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[ CAS No. 31560-06-2 ] {[proInfo.proName]}

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Chemical Structure| 31560-06-2
Chemical Structure| 31560-06-2
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Product Details of [ 31560-06-2 ]

CAS No. :31560-06-2 MDL No. :MFCD01569249
Formula : C5H10ClNO Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 135.59 Pubchem ID :-
Synonyms :

Calculated chemistry of [ 31560-06-2 ]

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 : 36.69
TPSA : 21.26 Ų

Pharmacokinetics

GI absorption : High
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) : -6.78 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 0.49
Log Po/w (WLOGP) : 0.17
Log Po/w (MLOGP) : 0.21
Log Po/w (SILICOS-IT) : 1.01
Consensus Log Po/w : 0.38

Druglikeness

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

Water Solubility

Log S (ESOL) : -0.99
Solubility : 13.9 mg/ml ; 0.102 mol/l
Class : Very soluble
Log S (Ali) : -0.51
Solubility : 42.3 mg/ml ; 0.312 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.51
Solubility : 41.8 mg/ml ; 0.308 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.75

Safety of [ 31560-06-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 31560-06-2 ]

* 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 [ 31560-06-2 ]

[ 31560-06-2 ] Synthesis Path-Downstream   1~69

  • 1
  • [ 31560-06-2 ]
  • [ 477313-07-8 ]
  • (1S,1'S,4'S)-N-{1-[3-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)phenyl]ethyl}3-phenylacrylamide [ No CAS ]
  • 2
  • [ 934989-28-3 ]
  • [ 31560-06-2 ]
  • C24H25F2NO3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
To the stirred solution of Q-2 (1.0 g) in CH2CI2 (10 mL) was added (IS, 4S)-2-oxa-5- azabicyclo[2.2.1 ]heptane HCl salt (1.23 g), DIPEA (1.58 mL) and molecular sieves (2g). After stirring for 30 minutes, Na(OAc)3BH (1.92 g) was added. The reaction suspension was stirred at room temperature overnight. After filtration, the filtrate was washed with saturated NaHCO3, brine and concentrated. The resulting residue was purified by a flash column chromatography on silica gel to give a racemic mixture of Q-3. ESI-MS calc. for C24H25F2NO3: 413; Found: 414 (M+H).
  • 3
  • [ 934989-28-3 ]
  • [ 31560-06-2 ]
  • C25H29F2NO3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
To the stirred solution of 47-2 (1.0 g) in CH2CI2 (10 mL) was added (IS, 4S)-2-oxa-5- azabicyclo[2.2.1]heptane HCl salt (1.23 g), DlPEA (1.58 mL) and molecular sieves (2g). After stirring for 30 minutes, Na(OAc)3BH (1.92 g) was added. The reaction suspension was stirred at room temperature overnight. After filtration, the filtrate was washed with saturated NaHCO3, brine and concentrated. The resulting residue was purified by a flash column chromatography on silica gel to give a racemic mixture of 47-3. ESI-MS calc. for C24H25F2NO3: 413; Found: 414 (M+H).
  • 4
  • [ 944154-58-9 ]
  • [ 31560-06-2 ]
  • [ 944154-60-3 ]
YieldReaction ConditionsOperation in experiment
70% Example 1; 9beta-13-O-[(2R,3S)-3-(tert-butyloxycarbonylamino)-2-hydroxyl-3-phenyl propionyl]-10-deacetyl-9-dihydro-9,10-O-[2-N-(2S,4S)-2-oxa-5-aza-bicyclo[2.2.1 ] hept-5-ylmethyl] baccatinIII ; [Show Image] The resulting compound from step 7, 9beta-13-O-[(2R,3S)-3-(tert-butyloxycarbonyl amino)-2-hydroxyl-3-phenylpropionyl]-10-deacetyl-9-dihydro-9,10-O-acetaldehyde baccatin H(0.545g, 0.63mmol, 1.0eq) was dissolved in 30ml anhydrous methanol in a 100ml three-neck flask to form a solution under an argon atmosphere. And then, a minor amount of drying molecular sieve (4A) and (S,S)-2-oxa-5-aza-bicyclo[2.2.1] heptane hydrochloride (0.568g, 4.16mmol, 6.6eq) were added into the solution during stirring at room temperature to form a mixture. Upon completion of the addition, the mixture was stirred for 30 minutes at room temperature. Sodium cyanoborohydride (0.261g, 4.16mmol, 6.6eq) was added into the mixture. Upon completion of the addition, the mixture was stirred for 1.5 hours at room temperature. It is shown that the starting materials are completely reacted during the reaction according to the Point-plate tracking (dichloromethane: ethyl acetate: methanol = 10:10:1). The resulting mixture was quenched with 70ml saturated sodium bicarbonate solution, extracted with ethyl acetate (100 ml.x.4) to form the organic extracts. The combined organic extracts were washed with 25ml water and 25ml saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to form a residue. The residue was purified by silica gel column chromatography with hexane: dichloromethane: ethyl acetate: methanol =20:10:10:2 as eluents firstly, then with dichloromethane: ethyl acetate: methanol =30:10:2 to provide 9beta-13-O-[(2R,3S)-3-(tert-butyloxycarbonylamino)-2-hydroxyl-3-phenylpropionyl] -10-deacetyl-9-dihydro-9,10-O-[2-N-(2S,4S)-2-Oxa-5-aza-bicyclo[2.2.1]hept-5-ylm ethyl] baccatinIII I (0.412 g, white-like solid) with a yield of 70percent. Rf=0.29(dichloromethane: ethyl acetate: methanol = 10:10:1(V/V)) MW=933, ESI-MS:[M+H]+=933.9. 1H-NMR(CD3Cl3, 400MHz): delta8.1(d, J=7.5Hz, 2H, Ar-H), 7.7-7.5(t, J=7.0Hz, 1H, Ar-H), 7.5-7.2(m, 7H), 6.1-6.0(m, 2H), 5.7-5.6(d, J=9.4Hz, 1H), 5.3(d, J=9.4Hz, 1H), 5.2(d, J=7.0Hz, 1H), 5.1(s, 1H), 5.0-4.9(b, 1H), 4.7-4.6(d, J=8.2Hz, 1H), 4.6(b, 1H), 4.4(b, 1H), 4.4-4.2(dd, AB-type, J=8.4Hz, 2H), 4.2-4.0(m, 2H), 4.0(d, J=7.9Hz, 1H), 3.8(d, J=7.1Hz, 1H), 3.7-3.6(d, J=7.8Hz, 1H), 3.6(b, 1H), 3.1-3.0(m, 2H), 3.0-2.9(m, 1H), 2.9(d, J=4.7Hz, 1H), 2.7(m, J=10.2Hz, 1H), 2.4(dd, J=9.7Hz, J'=14.6Hz, 1H), 2.3(s, 3H, CH3), 2.3-2.2(m, 1H), 2.2-2.0(m, 2H), 1.9(b, 1H), 1.9-1.8(m, 1H), 1.8-1.7(m, 1H), 1.65(s, 3H, CH3), 1.60(s, 3H, CH3), 1.55(s, 3H, CH3), 1.4(s, 9H, t-Bu), 1.3(s, 3H, CH3).
  • 5
  • [ 1075757-45-7 ]
  • [ 31560-06-2 ]
  • 5-fluoro-N4-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-N2-(5-methoxy-1H-pyrazol-3-yl)-6-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)pyrimidine-2,4-diamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
30% With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 150℃; for 4h;Microwave irradiation; Example 85-Fluoro-N4-r(y)-l-(5-fluoro-pyridin-2-yl)-ethyl1-N2-(5-methoxy-lH-pyrazol-3-yl)-6-(2-oxa-5- aza-bicvclo[2.2.11hept-5-yl)-pyrimidine-2,4-diamineA mixture of 6-chloro-5-fluoro-lambda^-[(S)-l-(5-fluoro-pyridin-2-yl)-ethyl]-N -(5-methoxy-lH- pyrazol-3-yl)-pyrimidine-2,4-diamine (Example 7, 70mg, 0.18 mmol), (l1S',41S)-2-oxa-5-aza- bicyclo[2.2.1]heptane hydrochloride (40mg, 0.3 mmol) and DIPEA (0.088ml, 0.5 mmol) in n- BuOH (0.8 ml) was heated in a microwave reactor at 1500C for 4 hours. Evaporation of the solvents under reduced pressure gave a residue. This residue was purified by silica gel chromatography (ISCO, DCMZMeOHZNH4OH: IOOZOZO tol00Z4Z0.4) to afford the title compound (24mg, 30percent). 1H NMR (CDCl3) delta 8.40 (s, IH), 7.37 (m, IH), 7.28 (m, IH), 5.96 (m, IH), 5.26 (m, IH), 5.10 (s, IH), 4.86 (br, IH), 4.59(s, IH), 3.85 (s, 3H), 3.80 (m, 2H), 3.46 (m, 3H), 1.83 (s, 2H), 1.54 (d, 3H). LCMS: 445 [M+H].
  • 6
  • [ 1108184-21-9 ]
  • [ 31560-06-2 ]
  • [ 1108184-22-0 ]
YieldReaction ConditionsOperation in experiment
39% With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 90℃; for 19h; 5-Bromo-1-(2-chloroethyl)-1H-indazole (183 mg, 0.703 mmol) was added to a suspension of <strong>[31560-06-2](1S,4S)-(+)-5-aza-2-oxabicyclo[2.2.1]heptane hydrochloride</strong> (286 mg, 2.11 mmol), K2CO3 (485 mg, 3.52 mmol) and KI (117 mg, 0.703 mmol) in DMF (10 mL) under N2. The resulting suspension was stirred at 90° C. for 19 h. The suspension was cooled, and H2O (10 mL) was added. The aqueous solution was extracted with EtOAc, and the combined organic extracts were washed with brine. The organic solution was dried over Na2SO4 and concentrated under reduced pressure to afford clear viscous oil. Flash chromatography on silica gel (100:0 to 0:100 hexanes/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH)) gave the title compound (88 mg, 39percent) as a clear oil: 1H NMR (300 MHz, CDCl3) delta 7.95-7.92 (m, 1H), 7.87-7.84 (m, 1H), 7.45 (dd, J=8.7, 1.8 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 4.43 (t, J=6.7 Hz, 2H), 4.34 (br s, 1H), 3.92 (d, J=7.8 Hz, 1H), 3.56 (dd, J=7.8, 1.5 Hz, 1H), 3.34 (br s, 1H), 3.15-3.01 (m, 2H), 2.92 (d, J=21.9 Hz, 1H), 2.81 (dd, J=9.9, 1.5 Hz, 1H), 2.47 (br d, J=9.9 Hz, 1H), 1.79-1.60 (m, 1H).
  • 7
  • [ 1195778-76-7 ]
  • [ 31560-06-2 ]
  • [ 1195779-88-4 ]
YieldReaction ConditionsOperation in experiment
73% With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In N,N-dimethyl-formamide; for 1h; 7H-Indolo[2,1-a][2]benzazepine-10-carboxamide, 6-[1-cyclobutyl-4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)carbonyl-1H-pyrazol-5-yl]-13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]- A 2 dram vial was charged with 1H-pyrazole-4-carboxylic acid, 1-cyclobutyl-5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-(70 mg, 0.107 mmol), DMF (1 mL), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane, HCl (28.9 mg, 0.213 mmol), 4-methylmorpholine (0.035 mL, 0.320 mmol) and o-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (37.6 mg, 0.117 mmol). The rxn was stirred for 1 hour. It was diluted with ether, washed with saturated ammonium chloride then brine, dried (MgSO4) and evaporated giving a yellow foam. The foam was dissolved in DCM, the solution was added to a Thompson silica gel cartridge and it was eluted with ethyl acetate/methanol (0percent to 10percent). The appropriate fractions (TLC) were combined and evaporated giving a light yellow film. The film was dissolved in DCM, re-evaporated, the residue triturated in hexane/ether (5percent) and filtered giving the product (58 mg, 0.078 mmol, 73.0percent yield) as light a yellow powder. HPLC: 99.9percent pure, 22.39 minutes. LCMS: 738.26 at 3.96 minutes, mp: 164-166° C. HRMS: calculate-738.3820, found-738.382.
  • 8
  • [ 1195782-58-1 ]
  • [ 31560-06-2 ]
  • [ 1195780-46-1 ]
YieldReaction ConditionsOperation in experiment
64.8% With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In N,N-dimethyl-formamide; 7H-Indolo[2,1-a][2]benzazepine-10-carboxamide, 6-[1-cyclobutyl-3-methyl-4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylcarbonyl)-1H-pyrazol-5-yl]-13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]- A 2 dram vial was charged with 1H-pyrazole-4-carboxylic acid-5-methyl, 1-cyclobutyl-5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-(70 mg, 0.104 mmol), DMF (1 mL), 4-methylmorpholine (0.023 mL, 0.209 mmol), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane, HCl (16.98 mg, 0.125 mmol) and o-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (36.9 mg, 0.115 mmol). The rxn was stirred over night. The rxn was diluted with DCM, washed with 0.1 N HCl (aqueous) then brine, dried (MgSO4) and evaporated giving a yellow syrup. The syrup was dissolved in DCM, the solution was added to a Thompson silica gel cartridge and it was eluted with DCM/methanol (0percent to 4percent). The appropriate fractions (TLC) were combined and evaporated giving a light yellow solid. The solid was triturated in ether/hexane and filtered giving the product (53 mg, 0.068 mmol, 64.8percent yield) as a creamy white powder. HPLC: 96.0percent pure, 24.07 minutes. LCMS: 752.20 at 3.83 minutes. LCMS neg/pos: 750.2/752.1 at 2.51 minutes. 1H NMR: (400 Mz, CD3OD) delta 1.18-1.24 (m, 2H), 1.41 (m, 5H), 1.53 (s, 2H), 1.78-1.80 (m, 3H), 1.95 (bs, 3H), 2.05 (m, 3H), 2.31 (s, 3H), 2.47-2.50 (m, 1H), 2.67-2.76 (m, 1H), 2.81 (s, 3 h), 2.87 (s, 3H), 2.94 (s, 2H), 3.31-3.38 (m, 1H), 3.84-3.89 (m, 1H), 3.95 (m, 3H), 4.03-4.12 (m, 2H), 4.55-4.58 (d, J=14 Hz, 1H), 4.82-4.85 (d, J=14 Hz, 2H), 6.71-6.83 (m, 1H), 6.93-6.96 (m, 1H), 7.11-7.12 (d, J=8 Hz, 1H), 7.54-7.72 (m, 3H), 7.86-7.95 (m, 1H) 10.99 (bs, 1H).
  • 9
  • [ 1223404-88-3 ]
  • [ 31560-06-2 ]
  • [ 530-62-1 ]
  • [ 1223404-67-8 ]
YieldReaction ConditionsOperation in experiment
86% Example 92; (lS.4S)-N-(5-((R)-2-(2.5-difluorophenvnpyrrolidin-l-vnpyrazolori.5-alpyrimidin-3- vD-Sigma-oxa-S-azabicvclo^^.?heptane-S-carboxamide; [00515] To a DCM (1.0 niL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l- yl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 50 mg, 0.16 mmol) was added CDI (51 mg, 0.32 mmol) at ambient temperature in one portion. After stirring 90 minutes, (lS,4S)-2- oxa-5-azabicyclo[2.2.1]heptane hydrochloride (43 mg, 0.32 mmol) was added in one portion, followed by DIEA (0.083 mL, 0.48 mmol). The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 60% acetonitrile/water to yield the final product as a pale-yellowish powder (60 mg, 86% yield). MS (apci) m/z = 441.2 (M+H).
  • 10
  • [ 1000295-82-8 ]
  • [ 31560-06-2 ]
