3.727-3.763 (m, 1H), 2.950-2.976 (m, 2H), 1.771 (m, 6H).
  • 67
  • [ 280-13-7 ]
  • [ 369-34-6 ]
  • 3-(2-fluoro-4-nitrophenyl)-8-oxa-3-azabicyclo[3.2.1]octane [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% With potassium carbonate; In N,N-dimethyl-formamide; at 25 - 80℃; for 2h;Inert atmosphere; To a solution of <strong>[280-13-7]8-oxa-3-aza-bicyclo[3.2.1]octane</strong> (1) (5.0 g, 44.2 mmol) and 1,2-difluoro-4-nitrobenzene (7.7 g, 48.6 mmol) in DMF (10 mL) was added K2C03 (12.2 g, 88.4 mmol) at 25C then the reaction mixture was stirred at 80C for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 5: 1) to afford3-(2-fluoro-4-nitrophenyl)-<strong>[280-13-7]8-oxa-3-aza-bicyclo[3.2.1]octane</strong> (3) (9.1 g, 82%) as a yellow solid.LC-MS (ESI) m/z = 253 [M+Hfb.
  • 68
  • [ 280-13-7 ]
  • [ 66684-58-0 ]
  • 3-(2,6-difluoro-4-nitrophenyl)-8-oxa-3-azabicyclo[3.2.1]octane [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% With potassium carbonate; In N,N-dimethyl-formamide; at 25 - 80℃; for 2h;Inert atmosphere; To a solution of 8-oxa-3-aza-bicyclo[3.2.1]octane (1) (5.0 g, 44.2 mmol) and <strong>[66684-58-0]1,2,3-trifluoro-5-nitrobenzene</strong> (8.6 g, 48.6 mmol) in DMF (10 mL) was added K2C03 (12.2 g, 88.4 mmol) at 25°C then the reaction mixture was stirred at 80°C for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 3: 1) to afford 3 -(2,6-difluoro-4-nitrophenyl)-8-oxa-3 -aza-bicyclo[3 .2.1 ]octane (3) (9.3 g, 78percent) as a yellow solid.LC-MS (ESI) m/z = 271 [M+H].
  • 69
  • [ 280-13-7 ]
  • [ 66684-58-0 ]
  • 8-(2,6-difluoro-4-nitrophenyl)-3-oxa-8-aza-bicyclo[3.2.1]octane [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% With potassium carbonate; In N,N-dimethyl-formamide; at 25 - 80℃; for 2h;Inert atmosphere; To a solution of 3-oxa-8-aza-bicyclo[3.2.1]octane (1) (5.0 g, 44.2 mmol) and<strong>[66684-58-0]1,2,3-trifluoro-5-nitrobenzene</strong> (8.6 g, 48.6 mmol) in DMF (10 mL) was addedK2C03 (12.2 g, 88.4 mmol) at 25°C then the reaction mixture was stirred at 80°C for 2 h under a nitrogen gas atmosphere, monitored by TLC. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (EA: PE = 3: 1) to afford8-(2,6-difluoro-4-nitrophenyl)-3 -oxa-8-aza-bicyclo[3 .2.1 ]octane (3) (9.3 g, 78percent) as a yellow solid.LC-MS (ESI) m/z = 271 [M+H].
  • 70
  • [ 280-13-7 ]
  • 4-nitrophenyl ((1R,2R)-2-(1-oxo-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl)carbamate [ No CAS ]
  • N-((1R,2R)-2-(1-oxo-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl)-8-oxa-3-azabicyclo[3.2.1]octane-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
104 mg With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 10 - 35℃; for 2h; A mixture of 4-nitrophenyl ((1R,2R)-2-(1-oxo-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl)carbamate (188 mg), 8-oxa-3-azabicyclo[3.2.1]octane (40 mg) and DIEA (0.185 mL) in DMF (4 mL) was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (104 mg). (1311) 1H NMR (300 MHz, CDCl3) δ 1.08-1.22 (1H, m), 1.31-2.03 (10H, m), 2.14 (1H, d, J=9.4 Hz), 2.81-2.92 (2H, m), 3.20 (1H, d, J=12.1 Hz), 3.31 (1H, d, J=12.5 Hz), 3.83-4.01 (1H, m), 4.15-4.26 (3H, m), 4.40 (1H, d, J=17.8 Hz), 4.70 (1H, d, J=17.4 Hz), 4.80 (1H, d, J=8.7 Hz), 7.63 (1H, d, J=7.9 Hz), 8.30 (1H, dd, J=7.9, 1.1 Hz), 8.57 (1H, s)
  • 71
  • [ 280-13-7 ]
  • [ 933190-51-3 ]
  • 8-(8-oxa-3-aza-bicyclo[3.2.1]octyl-3-yl)-6-chloro-imidazo[1,2-b]pyridazine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In tetrahydrofuran; for 12h;Reflux; General procedure: To a solution of 6a-6c (1 mmol) in THF (5 mL) was addedmorpholine (or (S)-3-methylmorpholine, or 8-oxa-3-azabicyclo[3.2.1]octane) (1.2 mmol) and Et3N (2.2 mmol). The mixture washeated under reflux for 12 h. The crude product was extracted with CH2Cl2, dried over Na2SO4, purified over silica gel chromatographyeluting with PE and EtOAc to give 7a-7g [43].
