Structure of 875629-26-8
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 875629-26-8 |
Formula : | C5H9NO2 |
M.W : | 115.13 |
SMILES Code : | O=C(C1CN(C)C1)O |
MDL No. : | MFCD11520621 |
InChI Key : | OQTWISXQJKXTEM-UHFFFAOYSA-N |
Pubchem ID : | 20653078 |
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 | 0.8 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 32.62 |
TPSA ? Topological Polar Surface Area: Calculated from |
40.54 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.12 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-2.71 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.75 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.38 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.23 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.59 |
Log S (ESOL):? ESOL: Topological method implemented from |
1.22 |
Solubility | 1910.0 mg/ml ; 16.6 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (Ali)? Ali: Topological method implemented from |
2.41 |
Solubility | 29600.0 mg/ml ; 257.0 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
0.48 |
Solubility | 347.0 mg/ml ; 3.01 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 |
-8.93 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 |
2.0 |
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) |
1.0 |
* 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 |
---|---|---|
94% | With hydrogen;palladium 10% on activated carbon; In methanol; water; under 3000.3 Torr; | EXAMPLE IX1-methyl-azetidine-3-carboxylic acid200 mg azetidine-3-carboxylic acid are dissolved in 10 ml of methanol, combined with 165 mul of a 37percent solution of formaldehyde in water as well as 20 mg 10percent palladium on charcoal and hydrogenated at 4 bar until the hydrogen uptake has ended.Then the catalyst is eliminated by suction filtering, the solvent is eliminated in vacuo, the residue is taken up in methanol and toluene and the solvents are again eliminated in vacuo.Yield: 214 mg (94percent of theory)Mass spectrum (ESI+): m/z=116 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0848] Synthesis of Compound B-8: N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)- 1 -isopropyl-6-( 1 -( 1 -methylazetidine-3 -carbonyl)piperidin-4-yl)- 1 H- pyrazolo[3,4-b]pyridine-4-carboxamideCompound B-8[0849] Step 1 : Synthesis of N-((4,6-dimethyl-2-oxo-l ,2-dihydropyridin-3-yl)methyl)-l- isopropyl-6-( 1 -( 1 -methylazetidine-3-carbonyl)- 1 ,2,3 ,6-tetrahydropyridin-4-yl)- 1 H- pyrazolo [3 ,4-b]pyridine-4-carboxamide[0850] N-((4,6-dimethyl-2-oxo-l ,2-dihydropyridin-3-yl)methyl)-l-isopropyl-6-(l , 2,3,6- tetrahydropyridin-4-yl)-lH-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was dissolved in DMSO, to which Et3N (3 equiv.) and 1 -methylazetidine-3 -carboxylic acid (2 equiv.) was added. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equiv.) was added to it and stirring was continued overnight. After completion of the reaction, water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2S04; filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; HATU; In fluorobenzene; at 20.0℃; for 3h; | 1 -methylazetidine-3 -carboxylic acid (172.5 mg, 1.50 mmol, 1.50 eq.), HATU (456 mg, 1.20 mmol, 1.20 eq.) andDIEA (387 mg, 2.99 mmol, 3.00 eq.) were added to a solution of 5-phenyl-N-trans-3- (hydrazinecarbonyl)cyclobutyl]isoxazole-3-carboxamide (300 mg, 1.00 mmol, 1.00 eq., prepared according to example 20) in DMF (15 mL). The resulting solution was stirred for 3 hours at room temperature and then it was concentrated under vacuum. The crude product waspurified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18; mobile phase, MeCN/H20 = 5:95 increasing to MeCN/H20 = 95:5 within 15 mm; Detector, UV 254 nm. This resulted in 337 mg (85percent) of 5-phenyl-N-[trans-3-[[(1-methylazetidin-3- yl)formohydrazido]carbonyl]cyclobutyl] isoxazole-3 -carboxamide as a yellow solid. LC-MS (ES, mlz): [M+H] = 398. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20.0℃; for 2h; | 1 -methylazetidine-3- carboxylic acid (172.5 mg, 1.50 mmol, 1.50 eq.), HATU (570 mg, 1.50 mmol, 1.50 eq.) and DIEA (387 mg, 2.99 mmol, 3.00 eq.) were added to a solution of 3-phenyl-N-[trans-3- (hydrazinecarbonyl)cyclobutyl]-isoxazole-5-carboxamide (300 mg, 1.00 mmol, 1.00 eq.) in DMF (10 mL) and then stirred for 2 hours at room temperature. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C I 8; mobile phase, MeCN/H20 = 5:95 increasing to MeCN/H20 = 95:5 within 30 min; Detector, UV 254 nm to give 200 mg (50percent) of 3-phenyl-N-[/ra5-3-[[(l -methylazetidin-3- yl)formohydrazido]carbonyl]cyclobutyl]-isoxazole-5-carboxamide as an off-white solid; LC- MS (ES, m/z): [M+H]+ = 398.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | 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 20.0℃; for 2h; | 1 -methylazetidine-3 - carboxylic acid (172.5 mg, 1.50 mmol, 1.50 eq.), HATU (570 mg, 1.50 mmol, 1.50 eq.) and DIEA (387 mg, 2.99 mmol, 3.00 eq.) were added to a solution of 3-phenyl-N-[trans-3- (hydrazinecarbonyl)cyclobutylj -isoxazole-5 -carboxamide (300 mg, 1.00 mmol, 1.00 eq.) inDMF (10 mL) and then stirred for 2 hours at room temperature. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18; mobile phase, MeCN/H20 = 5:95 increasing to MeCN/H20 = 95:5 within 30 mm; Detector, UV 254 nm to give 200 mg (50percent) of 3-phenyl-N-[trans-3-[[(1-methylazetidin-3- yl)formohydrazidoj carbonyll cyclobutyll -isoxazole-5-carboxamide as an off-white solid; LC20 MS (ES, m/z): [M+Hj = 398.0. |
50% | 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 20.0℃; for 2h; | 1 -methylazetidine-3 -carboxylic acid (172.5 mg, 1.50 mmol, 1.50 eq.), HATU (570 mg, 1.50 mmol, 1.50 eq.) andDIEA (387 mg, 2.99 mmol, 3.00 eq.) were added to a solution of 3-phenyl-N-[trans-3-(hydrazinecarbonyl)cyclobutylj -isoxazole-5 -carboxamide (300 mg, 1.00 mmol, 1.00 eq.) inDMF (10 mL) and then stirred for 2 hours at room temperature. The crude product waspurified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18;mobile phase, MeCN/H20 = 5:95 increasing to MeCN/H20 = 95:5 within 30 mm; Detector,UV 254 nm to give 200 mg (50percent) of 3-phenyl-N-[trans-3-[[(1-methylazetidin-3- yl)formohydrazidoj carbonyll cyclobutyll -isoxazole-5-carboxamide as an off-white solid; LCMS (ES, m/z): [M+Hj = 398.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20.0℃; for 3h; | l-methylazetidine-3- carboxylic acid (172.5 mg, 1.50 mmol, 1.50 eq.), HATU (456 mg, 1.20 mmol, 1.20 eq.) and DIEA (387 mg, 2.99 mmol, 3.00 eq.) were added to a solution of (hydrazinecarbonyl)cyclobutyl]isoxazole-3-carboxamide (300 mg, 1.00 mmol, 1.00 eq., prepared according to example 20) in DMF (15 mL). The resulting solution was stirred for 3 hours at room temperature and then it was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, CI 8; mobile phase, MeCN/H20 = 5:95 increasing to MeCN/H20 = 95:5 within 15 min; Detector, UV 254 nm. This resulted in 337 mg (85percent) of 5-phenyl-N-[fras-3-[[(l-methylazetidin-3- yl)formohydrazido]carbonyl]cyclobutyl]isoxazole-3-carboxamide as a yellow solid. LC-MS (ES, m/z): [M+H]+ = 398. