Structure of 70298-88-3
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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. : | 70298-88-3 |
Formula : | C10H14N2O |
M.W : | 178.23 |
SMILES Code : | CC(C(=O)NC1=CC=CN=C1)(C)C |
MDL No. : | MFCD00996243 |
InChI Key : | VQXVCVTZSTYIMG-UHFFFAOYSA-N |
Pubchem ID : | 4655044 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.4 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 52.71 |
TPSA ? Topological Polar Surface Area: Calculated from |
41.99 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.86 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.81 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.88 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.88 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.57 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.6 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.23 |
Solubility | 1.05 mg/ml ; 0.0059 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.31 |
Solubility | 0.87 mg/ml ; 0.00488 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.23 |
Solubility | 0.104 mg/ml ; 0.000585 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 |
-6.1 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) |
1.64 |
* 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 |
---|---|---|
70% | The reaction was performed according to a procedure in the literature (J. Org. Chem. 1988, 53, 2740-2744). A 3 L three-neck round-bottom flask was equipped with a mechanical stirrer, thermocouple, nitrogen inlet, and drying tube and placed in a cooling bath. The flask was charged with 2,2-dimethyl-N-(3-pyridyl)propanamide (42, 40 g), tetramethylethylenediamine (TMEDA, 84 mL) and THF (1400 mL), and stirring was initiated. The reaction mixture was cooled to -78 C. A suspension formed. n-BuLi (224 mL) was added over at least a 15 minute period at a rate to keep the temperature below -65 C. The reaction mixture was stirred continually at -78 C. for 15 minutes before being stirred for 2 h at -10 C. A yellow to white precipitate slowly developed. The reaction mixture was cooled back to -78 C. A solution of iodine (142 g) in THF (480 mL) was added over 30 minutes. The temperature increased from -78 C. to -65 C. The reaction mixture was stirred continually for 2 h at -78 C. The reaction mixture was continually stirred at -78 C. until the reaction was deemed complete, i.e., upon disappearance of 2,2-dimethyl-N-(3-pyridyl)propanamide (42). If reaction was not complete, it was stirred continually at -78 C. for additional 1 h then monitored again. The reaction was monitored by TLC (SiO2, [7:3] EtOAc:Hept, UV, two developments) by partitioning an aliquot of the reaction mixture (1 mL) between EtOAc (1 mL) and saturated ammonium chloride solution (3 mL), agitating, allowing the layers to separate, and spotting the organic layer. The starting material (2,2-dimethyl-N-(3-pyridyl)propanamide, 42) had an RF of 0.25, and the product (N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide, 43) had an RF of 0.33. Typically, the reaction conversion was 80% to product based on TLC. Materials used to synthesize N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide (43) are shown in Table 34. To isolate the product (N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide, 43), the reaction mixture was poured into a saturated (10%) NH4Cl solution (100 mL). The mixture was extracted with ethyl acetate (2×500 mL). The combined organic layer was washed with a saturated (10%) sodium thiosulfate solution (2×100 mL) to remove excess iodine and brine (200 mL). The organic layer was dried over MgSO4 and charcoal, filtered through glass fiber filter paper, and concentrated to dryness. The above crude material was purified by