  • {3-[4-(2-chloro-6-fluoro-phenyl)-piperidin-1-ylmethyl]-1H-indol-2-yl}-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example 9; {3-[4-(2-Chloro-6-fluoro-phenyl)-piperidin-1-ylmethyl]-1 H-indol-2-yl}-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-methanone; To a suspension of 204 mg (0.492 mmol) of 3-[4-(2-chloro-6-fluoro-phenyl)- piperidin-1 -ylmethyl]-1 H-indole-2-carboxylic acid ethyl ester (obtained as described in General Preparation 2) in EtOH (2.5 ml_), 1 ml_ of 1 N sodium hydroxide solution was added and the mixture was stirred at 80 °C for 2 h. The solvent was evaporated under reduced pressure and the pale yellow solid obtained (199 mg) was suspended in SOCI2 (2 ml_) and the reaction mixture was stirred at 50 °C for 2 h. Excess SOCI2 was evaporated under reduced pressure and the light brown solid obtained was suspended in dry DMF (1 ml_) and added dropwise at 0°C to a solution of (1 S,4S)-2-Oxa-5-aza-bicyclo[2.2.1 ]heptane hydrochloride (133 mg, 0.98 mmol) and thethylamine (0.34 ml_, 2.45 mmol) in CH2CI2 (3 ml_). The mixture was stirred at room temperature overnight, then it was washed with water (2x5 ml_) and with 1 N NaOH solution (2x5 ml_). Organic layers were collected, dried over Na2SO4 and evaporated under reduced pressure. The crude product obtained was purified by flash chromatography (CH2CI2/MeOH/NH4OH 96:3.5:0.5 to 93:6:1 respectively) yielding 25 mg of the title compound. NMR (300 MHz, CDCI3, delta ppm): 1 1.52 (s br, 1 H); 7.72 (d, 1 H); 7.60 (d br, 1 H); 7.24 (dd, 1 H); 7.13-7.05 (m, 3H); 6.91 (m, 1 H); 4.86 (m, 1 H); 4.62 (m, 1 H); 4.36- 4.05 (m, 2H); 4.00 (d, 1 H); 3.79 (m, 1 H); 3.57 (m, 1 H); 3.26 (m, 3H); 2.88-2.22 (m, 3H); 2.05 (m, 1 H); 1.90 (m, 1 H); 1.77 (m, 4H). ESI Pos, 3.2KV, 20V, 400°C MS (m/z): 468.04 (MH+).
  • 11
  • [ 31560-06-2 ]
  • [ 590-17-0 ]
  • [ 1319197-37-9 ]
YieldReaction ConditionsOperation in experiment
Bromoacetonitrile (0.208 mL, 3.12 mmol) was added to a slurry of (lS,4S)-2-oxa- 5-azabicyclo[2.2.1]heptane hydrochloride (0.353 g, 2.60 mmol) , DMSO (13 mL) and MP-carbonate (3.17 mmol/g, 2.5X, 6.5 mmol, 2.05 g). After shaking overnight, 0.52 mmol trisamine (4.17 mmol/g, 125 mg) was added, and the slurry was shaken for an additional 2 h. The slurry was filtered and the resulting 2-((lS,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)acetonitrile/DMSO solution was used directly in the next step.
  • 12
  • [ 31560-06-2 ]
  • [ 1319194-80-3 ]
  • 13
  • [ 1354947-81-1 ]
  • [ 31560-06-2 ]
  • [ 1354947-82-2 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 140℃; for 0.333333h;Microwave irradiation; Intermediate 32: 3-{5-[(1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]-1 H- tetrazol-1-yl}-5-(trifluoromethyl)benzamide; To a solution of 3-[5-(chloromethyl)-1 H-tetrazol-1 -yl]-5-(trifluoromethyl)benzamide (Intermediate 31 , 300mg, 0.982 mmol) in acetonitrile (0.5 mL) was added (1S,4S)-2- oxa-5-azabicyclo[2.2.1]heptane hydrochloride (160 mg, 1.18mmol) and di- idopropylethylamine (0.377 mL, 2.16 mmol). The reaction was heated to 140°C for 20 minutes in a microwave reactor.The reaction was cooled and the solvent removed under vacuum. The reaction was partitioned between water (5mL) and ethyl acetate (10mL). The organic layer was collected, passed through a hydrophobic frit and the solvent removed under vacuum to yield the title compound as a yellow gum 356mg.MS ES+ve m/z 369 (M+H)1H NMR (400 MHz, DMSO-cfe) delta ppm 1.52 - 1.59 (m, 1 H) 1.59 - 1 .66 (m, 1 H) 2.46 (d, J=9.9 Hz, 1 H) 2.67 (dd, J=10.0, 1.6 Hz, 1 H) 3.39 (s, 1 H) 3.48 (dd, J=7.7, 1.8 Hz, 1 H) 3.70 (d, J=7.7 Hz, 1 H) 4.10 (d, J=14.5 Hz, 1 H) 4.17 (d, J=14.5 Hz, 1 H) 4.33 (s, 1 H) 7.84 (s, 1 H) 8.41 (br. s., 1 H) 8.45 (s, 1 H) 8.52 (s, 1 H) 8.59 (s, 1 H)
  • 14
  • [ 1367874-84-7 ]
  • [ 31560-06-2 ]
  • [ 1367875-31-7 ]
YieldReaction ConditionsOperation in experiment
With potassium tert-butylate;chloro(2-dicyclohexylphosphino-2?,6?-diisopropoxy-1,1?-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II); ruphos; In 1,4-dioxane; at 130℃; for 0.5h;Microwave irradiation; Example 112( 1S, 4S)-5-(4-(4-(Tetrahydro-2H-pyran-4-yloxy)- 1H-pyrazolo[4, 3-c]pyridin-3-yl)pyridin-2-yl)-2-Step 1(1 S, 4S)-5-(4-(4-(Tetrahydro-2H-pyran-4-yloxy)-1-trityl- 1 H-pyrazolo[4, 3-c]pyridin-3-yl)pyridin-2- yl)-2-oxa-5-azabicyclo[2.2.1 JheptaneTo a microwave vial was added 3-(2-chloropyridin-4-yl)-4-(tetrahydro-2 -/-pyran-4-yloxy)-1-trityl- 1H-pyrazolo[4,3-c]pyridine (0.0823 g, 0.144 mmol), (1 S,4S)-2-oxa-5- azoniabicyclo[2.2.1]heptane chloride (0.0234 g, 0.172 mmol), RuPhos palladiumphenethylamine chloride (0.0073 g, 0.010 mmol), RuPhos (0.0047 g, 0.010 mmol) and sodium ferf-butoxide (0.0331 g, 0.344 mmol). 1 ,4-dioxane (1.6 mL, 20 mmol) was added and the reaction mixture was degassed for 5 minutes. The vial was capped and heated to 130 °C for 30 minutes under microwave irradiation. Upon reaction completion, the reaction mixture was diluted with methylene chloride and filtered through celite, eluting with methylene chloride and concentrated in vacuo to give the title compound
  • 15
  • [ 1263868-30-9 ]
  • [ 31560-06-2 ]
  • [ 1263868-46-7 ]
YieldReaction ConditionsOperation in experiment
60.6% With N-ethyl-N,N-diisopropylamine; In methanol; at 20℃; Preparation Hb(lS,4S)-5-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2- oxa-5-azabicyclo[2.2. ljheptaneTo a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine (Preparation H) (200 mg, 0.706 mmol) in MeOH (7064 muEpsilon) was added (l S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptane monohydrochloride (1 15 mg, 0.848 mmol) and DIPEA (271 mu, 1.554 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was then concentrated in vacuo. The resulting oil was purified by flash chromatography (Silica, EtOAc/Hexanes) to give (lS,4S)-5-(2-chloro-7- (4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-oxa-5- azabicyclo[2.2.1]heptane (148 mg, 0.428 mmol, 60.6 percent yield). LC-MS (M+H)+ = 346.1. 3/4 NMR (500 MHz, MeOD) delta ppm 7.12 - 7.21 (2 H, m), 7.00 - 7.08 (2 H, m), 5.11 - 5.21 (1 H, m), 4.69 - 4.74 (1 H, m), 4.15 - 4.26 (1 H, m), 3.88 - 3.94 (2 H, m), 3.68 - 3.86 (2 H, m), 3.11 - 3.21 (1 H, m), 2.56 - 2.69 (1 H, m), 1.92 - 2.11 (2 H, m), 1.24 - 1.42 (2 H, m).
  • 16
  • [ 31560-06-2 ]
  • [ 107-04-0 ]
  • (1S,4S)-5-(2-chloroethyl)-2-oxa-5-azabicyclo[2.2.1]heptane [ No CAS ]
YieldReaction ConditionsOperation in experiment
19.48% With caesium carbonate; In tetrahydrofuran; at 50℃; for 19h;Inert atmosphere; Step 1. Preparation of (1S,4S)-5-(2-chloroethyl)-2-oxa-5-azabicyclo[2.2.1]heptane [0432] (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane, HCl (0.5 g, 3.69 mmol) and cesium carbonate (4.25 g, 12.91 mmol) was dried in a vacuum oven at 50° C. for 20 mins and the flask was back filled with a N2(g). THF (45 mL) was added to the mixture, followed by 1-bromo-2-chloroethane (0.936 mL, 11.06 mmol). The resulting slurry was stirred at 50° C. for 19 h. Then, the excess cesium carbonate was filtered and washed with EtOAc (2×25 mL). The liquid filtrate was concentrated and the light yellow crude was purified by flash column chromatography (SiO2, 25 g, eluted with 95:5 DCM:MeOH) and dried under reduced pressure briefly to give (1S,4S)-5-(2-chloroethyl)-2-oxa-5-azabicyclo[2.2.1]heptane (129 mg, 19.48percent yield) as clear viscous oil. 1H NMR (400 MHz, CHLOROFORM-d) delta 4.33 (s, 1H), 3.93 (d, J=8.1 Hz, 1H), 3.57 (dd, J=8.1, 1.7 Hz, 1H), 3.46 (d, J=6.8 Hz, 3H), 2.92 (dd, J=10.1, 1.6 Hz, 1H), 2.90-2.79 (m, 2H), 2.50 (dd, J=9.8, 1.0 Hz, 1H), 1.79 (dd, J=9.8, 2.0 Hz, 1H), 1.71-1.63 (m, 1H). 13C NMR (101 MHz, CHLOROFORM-d) delta 76.6, 69.1, 61.8, 61.0, 55.5, 42.8, 35.6.
  • 17
  • [ 31560-06-2 ]
  • 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid dihydrochloride [ No CAS ]
  • 18
  • [ 1392314-82-7 ]
  • [ 31560-06-2 ]
  • methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
32.4% With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 100℃; for 68h;Inert atmosphere; Molecular sieve; Step 1. Preparation of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate [0482] Methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (200 mg, 0.351 mmol), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane, HCl (238 mg, 1.755 mmol), and 4° A molecular sieves (250 mg, 0.351 mmol) were combined in a 20 mL scintillation vial. The mixture was dried in a 50° C. vacuum oven for 1 h. THF (5 mL) and N,N-diisopropylethylamine (0.428 mL, 2.457 mmol) were added. The solution was purged with N2(g) and stirred at 100° C. After 68 h, reaction was concentrated to a viscous brown oil which was purified by reverse phase HPLC using HPLC method 6 and dried under vacuum to give the title compound (104 mg, 0.114 mmol, 32.4percent yield) as a white solid. LC/MS: m/e 669.5 (M+H)+, 4.42 min (method 8). 1H NMR (400MHz, CHLOROFORM-d) delta 7.91 (d, J=8.1 Hz, 2H), 7.18 (d, J=8.1 Hz, 2H), 5.28 (d, J=4.9 Hz, 1H), 4.78 (s, 1H), 4.69 (s, 1H), 4.64 (br. s., 1H), 4.28 (br. s., 1H), 4.17 (d, J=9.8 Hz, 1H), 3.90 (s, 3H), 3.79 (d, J=9.5 Hz, 1H), 3.74-3.61 (m, 1H), 3.44 (br. s., 2H), 3.36 (br. s., 1H), 2.77 (d, J=6.8 Hz, 1H), 2.27-1.99 (m, 6H), 1.98-1.83 (m, 2H), 1.77 (d, J=12.2 Hz, 1H), 1.69 (s, 3H), 1.66-1.61 (m, 1H), 1.59-1.30 (m, 13H), 1.21 (d, J=6.4 Hz, 1H), 1.10 (s, 3H), 1.04 (s, 3H), 0.98 (s, 3H), 0.93 (s, 6H). 13C NMR (101MHz, CHLOROFORM-d) delta 167.2, 148.5, 146.8, 146.2, 130.0, 128.5, 127.9, 123.8, 111.9 (br. s., 1C), 74.9, 73.1 (br. s., 1C), 64.3 (br. s., 1C), 61.3 (br. s., 1C), 54.1, 52.8, 51.9, 49.3, 49.0, 45.4, 42.0, 41.7, 40.7, 38.8 (br. s., 1C), 37.4, 37.3, 36.2, 33.5, 32.5, 29.4, 28.0, 27.5, 26.3, 25.0, 20.9, 20.8, 19.6, 18.8, 18.4, 17.2, 16.4, 15.4, 14.5, 11.8.
  • 19
  • [ 1449661-96-4 ]
  • [ 31560-06-2 ]
  • (R)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
62.8% With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 100℃; for 70h;Molecular sieve; Step 1. Preparation of (R)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate, 2 TFA [0526] (R)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5 a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (50 mg, 0.077 mmol), 4° A mol. sieves (100 mg, 0.077 mmol) and N,N-diisopropylethyl amine (0.094 mL, 0.538 mmol) in THF (2 mL) was added (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane, HCl (52.2 mg, 0.385 mmol). The reaction was stirred at 100° C. After 70 h, the reaction was cooled to rt, purified by prep-HPLC using prep-HPLC method 15 and dried under vacuum at 50° C. to give the title compound (47.2 mg, 0.048 mmol, 62.8percent yield) as a white solid. LC/MS: m/e 749.6 (M+H)+, 4.62 min (method 9). 1H NMR (400 MHz, CHLOROFORM-d) delta 7.75-7.44 (m, 2H), 7.43-7.29 (m, 5H), 5.35 (br. s., 1H), 5.17 (d, J=4.6 Hz, 1H), 5.14 (s, 2H), 4.78 (s, 1H), 4.69 (s, 1H), 4.65 (br. s., 1H), 4.27 (br. s., 1H), 4.18 (d, J=10.3 Hz, 1H), 3.81 (d, J=9.8 Hz, 1H), 3.71 (d, J=16.1 Hz, 2H), 3.51-3.28 (m, 3H), 2.81-2.67 (m, 1H), 2.65-2.54 (m, 1H), 2.34 (br. s., 2H), 2.26-2.10 (m, 4H), 2.10-1.80 (m, 6H), 1.79-1.71 (m, 2H), 1.69 (s, 3H), 1.64-1.23 (m, 12H), 1.07 (s, 3H), 1.01 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.86 (s, 3H).
  • 20
  • [ 1449662-03-6 ]
  • [ 31560-06-2 ]
  • (S)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
37.1% With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 100℃; for 70h;Molecular sieve; Step 1. Preparation of (S)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a- ((2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate [0529] (S)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (50 mg, 0.077 mmol), 4° A mol. sieves (100 mg, 0.077 mmol) and N,N-diisopropylethylamine (0.094 mL, 0.538 mmol) in THF (2 mL) was added (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane, HCl (52.2 mg, 0.385 mmol). The reaction mixture was stirred at 100° C. After 70 h, the reaction was cooled to rt, purified by prep-HPLC using prep-HPLC method 15 and dried under vacuum at 50° C. to give the title compound (27.9 mg, 0.029 mmol, 37.1percent yield) as a white solid. LC/MS: m/e 749.6 (M+H)+, 4.65 min (method 9). 1H NMR (400 MHz, CHLOROFORM-d) delta 7.90 (br. s., 3H), 7.44-7.29 (m, 5H), 5.35 (br. s., 1H), 5.20-5.09 (m, 3H), 4.78 (br. s., 1H), 4.67 (d, J=18.1 Hz, 2H), 4.27 (br. s., 1H), 4.18 (d, J=10.0 Hz, 1H), 3.81 (d, J=9.8 Hz, 1H), 3.71 (d, J=19.8 Hz, 2H), 3.53-3.26 (m, 4H), 2.87-2.67 (m, 1H), 2.64-2.51 (m, 1H), 2.34 (br. s., 2H), 2.15 (br. s., 5H), 2.07-1.89 (m, 5H), 1.88-1.72 (m, 3H), 1.69 (s, 3H), 1.63-1.21 (m, 13H), 1.07 (br. s., 3H), 1.01 (s, 3H), 0.96 (s, 3H), 0.89 (s, 3H), 0.86 (s, 3H).
  • 21
  • [ 1260585-11-2 ]
  • [ 31560-06-2 ]
  • (2S)-8-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-(trifluoromethyl)-1,2,3,4-tetrahydropyrimido[1,2-a]pyrimidin-6-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.2 g With triethylamine; at 130℃; for 6h;Sealed tube; 1.60 g (6.31 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 1.30 g (9.46 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 2.21 mL (15.77 mmol) of triethylamine are added. The tube is sealed and heated at 130°C in an oil bath for 6 hours. After cooling, the crude product is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH). After evaporating the fractions under reduced pressure, 1.20 g of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows: LC/MS (method G): ESI+: [M+H]+: m/z 317 tr (min) = 1.37. 1H NMR (300 MHz, delta in ppm, CDCl3): 2 (m, 2H), 2.35 (m, 2H), 3.45 (m, 2H), 3.92 (s, 1 H), 3.95-4.32 (m, 4H), 4.78 (s, 1 H), 4.89-5.2 (bs, 1 H), 5.49-5.77 (bs, 1 H).