  • 72
  • 5-hydroxymethyltetrahydrofurfurylamine [ No CAS ]
  • [ 280-13-7 ]
YieldReaction ConditionsOperation in experiment
60%Chromat. With ammonia; hydrogen; In toluene; at 200℃; under 3000.3 Torr; for 11h;Autoclave; General procedure: All the reactions were performed in an 80 mL autoclave containing aglass tube inside and equipped with a magnetic stirrer. In each catalytictest, 1.0 mmol of 2,5-THFDM, 30-100 mg of catalyst and 2 mL of the target solvent were added. The autoclave was sealed and pressurized/depressurized with either nitrogen or hydrogen (0.1-1.0 MPa) for 3times. Then, ammonia (0.4 MPa) was introduced and the reaction wasconducted at 200 C for 6-16 h. After the reaction, the autoclave wascooled down to room temperature and 40 mg biphenyl and 10 mLethanol were added for quantitative analysis (GC-FID, Agilent 6890A).Specic analyses were performed on an HP 6890/5973 GC-MS to assistthe identication of reaction intermediates.
  • 73
  • [ 280-13-7 ]
  • [ 1121-60-4 ]
  • [ 1379820-13-9 ]
  • C22H26N2O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
42% With hydrogenchloride; In 1,4-dioxane; acetonitrile; at 80℃; for 48h;Sealed tube; General procedure: To a mixture of 4-phenyl-1, 2-oxaborol-2(5H)-ol 2a (120 mg, 0.75 mmol), 2-pyridinecarbaldehyde 1a (53.5 mg, 0.5 mmol) and morpholine 3a (43.5 mg, 0.5 mmol) in a sealed tube was added HCl (2.0 M in dioxane, 125 μL, 0.5 mmol) and acetonitrile (4.0 mL). The mixture was stirred at 80C for 48 h and then cooled to room temperature. The reaction mixture was quenched with saturated Na2CO3 (aq. 1 mL) and filtered through a pad of Celite eluting with CH2Cl2 (20 mL). The filtrate was washed with an aq solution of NaOH (1N15 mL). The aqueous phase was re-extracted with CH2Cl2 (3 × 10 mL).All organic phases were combined and concentrated in vacuo. The product was isolated by a short silica gel chromatography (petroleum ether : EtOAc = 3 : 1) to give 4a (136.9 mg, 88 %) as a yellow solid.
  • 74
  • furan-2,5-dicarboxaldehyde dioxime [ No CAS ]
  • [ 280-13-7 ]
  • (tetrahydrofuran-2,5-diyl) dimethanamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
5%; 50% With 5%-palladium/activated carbon; hydrogen; In methanol; at 50℃; under 26601.8 Torr; for 18h;Autoclave; Into a 30m1 autoclave, furan-2,5-dicarbaldehyde dioxime (153 mg, 1.0mmol) and 5% Pd/C (47 mg) from Johnson Matthey were added and dissolved inmethanol (5 ml). The mixture was stirred at 50C under 35 atms H2 atmosphere for 18 h. The reaction mixture, after completion of the reaction, was analysed by GC. It was shown 2,5-bis(aminomethyl) tetrahydrofuran was obtained in 50% yield while the bicyclic compound 8-oxa-3-azabicyclo[3.2.1]octane appeared as byproduct in 5% yield.