passing through a silica plug (4 g of SiO2/1 g of crude mixture), and eluting the plug with 10-50% ethyl acetate in heptanes. All fractions that contained compound were combined and concentrated under reduced pressure at 45 C. to yield a beige solid. The solid was dried under vacuum at 25 C. for a minimum of 5 hours.N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide (43, lot No. 1358-77-1) was a beige solid, synthesized with a yield of 48 g (70%). N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide (43) was analyzed using HPLC (MPP-LC1, 240 nm), and according to results, it was 95.9% pure. 1H-NMR (300 MHz, CDCl3) was used to confirm the identity of N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide (43). | |
38% | A solution of 2,2-dimethyl-N-pyridin-3-ylpropanamide [(1g, 5.61mmol), J. Org. Chem, 48(20), 3401;1998] in tetrahydrofuran (10mL) and diethyl ether (30mL) was cooled to -78C and TMEDA (2.1mL, 14mmol) and nbutyl lithium (1.6M in hexane, 8.8mL, 14mmol,) were added dropwise. The mixture was stirred for 15 minutes and was then warmed to -10C and stirred for a further 2 hours. The reaction mixture was again cooled to -78C and a solution of iodine (3.56g, 14mmol) in tetrahydrofuran (10mL) was added dropwise. The resulting slurry was stirred at -78C for 2 hours. The mixture was warmed to 0C and was quenched with saturated aqueous sodium thiosulfate solution (50mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2x30mL). The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluding with pentane:ethyl acetate, 50:50 afforded the title compound as a yellow solid in 38% yield, 655mg. 1H-NMR(CDCl3, 400MHz) δ: 1.38(s, 9H), 7.65(bs, 1H), 7.73(d, 1H), 7.97(d, 1H), 9.35(s, 1H) MS APCI+ m/z 305 [MH]+ | |
37% | To a solution of 2,2-dimethyl-N-pyridin-3-yl-propionamide (7 g, 39.32 mmol) in THF (50 mL) was added TMEDA (20 mL, CAS RN 110-18-9) at 25 C. The mixture was cooled to-70 C., n-butyllithium was added (66 mL, 1.6M solution in n-hexane, CAS RN 109-72-8) within a period of 30 min under an atmosphere of argon. The reaction mixture was allowed to stir at -15 C. for 1 h, followed by another 1 h at 0 C. The reaction mixture was re-cooled to -70 C., then a solution of iodine (29.2 g, 115.1 mmoL) in THF (120 mL) was added slowly during 1 h, and the resultant mixture was allowed to stir at 25 C. for 16 h. Water and saturated aqueous Na2S2O3 solution was added to the mixture, and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude residue which was purified by column chromatography over silica gel (40% EtOAc in n-hexane) to give the title compound. Pale yellow solid (800 mg, 37%). MS (ESI): m/z=305.4 [M+H]+. |
23% | Preparation 5; N-(4-Iodo-pyridin-3-yl)-2,2-dimethyl-propionamide; Equip a 250 mL 3 -neck round bottom flask with: a magnetic stirrer, a thermocouple, a dry ice/acetone bath, a nitrogen atmosphere, and an addition funnel. Charge 2,2-dimethyl-N-pyridin-3-yl-propionamide (3.0 g, 16.8 mmol), diethyl ether (67 mL), tetramethylene diamine (4.68 g, 6.08 mL, 40.3 mmol). Cool the reaction to -78 0C. Add slowly via glass syringe w-butyllithium (2.5 M solution in hexane, 16.2 mL, 40.3 mmol) over 10 min. Allow the reaction to warm to -13 0C over 2 hours. Cool the <n="10"/>-9-reaction to -78 0C. Add an iodine solution (8.5 g, 33.6 mmol in 20 mL THF) to the reaction via the addition funnel and mix 2.5 hours at -68 0C. Quench the reaction by the addition of saturated aqueous NH4Cl solution (40 mL). Extract with ethyl acetate (100 mL) and discard the aqueous phase. Wash the organic layer with a saturated aqueous sodium thiosulfate solution (100 mL) and saturated aqueous sodium chloride. Dry the organic phase over sodium sulfate and filter. Concentrate in vacuo to give brown oil. Chromatograph on silica (80 g) eluting with a gradient of 100 % dichloromethane to 70 % ethyl acetate /30 % dichloromethane to afford the title compound (1.19 g, 23 %). MS (ES) m/z 305 [M+ 1]+ | |