1.20 g With triethylamine; at 130℃; for 6h;Sealed tube; 1.60 g (6.31 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 1.30 g (9.46 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 2.21 mL (15.77 mmol) of triethylamine are added. The tube is sealed and heated at 130° C. in an oil bath for 6 hours. After cooling, the crude product is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH). After evaporating the fractions under reduced pressure, 1.20 g of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows: LC/MS (method G): ESI+: [M+H]+: m/z 317 tr (min)=1.37 1H NMR (300 MHz, delta in ppm, CDCl3): 2 (m, 2H), 2.35 (m, 2H), 3.45 (m, 2H), 3.92 (s, 1H), 3.95-4.32 (m, 4H), 4.78 (s, 1H), 4.89-5.2 (bs, 1H), 5.49-5.77 (bs, 1H).
  • 22
  • (8S)-2-chloro-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one [ No CAS ]
  • [ 31560-06-2 ]
  • (8S)-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; at 130℃; for 6h;Sealed tube; 200 mg (0.51 mmol) of (8S)-2-chloro-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 83.28 mg (0.61 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 178 mul (1 .28 mmol) of triethylamine are added. The tube is sealed and heated at 130°C in an oil bath for 6 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 130 mg of (8S)-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-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 454 tr (min) = 0.58. 1H NMR (300 MHz, delta in ppm, CDCl3): 2.44 (s, 2H), 2.7 (s, 3H), 3.46 (m, 1 H), 4 (m, 2H), 4.54 (m, 1 H), 5.23 (s, 3H), 5.53 (d, 1 H), 5.92 (s, 1 H).
130 mg With triethylamine; at 130℃; for 6h;Sealed tube; 200 mg (0.51 mmol) of (8S)-2-chloro-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 83.28 mg (0.61 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 178 mul (1.28 mmol) of triethylamine are added. The tube is sealed and heated at 130° C. in an oil bath for 6 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 130 mg of (8S)-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-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 454 tr (min)=0.58 1H NMR (300 MHz, delta in ppm, CDCl3): 2.44 (s, 2H), 2.7 (s, 3H), 3.46 (m, 1H), 4 (m, 2H), 4.54 (m, 1H), 5.23 (s, 3H), 5.53 (d, 1H), 5.92 (s, 1H).
  • 23
  • (8S)-2-chloro-9-(3-methyl-2-oxobutyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one [ No CAS ]
  • [ 31560-06-2 ]
  • (8S)-9-(3-methyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
100 mg With triethylamine; at 130℃; for 3h;Sealed tube; 220 mg (0.51 mmol) of (8S)-2-chloro-9-(3-methyl-2-oxobutyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 105.99 mg (0.78 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 227 mul (1.63 mmol) of triethylamine are added. The tube is sealed and heated at 130 °C in an oil bath for 3 hours. The crude product obtained is taken up in ethyl acetate and the organic phase is washed with water, dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 100 mg of (8S)-9-(3-methyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-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 401 tr (min) = 0.6. 1H NMR (600 MHz, delta in ppm, DMSO-d6): 1.02 (m, 6H), 1.79 (m, 2H), 2.16 (m, 1 H), 2.37 (m, 1 H), 2.68 (m, 1 H), 2.84-3.26 (bs, 3H), 3.30-3.75 (bs, 2H), 4.18 (d, 1 H), 4.30 (m, 1 H), 4.46 (m, 1 H), 4.60 (s, 1 H), 4.63-4.96 (bs, 2H), 5 (m, 1 H).
100 mg With triethylamine; at 130℃; for 3h;Sealed tube; 220 mg (0.51 mmol) of (8S)-2-chloro-9-(3-methyl-2-oxobutyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 105.99 mg (0.78 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 227 mul (1.63 mmol) of triethylamine are added. The tube is sealed and heated at 130° C. in an oil bath for 3 hours. The crude product obtained is taken up in ethyl acetate and the organic phase is washed with water, dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 100 mg of (8S)-9-(3-methyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-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 401 tr (min)=0.6 1H NMR (600 MHz, delta in ppm, DMSO-d6): 1.02 (m, 6H), 1.79 (m, 2H), 2.16 (m, 1H), 2.37 (m, 1H), 2.68 (m, 1H), 2.84-3.26 (bs, 3H), 3.30-3.75 (bs, 2H), 4.18 (d, 1H), 4.30 (m, 1H), 4.46 (m, 1H), 4.60 (s, 1H), 4.63-4.96 (bs, 2H), 5 (m, 1H).
  • 24
  • (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 ]
  • [ 31560-06-2 ]
  • (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
980 mg With triethylamine; at 130℃; for 6h;Sealed tube; 1 g (2.68 mmol) of (8S)-2-chloro-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 545.67 mg (4.02 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 934.86 mul (6.71 mmol) of triethylamine are added. The tube is sealed and heated at 130 °C in an oil bath for 6 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 980 mg of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-3-ylethyl)-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 436 tr (min) = 0.51. 1H NMR (600 MHz, delta in ppm, DMSO-d6): 1.67 (d, 1 H), 1.75 (d, 1 H), 2.32 (m, 1 H), 2.5 (m, 1 H), 3.04 (d, 1 H), 3.17-3.25 (bs, 1 H), 3.25-3.4 (bs, 3H), 4.44 (dd, 1 H), 4.48 (s, 1 H), 4.52 (s, 1 H), 4.66 (m, 1 H), 4.72 (s, 1 H), 4.77 (d, 1 H), 5.7 (d, 1 H), 7.64 (m, 1 H), 8.41 (m, 11-1) 8.88 (m, 1 H), 9.24 (s, 1 H).
980 mg With triethylamine; at 130℃; for 6h;Sealed tube; 1 g (2.68 mmol) of (8S)-2-chloro-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 545.67 mg (4.02 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 934.86 mul (6.71 mmol) of triethylamine are added. The tube is sealed and heated at 130° C. in an oil bath for 6 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 980 mg of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-3-ylethyl)-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 436 tr (min)=0.51 1H NMR (600 MHz, delta in ppm, DMSO-d6): 1.67 (d, 1H), 1.75 (d, 1H), 2.32 (m, 1H), 2.5 (m, 1H), 3.04 (d, 1H), 3.17-3.25 (bs, 1H), 3.25-3.4 (bs, 3H), 4.44 (dd, 1H), 4.48 (s, 1H), 4.52 (s, 1H), 4.66 (m, 1H), 4.72 (s, 1H), 4.77 (d, 1H), 5.7 (d, 1H), 7.64 (m, 1H), 8.41 (m, 1H) 8.88 (m, 1H), 9.24 (s, 1H).
  • 25
  • [ 1260983-01-4 ]
  • [ 31560-06-2 ]
  • 2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1] hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
750 mg With triethylamine; at 140℃; for 4h;Sealed tube; 1 g (3.84 mmol) of (S)-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one and 844.18 mg (5.91 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 1.38 mL (9.86 mmol) of triethylamine are added. The tube is sealed and heated at 140 °C in an oil bath for 4 hours. After cooling, the crude product is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH). After evaporating the fractions under reduced pressure, 750 mg of 2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one are obtained, the characteristics of which are as follows: LC/MS (method G): ESI+: [M+H]+: m/z 317. tr (min) =1.34. 1H NMR (300 MHz, delta in ppm, CDCl3): 1 .34 (s, 3H), 1 .65 (m, 2H), 3.13 (m, 2H), 3.43 (m, 1 H), 3.53 (m, 1 H), 3.72 (d, 1 H), 3.89 (d, 1 H), 4.1-4.81 (bs, 3H), 8.77 (s, 1 H).
750 mg With triethylamine; at 140℃; for 4h;Sealed tube; 1 g (3.84 mmol) of (S)-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one and 844.18 mg (5.91 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 1.38 mL (9.86 mmol) of triethylamine are added. The tube is sealed and heated at 140° C. in an oil bath for 4 hours. After cooling, the crude product is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH). After evaporating the fractions under reduced pressure, 750 mg of 2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one are obtained, the characteristics of which are as follows: LC/MS (method G): ESI+: [M+H]+: m/z 317 tr (min)=1.34 1H NMR (300 MHz, delta in ppm, CDCl3): 1.34 (s, 3H), 1.65 (m, 2H), 3.13 (m, 2H), 3.43 (m, 1H), 3.53 (m, 1H), 3.72 (d, 1H), 3.89 (d, 1H), 4.1-4.81 (bs, 3H), 8.77 (s, 1H).
  • 26
  • (8S)-2-chloro-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one [ No CAS ]
  • [ 31560-06-2 ]
  • (8S)-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
120 mg With triethylamine; at 130℃; for 3h;Sealed tube; 170 mg (0.511 mmol) of (8S)-2-chloro-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 70.42 mg (0.52 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 151 muIota (1 .08 mmol) of triethylamine are added. The tube is sealed and heated at 130°C in an oil bath for 3 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 120 mg of (8S)-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-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 456. tr (min) = 0.55. 1H NMR (600 MHz, delta in ppm, DMSO-d6): 1.69 (m, 2H), 2.28 (m, 1 H), 2.43 (m, 1 H), 2.7 (s, 3H), 2.98 (d, 1 H), 3.12 (d, 1 H), 3.21-3.33 (m, 3H), 4.37 (m, 1 H), 4.42 (s, 1 H), 4.5 (s, 1 H), 4.55-4.62 (m, 2H), 4.67 (s, 1 H), 5.22 (d, 1 H), 9.19 (s, 1 H).
120 mg With triethylamine; at 130℃; for 3h;Sealed tube; 170 mg (0.511 mmol) of (8S)-2-chloro-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 70.42 mg (0.52 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 151 mul (1.08 mmol) of triethylamine are added. The tube is sealed and heated at 130° C. in an oil bath for 3 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 120 mg of (8S)-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-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 456 tr (min)=0.55 1H NMR (600 MHz, delta in ppm, DMSO-d6): 1.69 (m, 2H), 2.28 (m, 1H), 2.43 (m, 1H), 2.7 (s, 3H), 2.98 (d, 1H), 3.12 (d, 1H), 3.21-3.33 (m, 3H), 4.37 (m, 1H), 4.42 (s, 1H), 4.5 (s, 1H), 4.55-4.62 (m, 2H), 4.67 (s, 1H), 5.22 (d, 1H), 9.19 (s, 1H).
  • 27
  • (8S)-2-chloro-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one [ No CAS ]
  • [ 31560-06-2 ]
  • (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
220 mg With triethylamine; at 130℃; for 3h;Sealed tube; 220 mg (0.58 mmol) of (8S)-2-chloro-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 94.26 mg (0.69 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 202 mul (1 .45 mmol) of triethylamine are added. The tube is sealed and heated at 130 °C in an oil bath for 3 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 220 mg of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-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 443. tr (min) = 0.52. 1H NMR (600 MHz, delta in ppm, DMSO-d6): 1.49 (m, 1 H), 1 .52 (m, 1 H), 1.7 (m, 2H), 1.79 (bs, 2H), 2.15 (m, 1 H), 2.36 (m, 1 H), 2.7 (m, 1 H), 2.84-3.25 (bs, 3H), 3.31-3.59 (bs, 3H), 3.65 (d, 1 H), 3.86 (m, 2H), 4.17 (d, 1 H), 4.3 (m, 1 H), 4.35-5.3 (bs, 5H).
220 mg at 130℃; for 3h;Sealed tube; 220 mg (0.58 mmol) of (8S)-2-chloro-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 94.26 mg (0.69 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 202 mul (1.45 mmol) of triethylamine are added. The tube is sealed and heated at 130° C. in an oil bath for 3 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 220 mg of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-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 443 tr (min)=0.52 1H NMR (600 MHz, delta in ppm, DMSO-d6): 1.49 (m, 1H), 1.52 (m, 1H), 1.7 (m, 2H), 1.79 (bs, 2H), 2.15 (m, 1H), 2.36 (m, 1H), 2.7 (m, 1H), 2.84-3.25 (bs, 3H), 3.31-3.59 (bs, 3H), 3.65 (d, 1H), 3.86 (m, 2H), 4.17 (d, 1H), 4.3 (m, 1H), 4.35-5.3 (bs, 5H).
  • 28
  • (8S)-2-chloro-9-[2-(4-methyl pyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one [ No CAS ]
  • [ 31560-06-2 ]
  • (8S)-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
120 mg With triethylamine; at 120℃; for 2h;Sealed tube; 140 mg (0.36 mmol) of (8S)-2-chloro-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 94.26 mg (0.69 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 126 mul (0.90 mmol) of triethylamine are added. The tube is sealed and heated at 120°C in an oil bath for 2 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 120 mg of (8S)-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-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 450. tr (min) = 0.48. 1H NMR (600 MHz, delta in ppm, DMSO-d6): 1 .7 (m, 2H), 2.25 (m, 1 H), 2.42 (m, 1 H), 2.45 (s, 3H), 3-3.2 (m, 2H), 3.24-3.53 (bs, 3H), 3.36 (m, 1 H), 4.51 (s, 1 H), 4.54 (s, 1 H), 4.59 (m, 1 H), 4.65-4.76 (m, 2H), 5.55 (d, 1 H), 7.37 (d, 1 H), 8.59 (d, 1 H), 9.05 (s, 1 H).
120 mg With triethylamine; at 120℃; for 2h;Sealed tube; 140 mg (0.36 mmol) of (8S)-2-chloro-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 94.26 mg (0.69 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 126 mul (0.90 mmol) of triethylamine are added. The tube is sealed and heated at 120° C. in an oil bath for 2 hours. The crude product obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 120 mg of (8S)-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-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 450 tr (min)=0.48 1H NMR (600 MHz, delta in ppm, DMSO-d6): 1.7 (m, 2H), 2.25 (m, 1H), 2.42 (m, 1H), 2.45 (s, 3H), 3-3.2 (m, 2H), 3.24-3.53 (bs, 3H), 3.36 (m, 1H), 4.51 (s, 1H), 4.54 (s, 1H), 4.59 (m, 1H), 4.65-4.76 (m, 2H), 5.55 (d, 1H), 7.37 (d, 1H), 8.59 (d, 1H), 9.05 (s, 1H).
  • 29
  • (8S)-2-chloro-9-(tetrahydropyran-4-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one [ No CAS ]
  • [ 31560-06-2 ]
  • (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(tetrahydropyran-4-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
