Structure of 99724-19-3
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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. : | 99724-19-3 |
Formula : | C9H18N2O2 |
M.W : | 186.25 |
SMILES Code : | O=C(NC1CNCC1)OC(C)(C)C |
MDL No. : | MFCD00059040 |
InChI Key : | DQQJBEAXSOOCPG-UHFFFAOYSA-N |
Pubchem ID : | 2757234 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.89 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 54.49 |
TPSA ? Topological Polar Surface Area: Calculated from |
50.36 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.24 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.7 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.49 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.56 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.55 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.91 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.17 |
Solubility | 12.5 mg/ml ; 0.0673 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.34 |
Solubility | 8.61 mg/ml ; 0.0462 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.76 |
Solubility | 3.21 mg/ml ; 0.0173 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 |
Yes |
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 |
-6.94 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) |
2.64 |
* 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 |
---|---|---|
0.4%; 81.7% | With potassium hydroxide; In methanol; at 15 - 20℃; for 1h;pH 11.8 - 12.2; | 60 g of methanol and 8.6 g (0.1 mols) of (S)-3-aminopyrrolidine (Chemical purity 99.8 %, optical purity 99.5 % ee - hereinafter referred to as S-AP) were fed into a 200-ml 4-neck flask equipped with a stirrer, a pH sensor and two strapped dropping funnels, and stirred at 15 to 20C. 21.8 g (0.1 mols) of di-tertiary butyl dicarbonate (by Tokyo Chemical) was fed into it via one dropping funnel, and 25 g (0.11 mols) of methanolic solution of 25 % potassium hydroxide was thereinto via the other dropping funnel. With stirring at 15 to 20C, di-tertiary butyl dicarbonate was dropwise added to the reaction system over a period of about 1 hour. During this, the methanolic solution of 25 % potassium hydroxide was dropwise added thereto so as to make the reaction system have a pH of from 11.8 to 12.2. The reaction mixtures were analyzed for its composition, and it comprised 4 % of the starting 3-aminopyrrolidine, 86.7 % of the product, 3-amino-1-tertiary butoxycarbonylpyrrolidine (hereinafter referred to as 1-BocAP), and 8.4 % of 1-tertiary butoxycarbonyl-3-tertiary butoxycarbonylaminopyrrolidine (hereinafter referred to as DiBocAP). After the reaction, the reaction mixtures were concentrated under reduced pressure to make 32 g. 100 g of toluene was added to the concentrated solution, and inorganic salts were precipitated with stirring. The precipitated crystals were filtered away, and the filtrate was distilled under reduced pressure to obtain a fraction at 120 to 125C/0.7 kPa, (S)-3-amino-1-tertiary butoxycarbonylpyrrolidine. Its weight was 15.2 g, and its yield was 81.7 %. (Chemical purity 99.1 %; optical purity 99.5 % ee. ) The positional isomer, 3-tertiary butoxycarbonylaminopyrrolidine was 0.4 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20 - 100℃; for 0.375h; | A vial was charged with 4-chloro-7-fluoro-quinazoline (2.00 g, 11.0 mmol) (WO 9609294 A1), pyrrolidin-3-yl-carbamic acid tert-butyl ester (2.05 g, 11.0 mmol), DMSO (2.64 mL), and DIPEA (2.10 mL, 12.0 mmol) in quick succession. The mixture was stirred at "rt" for 20 min, during which time the reaction spontaneously warmed and became a homogeneous reddish-brown solution. The reaction was then stirred at 100 C. for 2.5 min to ensure complete reaction. The solution was shaken with water (20 mL) to dissolve the DMSO into the aqueous phase, and was extracted with EtOAc (1*20 mL). The organic layer was washed with 4 M NaCl (1*20 mL) and dried (Na2SO4). Upon addition of Na2SO4 to the organic phase, the title compound began to precipitate out. This was collected by filtration (easily decanted from the wet drying agent), dried, and powdered to afford the title compound as an off-white powder (1.42 g, 39%). |
39% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20 - 100℃; for 0.375h; | EXAMPLE NO. 70; 1-(4-Isopropyl-phenyl)-3-(1-{7-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-quinazolin-4-yl}-pyrrolidin-3-yl)-urea (Compound No. 70); a. [1-(7-Fluoro-quinazolin-4-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester; A vial was charged with 4-chloro-7-fluoro-quinazoline (2.00 g, 11.0 mmol) (WO 9609294 A1), pyrrolidin-3-yl-carbamic acid tert-butyl ester (2.05 g, 11.0 mmol), DMSO (2.64 mL), and DIPEA (2.10 mL, 12.0 mmol) in quick succession. The mixture was stirred at “rt” for 20 min, during which time the reaction spontaneously warmed and became a homogeneous reddish-brown solution. The reaction was then stirred at 100 C. for 2.5 min to ensure complete reaction. The solution was shaken with water (20 mL) to dissolve the DMSO into the aqueous phase, and was extracted with EtOAc (1×20 mL). The organic layer was washed with 4 M NaCl (1×20 mL) and dried (Na2SO4). Upon addition of Na2SO4 to the organic phase, the title compound began to precipitate out. This was collected by filtration (easily decanted from the wet drying agent), dried, and powdered to afford the title compound as an off-white powder (1.42 g, 39%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of EXAMPLE 7A (168.3 mg), <strong>[162167-97-7]tert-butyl 3-(aminomethyl)piperidine-1-carboxylate</strong> (107 mg), and N,N-diisopropylethylamine (450 muL) in acetonitrile (4.0 mL) was heated in a microwave reactor for 10 minutes at 50° C., and 20 minutes at 190° C., cooled, treated with tert-butyl pyrrolidin-3-ylcarbamate (112 mg), heated in a microwave reactor for 30 minutes at 100° C., cooled and concentrated. A solution of the concentrate in a mixture of tetrahydrofuran (2 mL) and methanol (1 mL) was treated with sodium hydroxide (2M, 800 muL), stirred for 4 hours at 50° C., cooled, concentrated, treated with water, acidified to pH 6 with 1M HCl, and filtered. The solid was treated with trifluoroacetic acid (2 mL), stirred for 2 hours at 25° C., and concentrated. The concentrate was purified by reverse phase high performance liquid chromatography (HPLC) on a C8 column with 10-100percent acetonitrile in water containing 0.1percent trifluoroacetic acid. NMR (300 MHz, DMSO-d6) delta ppm 8.94 (s, 1H), 8.80-8.67 (m, 1H), 8.44-8.16 (m, 4H), 8.10 (d, 1H), 4.46-4.34 (m, 2H), 4.08-3.82 (m, 4H), 3.28-3.10 (m, 2H), 2.86-2.67 (m, 2H), 2.44-2.26 (m, 2H), 2.19-2.06 (m, 1H), 1.87-1.20 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.48 g | With sodium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h; | To a stirred solution of <strong>[10386-27-3]2-bromo-4-cyanopyridine</strong> (CAS Number 10386-27-3; 0.500 g, 2.73 mmol) and tert-butyl pyrrolidin-3-ylcarbamate (CAS Number 99724-19- 3; 0.509 g, 2.73 mmol) in DMF (10 ml) was added Na2CO3 (0.578 g, 5.46 mmol). The reaction mixture was stirred at rt for 16 h. The resulting mixture was diluted with water (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with brine solution (50 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (18percent EtOAc in hexane) yielding tert-butyl (1 -(4-cyanopyridin-2- yl)pyrrolidin-3-yl)carbamate (0.480 g, 1 .67 mmol). LCMS: Method C, 1 .871 min, MS: ES+ 289.48. |
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