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10 mg | A mixture of 2-(4-aminophenyl)-3-(pyridin-3-yl)quinazolin-4(3H)-one hydrochloride (50 mg, 0.13 mmol), l-methylazetidine-3-carboxylic acid (41 uL, 0.33 mmol), (1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (162 mg, 0.42mmol), diisopropylethyl amine ( 0.15 mL, 0.7 mmol) in dimethylformamide (1 mL) was stirred for 18 hours. The reaction was filtered and then purified by reverse phase -HPLC (3-35percent acetonitrile /water) to give the title compound (23 mg). The sample was converted to an HCl salt with 4N HCl in dioxane (10 mg). LC/MS: RT = 2.76 minutes, purity > 95percent, (M+l)+ = 412.02. NMR (300MHz, CD3OD) delta = 8.53 (d, /=8.2 Hz, 1H), 8.46 - 8.30 (m, 1H), 8.17 - 7.92 (m, 3H), 7.92 - 7.81 (m, 1H), 7.81 - 7.65 (m, 3H), 7.58 - 7.42 (m, 2H), 4.62 - 4.39 (m, 2H), 4.30 - 4.05 (m, 2H), 3.92 - 3.69 (m, 1H), 3.02 - 2.85 (m, 4H), 1.41 - 1.21 (m, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12 mg | A mixture of 2-(4-aminophenyl)thieno[3,2-d]pyrirnidin-4(3H)-one hydrochloride (43 mg, 0.15 mmol), diisopropylethyl amine (0.15 mL), (l-[bis(dimethylamino)methylene]-l.H-l ,2,3-triazoo[4,5- b]pyridinium 3-oxid hexafluorophosphate) (134 mg, 0.35 mmol), l-methylazetidine-3-carboxylic acid (36 mg, 0.31 mmol) and dimethylformamide (2 mL) was stirred for 18 hours. The reaction was filtered and then purified by reverse phase HPLC (3-35percent acetonitrile/water). To the product (26 mg) in ethyl acetate/methanol was added 4N HC1 in dioxane. The mixture was stirred 30 mins. The solid was collected by filtration, washed with ethyl acetate and dried to give the desired HC1 salt (12 mg). LC/MS: RT = 2.59 minutes, purity > 95percent, (M+l)+ = 341.02.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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 20.0℃; for 18h; | [0377] To 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S,4S)-2-(methylamino)-4-(3-(trifluoromethyl)-phenyl)cyclohexyl)amino)-N-(pyrimidin-4-yl)benzenesulfonamide (20 mg, 0.03 mmol) in DMF (0.3 mL) was added <strong>[875629-26-8]1-methylazetidine-3-carboxylic acid</strong> (5 mg, 0.04 mmol) followed by N,N-diisopropylethylamine (20 uL, 0.11 mmol) and HATU (13 mg, 0.03 mmol). The reaction mixture was stirred at room temperature for 18 hours then diluted with water and EtOAc. The organic layer was separated and washed with saturated aqueous NaHCO3, then aqueous saturated brine solution, dried over Na2SO4, filtered and concentrated to provide N-((1S,2S,5S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(pyrimidin-4-yl)sulfamoyl)-5-fluorophenyl)amino)-5-(3-(trifluoromethyl)phenyl)cyclohexyl)-N,1-dimethylazetidine-3-carboxamide which was used directly in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 47 2-((2-ethyl-7-methyl-5-(6-(1-methylazetidine-3-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrazolo[1,5-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile (Compound 47) Compound 47 was prepared from 44b and <strong>[875629-26-8]1-methylazetidine-3-carboxylic acid</strong> in a manner analogous to Example 31. 1H NMR (400 MHz, CDCl3) delta 8.15 (dd, J=8.6, 5.5 Hz, 2H), 7.15 (t, J=8.6 Hz, 2H), 5.97 (s, 1H), 5.83 (d, J=2.6 Hz, 1H), 3.91-3.81 (m, 6H), 3.69 (s, 1H), 3.56 (t, J=5.9 Hz, 6H), 3.48-3.40 (m, 3H), 2.78-2.71 (m, 2H), 2.69 (d, J=2.1 Hz, 3H), 2.45 (d, J=4.1 Hz, 3H), 2.24 (t, J=6.9 Hz, 1H), 2.14 (t, J=7.0 Hz, 1H), 1.35-1.28 (m, 3H). LC-MS (ESI): m/z=599.3 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 84 2-((2-cyclopropyl-7-methyl-5-(6-(1-methylazetidine-3-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile (Compound 84) The title compound was prepared by the method substantially similar to that mentioned in Step 3 (Example 77), using <strong>[875629-26-8]1-methylazetidine-3-carboxylic acid</strong> afford Compound 84 as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 8.21-8.11 (m, 2H), 7.16 (t, 2H), 5.92 (s, 1H), 5.81 (d, 1H), 4.27 (s, 2H), 4.18 (s, 2H), 4.10-3.98 (m, 4H), 3.89 (t, 2H), 3.61 (s, 3H), 3.44 (dt, 3H), 2.62 (s, 3H), 2.50 (s, 3H), 1.93-1.78 (m, 1H), 1.12-0.88 (m, 4H). LC-Ms m/z (ESI): 597.3[M+H+] |
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