180 mg With triethylamine; at 130℃; for 4h; 220 mg (0.62 mmcl) of (8S)-2-chloro-9-(tetrahydropyran-4-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 127 mg (0.93 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 244 muL (1 .75 mmol) of triethylamine are added. The tube is sealed and heated at 130°C in an oil bath for 4 hours. The crude product obtained is taken up in ethyl acetate and the organic phase is washed with water, dried over magnesium sulfate and then evaporated to dryness. The residue is purified bychromatography on silica gel (eluent: 95/5 DCM/MeOH) to give 180 mg of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(tetrahydropyran-4-ylmethyl)-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 415. tr (min) = 0.57. 1H NMR (600 MHz, delta in ppm, DMSO-d6): 1.10-1.38 (m, 2H), 1.40-1.56 (m, 2H), 1.79-1.89 (m, 2H), 2.06-2.22 (m, 2H), 2.32 (m, 1H), 2.89 (m, 1H), 2.95-3.14 (m, 2H), 3.20(m, 3H), 3.61 (m, 1H), 3.73 (m, 1H), 3.83 (m, 2H), 4.07-4.17 (m, 2H), 4.56 (m, 1H),4.60-4.96 (m, 3H).
180 mg With triethylamine; at 130℃; for 4h;Sealed tube; 220 mg (0.62 mmol) of (8S)-2-chloro-9-(tetrahydropyran-4-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 127 mg (0.93 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 244 muL (1.75 mmol) of triethylamine are added. The tube is sealed and heated at 130° C. in an oil bath for 4 hours. The crude product obtained is taken up in ethyl acetate and the organic phase is washed with water, dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 DCM/MeOH) to give 180 mg of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(tetrahydropyran-4-ylmethyl)-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 415 tr (min)=0.57 1H NMR (600 MHz, delta in ppm, DMSO-d6): 1.10-1.38 (m, 2H), 1.40-1.56 (m, 2H), 1.79-1.89 (m, 2H), 2.06-2.22 (m, 2H), 2.32 (m, 1H), 2.89 (m, 1H), 2.95-3.14 (m, 2H), 3.20 (m, 3H), 3.61 (m, 1H), 3.73 (m, 1H), 3.83 (m, 2H), 4.07-4.17 (m, 2H), 4.56 (m, 1H), 4.60-4.96 (m, 3H).
  • 30
  • (8S)-2-chloro-9-quinolin-5-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one [ No CAS ]
  • [ 31560-06-2 ]
  • (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-quinolin-5-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
125 mg With triethylamine; at 130℃; for 7h;Sealed tube; 160 mg (0.40 mmol) of (8S)-2-chloro-9-quinolin-5-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 82 mg (0.60 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 158 muL (1.13 mmol) of triethylamine are added. The tube is sealed and heated at 130°C in an oil bath for 7 hours. The crude product obtained is taken up in DCM and the organic phase is washed with water, dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 DCM/MeOH) to give 125 mg of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-quinolin-5-ylmethyl-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 458. tr (min) = 0.47. 1H NMR (600 MHz, delta in ppm, DMSO-d6): 1.42-1.67 (bm, 2H), 2.29-2.46 (m, 2H), 2.74- 3.20 (bm, 4H), 3.27-3.36 (m, 1 H), 4.27 (m, 2H), 4.42 (m, 1 H), 4.52-4.80 (bm, 2H), 4.85 (m, 1 H), 5.91 (d, 1 H), 7.39 (d, 1 H), 7.56 (m, 1 H), 7.71 (t, 1 H), 7.93 (d, 1 H), 8.62 (m, 1 H), 8.92 (m, 1 H)
125 mg With triethylamine; In triethylamine; at 130℃; for 7h;Sealed tube; 160 mg (0.40 mmol) of (8S)-2-chloro-9-quinolin-5-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 82 mg (0.60 mmol) of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> are mixed together. The powder obtained is placed in a tube and 158 muL (1.13 mmol) of triethylamine are added. The tube is sealed and heated at 130° C. in an oil bath for 7 hours. The crude product obtained is taken up in DCM and the organic phase is washed with water, dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 DCM/MeOH) to give 125 mg of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-quinolin-5-ylmethyl-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 458 tr (min)=0.47 1H NMR (600 MHz, delta in ppm, DMSO-d6): 1.42-1.67 (bm, 2H), 2.29-2.46 (m, 2H), 2.74-3.20 (bm, 4H), 3.27-3.36 (m, 1H), 4.27 (m, 2H), 4.42 (m, 1H), 4.52-4.80 (bm, 2H), 4.85 (m, 1H), 5.91 (d, 1H), 7.39 (d, 1H), 7.56 (m, 1H), 7.71 (t, 1H), 7.93 (d, 1H), 8.62 (m, 1H), 8.92 (m, 1H).
  • 31
  • N-(biphenyl-4-yl)-3-[(chloroacetyl)amino]-4-methoxybenzamide [ No CAS ]
  • [ 31560-06-2 ]
  • N-(biphenyl-4-yl)-4-methoxy-3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylacetyl]amino}benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
13% With triethylamine; potassium iodide; In N,N-dimethyl-formamide; at 20℃; 200 mg (507 muiotatauiotaomicronIota) of the compound from example 12A were provided in 2 mL of DMF. 212 mu (1.52 mmol) of triethylamine, 103 mg (760 muiotatauiotaomicronIota) of (lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 13.0 mg (79 muiotatauiotaomicronIota) of potassium iodide were added, and the mixture was stirred at room temperature over night. After filtration, purification by HPLC (method 2) yielded 32.0 mg (13percent of theory) of the title compound.1H-NM (300 MHz, DMSO-d6): delta [ppm] = 1.61 - 1.77 (m, 1H), 1.78 - 1.94 (m, 1H), 2.64 - 2.80 (m, 1H), 2.81 - 2.99 (m, 1H), 3.33 - 3.47 (m, 2H), 3.51 - 3.71 (m, 2H), 3.80 - 3.92 (m, 1H), 3.97 (s, 3H), 4.40 - 4.52 (m, 1H), 7.21 (d, 1H), 7.29 - 7.38 (m, 1H), 7.40 - 7.51 (m, 2H), 7.62 - 7.72 (m, 4H), 7.73 - 7.82 (m, 1H), 7.83 - 7.91 (m, 2H), 8.79 (s, 1H), 9.82 (s, 1H), 10.23 (s, 1H). LC-MS (Method 1): Rt= 0.94 min; MS (ESIpos): m/z = 458 [M+H]+.
  • 32
  • 3-[(chloroacetyl)amino]-N-[6-(2-fluorophenyl)pyridin-3-yl]-4-methoxybenzamide [ No CAS ]
  • [ 31560-06-2 ]
  • N-[6-(2-fluorophenyl)pyridin-3-yl]-4-methoxy-3-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylacetyl]amino}benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% With triethylamine; potassium iodide; In N,N-dimethyl-formamide; at 20℃; The preparation of the title compound was conducted in analogy to the synthesis of the compound from example 1 starting with 253 mg (611 muiotatauiotaomicronIota) of the compound from intermediate 12, 124 mg (917 muiotatauiotaomicronIota) of (lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 256 mu (1.83 mmol) of triethylamine. Ill mg (37percent of theory) of the title compound were obtained. 1H-NMR (400 MHz, DMSO-d6): delta [ppm] = 1.64 - 1.71 (m, 1H), 1.81 - 1.87 (m, 1H), 2.68 - 2.74 (m, 1H), 2.85 - 2.92 (m, 1H), 3.40 (s, 2H), 3.57 - 3.65 (m, 2H), 3.84 (d, 1H), 3.97 (s, 3H), 4.44 (s, 1H), 7.24 (d, 1H), 7.29 - 7.37 (m, 2H), 7.43 - 7.50 (m, 1H), 7.81 (ddd, 2H), 7.93 - 7.99 (m, 1H), 8.30 (dd, 1H), 8.84 (d, 1H), 9.06 (d, 1H), 9.84 (s, 1H), 10.50 (s, 1H). LC-MS (Method 4): Rt = 0.82 min; MS (ESIpos): m/z = 477 [M+H]+.
  • 33
  • [ 1003845-08-6 ]
  • [ 31560-06-2 ]
  • (1S,4S)-5-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-2-oxa-5-azabicyclo[2.2.1]heptane [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With triethylamine; In ethanol; at 80℃; for 4h; 2-chloropyrimidine-5-boronic acid (52.3 mmol, 8.53 g), thiomorpholine (52.3 mmol, 5.3 ml) and TEA (52.3 mmol, 7.3 ml) were dissolved in EtOH (100 ml) and heated at 80°C for 4h. The solvent was removed in vacuo and the resulting solid triturated with Et20 yielding the title compound (8.64 g, 74percent). The title compound was prepared from (15',45)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (1 : 1) (406 mg, 2.99 mmol) and 2-chloro-5-(tetramethyl-l,3,2- dioxaborolan-2-yl)pyrimidine (650 mg, 2.70 mmol) by the Method E (580 mg, 70 percent). 1H NMR (500 MHz, CDC13) delta ppm 8.59 (s, 2H), 5.11 (s, 1H), 4.71 (s, 1H), 3.92 - 3.83 (m,2H), 3.66 - 3.53 (m, 2H), 2.02 - 1.89 (m, 2H), 1.32 (s, 12H).
  • 34
  • [ 31560-06-2 ]
  • (1R,3S)-1-[2-(difluoromethoxy)phenyl]-3-methyl-7-{2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyrimidin-5-yl}-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-3-ol [ No CAS ]
  • (1R,3R)-1-[2-(difluoromethoxy)phenyl]-3-methyl-7-{2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]pyrimidin-5-yl}-2,3-dihydro-1H-cyclopenta[4,5]imidazo[1,2-a]pyridin-3-ol [ No CAS ]
  • 35
  • [ 1268241-94-6 ]
  • [ 31560-06-2 ]
  • 4-(1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl]-8-oxa-3,5,10-triazatricyclo[7.4.0.0.2,7]trideca-1(13),2(7),3,5,9,11-hexaene [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With sodium acetate; sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; 4 -(1 H-Indol-4 -yl) -6-(morpholin -4 -yl) - 12-1(1 S, 4S) -2-oxa -5-azabicyclo[2.2. 1]heptan -5-ylmethyl]-8-oxa -3,5,10 -triazatricyclo[7.4.0. 02?7]trideca -1(13),2(7),3,5,9, 1 1-hexaene To a suspension of intermediate X (7.OOg, 17.S3mmol, Ieq), (IS,45)-2-oxa-5- azabicyclo[2.2.I]heptane hydrochloride (7.13g, 52.S8mmol, 3eq) and NaOAc (4.31g, 52.S8mmol, 3eq) in anhydrous CH2CI2 (I5OmL) was added NaBH(OAc)3 (7.43g, 35.O6mmol, 2eq). The reaction mixture was stirred at rt overnight. Then, it was partitioned with IN NaOH (100mL) and extracted with CH2CI2 (3 x 200mL). The combined organic extracts were washed with brine (50mL) then dried over MgSO4 and the solvent was removed in vacuo. Purification by silica gel column chromatography with EtOAc/MeOH (1:0-7:1) yielded the product Aas a white solid (6.02g, 71percent).1H NMR (300MHz, ODd3) oH. 8.65 (d, J=2.1 Hz, IH), 8.58 (d, J=2.1 Hz, IH),8.37 (br. 5., IH), 8.24 (dd, J=7.5, 0.9 Hz, IH), 7.62 (td, J=2.6, 0.8 Hz, IH), 7.53(d, J=8.1 Hz, IH), 7.37-7.41 (m, IH), 7.31-7.37 (m, IH), 4.47 (5, IH), 4.22-4.30(m, 4H), 4.18 (d, J=8.1 Hz, IH), 3.98 (d, J=2.3 Hz, 2H), 3.91 -3.97 (m, 4H), 3.70(dd, J=7.9, 1.7 Hz, IH), 3.53 (5, IH), 2.94 (dd, J=10.0, 1.5 Hz, IH), 2.64 (d,J=10.2 Hz, IH), 1.97 (dd, J=9.8, 1.9 Hz, IH), 1.80 (dt, J=9.8, 1.1 Hz, IH). MS (ESj 483.1 (100percent, [M+H]j.
71% With sodium acetate; sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; To a suspension of intermediate X (7.OOg, 17.S3mmol, leq), (1S,45)-2-oxa-5- azabicyclo[2.2.1]heptane hydrochloride (7.13g, 52.S8mmol, 3eq) and NaOAc (4.31g, 52.S8mmol, 3eq) in anhydrous CH2CI2 (l5OmL) was added NaBH(OAc)3 (7.43g, 35.O6mmol, 2eq). The reaction mixture was stirred at rt overnight. Then, it was partitioned with iN NaOH (lOOmL) and extracted with CH2CI2 (3 x200mL). The combined organic extracts were washed with brine (5OmL) then dried over Mg504 and the solvent was removed in vacuo. Purification by silica gel column chromatography with EtOAc/MeOH (1:0-7:1) yielded the product A as a white solid (6.02g, 71percent).1H NMR (300MHz, ODd3) 0H. 8.65 (d, J=2.1 Hz, 1H), 8.58 (d, J2.1 Hz, 1H),8.37 (br. 5., 1H), 8.24 (dd, J=7.5, 0.9 Hz, 1H), 7.62 (td, J=2.6, 0.8 Hz, 1H), 7.53(d, J=8.1 Hz, 1H), 7.37-7.41 (m, 1H), 7.31-7.37 (m, 1H), 4.47 (5, 1H), 4.22-4.30(m, 4H), 4.18 (d, J=8.1 Hz, 1H), 3.98 (d, J=2.3 Hz, 2H), 3.91-3.97 (m, 4H), 3.70(dd, J=7.9, 1.7 Hz, 1H), 3.53 (5, 1H), 2.94 (dd, J=10.0, 1.5 Hz, 1H), 2.64 (d,J=10.2 Hz, 1H), 1.97 (dd, J=9.8, 1.9 Hz, 1H), 1.80 (dt, J=9.8, 1.1 Hz, 1H).MS (ESj 483.1 (100percent, [M+H]j.
71% With sodium acetate; sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; To a suspension of intermediate X (7.00g, 17.53mmol, 1 eq), (1 S,4S)-2-oxa-5- azabicyclo[2.2.1 ]heptane hydrochloride (7.13g, 52.58mmol, 3eq) and NaOAc (4.31 g, 52.58mmol, 3eq) in anhydrous CH2CI2 (150mL) was added NaBH(OAc)3 (7.43g, 35.06mmol, 2eq). The reaction mixture was stirred at rt overnight. Then, it was partitioned with 1 N NaOH (100ml_) and extracted with CH2CI2 (3 x 200ml_). The combined organic extracts were washed with brine (50ml_) then dried over MgS04 and the solvent was removed in vacuo. Purification by silica gel column chromatography with EtOAc/MeOH (1 :0-7: 1 ) yielded the product A as a white solid (6.02g, 71 percent). 1 H NMR (300MHz, CDCI3) deltaEta: 8.65 (d, J=2.1 Hz, 1 H), 8.58 (d, J=2.1 Hz, 1 H), 8.37 (br. s., 1 H), 8.24 (dd, J=7.5, 0.9 Hz, 1 H), 7.62 (td, J=2.6, 0.8 Hz, 1 H), 7.53 (d, J=8.1 Hz, 1 H), 7.37-7.41 (m, 1 H), 7.31 -7.37 (m, 1 H), 4.47 (s, 1 H), 4.22-4.30 (m, 4H), 4.18 (d, J=8.1 Hz, 1 H), 3.98 (d, J=2.3 Hz, 2H), 3.91 -3.97 (m, 4H), 3.70 (dd, J=7.9, 1 .7 Hz, 1 H), 3.53 (s, 1 H), 2.94 (dd, J=10.0, 1 .5 Hz, 1 H), 2.64 (d, J=10.2 Hz, 1 H), 1 .97 (dd, J=9.8, 1 .9 Hz, 1 H), 1 .80 (dt, J=9.8, 1 .1 Hz, 1 H). MS (ES+) 483.1 (100percent, [M+H]+).
71% With sodium acetate; sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; 4 -(1H-lndol-4 -yl) -6-(morpholin -4 -yl) -12-[(1 S,4S) -2-oxa -5- azabicyclo[2.2.1 ]heptan-5-ylmethyl]-8 -oxa -3, 5,10 -triazatricyclo[7.4.0.02, 7]trideca - 1(13),2(7), 3,5,9, 11 -hexaene To a suspension of intermediate X (7.00g, 17.53mmol, 1eq), (1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptane hydrochloride (7.13g, 52.58mmol, 3eq) and NaOAc (4.31 g, 52.58mmol, 3eq) in anhydrous CH2CI2 (150mL) was added NaBH(OAc)3 (7.43g, 35.06mmol, 2eq). The reaction mixture was stirred at rt overnight. Then, it was partitioned with 1N NaOH (100ml_) and extracted with CH2CI2 (3 x 200ml_). The combined organic extracts were washed with brine (50ml_) then dried over MgS04 and the solvent was removed in vacuo. Purification by silica gel column chromatography with EtOAc/MeOH (1:0-7:1) yielded the product A as a white solid (6.02g, 71 percent). 1H NMR (300MHz, CDCI3) deltaEta: 8.65 (d, J=2.1 Hz, 1H), 8.58 (d, J=2.1 Hz, 1H), 8.37 (br. s., 1H), 8.24 (dd, J=7.5, 0.9 Hz, 1H), 7.62 (td, J=2.6, 0.8 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.37-7.41 (m, 1H), 7.31-7.37 (m, 1H), 4.47 (s, 1H), 4.22-4.30 (m, 4H), 4.18 (d, J=8.1 Hz, 1H), 3.98 (d, J=2.3 Hz, 2H), 3.91-3.97 (m, 4H), 3.70 (dd, J=7.9, 1.7 Hz, 1H), 3.53 (s, 1H), 2.94 (dd, J=10.0, 1.5 Hz, 1H), 2.64 (d, J=10.2 Hz, 1H), 1.97 (dd, J=9.8, 1.9 Hz, 1H), 1.80 (dt, J=9.8, 1.1 Hz, 1H). MS (ES+) 483.1 (100percent, [M+H]+).

