Structure of 10429-82-0
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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. : | 10429-82-0 |
Formula : | C11H16Cl3N |
M.W : | 268.61 |
SMILES Code : | ClCCN(CC1=CC=CC=C1)CCCl.[H]Cl |
MDL No. : | MFCD00185654 |
InChI Key : | AZRWNJFEUSHORT-UHFFFAOYSA-N |
Pubchem ID : | 2777881 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 15 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.45 |
Num. rotatable bonds | 6 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 70.09 |
TPSA ? Topological Polar Surface Area: Calculated from |
3.24 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 |
3.74 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.62 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.6 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.47 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.88 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.76 |
Solubility | 0.0465 mg/ml ; 0.000173 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.5 |
Solubility | 0.0849 mg/ml ; 0.000316 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-5.0 |
Solubility | 0.0027 mg/ml ; 0.0000101 mol/l |
Class? Solubility class: Log S scale |
Moderately 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) |
Yes |
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 |
-5.28 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 |
1.0 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) |
1.38 |
* 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 |
---|---|---|
85% | Step 1: A stirred solution of <strong>[99365-48-7]4-bromoindolin-2-one</strong> (13.0 g, 61.3 mmol) inTHF (500 mL) was treated by the dropwise addition of a l.OM THF solution of NaHMDS (306 mL, 306 mmol) at -780C under nitrogen. After stirring at -78C for 30 minutes, N- benzylbis(2-chloroethyl)amine hydrochloride (18.05 g, 67.4 mmol) was added as a solid. The reaction mixture was stirred at -78C for 30 minutes and then allowed to warm to room temperature. The reaction mixture was then heated to reflux for 12 hours. After cooling to 00C, the reaction was quenched by the addition of saturated aqueous NH4Cl solution. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3 X 200 mL). The combined organics layers were washed with brine, dried with MgSO4 and concentrated under reduced pressure. The resulting solid was triturated with DCM/EtOAc to give r-benzyl-4-bromospiro[indoline-3,4'-piperidin]-2-one (19.3 g, 85%) as a solid. LCMS (APCI+) m/z 371/373 [M+H]+; Rt = 2.71 min. | |
General procedure: To a suspension of 5-methoxy-1H-pyffolo[3,2-b]pyridin-2(3H)-one (1.85 g, 11.3 mmol, CAS RN 178393-14-1) in THF (80 mL) at -78C was added dropwise LiHMDS (50.3 mL, 50.3 mmol, 1M solution in THF) and the brown solution was stirred at this temperature over 30 mm. before N-benzyl-2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (3 g, 11.2 mmol, CAS RN 10429-82-0) was added in one portion. The cooling bath was then removed and the mixture wasallowed to warm up to RT. Heating was installed and the light brown suspension was stuffed at reflux for 24 hours. The light brown reaction mixture was poured on saturated aqueous NH4C1 solution and EtOAc and the layers were separated. The aqueous layer was twice extracted with EtOAc. The organic layer was dried over Mg504, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 40 g column using an MPLCsystem eluting with a gradient of n-heptane : EtOAc (100: 0 to 0: 100). The product containing fractions were combined. The precipitate formed during evaporation was filtered off to afford the title product as a light brown solid (0.288 g; 8%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.8% | With