  • 75
  • [ 2213-51-6 ]
  • [ 280-13-7 ]
  • (tetrahydrofuran-2,5-diyl) dimethanamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
6%; 82% With hydrogen; In para-xylene; at 100℃; under 68404.6 Torr; for 12h;Autoclave; Into a 30m1 autoclave, 2,5-bis(aminomethyl)furan (133 mg, 1.05 mmol) and doped Raney Ni (120 mg) from Ningbo HanYi were added and dissolved in p-xylene (5 ml). The mixture was stirred at 100C under 90 atms H2 atmosphere for 12 h. The reaction mixture, after completion of the reaction, was analysed by GC and 2,5-bis(aminomethyl) tetrahydrofuran was obtained in 82% yield whilethe bicyclic compound 8-oxa-3-azabicyclo[3.2.1] octane appeared as byproduct in 6% yield.
  • 76
  • [ 280-13-7 ]
  • 3,6-di-bromo-isothiazolo[4,3-b]pyridine [ No CAS ]
  • 3-(6-bromoisothiazolo[4,3-b]pyridin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane [ No CAS ]
  • 77
  • [ 280-13-7 ]
  • [ 27816-36-0 ]
  • 2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)propanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% With triethylamine; potassium iodide; In N,N-dimethyl-formamide; at 50℃; for 72h;Inert atmosphere; 2-Chloropropanamide (racemate) (250 mg, 98 % purity, 2.28 mmol) was disolved in DMF (7.3 ml) and treated with triethylamine (350 jil, 2.5 mmol), 8-oxa-3-azabicyclo[3.2.1]octane (284 mg, 2.51 mmol) and potassium iodide (75.6 mg, 456 jimol). This mixture was heated at 50C under argon for 3 days.After cooling to rt, the solvent was removed under reduced pressure and the residue was purified by chromatography through a silica column eluting with a gradient of dichloromethane/methanol from 100:0 to 85:15 to deliver 229 mg (96 % purity, 52 % yield) of the title compound.1HNMR (400 MHz, DMSO-d6) [ppm]: 1.030 (15.74), 1.048 (16.00), 1.500(1.11), 1.517 (1.12), 1.670 (2.17), 1.689 (3.58), 1.707 (2.64), 1.730 (0.44), 1.835 (0.59), 1.861 (4.48), 1.873 (2.35), 1.878 (2.22),1.890 (3.99), 1.913 (0.47), 2.298 (1.97), 2.302 (2.01), 2.325 (3.17), 2.329 (3.18), 2.388 (1.42), 2.392 (1.49), 2.415 (6.95), 2.445 (5.40), 2.474 (1.49), 2.803 (1.21), 2.820 (3.87), 2.837 (3.75), 2.855 (1.13), 4.181 (2.22), 4.192 (3.39), 4.203 (2.22), 6.973 (1.57), 7.045 (1.58).
  • 78
  • [ 280-13-7 ]
  • N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(morpholin-4-yl)propanamide [ No CAS ]
  • N-[5-(7-bromo-4-oxoquinazolin-3(4H)-yl)-2-(trifluoromethoxy)phenyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)propanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
34% With triethylamine; potassium iodide; In N,N-dimethyl-formamide; at 50℃; for 16h; A solution of N- [5 -(7-bromo-4-oxoquinazolin-3 (4H)-yl)-2-(trifluoromethoxy)phenyl] -2-chloropropanamide (racemate) (250 mg, 96% purity, 489 jimol) in N,N-dimethylformamide (1.5 ml) was treated with triethylamine (200 jil, 1.5 mmol), 8-oxa-3-azabicyclo[3.2.1]octane (166 mg, 1.47 mmol) and potassium iodide (16.2 mg, 97.8 jimol) and stirred at 50C for 16 h. The reaction mixture was then partitioned between 6 mL of water and 20 mL of ethyl acetate and extractive work-up wasperformed. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel eluting with a gradient of cyclohexane/ethyl acetate 100:0 to 50:50 to provide 95.0 mg (34 % yield) of the title product.LC-MS (Method 6): R = 2.16 mm; MS (ESIpos): m/z = 567 [M+H]1HNMR (400 MHz, DMSO-d6) [ppm]: -0.008 (1.57), 1.149 (14.41), 1.157 (6.08), 1.166 (15.12),1.175 (8.63), 1.193 (3.93), 1.398 (1.47), 1.798 (4.44), 1.809 (3.16), 1.826 (1.00), 1.844 (0.66), 1.910(1.04), 1.935 (3.07), 1.952 (1.88), 1.966 (1.89), 1.980 (2.73), 1.988 (14.55), 2.005 (0.83), 2.451 (10.70),2.581 (10.88), 3.282 (1.21), 3.299 (4.48), 3.333 (1.34), 4.003 (1.08), 4.021 (3.25), 4.039 (3.22), 4.056(1.10), 4.260 (5.22), 4.265 (5.24), 5.754 (16.00), 7.423 (3.30), 7.430 (3.42), 7.445 (3.89), 7.452 (4.11),7.655 (3.03), 7.659 (3.25), 7.677 (2.59), 7.681 (2.59), 7.765 (3.36), 7.770 (3.64), 7.787 (3.75), 7.791(4.19), 7.978 (5.47), 7.982 (5.67), 8.103 (6.76), 8.124 (6.06), 8.415 (13.12), 8.429 (6.39), 8.436 (6.40),9.711 (6.78).