  • 36
  • 8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid [ No CAS ]
  • [ 31560-06-2 ]
  • (1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl(8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
113 mg With triethylamine; 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 10 - 35℃; for 12h; To a mixture of ethyl 8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate (150 mg), THF (6 mL) and ethanol (6 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was acidified with 1N hydrochloric acid, water was added thereto, and the mixture was extracted with ethyl acetate and THF. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in DMF (12 mL), and HATU (263 mg), <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> (94 mg) and triethylamine (257 muL) were added thereto. The reaction mixture was stirred at room temperature for 12 hr, saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (113 mg). 1H NMR (300 MHz, DMSO-d6) delta 1.83-2.01 (2H, m), 3.37-4.10 (4H, m), 4.73 (1H, br. s), 4.95-5.15 (1H, m), 7.96 (1H, s), 8.21-8.35 (1H, m), 8.35-8.50 (1H, m), 8.65-8.79 (1H, m), 9.41-9.92 (1H, m).
  • 37
  • 8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid [ No CAS ]
  • [ 31560-06-2 ]
  • (6-methyl-8-(1,3-oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
86 mg With triethylamine; 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 10 - 35℃; To a mixture of ethyl 6-methyl-8-(1,3-oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxylate (200 mg), THF (4 mL) and ethanol (4 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was acidified with 1N hydrochloric acid, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in anhydrous DMF (5 mL), and <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> (100 mg), HATU (421 mg) and triethylamine (154 muL) were added thereto. The reaction mixture was stirred overnight at room temperature, saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (86 mg). 1H NMR (300 MHz, CDCl3) delta 1.93-2.08 (2H, m), 2.45 (3H, d, J=0.8 Hz), 3.81 (2H, brs), 3.96 (1H, d, J=7.2 Hz), 4.09 (1H, d, J=7.6 Hz), 4.77 (1H, s), 5.13 (1H, brs), 7.26 (1H, s), 7.67 (1H, d, J=1.5 Hz), 7.93-8.05 (2H, m), 8.28 (1H, s).
  • 38
  • 7-iodo-5-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid [ No CAS ]
  • [ 31560-06-2 ]
  • (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl(7-iodo-5-methylpyrazolo[1,5-a]pyridin-3-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
300 mg With triethylamine; 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 10 - 35℃; for 1.05h; To a solution of 7-iodo-5-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (500 mg) in DMF (10 mL) were added HATU (755 mg) and triethylamine (0.531 mL), and the mixture was stirred at room temperature for 3 min. To the reaction mixture was added <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> (247 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate solution and 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 (NH, ethyl acetate/hexane) to give the title compound (300 mg). 1H NMR (300 MHz, CDCl3) delta 1.96 (2H, brs), 2.41 (3H, s), 3.77 (2H, brs), 3.91 (1H, d, J=7.2 Hz), 4.06 (1H, d, J=7.6 Hz), 4.73 (1H, s), 5.12 (1H, brs), 7.36 (1H, d, J=1.5 Hz), 8.15 (2H, brs).
  • 39
  • C8H4BrClN2O2 [ No CAS ]
  • [ 31560-06-2 ]
  • (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl(8-bromo-6-chloroimidazo[1,2-a]pyridin-3-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
548 mg With triethylamine; 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 10 - 35℃; To a mixture of ethyl 8-bromo-6-chloroimidazo[1,2-a]pyridine-3-carboxylate (537 mg), THF (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.95 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was acidified with 1N hydrochloric acid, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in anhydrous DMF (5 mL), and <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> (200 mg), HATU (841 mg) and triethylamine (308 muL) were added thereto. The reaction mixture was stirred overnight at room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and 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) to give the title compound (548 mg). MS (APCI+). found: 356.0
  • 40
  • C9H4BrN3O2 [ No CAS ]
  • [ 31560-06-2 ]
  • ethyl 3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-8-bromoimidazo[1,2-a]pyridine-6-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.2 g With triethylamine; 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 10 - 35℃; for 12h; To a mixture of ethyl 8-bromo-6-cyanoimidazo[1,2-a]pyridine-3-carboxylate (2.0 g), THF (20 mL) and ethanol (20 mL) was added 1N aqueous sodium hydroxide solution (13 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was acidified with 1N hydrochloric acid, water was added thereto, and the mixture was extracted with THF. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in DMF (20 mL), and HATU (2.6 g), <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> (0.92 g) and triethylamine (2.8 mL) were added thereto. The reaction mixture was stirred at room temperature for 12 hr, saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.2 g). MS (APCI+). found: 394.0, 396.1
  • 41
  • ethyl 8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate [ No CAS ]
  • [ 31560-06-2 ]
  • (1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl(8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
47 mg To a mixture of <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> (100 mg) and anhydrous THF (4 mL) was added dropwise trimethylaluminium toluene solution (1.8 M, 0.410 mL) in an ice bath. The reaction solution was stirred at the same temperature for 1 hr under argon gas atmosphere, ethyl 8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (180 mg) was added thereto, and the mixture was stirred at room temperature for 2 days. The reaction mixture was slowly added to 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (47 mg). MS (APCI+): [M+H]+ 347.0.
  • 42
  • 2-(3-(1-(2-fluorophenyl)-1H-indazol-4-yl)-2-oxoimidazolidin-1-yl)acetic acid [ No CAS ]
  • [ 31560-06-2 ]
  • 1-[1-(2-fluorophenyl)-1H-indazol-4-yl]-3-{2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-2-oxoethyl}imidazolidin-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
49% With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran; at 20℃; for 16h; To a solution of the product of Example 7B (0.75 g, 2.117 mmol), (1S,4S)-2-oxa-5-azabicylco[2.2.1]heptane hydrochloride (Arkpharm., 0.316 g, 2.33 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.48 mL, 8.47 mmol) in tetrahydrofuran (10 mL) was added N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU, 0.885 g, 2.328 mmol). This mixture was allowed to stir at ambient temperature for 16 hours and then was quenched with H2O (5 mL) and extracted with ethyl acetate (10 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3*5 mL). The combined organic fractions were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via column chromatography (SiO2, 20percent hexanes/ethyl acetate to 100percent ethyl acetate to 9:1:0.1 ethyl acetate/methanol/triethylamine) to provide the titled compound (0.45 g, 1.03 mmol, 49percent yield). 1H NMR (300 MHz, methanol-d4) delta ppm 8.42 (t, J=1.2 Hz, 1H), 7.62 (td, J=7.6, 1.6 Hz, 1H), 7.58-7.50 (m, 1H), 7.49-7.36 (m, 3H), 7.13 (t, J=7.1 Hz, 2H), 4.78-4.65 (m, 3H), 4.17-4.07 (m, 3H), 3.88-3.71 (m, 4H), 3.66-3.51 (m, 1H), 3.44 (s, 1H), 1.99 (s, 1H), 1.92 (t, J=2.9 Hz, 1H); MS (ESI+) m/z 436 [M+H]+.
  • 43
  • [ 32315-10-9 ]
  • 2-((1R,2R)-2-aminocyclohexyl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)isoindolin-1-one hydrochloride [ No CAS ]
  • [ 31560-06-2 ]
  • N-((1R,2R)-2-(1-oxo-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-1,3-dihydro-2H-isoindol-2-yl)cyclohexyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
36 mg To a mixture of 2-((1R,2R)-2-aminocyclohexyl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)isoindolin-1-one hydrochloride (50 mg), DIEA (0.106 mL) and THF (5 mL) was added bis(trichloromethyl) carbonate (12.9 mg) at room temperature, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> (25.2 mg), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, 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 (hexane/ethyl acetate) to give the title compound (36 mg). (1335) 1H NMR (300 MHz, CDCl3) delta 1.32-1.55 (3H, m), 1.61-1.78 (3H, m), 1.81-2.03 (3H, m), 2.08-2.20 (1H, m), 2.85-2.97 (1H, m), 3.05-3.14 (1H, m), 3.16-3.25 (1H, m), 3.33-3.41 (1H, m), 3.85-4.01 (1H, m), 4.14-4.27 (1H, m), 4.29-4.54 (4H, m), 4.67-4.77 (1H, m), 7.58-7.66 (1H, m), 8.29 (1H, dd, J=7.9, 1.5 Hz), 8.59-8.64 (1H, m).
  • 44
  • 4-(6-fluoro-1H-indol-4-yl)-6-(morpholin-4-yl)-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene-12-carbaldehyde [ No CAS ]
  • [ 31560-06-2 ]
  • 4-(6-fluoro-1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methyl}-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With sodium acetate; sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; Example A 4-(6-Fluoro-1 H-indol-4-yl)-6-(morpholin-4-yl)-12-r(1 S,4S)-2-oxa-5- azabicyclor2.2.11heptan-5-ylmethyl1-8-oxa-3,5, 10-triazatricyclor7.4.0.02'71trideca- -hexaene To a suspension of Intermediate 7 (25 mg, 0.06 mmol, 1 eq), (1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptane hydrochloride (25 mg, 0.18 mmol, 3 eq) and NaOAc (15 mg, 0.18 mmol, 3 eq) in anhydrous CH2CI2 (5 mL) was added NaBH(OAc)3 (26 mg, 0.12 mmol, 2 eq). The reaction mixture was stirred at rt overnight. It had not reached completion, thus more reagents were added: (1 S,4S)-2-oxa-5- azabicyclo[2.2.1]heptane hydrochloride (9 mg, 0.06 mmol, 1 eq) and NaOAc (5 mg, 0.06 mmol, 1 eq). The mixture was left to stir at rt overnight. Then, it was partitioned with H20 (10 mL) and extracted with CH2CI2 (3 x 10 mL). The combined organic extracts were dried over MgS04 and the solvent was removed by evaporation in vacuo. The residue was dissolved in CH2CI2/MeOH (1:1, 20 mL) and swirled with MP-TMT resin (150 mg, 5 eq) overnight. The resin was then filtered off, washed with CH2CI2/MeOH (1:1, 20 mL) and the solvent was removed in vacuo. Purification by silica gel column chromatography with EtOAc/MeOH (1:0-6:1) yielded Example A as a white solid (18.1 mg, 60percent). 1H NMR (300MHz, CDCI3) deltaEta: 8.64 (d, J=1.9 Hz, 1H), 8.59 (d, J=1.9 Hz, 1H), 8.33 (brs, 1H), 8.02 (dd, J=11.3, 2.3 Hz, 1H), 7.58-7.66 (m, 1H), 7.37 (t, J=2.6 Hz, 1H), 7.22 (dd, J=8.5, 1.7 Hz, 1H), 4.43-4.51 (m, 1H), 4.22-4.31 (m, 4H), 4.19 (d, J=7.9 Hz, 1H), 3.90-4.03 (m, 6H), 3.70 (dd, J=7.6, 1.2 Hz, 1H), 3.54 (s, 1H), 2.94 (d, J=9.8 Hz, 1H), 2.64 (d, J=10.2 Hz, 1H), 1.97 (d, J=8.7 Hz, 1H), 1.80 (d, J=9.2 Hz, 1H). MS (ES+) 500.9 (100percent, [M+H]+).
  • 45
  • 4-(5-fluoro-1H-indol-4-yl)-6-(morpholin-4-yl)-8-oxa-3,5,10-triazatricyclo[7.4.0.02'7]trideca-1(13),2(7),3,5,9,11-hexaene-12-carbaldehyde [ No CAS ]
