Structure of 31560-06-2
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CAS No. : | 31560-06-2 |
Formula : | C5H10ClNO |
M.W : | 135.59 |
SMILES Code : | Cl.[C@H]12CN[C@H](CO1)C2 |
MDL No. : | MFCD01569249 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
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 ? Topological Polar Surface Area: Calculated from |
21.26 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.49 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.17 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.21 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.01 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.38 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.99 |
Solubility | 13.9 mg/ml ; 0.102 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.51 |
Solubility | 42.3 mg/ml ; 0.312 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.51 |
Solubility | 41.8 mg/ml ; 0.308 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.78 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.75 |
* 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.
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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]. |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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+). |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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) |
Yield | Reaction Conditions | Operation 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 |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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]+. |
Yield | Reaction Conditions | Operation 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]+. |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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]+). |
Yield | Reaction Conditions | Operation 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). |
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