  • 79
  • [ 280-13-7 ]
  • [ 17973-86-3 ]
  • C10H12BrN3O [ No CAS ]
YieldReaction ConditionsOperation in experiment
67% With triethylamine; In acetonitrile; at 160℃; for 1.66667h;Microwave irradiation; <strong>[17973-86-3]3,6-Dibromopyridazine</strong> (0.2 g, 0.841 mmol) was dissolved in acetonitrile (2.5 ml_). Then 8-oxa-3- azabicyclo[3.2.1]octane (0.105 g, 0.925 mmol) and triethylamine (0.176 ml_, 1.261 mmol) were added and the suspension was irradiated in the microwave to 160C for 1 h and 20 minutes. The reaction mixture was diluted with dichloromethane and water. The organic layer was separated and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The crude product was purified on a silica gel column using a Biotage Isolera One purification system employing an n-heptane/ethyl acetate gradient (100/0 -> 0/100) to afford the title compound as a beige solid (0.152 g, 67 %). (0609) MS: 271.5 (M+H)+. (0610) 1H-NMR (400 MHz, Chloroform-d) d = 7.32 (d, J = 9.5 Hz, 1 H), 6.70 (d, J = 9.5 Hz, 1 H), 4.60 - 4.43 (m, 2H), 3.83 (d, J = 12.8 Hz, 2H), 3.23 (dd, J = 12.4, 2.7 Hz, 2H), 2.08 - 1.94 (m, 2H), 1.90 - 1.76 (m, 2H).
  • 80
  • [ 280-13-7 ]
  • [ 121-02-8 ]
  • 3-(2-methyl-5-nitro-phenyl)sulfonyl-8-oxa-3-azabicyclo[3.2.1]octane [ No CAS ]
  • 81
  • [ 280-13-7 ]
  • [ 1229583-72-5 ]
  • 3-(4-(3-(1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)-8-oxa-3-azabicyclo[3.2.1]octane [ No CAS ]
YieldReaction ConditionsOperation in experiment
37.2 mg General procedure: The aldehyde (10a-c, or 11 (Goodfellow VS et a., 2013)) (0.5 mmol, 1.0 eq) was dissolved in dichloromethane and the corresponding amine (1 .0 mmol, 2.0 eq) and Na(OAc)3BH (159 mg, 0.75 mmol, 1 .5 eq) were added. The reaction mixture was stirred at room temperature overnight, partitioned between dichloromethane and brine. The aqueous layer was extracted with dichloromethane (2x), the combined organic layers dried with Na2S04, filtered, and the solvent evaporated. The crude product was used in the deprotection step without further purification. The intermediate was dissolved in a mixture of acetone (20 ml_), methanol (30 ml.) and aqueous NaOH (2.0 M, 15 mL) and stirred at 65 C for 3 h. The reaction mixture was partitioned between ethyl acetate and aqueous NaOH (1.0 M). The layers were separated and the aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried with Na2S04, filtered and the solvent evaporated. The crude material was purified by preparatory HPLC purification to afford the product (12a-l). Preparation of 3-(4-(3-(1W-lndol-5-yl)-1 H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)-8-oxa-3- azabicyclo[3.2.1]octane (Compound 12a) Following the general procedure described above, with 4-(3-(1 /-/-lndol- 5-yl)-1 -tosyl-1 H-pyrrolo[2,3- ]pyridin-5-yl)benzaldehyde (11 , 100 mg, 0.2 mmol) and 8-oxa-3-azabicyclo[3.2.1 ]octane (45 mg, 0.4 mmol, 2.0 eq) as the starting materials, 3-(4-(3-(1 /-/-indol-5-yl)-1 H-pyrrolo[2,3-Jb]pyridin-5-yl)benzyl)-8-oxa-3- azabicyclo[3.2.1 ]octane (12a) was isolated as a light-brown solid (37.2 mg, 43% yield over two steps). 