  • [ 31560-06-2 ]
  • 4-(5-fluoro-1H-indol-4-yl)-6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methyl}-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With sodium acetate; sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; Example C 4-(5-Fluoro-1 H-indol-4-yl)-6-(morpholin-4-yl)-12-r(1 S,4S)-2-oxa-5- azabicyclo[2.2.11heptan-5-ylmethyl1-8-oxa-3,5, 10-triazatricyclo[7.4.0.02,71thdeca- -hexaene To a suspension of Intermediate 8 (50 mg, 0.12 mmol, 1 eq), (1 S,4S)-2-oxa-5- azabicyclo[2.2.1 ]heptane hydrochloride (49 mg, 0.36 mmol, 3 eq) and NaOAc (30 mg, 0.36 mmol, 3 eq) in anhydrous CH2CI2 (5 mL) was added NaBH(OAc)3 (51 mg, 0.24 mmol, 2 eq). The reaction mixture was stirred at rt overnight. It had not reached completion, thus more reagents were added: (1 S,4S)-2-oxa-5- azabicyclo[2.2.1]heptane hydrochloride (18 mg, 0.12 mmol, 1 eq) and NaOAc (10 mg, 0.12 mmol, 1 eq). The mixture was left to stir at rt overnight. Then, it was partitioned with H20 (10 mL) and extracted with CH2CI2 (3 x 10 mL). The combined organic extracts were dried over MgS04 and the solvent was removed by evaporation in vacuo. The residue was dissolved in CH2CI2/MeOH (1:1, 20 mL) and swirled with MP-TMT resin (300 mg, 5 eq) overnight. The resin was then filtered off, washed with CH2CI2/MeOH (1:1, 20 mL) and the solvent was removed in vacuo. Purification by silica gel column chromatography with EtOAc/MeOH (1 :0-6:1) yielded Example C as a white solid (39.1 mg, 65percent). 1H NMR (300MHz, CDCI3) deltaEta: 8.65 (d, J=2.3 Hz, 1H), 8.58 (d, J=2.1 Hz, 1H), 8.35 (br s, 1H), 7.37-7.45 (m, 1H), 7.33 (t, J=2.8 Hz, 1H), 7.08 (dd, J=10.9, 8.9 Hz, 1H), 6.95 (t, J=2.2 Hz, 1H), 4.45 (s, 1H), 4.19-4.27 (m, 4H), 4.16 (d, J=7.9 Hz, 1H), 3.97 (d, J=1.7 Hz, 2H), 3.85-3.94 (m, 4H), 3.68 (dd, J=7.9, 1.5 Hz, 1H), 3.52 (s, 1H), 2.93 (dd, J=10.1, 1.4 Hz, 1H), 2.60 (d, J=10.0 Hz, 1H), 1.94 (dd, J=9.6, 1.5 Hz, 1H), 1.78 (d, J=9.8 Hz, 1H). MS (ES+) 500.9 (100percent, [M+H]+).
  • 46
  • 6-(morpholin-4-yl)-4-[2-(trifluoromethyl)-1H-indol-4-yl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02'7]trideca-1(13),2(7),3,5,9,11-hexaene-12-carbaldehyde [ No CAS ]
  • [ 31560-06-2 ]
  • 6-(morpholin-4-yl)-12-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methyl}-4-[2-(trifluoromethyl)-1H-indol-4-yl]-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),3,5,9,11-hexaene [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% With sodium acetate; sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; Example F 6-(Morpholin-4-yl)-12-r(1S,4S)-2-oxa-5-azabicvclor2.2.11heptan-5-ylmethyl1-4-r2- (thfluoromethyl)-1H-indol-4-yl1-8-oxa-3,5,10-thazathcyclor7.4 2'71thdeca- 1(13),2(7),3,5,9,11-hexaene Intermediate 9 Example F To a suspension of Intermediate 9 (50 mg, 0.11 mmol, 1 eq), (1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptane hydrochloride (44 mg, 0.32 mmol, 3 eq) and NaOAc (26 mg, 0.36 mmol, 3 eq) in anhydrous CH2CI2 (5 mL) was added NaBH(OAc)3 (46 mg, 0.21 mmol, 2 eq). The reaction mixture was stirred at rt overnight. It had not reached completion, thus more reagents were added: (1 S,4S)-2-oxa-5- azabicyclo[2.2.1]heptane hydrochloride (15 mg, 0.11 mmol, 1 eq) and NaOAc (9 mg, 0.11 mmol, 1 eq). The mixture was left to stir at rt overnight. Then, it was partitioned with H20 (10 mL) and extracted with CH2CI2 (3 x 10 mL). The combined organic extracts were dried over MgS04 and the solvent was removed by evaporation in vacuo. The residue was dissolved in CH2CI2/MeOH (1:1, 20 mL) and swirled with MP-TMT resin (300 mg, 5 eq) overnight. The resin was then filtered off, washed with CH2CI2/MeOH (1:1, 20 mL) and the solvent was removed by evaporation in vacuo. Purification by silica gel column chromatography with EtOAc/MeOH (1:0-4:1) yielded Example F as a pale yellow solid (49.1 mg, 83percent). 1H NMR (300MHz, CDCI3) deltaEta: 8.68 (br s, 1H), 8.62-8.64 (m, 1H), 8.58-8.61 (m, 1H), 8.28 (dd, J=7.3, 0.9 Hz, 1H), 8.01-8.06 (m, 1H), 7.42-7.59 (m, 2H), 4.44- 4.51 (m, 1H), 4.22-4.30 (m, 4H), 4.20 (d, J=7.9Hz, 1H), 4.01 (d, J=2.1 Hz, 2H), 3.90-3.98 (m, 4H), 3.71 (dd, J=7.9, 1.7 Hz, 1H), 3.53-3.60 (m, 1H), 2.96 (dd, J=10.1, 1.6 Hz, 1H), 2.66 (d, J=10.2 Hz, 1H), 1.98 (dd, J=9.7, 1.6 Hz, 1H), 1.77- 1.86 (m, 1H). MS (ES+) 551.2 (100percent, [M+H]+).
  • 47
  • di-tert-butyl 8-chloro-9-fluoro-5H-benzo[b]pyrido[2,3-e][1,4]diazepine-6,11-dicarboxylate [ No CAS ]
  • [ 31560-06-2 ]
  • tert-butyl 8-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-9-fluoro-5H-benzo[b]pyrido[2,3-e][1,4]diazepine-11(6H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Step 1: To an oven-dried, N2(g) cooled 20 mL microwave vial was added di-tert-butyl 8-chloro- 9-fluoro-5H-benzo[b]pyrido[2,3-e][1,4]diazepine-6,11-dicarboxylate (237mg, 0.527mmol), chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)[2-(2- aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (43.0mg, 0.053mmol), and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane, HCl (107mg, 0.790mmol). Sodium tert-butoxide (506mg, 5.27mmol) was added and the vial was evacuated and filled with N2(g). THF (10mL) was added, the vial was sealed and the reaction mixture was heated to 80°C overnight. Upon cooling to room temperature, trifluoroacetic acid (0.807mL, 10.5mmol) was added. After 1 hour, saturated aqueous sodium hydrogen carbonate (50mL) was added and the mixture was extracted with EtOAc (3 x 30mL). The combined organic fractions were washed with brine (30mL), dried over Na2SO4, filtered and the mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ISCO 24g, eluting with 0-30percent ethyl acetate gradient in isohexane) to afford tert-butyl 8-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-9- fluoro-5H-benzo[b]pyrido[2,3-e][1,4]diazepine-11(6H)-carboxylate as a foam.
  • 48
  • [ 31560-06-2 ]
  • (8-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-9-fluoro-5H-benzo[b]pyrido[2,3-e][1,4]diazepin-6(11H)-yl)((2R,5S)-5-isopropoxytetrahydro-2H-pyran-2-yl)methanone [ No CAS ]
  • 49
  • [ 31560-06-2 ]
  • (1S,4S)-5-(9-fluoro-6,11-dihydro-5H-benzo[b]pyrido[2,3-e][1,4]diazepin-8-yl)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride [ No CAS ]
  • 50
  • (6-chloro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol [ No CAS ]
  • [ 31560-06-2 ]
  • (6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With caesium carbonate; In acetonitrile; at 100℃; for 18h;Sealed tube; A mixture of (6-chloro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol(Intermediate 2) (126 mg, 0.52 mmol), <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> (140 mg, 1.03 mmol) and cesium carbonate (674 mg, 2.07 mmol) in acetonitrile (2 mL) was stirred 100 oC for 18h in a sealed tube. After filtered and concentrated, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:2) as eluting solvents to afford (6- ((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-2- yl)methanol (120 mg, 76percent) as a yellow solid. MS (ESI): m/z = 307.3 [M+1]+.
  • 51
  • 4-(1-(6-iodo-2-methylpyrimidin-4-yl)-5-methyl-1H-indazol-6-yl)cyclohexanone [ No CAS ]
  • [ 31560-06-2 ]
  • 4-(1-(6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methylpyrimidin-4-yl)-5-methyl-1H-mndazol-6-yl)cyclohexanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
79.6% With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 50℃; To a solution of 4-( 1 -(6-iodo-2-methylpyrimidin-4-yl)-5-methyl-1 H-indazol-6-yl)cyclohexanone(223 mg, 0.50 mmol), <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> (102 mg, 0.75mmcl) in NMP (5.0 mL) added DIPEA (0.5 mL), then the reaction mixture was stirred at 50°C overnight. The reaction mixture was poured into brine (30 mL) and the mixture was extracted with EtOAc (30 mL x 3). The organic layers were dried over Na2SO4 and concentrated by vacuum. The crude was purified by silica gel (silica del: lOg, CH2CI2:CH3OH = 15:1)to give a white solid (166 mg, yield 79.6percent).LC-MS [mobile phase: from 95percent water (0.1percent FA) and 5percent ACN (0.1percent FA) to 5percent water (0.1percent FA) and 95percent ACN (0.1percent FA) in 10 mm]: purity: 65.4percent; Rt = 1.567 mm; MS Calcd: 417, MS Found: 418.0 [M + H].
  • 52
  • [ 31560-06-2 ]
  • 4,6-diiodo-2-(methylthio)pyrimidine [ No CAS ]
  • (1S,4S)-5-(6-iodo-2-(methylthio)pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; isopropyl alcohol; at 50℃; To a solution of 4,6-diiodo-2-(methylthio)pyrimidine (500 mg, 1.32 mmol) and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (179 mg, 1.32 mmol) in i-PrOH (10 mL) and THE (10 mL) wasadded DIEA (513 mg, 3.97 mmol). The reaction was stirred at 50 °C overnight. The reaction solution was concentrated and the residue was diluted with EtOAc (30 mL). The resulting mixture was washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (silica gel: 3 g, PE:EtOAc3:1)to giveproduct as a white solid (405 mg, yield: 88percent)LC-MS [mobile phase: from 60percent water (0.1percent FA) and 40percent ACN (0.1percent FA) to 5percent water(0.1percent FA) and 95percent ACN (0.1percent FA) in 2.0 mm]: Rt = 1.63 mm; MS Calcd.: 349, MS Found:350 [M + H].
  • 53
  • cis-1-(6-chloro-2-methoxypyrimidin-4-yl)-6-(3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-methyl-1H-indazole [ No CAS ]
  • [ 31560-06-2 ]
  • cis-(1S,4S)-5-(6-(6-(3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-methyl-1H-indazol-1-yl)-2-methoxypyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 3h; A mixture of cis-1-(6-chloro-2-methoxypyrimidin-4-yl)-6-(3-fluoro-1 -(oxetan-3-yl)piperidin-4- yl)-5-methyl-1H-indazole (from peakl) (20 mg, 0.046 mmol), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (13 mg, 0.092 mmol) and DIEA (18 mg, 0.138 mmol) in DMF (1 mL) was stirred at 60 °C for 3h. The reaction mixture was purified by Prep-HPLC (A: water, B:ACN, A:B80:20 to A:B=5:95) to give a white solid. (9 mg, yield 40percent).1H NMR (400 MHz, CDCI3): 68.88 (s, IH), 8.08 (s, 1H), 7.54 (s, 1H), 6.54 (br 0.7H), 5.25 (br 0.5H), 4.93?4.90 (m, 1H), 4.78?4.62 (m, 6H), 4.15 (s, 3H), 3.94?3.88 (m, 2H), 3.69?3.46 (m,3H), 3.24?3.08 (m, 2H), 2.82?2.80 (m, 1H), 2.47 (s, 3H), 2.13?1.64 (m, 6H).19F NMR (376 MHz, CDCI3): 6 -183.97.LC-MS [mobile phase: from 50percent water (0.1percent NH3H2O) and 50percent ACN (0.1percent NH3H2O) to 5percentwater (0.1percent NH3H2O) and 95percent ACN (0.1percent NH3H2O) in 12 mm]: Rt 5.36 mm; MS Calcd:494, MS Found: 495 [M + H].Chiral HPLC [Phase: C02: MeOH(0.03percent DEA) = 70/ 30, Flow rate: 1 .8mL / mm, Wave lenghth: 254 nm]: Rt: 3.622 mm, 100percent ee. A mixture of cis-1-(6-chloro-.2-methoxypyrimidin-4-yl)-6-(3-fluoro-1-(oxetan-3-yl)piperidin-4- yl)-5-methyl-1 H-indazole (from peak2) (20 mg, 0.046 mmol), (1 S,4S)-2-oxa-5- azabicyclo[2.2.1]heptane (13 mg, 0.092 mmcl) and DIEA (18 mg, 0.138 mmol) in DMF (1 mL) was stirred at rt overnight. The reaction mixture was purified by Prep-HPLC (A: water, B:ACN, A:B=80:20 to A:B5:95) to give a white solid. (17 mg, yield 64percent).1 H NMR (400 MHz, CDCI3): 6 8.88 (s, 1 H), 8.08 (s, I H), 7.54 (s, I H), 7.54 (s, 0.6H), 5.25 (s,0.4H), 4.93?4.90 (m, 1H), 4.78?4.62 (m, 6H), 4.15 (s, 3H), 3.94?3.88 (m, 2H), 3.67?3.65 (m, IH), 3.55?3.51 (m, 2H), 3.21?3.19 (m, 1H), 3.13?3.09 (m, 1H), 2.82?2.80 (m, 1H), 2.47 (s, 3H), 2.10?2.09 (m, 1H), 2.05?1.96 (m, 4H), 1.87?1.64 (m, 1H).19F NMR (376 MHz, CDCI3): 6 -183.97.LC-MS [mobile phase: from 95percent water (0.1percent FA) and 5percent ACN (0.1percent FA) to 5percent water (0.1percentFA) and 95percent ACN (0.1percent FA) in 9 mm]: Rt = 5.26 mm; MS Calcd: 494, MS Found: 495 [M +H].Chiral HPLC [Phase: CC2: MeOH(0.02percent DEA) = 80/ 20, Flow rate: 1.8 mL / mm, Wavelenghth: 254 nm]: Rt: 4.377 mm, 100percent ee.