23% | Preparation 65N-(4-Iodo-pyridin-3-yl)-2,2-dimethyl-propionamide Equip a 250-mL round bottom flask with a magnetic a stirrer, a thermocouple, a dry ice/acetone bath, a ν2 atmosphere, and an addition funnel. Charge with 2,2-dimethyl- N-pyridin-3-yl-propionamide (3.0 g, 16.8 mmol), diethylether (67 mL), and tetramethylene diamine (4.68 g, 6.08 mL, 40.3 mmol). Cool the reaction to -78 0C. Add slowly via glass syringe w-butyllithium (2.5 M solution in hexane, 16.2 mL, 40.3 mmol) over 10 min. Warm the reaction to -13 0C over 2 h. Cool the reaction to -78 0C. Prepare an iodine solution (I2 8.5 g, 33.6 mmol in THF (20 mL)). Add the iodine solution to the reaction via the addition funnel and stir 2.5 h. at -68 0C. Quench the reaction with the addition of a saturated NH4Cl solution (40 mL) and transfer into a separatory funnel. Add ethyl acetate (100 mL). Extract and discard the lower aqueous phase. Wash the organic layer with a saturated sodium thiosulfate solution (100 mL) and extract. Wash the organic phase with saturated aqueous sodium chloride and extract. Dry the organic phase over Na2SO4 and filter. Concentrate the product via rotary evaporation. Chromatograph on silica (80 g) eluting with gradient of 100 % DCM to 70 % ethyl acetate/30 % DCM to afford 1.19 g (23 %) of the title compound. MS (ES) mk 306 [M+ 1]+. | |
To a solution of 2,2-dimethyl-N-pyridin-3-yl-propionamide (7 g, 39.32 mmol) in THF (50 mL) was added TMEDA (20 mL, CAS RN 110-18-9) at 25 C. The mixture was cooled to -70 C, n-butyllithium was added (66 mL, 1.6M solution in n-hexane, CAS RN 109-72-8) within a period of 30 min under an atmosphere of argon. The reaction mixture was allowed to stir at -15 C for 1 h, followed by another 1 h at 0 C. The reaction mixture was re-cooled to -70 C, then a solution of iodine (29.2 g, 115.1 mmoL) in THF (120 mL) was added slowly during 1 h, and the resultant mixture was allowed to stir at 25 C for 16 h. Water and saturated aqueous Na2S203 solution was added to the mixture, and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo to afford the crude residue which was purified by column chromatography over silica gel (40% EtOAc in n-hexane) to give the title compound. Pale yellow solid (800 mg, 37%). MS (ESI): m/z = 305.4 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
700 mg (23%) | With n-butyllithium; iodine; In tetrahydrofuran; | EXAMPLE 10 Compounds of the following general formula II-10 may be made, for example by the following general scheme. Iodopyridine 16. The 3-(Pivaloylamino)pyridine 15 (1.9 g, 11 mmol) and tetramethylethylene-diamine (4.0 mL, 26 mmol) were dissolved in dry THF (60 mL) and cooled to -78 C. While maintaining the temperature between -78 C. and -65 C., nBuLi (2.5 M solution in hexanes, 10.6 mL, 26.5 mmol) was added dropwise. The reaction was allowed to warm to -10 C. for 2 h, and then cooled back down to -78 C. Iodine (6.73 g, 26.5 mmol) dissolved in dry THF (20 mL) was added slowly. After stirring for 2 h at -78 C., the reaction was quenched with ice. Excess iodine was destroyed with addition of saturated potassium thiosulfate solution. The product was extracted with CH2Cl2, and the organic layers were washed with brine. The mixture was concentrated in vacuo to a black oil which was chromatographed (1:1 EtOAc/Hexanes; 2:1 EtOAc/Hexanes) to give 700 mg (23%) of 2,2-dimethyl-N-(4-iodo-3-pyridinyl)propanamide as a yellow solid. 1H-NMR (DMSO-d6 300 MHz) δ 9.24 (s, 1H), 8.35 (s, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 1.26 (s, 9H). MS (ES+)=305. |
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