1H NMR (500 MHz, Methanol-d4) d 8.42 (d, J = 2.1 Hz, 1 H), 8.40 (d, J = 2.1 Hz, 1 H), 7.83 (d, J = 1.5 Hz, 1 H), 7.55 (s, 1 H), 7.52 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.4 Hz, 1 H), 7.46 - 7.39 (m, 1 H), 7.33 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 3.1 Hz, 1 H), 6.49 (dd, J = 3.1 , 0.8 Hz, 1 H), 4.20 (dd, J = 4.7, 2.3 Hz, 2H), 3.41 (s, 2H), 2.52 (d, J = 1 1.5 Hz, 2H), 2.25 (dd, J = 1 1.4, 2.1 Hz, 2H), 2.00 - 1 .90 (m, 3H), 1.86 - 1.73 (m, 2H) ppm. HRMS (APCI+, m/z): calcd. for C H N O [M+H+]: 517.2716, found: 517.2713.
  • 82
  • [ 280-13-7 ]
  • 4-(2-[1-(4-oxocyclohexyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-4-yl]amino}pyrimidin-5-yl)-2-[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}benzonitrile [ No CAS ]
  • 2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclohexyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
80.5 mg With 2-picoline borane complex; acetic acid; In methanol; at 60℃; for 1.5h; A mixture of 4- ( 2- { [ 1- ( 4-oxocyclohexyl) -3- ( 2 , 2 , 2- trifluoroethoxy) -lH-pyrazol-4-yl] amino}pyrimidin-5-yl) -2- { [ (2S) -1- (lH-tetrazol-l-yl) propan-2-yl] oxy}benzonitrile (200 mg), 8-oxa-3-azabicyclo [3.2.1 ] octane (220 mg) and 2- methylpyridine-borane (107 mg) in MeOH (5.0 mL) and AcOH (0.50 mL) was stirred at 60C for 1.5 hr. The reaction mixture was concentrated under reduced pressure. The residue waspartitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, MeOH/ethyl acetate/hexane) to give the title compound (80.5 mg) . NMR (300 MHz, DMSO-de) d 1.29-1.40 (5H, m) , 1.62-1.74 (4H, m) , 1.75-1.83 (2H, m) , 1.89 (2H, d, J = 12.6 Hz) , 2.05 (2H, d,J = 9.7 Hz) , 2.15-2.25 (1H, m) , 2.38 (2H, d, J = 10.5 Hz), 2.56 ( 2H, s), 3.85-3.98 (1H, m) , 4.21 (2H, brs) , 4.71-4.80 (2H, m) , 4.81-4.89 (1H, m) , 4.90-4.99 (1H, m) , 5.30-5.40 (1H, m) , 7.39 (1H, d, J = 8.3 Hz) , 7.47 (1H, s) , 7.75 (1H, d, J = 8.2 Hz), 7.78 (1H, s), 8.80 (2H, s), 8.89 (1H, s) , 9.35 (1H, s) .
  • 83
  • [ 280-13-7 ]
  • [ 1224944-77-7 ]
  • ethyl 5-[8-oxa-3-azabicyclo[3.2.1]octan-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 1h;Inert atmosphere; To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1.80 g, 7.98 mmol, CAS 1224944-77-7), (1S,5R)-8-oxa-3-azabicyclo[3.2.1]octane (1.79 g, 12.0 mmol, CAS 280-13-7) in ACN (30 mL) was added DIPEA (4.12 g, 31.9 mmol). The mixture was stirred at 60 C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase flash (0.1% FA condition) to give the title compound (2.20 g, 91% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) d 8.74 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.47 (d, J = 2.4 Hz, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.30 (s, 2H), 3.17 (d, J = 12.4 Hz, 2H), 1.92 - 1.80 (m, 2H), 1.75 - 1.63 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H).