  • 54
  • cis-1-(6-chloro-2-methoxypyrimidin-4-yl)-6-(3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-methyl-1H-indazole [ No CAS ]
  • [ 31560-06-2 ]
  • cis-(1S,4S)-5-(6-(6-(3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-methyl-1H-indazol-1-yl)-2-methoxypyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 3h; A mixture of cis-1-(6-chloro-2-methoxypyrimidin-4-yl)-6-(3-fluoro-1 -(oxetan-3-yl)piperidin-4- yl)-5-methyl-1H-indazole (from peakl) (20 mg, 0.046 mmol), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (13 mg, 0.092 mmol) and DIEA (18 mg, 0.138 mmol) in DMF (1 mL) was stirred at 60 °C for 3h. The reaction mixture was purified by Prep-HPLC (A: water, B:ACN, A:B80:20 to A:B=5:95) to give a white solid. (9 mg, yield 40percent).1H NMR (400 MHz, CDCI3): 68.88 (s, IH), 8.08 (s, 1H), 7.54 (s, 1H), 6.54 (br 0.7H), 5.25 (br 0.5H), 4.93?4.90 (m, 1H), 4.78?4.62 (m, 6H), 4.15 (s, 3H), 3.94?3.88 (m, 2H), 3.69?3.46 (m,3H), 3.24?3.08 (m, 2H), 2.82?2.80 (m, 1H), 2.47 (s, 3H), 2.13?1.64 (m, 6H).19F NMR (376 MHz, CDCI3): 6 -183.97.LC-MS [mobile phase: from 50percent water (0.1percent NH3H2O) and 50percent ACN (0.1percent NH3H2O) to 5percentwater (0.1percent NH3H2O) and 95percent ACN (0.1percent NH3H2O) in 12 mm]: Rt 5.36 mm; MS Calcd:494, MS Found: 495 [M + H].Chiral HPLC [Phase: C02: MeOH(0.03percent DEA) = 70/ 30, Flow rate: 1 .8mL / mm, Wave lenghth: 254 nm]: Rt: 3.622 mm, 100percent ee. A mixture of cis-1-(6-chloro-.2-methoxypyrimidin-4-yl)-6-(3-fluoro-1-(oxetan-3-yl)piperidin-4- yl)-5-methyl-1 H-indazole (from peak2) (20 mg, 0.046 mmol), (1 S,4S)-2-oxa-5- azabicyclo[2.2.1]heptane (13 mg, 0.092 mmcl) and DIEA (18 mg, 0.138 mmol) in DMF (1 mL) was stirred at rt overnight. The reaction mixture was purified by Prep-HPLC (A: water, B:ACN, A:B=80:20 to A:B5:95) to give a white solid. (17 mg, yield 64percent).1 H NMR (400 MHz, CDCI3): 6 8.88 (s, 1 H), 8.08 (s, I H), 7.54 (s, I H), 7.54 (s, 0.6H), 5.25 (s,0.4H), 4.93?4.90 (m, 1H), 4.78?4.62 (m, 6H), 4.15 (s, 3H), 3.94?3.88 (m, 2H), 3.67?3.65 (m, IH), 3.55?3.51 (m, 2H), 3.21?3.19 (m, 1H), 3.13?3.09 (m, 1H), 2.82?2.80 (m, 1H), 2.47 (s, 3H), 2.10?2.09 (m, 1H), 2.05?1.96 (m, 4H), 1.87?1.64 (m, 1H).19F NMR (376 MHz, CDCI3): 6 -183.97.LC-MS [mobile phase: from 95percent water (0.1percent FA) and 5percent ACN (0.1percent FA) to 5percent water (0.1percentFA) and 95percent ACN (0.1percent FA) in 9 mm]: Rt = 5.26 mm; MS Calcd: 494, MS Found: 495 [M +H].Chiral HPLC [Phase: CC2: MeOH(0.02percent DEA) = 80/ 20, Flow rate: 1.8 mL / mm, Wavelenghth: 254 nm]: Rt: 4.377 mm, 100percent ee.
  • 55
  • cis-1-(6-chloro-2-methylpyrimidin-4-yl)-6-(3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-methyl-1H-indazole [ No CAS ]
  • [ 31560-06-2 ]
  • cis-(1S,4S)-5-(6-(6-(3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-methyl-1H-indazol-1-yl)-2-methylpyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; A mixture of cis-1-(6-chloro-2-methylpyrimidin-4-yl)-6-(3-fluoro-i-(oxetan-3-yI)piperidin-4-yl)- 5-methyl-i H-indazole (from peakl) (20 mg, 0.048 mmol), (IS,4S)-2-oxa-5- azabicyclo[2.2.1]heptane (13 mg, 0.096 mmol) and DIEA (19 mg, 0.144 mmol) in DMF (1 mL)was stirred at 60 °C for 3h. The reaction mixture was purified by Prep-HPLC (A: water, B:ACN, A:B80:20 to A:B=5:95) to give a white solid. (10 mg, yield 42percent).1H NMR (400 MHz, CDCI3): 6 8.91 (s, 1 H), 8.07 (s, I H), 7.53 (s, 1 H), 6.67 (br 0.8H), 5.25 (s,0.4H), 4.97?4.85 (m, 1 H), 4.78?4.67 (m, 6H), 3.91 (s, 2H), 3.89?3.48 (m, 3H), 3.28?3.25 (m,IH), 3.12?3.10 (m, IH), 2.88?2.85 (m, IH), 2.64(s, 3H), 2.47 (s, 3H), 2.15?1.94 (m, 6H).19F NMR (376 MHz, CDCI3): 6 -183.94.LC-MS [mobile phase: from 70percent water (0.1percent NH3H2O) and 30percent ACN (0.1percent NH3H2C) to 5percentwater (0.1percent NH3H2C) and 95percent ACN (0.1percent NH3H2O) in 12 mm]: Rt = 7.99 mm; MS Cacd:478, MS Found: 479 [M + Hj.Chiral method: Phase: CC2: MeOH(0.03percent DEA) 70/ 30, F: I .8mL / mm, W: 254 nm, Rt:5.285 mi 100percent ee. A mixture of cis-l-(6-chloro-2-methylpyrimidin-4-yl)-6-(3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-methyl-i H-indazole (from peak2) (20 mg, 0.048 mmol), (1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptane (13 mg, 0.096 mmol) and DIEA (19 mg, 0.144 mmol) in DMF (1 mL) was stirred at rt overnight. The reaction mixture was purified by Prep-HPLC (A: water, B:ACN, A:B80:20 to A:B=5:95) to give a white solid. (12 mg, yield 52percent).1H NMR (400 MHz, CDCI3): O 8.91 (s, I H), 8.07 (s, 1 H), 7.53 (s, I H), 6.54 (s, 0.6H), 5.25 (s,0.4H), 4.97?4.90 (m, 1H), 4.78?4.62 (m, 6H), 3.91 (s, 2H), 3.68?3.65 (m, IH), 3.53?3.48 (m,2H), 3.28?3.25 (m, 1H), 3.12?3.08 (m, 1H), 2.88?2.85 (m, 1H), 2.64 (s, 3H), 2.47 (s, 3H),2.22?2.14 (m, 1H), 2.05?1.96 (m, 5H).19F NMR (376 MHz, CDCI3): oe -183.94.LC-MS [mobile phase: from 95percent water (0.1percent FA) and 5percent ACN (0.1percent FA) to 5percent water (0.1percent FA) and 95percent ACN (0.1percent FA) in 9 mm]: Rt 4.83 mm; MS Calcd: 478, MS Found: 479 [M +H].Chiral HPLC [Phase: CC2: EtOH:ACN (0.025percent DEA) = 75/ 21/9, Flow rate: 3.OmL / mm, Wave Ienghth: 254 nm]: Rt: 7.705 mm, 100percent ee.
  • 56
  • cis-1-(6-chloro-2-methylpyrimidin-4-yl)-6-(3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-methyl-1H-indazole [ No CAS ]
  • [ 31560-06-2 ]
  • cis-(1S,4S)-5-(6-(6-(3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-methyl-1H-indazol-1-yl)-2-methylpyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; A mixture of cis-1-(6-chloro-2-methylpyrimidin-4-yl)-6-(3-fluoro-i-(oxetan-3-yI)piperidin-4-yl)- 5-methyl-i H-indazole (from peakl) (20 mg, 0.048 mmol), (IS,4S)-2-oxa-5- azabicyclo[2.2.1]heptane (13 mg, 0.096 mmol) and DIEA (19 mg, 0.144 mmol) in DMF (1 mL)was stirred at 60 °C for 3h. The reaction mixture was purified by Prep-HPLC (A: water, B:ACN, A:B80:20 to A:B=5:95) to give a white solid. (10 mg, yield 42percent).1H NMR (400 MHz, CDCI3): 6 8.91 (s, 1 H), 8.07 (s, I H), 7.53 (s, 1 H), 6.67 (br 0.8H), 5.25 (s,0.4H), 4.97?4.85 (m, 1 H), 4.78?4.67 (m, 6H), 3.91 (s, 2H), 3.89?3.48 (m, 3H), 3.28?3.25 (m,IH), 3.12?3.10 (m, IH), 2.88?2.85 (m, IH), 2.64(s, 3H), 2.47 (s, 3H), 2.15?1.94 (m, 6H).19F NMR (376 MHz, CDCI3): 6 -183.94.LC-MS [mobile phase: from 70percent water (0.1percent NH3H2O) and 30percent ACN (0.1percent NH3H2C) to 5percentwater (0.1percent NH3H2C) and 95percent ACN (0.1percent NH3H2O) in 12 mm]: Rt = 7.99 mm; MS Cacd:478, MS Found: 479 [M + Hj.Chiral method: Phase: CC2: MeOH(0.03percent DEA) 70/ 30, F: I .8mL / mm, W: 254 nm, Rt:5.285 mi 100percent ee. A mixture of cis-l-(6-chloro-2-methylpyrimidin-4-yl)-6-(3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-5-methyl-i H-indazole (from peak2) (20 mg, 0.048 mmol), (1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptane (13 mg, 0.096 mmol) and DIEA (19 mg, 0.144 mmol) in DMF (1 mL) was stirred at rt overnight. The reaction mixture was purified by Prep-HPLC (A: water, B:ACN, A:B80:20 to A:B=5:95) to give a white solid. (12 mg, yield 52percent).1H NMR (400 MHz, CDCI3): O 8.91 (s, I H), 8.07 (s, 1 H), 7.53 (s, I H), 6.54 (s, 0.6H), 5.25 (s,0.4H), 4.97?4.90 (m, 1H), 4.78?4.62 (m, 6H), 3.91 (s, 2H), 3.68?3.65 (m, IH), 3.53?3.48 (m,2H), 3.28?3.25 (m, 1H), 3.12?3.08 (m, 1H), 2.88?2.85 (m, 1H), 2.64 (s, 3H), 2.47 (s, 3H),2.22?2.14 (m, 1H), 2.05?1.96 (m, 5H).19F NMR (376 MHz, CDCI3): oe -183.94.LC-MS [mobile phase: from 95percent water (0.1percent FA) and 5percent ACN (0.1percent FA) to 5percent water (0.1percent FA) and 95percent ACN (0.1percent FA) in 9 mm]: Rt 4.83 mm; MS Calcd: 478, MS Found: 479 [M +H].Chiral HPLC [Phase: CC2: EtOH:ACN (0.025percent DEA) = 75/ 21/9, Flow rate: 3.OmL / mm, Wave Ienghth: 254 nm]: Rt: 7.705 mm, 100percent ee.
  • 57
  • [ 31560-06-2 ]
  • [ 66298-49-5 ]
  • (1S,4S)-5-(6-iodo-2-methylpyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ No CAS ]
YieldReaction ConditionsOperation in experiment
58.7% With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethanol; at 25℃; for 48h; To a solution of 4,6-diiodo-2-methylpyrimidine (1.0 g, 2.9 mmol) and <strong>[31560-06-2](1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride</strong> (392 mg, 2.9 mmol) in THF (30 ml) and EtCH (30 ml)at room temperature was added DIPEA (1.45 ml, 8.7 mmol). The reaction was stirred atroom temperature for 48 hours. Removal solvents and purification (EtOAc/PE = 1/5) viasilica gel chromatography gave the title compound as white oil (540 mg, Yield: 58.7percent).LC-MS [mobile phase: from 90percent water (0.1percent FA) and 10percent ACN (0.1percent FA) to 5percent water(0.1percent FA) and 95percent ACN (0.1percent FA) in 2.0 mm]: Rt 0.31 mm; MS Calcd: 317.0, MS Found:318.0 [M + H].
  • 58
  • [ 31560-06-2 ]
  • 4,6-diiodo-2-methoxypyrimidine [ No CAS ]
  • (1S,4S)-5-(6-iodo-2-methoxypyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethanol; at 25℃; for 48h; 4, 6-diiodo-2-methoxypyrimidine (822 mg, 2.27 mmol) and DIEA (1.2 mL) was dissolved in a mixture of THF (5 mL) and EtOH (5 mL) , then (1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptane hydrochloride (280 mg, 2.07 mmol) was added and the reaction was stirred at rt for 2 days. The reaction solution was concentrated and the residue was purified by silica gel chromatography (eluted with PE/EtOAc = 3/1) to give product as white solid (610 mg, yield 81percent) .[0532]LC-MS [mobile phase: from 80percentwater (0.1percentTFA) and 20percentACN (0.1percentTFA) to 20percentwater (0.1percentTFA) and 80percentACN (0.1percentTFA) in 2 min] : Rt = 0.41 min; MS Calcd.: 333, MS Found: 334 [M + H]+.
  • 59
  • [ 108-77-0 ]
  • [ 31560-06-2 ]
  • (1S,4S)-5-{4-chloro-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl}-2-oxa-5-azabicyclo[2.2.1]heptane [ No CAS ]
  • 60
  • [ 14625-39-9 ]
  • [ 31560-06-2 ]
  • (1S,4S)-5-((5-nitro-1H-benzo[d]imidazol-2-yl)methyl)-2-oxa-5-azabicyclo[2.2.1]heptane [ No CAS ]
  • 61
  • [ 149849-94-5 ]
  • [ 31560-06-2 ]