  • 84
  • [ 280-13-7 ]
  • methyl 4-chloro-2-(6-pivalamido-4-(trifluoromethyl)pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate [ No CAS ]
  • methyl 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-(6-pivalamido-4-(trifluoromethyl)pyridine-3-yl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% In tetrahydrofuran; at 0 - 20℃; for 2h; General procedure: A mixture of compound 11 (4.7 g, 15.1mmol) and 4-dimethylaminopyridine (3.7 g, 30.2 mmol) in POCl3 (20 mL) was allowed to reflux for 10 h. The volatiles were evaporated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and cool water (20 mL).The organic layer was washed with ice water, dried with Na2SO4, and evaporated to give the desired product 12 as a yellow solid (4.6 g, 92%). 1H NMR (300 MHz, CDCl3) δ 8.54 (d, J = 8.9 Hz, 2H), 8.36 (s, 1H), 8.34 (d,J= 8.9 Hz, 2H), 7.46 (s, 1H), 3.96 (s, 3H); MS (ESI) m/z: 333 [M+H]+. To the solution of compound 12(4.6 g, 13.8 mmol) in dry THF (100 mL) was added morpholine (1.8 mL, 20.7 mmol) at 0 oC. The reaction was then stirred at room temperature for 2 h. The solvent was evaporated in vacuo to give the crude product, which was purified by column chromatography on silica gel with CH2Cl2 as eluent to give a yellow solid 13 (5.0 g, 94%);
  • 85
  • [ 280-13-7 ]
  • [ 1194-02-1 ]
  • 4-[8-oxa-3-azabicyclo[3.2.1]octan-3-yl]benzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h; To a stirred solution of 4-fluorobenzonitrile (474 mg, 3.92 mmol) and 8-oxa-3- azabicyclo[3.2.1 ]octane (443 mg, 3.92 mmol) in DMF (8 ml_) is added cesium carbonate (2.55 g, 7.84 mmol). The resulting mixture is stirred for 16 h at 80 C. The resulting mixture is filtered, the filter cake is washed with methanol and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluted with PE/EtOAc (1 :1 ) to afford 4-[8-oxa-3- azabicyclo[3.2.1 ]octan-3-yl]benzonitrile as white solid; HPLC/MS [M+H]+ 215.
  • 86
  • [ 280-13-7 ]
  • 1-(bromomethyl)-3-chloro-2-methyl-5-nitrobenzene [ No CAS ]
  • 3-(3-chloro-2-methyl-5-nitrobenzyl)-8-oxa-3-azabicyclo[3.2.1]octane [ No CAS ]
  • 87
  • [ 280-13-7 ]
  • N-benzyl-2-(5-(4-(2-bromoethoxy)phenyl)pyridin-2-yl)acetamide [ No CAS ]
  • 2-(5-(4-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)ethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; potassium iodide; In N,N-dimethyl-formamide; at 50℃; Add 1 equivalent of Intermediate 6a to the reaction flask, dissolve it with sufficient DMF, add 1.5 equivalents of the corresponding amine, 4 equivalents of KI and 2 equivalents of Et3N, react overnight at 50C, and monitor the reaction by thin layer chromatography .After the reaction is completed, add water with a volume of 5 times the amount of DMF to precipitate a light brown solid, which is filtered by suction.The filter cake was washed twice with water, purified with a silica gel column, and eluted with a MeOH/DCM system to obtain the target product II-3
  • 88
  • [ 280-13-7 ]
  • N-benzyl-2-(5-(4-(3-bromopropoxy)phenyl)pyridin-2-yl)acetamide [ No CAS ]
  • 2-(5-(4-(3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)propoxy)phenyl)pyridin-2-yl)-N-benzylacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; potassium iodide; In N,N-dimethyl-formamide; at 50℃; Add 1 equivalent of Intermediate 7 to the reaction flask, dissolve it with enough DMF, add 1.5 equivalents of the corresponding amine, 4 equivalents of KI and 2 equivalents of Et3N, react overnight at 50C, and monitor the reaction by thin layer chromatography .After the reaction is completed, add water with a volume of 5 times the amount of DMF to precipitate a light brown solid, which is filtered by suction.The filter cake was washed twice with water, purified with a silica gel column, and eluted with a MeOH/DCM system to obtain the target product III-17.