  • methyl 2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrimidine-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With trimethylamine; In 1,4-dioxane; at 50℃;Inert atmosphere; Example 89A methyl 2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrimidine-4-carboxylate Methyl 2-chloropyrimidine-4-carboxylate (2.4 g) and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (2.0 g) were dissolved in dioxane (20 mL). Trimethylamine (4.0 mL) was added and the reaction was stirred at 50° C. under nitrogen overnight. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate. After filtration, the crude residue was purified by silica gel chromatography, eluting with 30/70 heptanes/ethyl acetate, to provide the title compound. MS (DCI) m/z 235.9 (M+H)+.
  • 62
  • [ 31560-06-2 ]
  • (2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrimidin-4-yl)methanol [ No CAS ]
  • 63
  • [ 31560-06-2 ]
  • (2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrimidin-4-yl)methyl methanesulfonate [ No CAS ]
  • 64
  • 2-{14-chloro-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.03,7]heptadeca-1(16),3,6,13(17),14-pentaen-5-yl}acetaldehyde trifluoroaceic acid salt [ No CAS ]
  • [ 31560-06-2 ]
  • 14-chloro-4,11-dimethyl-5-{2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]ethyl}-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.03,7]heptadeca-1(16),3,6,13(17),14-pentaene [ No CAS ]
  • 14-chloro-4,11-dimethyl-5-{2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]ethyl}-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.03,7]heptadeca-1(16),3,6,13(17),14-pentaene [ No CAS ]
  • 65
  • 4-{14-chloro-4-methyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.03,7]heptadeca-1(16),3,6,13(17),14-pentaen-5-yl}cyclohexan-1-one [ No CAS ]
  • [ 31560-06-2 ]
  • 14-chloro-4-methyl-5-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]cyclohexyl}-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.03,7]heptadeca-1(16),3,6,13(17),14-pentaene [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium cyanoborohydride; acetic acid; In dichloromethane; at 0 - 20℃; for 15h;Molecular sieve; Inert atmosphere; To a solution of D85 (100 mg, 0.265 mmol), (1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (43 mg, 0.319 mmol), 4A molecular sieves (100 mg), AcOH (10 mg) in CH2CI2 (5 mL) under argon at 0 °C was added NaBHsCN (35 mg, 0.557 mmol). The reaction was stirred for 15 hrs at room temperature. The mixture was filtered and aq. NaHCC (20 mL) was added. The organic layer was concentrated and the crude was purified by prep-TLC (CH2CI2: MeOH = 8: 1) to give the mixture as a yellow solid (88 mg, yield 72percent). The title compounds E50 (10 mg) and E51 (21 mg) were obtained as white solids from chiral separation of the mixture (chiral method F). E50: LC-MS: 460.3 [M+H] +.1H NMR (400 MHz, CDCl3): delta 7.81 (s, 1 H), 6.07 (br, 1 H), 5.53 (br, 1H), 4.40 (br, 3H), 4.05 (d, J= 8.0 Hz, 1H), 3.85 (br, 1H), 3.74 (br, 1H), 3.68-3.46 (m, 3H), 3.11 (d, J= 9.6 Hz, 1H), 2.48 (d, J= 9.2 Hz, 2H), 2.19 (s, 3H), 2.13-1.82 (m, 9H), 1.83- 1.72 (m, 1H), 1.40-1.18 (m, 2H). Chiral RT =4.549 min. E51: LC-MS: 460.3 [M+H]+.1H NMR (400 MHz, CDCl3): delta 7.81 (br, 1H), 6.07 (br, 1H), 5.53 (br, 1H), 4.40 (br, 3H), 4.06 (d, J= 7.6 Hz, 1H), 3.91 (br, 1H), 3.70-3.58 (m, 2H), 3.52 (d, J= 4.8 Hz, 2H), 3.07 (d, J= 8.4 Hz, 1H), 2.72 (br, 1H), 2.44-2.23 (m, 3H), 2.23-2.14 (m, 4H), 1.93 (br, 5H), 1.68-1.43 (m, 4H). Chiral RT =5.341 min.
  • 66
  • 4-{14-chloro-4,11-dimethyl-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.03,7] heptadeca-1(16),3,6,13(17),14-pentaen-5-yl}cyclohexan-1-one [ No CAS ]
  • [ 31560-06-2 ]
  • 14-chloro-4,11-dimethyl-5-{4-[2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]cyclohexyl}-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.03,7]heptadeca-1(16),3,6,13(17),14-pentaene [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium cyanoborohydride; In methanol; for 16h; To a solution of D94 (200 mg, 0.51 mmol) and (1 S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (346 mg, 2.56 mmol) in MeOH (25 mL) was slowly added NaBH3CN (97 mg, 1 .55 mmol) and the reaction was stirred for 16 hrs. Sat. NaHCC>3 (50 mL) was added and the mixture was stirred for 30 min. MeOH was evaporated and the mixture was filtered and extracted with DCM (3x25 mL). The combined organic layer was washed with brine, dried over Na2S04, filtered and concentrated. The crude was further chiral separated (chiral method A) to give the title compounds as yellow solids. E102: LC-MS: 474.2[M+H] +. 1H NMR (400 MHz, CDCI3): delta 7.84 (s, 1 H), 6.05 (br, 1 H), 5.1 1 (d, J= 6.8 Hz, 1 H), 4.56-4.25 (m, 3H), 4.05 (d, J= 7.6 Hz, 2H), 3.91 -3.53 (m, 3H), 3.1 1 (d, J= 9.6 Hz, 1 H), 2.47 (d, J= 10.2 Hz, 2H), 2.18 (s, 3H), 2.13-1 .72 (m, 1 1 H), 1.32 (d, J= 6.8 Hz, 3H). Chiral RT=2.841 min; ee=100percent. E103: LC-MS: 474.2[M+H] +. 1H NMR (400 MHz, CDC ): delta 7.81 (s, 1 H), 6.06 (br, 1 H), 5.1 1 (d, J= 6.8 Hz, 1 H), 4.58-4.22 (m, 3H), 4.13-3.81 (m, 3H), 3.72-3.52 (m, 2H), 3.05 (d, J= 9.6 Hz, 1 H), 2.72 (br, 1 H), 2.47-2.20 (m, 3H), 2.20 (s, 3H), 2.04-1.47 (m, 10H), 1.32 (d, J= 6.8 Hz, 3H) Chiral RT=3.031 min; ee=99.7percent. E104: LC-MS: 474.3[M+H] +. 1H NMR (400 MHz, CDCI3): delta 7.82 (s, 1 H), 6.05 (br, 1 H), 5.1 1 (d, J= 6.4 Hz, 1 H), 4.58-4.25 (m, 3H), 4.05 (d, J= 8.0 Hz, 2H), 3.90-3.53 (m, 3H), 3.10 (d, J= 9.6 Hz, 1 H), 2.47 (d, J= 9.6 Hz, 2H), 2.18 (s, 3H), 2.1 1 -1 .74 (m, 1 1 H), 1.31 (d, J= 6.8 Hz, 3H). Chiral RT=3.296 min; ee= 97.5percent E105: LC-MS: 474.2[M+H] +. 1H NMR (400 MHz, CDCI3): delta 7.81 (s, 1 H), 6.08 (br, 1 H), 5.1 1 (d, J= 6.8 Hz, 1 H), 4.61 -4.20 (m, 3H), 4.1 1 -3.80 (m, 3H), 3.70-3.56 (m, 2H), 3.09 (d, J= 9.6 Hz, 1 H), 2.73 (br, 1 H), 2.44-2.21 (m, 3H), 2.19 (s, 3H), 1.99-1.71 (m, 6H), 1.68-1.48 (m, 4H), 1 .31 (d, J= 6.8 Hz, 3H). Chiral RT= 3.539 min; ee= 99.3percent.
  • 67
  • [ 40473-01-6 ]
  • [ 31560-06-2 ]
  • C10H11ClN2O [ No CAS ]
YieldReaction ConditionsOperation in experiment
26% With triethylamine; In acetonitrile; at 160℃; for 1.66667h;Microwave irradiation; 2-bromo-5-chloropyridine (200 mg, 1.039 mmol) was dissolved in acetonitrile (2.5 mL), to this (1 S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (211 mg, 1.559 mmol) and triethylamine (0.362 mL, 2.60 mmol) were added and the suspension was irradiated in the microwave to 160C for 1 h20. The sample was then extracted between water (20 mL) and dichloromethane (20 mL). The aqueous layer was washed twice with dichloromethane. The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The crude was purified on a silica gel column using a Biotage Isolera One purification system with a dichloromethane/methanol gradient (100/0 -> 90/10) to get the product as a beige solid (57 mg, 26 %). (0876) MS: 21 1.03 (M+H)+. (0877) 1H-NMR (400 MHz, DMSO -d6) d = 8.06 (d, J = 2.6 Hz, 1 H), 7.56 (dd, J = 9.0, 2.7 Hz, 1 H), 6.57 (d, J = 9.0 Hz, 1 H), 4.80 (d, J = 2.3 Hz, 1 H), 4.65 (d, J = 2.4 Hz, 1 H), 3.76 (dd, J = 7.3, 1.5 Hz, 1 H), 3.61 (d, J = 7.3 Hz, 1 H), 3.43 (dd, J = 10.1 , 1.5 Hz, 1 H), 3.20 (d, J = 10.3 Hz, 1 H), 1.90 (dd, J = 9.7, 2.3 Hz, 1 H), 1.87 - 1.81 (m, 1 H).
  • 68
  • 6-[(pyrazin-2-yl)({5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]thiophen-2-yl}methyl)amino]pyridazine-3-carboxylic acid [ No CAS ]
  • [ 31560-06-2 ]
  • 6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl]-N-(pyrazin-2-yl)-N-({5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]thiophen-2-yl}methyl)pyridazin-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% With 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 17.5h; To a solution of compound 1 (21.0 mg, 0.0467 mmol, 1.0 eq) in DMF (1 ml_) was added A/,A/-diisopropylethylamine (32.6 mI_, 0.187 mmol, 4.0 eq), HATU (26.7 mg, 0.0701 mmol, 1.5 eq) and (1 S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (2) (12.7 mg, 0.0935 mmol, 2.0 eq). The reaction was stirred at room temperature for 17.5 h then diluted with EtOAc (10 ml_), washed with 1 M HCI (2 x 10 ml_) and brine (10 ml_), dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel chromatography using hexane/EtOAc/MeOH (1 :0:0 - 0:1 :0 - 0:4: 1 ) yielded compound FE as an off-white solid (22.2 mg, 68%). (1248) LCMS (ES): Found 530.9 [M+Hf. (1249) 1H NMR (300MHz, DMSO-cf6), d: Two rotamers in 3:2 ratio; 8.82-8.91 (m, 1 H major rotamer + 1 H minor rotamer), 8.43-8.51 (m, 1 H major + 1 H minor), 8.32- 8.40 (m, 1 H major + 1 H minor), 7.79-7.97 (m, 2H major + 2H minor), 7.70-7.78 (m, 1 H major + 1 H minor), 7.27-7.37 (m, 1 H major + 1 H minor), 5.72-5.81 (m, 2H major + 2H minor), 5.14-5.20 (m, 1 H major), 4.94-5.01 (m, 1 H minor), 4.66-4.70 (m, 1 H major), 4.60-4.66 (m, 1 H minor), 3.85-3.93 (m, 1 H major + 1 H minor), 3.77-3.85 (m, 1 H major + 2H minor), 3.69-3.76 (m, 1 H minor), 3.52-3.58 (m, 1 H major), 3.38-3.43 (m, 1 H major), 1.88-1.97 (m, 1 H major + 1 H minor), 1.79-1.88 (m, 1 H major + 1 H minor). (1250) 19F NMR (282MHz, DMSO-cf6), d: -64.79 (s, 3F).
  • 69
  • 6-[(pyrazin-2-yl)({5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]thiophen-2-yl}methyl)amino]pyridazine-4-carboxylic acid [ No CAS ]
  • [ 31560-06-2 ]
  • 5-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl]-N-(pyrazin-2-yl)-N-({5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]thiophen-2-yl}methyl)pyridazin-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% To a solution of acid 1 (50 mg, 0.1 1 mmol) in DMF (1 ml_) was added N- methylmorpholine (49 pl_, 0.45 mmol) followed by PyBOP (87 mg, 0.17 mmol). The reaction mixture was stirred for 30 min at rt before addition of (1 S,4S)-2- oxa-5-azabicyclo[2.2.1]heptane hydrochloride (30 mg, 0.22 mmol). After 2 h 20 min the reaction mixture was diluted with EtOAc (30 ml_), washed with HCI solution (5%, 3 x 10 ml_), water (10 ml_), sodium bicarbonate solution (5%, 3 x 5 ml_), and brine (10 ml_), before being dried over MgS04, filtered and concentrated in vacuo. Purification by flash column chromatography with EtOAc/MeOH (1 :0 to 9:1 ) afforded FV as pale yellow solids (45 mg, 76%). (1398) LCMS (ES): Found 530.9 [M+Hf. (1399) 1H NMR (300 MHz, DMSO-cf6) d: Two rotamers in 3:2 ratio; 9.01 (d, J=1.7 Hz, 1 H minor), 8.99 (d, J=1.7 Hz, 1 H major), 8.87 (d, J=1.5 Hz, 1 H major), 8.81 (d, J=1.3 Hz, 1 H minor), 8.36-8.43 (m, 1 H major + 1 H minor), 8.31 (d, J=2.6 Hz, 1 H major + 1 H minor), 7.87 (d, J=1.7 Hz, 1 H minor), 7.82 (d, J=1.7 Hz, 1 H major), 7.72-7.78 (m, 1 H major + 1 H minor), 7.28-7.36 (m, 1 H major + 1 H minor), 5.69- 5.86 (m, 2H major + 2H minor), 4.87 (br s, 1 H minor), 4.67 (br s, 1 H major), 4.61 (br s, 1 H minor), 4.42 (br s, 1 H major), 3.89 (d, J=7.7 Hz, 1 H major), 3.81 (d, J=7.0 Hz, 1 H minor), 3.75 (dd, J=7.9, 1.9 Hz, 1 H minor), 3.64 (dd, J=7.6, 1.4 Hz, 1 H major), 3.45-3.52 (m, 1 H major + 1 H minor), 3.26-3.32 (m, 1 H major + 1 H minor), 1.76-1.94 (m, 2H major + 2H minor). (1400) 19F NMR (282 MHz, DMSO-cf6) d: -64.80 (s, 3F).
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