  • 89
  • [ 280-13-7 ]
  • N-benzyl-2-(5-(4-(4-bromobutoxy)phenyl)pyridin-2-yl)acetamide [ No CAS ]
  • 2-(5-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)butoxy)phenyl)pyridin-2-yl)-N-benzylacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; potassium iodide; In N,N-dimethyl-formamide; at 50℃; Add 1 equivalent of Intermediate 8 to the reaction flask, dissolve it with enough DMF, add 1.5 equivalents of the corresponding amine, 4 equivalents of KI and 2 equivalents of Et3N, react overnight at 50C, and monitor the reaction by thin layer chromatography .After the reaction is completed, add water with a volume of 5 times the amount of DMF to precipitate a light brown solid, which is filtered by suction.The filter cake was washed twice with water, purified with a silica gel column, and eluted with a MeOH/DCM system to obtain the target product IV-19
  • 90
  • [ 280-13-7 ]
  • 3-(2-chloropyrimidin-4-yl)pyrazolo[1,5-b]pyridazine [ No CAS ]
  • 3-(4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane [ No CAS ]
  • 91
  • [ 280-13-7 ]
  • (+)-2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-ylamine [ No CAS ]
  • [ 1041054-15-2 ]
YieldReaction ConditionsOperation in experiment
73.8% With triethylamine; In isopropyl alcohol; at 100℃; The mixture of 8-oxa-3-aza-bicy clo [3.2.1 ]octane(226 mg, 2.0mmol), 2-chloropyrimidin-4-amine (260 mg, 2.0 mmol) and TEA (300 mg, 3.0 mmol) in IPA (5 mL) was stirred overnight at 100 C. The solvent was removed and the residue was purified by Prep-TLC (5% MeOH in DCM) to afford the title compound (300 mg, 73.8%) as yellow solid. Analytical Data: LC-MS: (ES, m/z) = 207 [M+l]
  • 92
  • [ 280-13-7 ]
  • (E)-N-(5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-2-yl)-4-ethyl-2-methylthiazole-5-carboxamide [ No CAS ]
  • C44H52N12O7S [ No CAS ]
YieldReaction ConditionsOperation in experiment
15 mg Under an ice bath, to a solution of compound 55 (100 mg, 0.12 mmol) in tetrahydrofuran (5 mL), triethylamine (36 mg, 0.36 mmol) and methanesulfonyl chloride (14 mg, 0.13 mmol) were added. The temperature was raised to room temperature and reacted for 2 h. LCMS showed that the reaction was completed. Potassium carbonate (50 mg, 0.36 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane (68 mg, 0.6 mmol) were added to the reaction solution, and the temperature was raised to 50C for reaction for 2h, and the solvent was spin-dried. The crude product was purified by preparative HPLC to obtain compound 56 (15 mg).
  • 93
  • [ 280-13-7 ]
  • 2-(1H-indol-4-yl)-6-(1-methyl-1H-pyrazol-5-yl)quinazolin-4(3H)-one [ No CAS ]
  • 3-(2-(1H-indol-4-yl)-6-(1-methyl-1H-pyrazol-5-yl)quinazolin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane [ No CAS ]
YieldReaction ConditionsOperation in experiment
18% General procedure: To a solution of intermediate 10 (0.3 g, 0.88 mmol), DMAP(10.74 mg, 0.088 mmol), TEA (178 mg, 1.76 mmol) in DMF (3 mL)were added TsCl (0.18 g, 0.97 mmol). The reaction was heated at80 C for 1 h under nitrogen protection. The corresponding amines(1.76 mmol) were added for another 2 h at 80 C. The reaction wascompleted as monitored by TLC. Posttreatment: The reaction solutionwas concentrated and purified by prep-column chromatography(petroleum ether/ethyl acetate 1:1e0:1). Compounds 11amwere afforded in 10e35% yield.
18% General procedure: To a solution of intermediate 10 (0.3 g, 0.88 mmol), DMAP(10.74 mg, 0.088 mmol), TEA (178 mg, 1.76 mmol) in DMF (3 mL)were added TsCl (0.18 g, 0.97 mmol). The reaction was heated at80 C for 1 h under nitrogen protection. The corresponding amines(1.76 mmol) were added for another 2 h at 80 C. The reaction wascompleted as monitored by TLC. Posttreatment: The reaction solutionwas concentrated and purified by prep-column chromatography(petroleum ether/ethyl acetate 1:1e0:1). Compounds 11amwere afforded in 10e35% yield.
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