N-ethyl-N,N-diisopropylamine; In ethanol; for 16h;Reflux; | A mixture of <strong>[42303-42-4]ethyl <strong>[42303-42-4]1-aminocyclopropanecarboxylate hydrochloride</strong></strong> (120 g, 0.725 mol), N,N- diisopropylethylamine (942 g, 7.29 mol), N-benzyl-2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (213 g, 0.793 mol) in anhydrous ethanol (1.6 L) was stirred under reflux for 16 h. TLC (PE:EtOAc = 5:1,f= 0.4) showed that most of the starting material was consumed. Then the mixture was concentrated. The residue was partitioned between dichloromethane (1 L) and water (0.5 L). The layers were separated and the aqueous layer was extracted with dichloromethane (0.5 L x 2). The combined organic layers were concentrated. The residue was purified by chromatography on silica gel (PE:EtOAc = 20:1 to 10:1) to give ethyl l-(4-benzylpiperazin-l-yl)cyclopropanecarboxylate (100 g, 47.8%) as a light yellow oil.1H-NMR (400MHz, chloroform-di): delta [ppm] = 0.88-0.97 (m, 2H), 1.23-1.36 (m, 5H), 2.37 (br. S, 4H), 2.98 (br. S, 4H), 3.51 (s, 2H), 4.15 (q, 2H), 7.23-7.36 (m, 5H). |
47.8% | With N-ethyl-N,N-diisopropylamine; In ethanol; for 16h;Reflux; | A mixture of <strong>[42303-42-4]ethyl <strong>[42303-42-4]1-aminocyclopropanecarboxylate hydrochloride</strong></strong> (120 g, 0.725 mol), N,N- diisopropylethylamine (942 g, 7.29 mol), N-benzyl-2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (213 g, 0.793 mol) in anhydrous ethanol (1.6 L) was stirred under reflux for 16 h. TLC (PE:EtOAc = 5:1, Rf = 0.4) showed that most of the starting material was consumed. Then the mixture was concentrated. The residue was partitioned between dichloromethane (1 L) and water (0.5 L). The layers were separated and the aqueous layer was extracted with dichloromethane (0.5 L x 2). The combined organic layers were concentrated. The residue was purified by chromatography on silica gel (PE:EtOAc = 20:1 to 10:1) to give ethyl l-(4-benzylpiperazin-l-yl)cyclopropanecarboxylate (100 g, 47.8%) as a light yellow oil. 1H-NM (400MHz, chloroform-di): delta [ppm] = 0.88-0.97 (m, 2H), 1.23-1.36 (m, 5H), 2.37 (br. S, 4H), 2.98 (br. S, 4H), 3.51 (s, 2H), 4.15 (q, 2H), 7.23-7.36 (m, 5H). |
43% | With N-ethyl-N,N-diisopropylamine; In ethanol; for 16h;Reflux; | A mixture of ethyl 1- aminocyclopropanecarboxylate hydrochloride (2.4 g, 14.5mmol), N-benzyl-2-chloro-N-(2- chloroethyl)ethanamine hydrochloride (4.26 g, 15.8 mmol), and N,N-Diisopropylethylamine (25 mL) in ethanol (32 mL) was stirred at reflux for 16 hours. The reaction mixture was concentrated to dryness. The residue was partitioned between dichloromethane and water. Two layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were concentrated. The residue was purified by silica gel column (pet. ether/EtOAc = 1 :0-10: 1 ) to give ethyl l-(4-benzylpiperazin-l-yl)cyclopropanecarboxylate (1-61-2, 1.8 g, yield: 43%) as a yellow oil. 1H NMR (400 MHz, CDC13) delta: 7.37-7.27 (m, 5H), 4.19-4.13 (m, 2H), 3.54 (s, 2H), 3.00(brs, 2H), 2.39 (brs, 2H), 1.31-1.26 (m, 5H), 7.52 (m 1H), 0.93-0.91 (m, 2H). |
24% | With sodium hydrogencarbonate; In ethanol; at 80℃; for 4h; | N-Benzyl-2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (obtained in the previous step, 10.37 g, 38.61 mmol) was added to a solution of <strong>[42303-42-4]ethyl <strong>[42303-42-4]1-aminocyclopropanecarboxylate hydrochloride</strong></strong> (6.4 g, 38.6 mmol) and NaHCO3 (17.5 g, 208.5 mmol) in EtCH (200 mL). The reaction mixture was stirred at 80 C for 4 hand overnight at rt. The solvent was concentrated and the crude product was diluted with AcOEt and water. The layers were separated and the organic layer was driedover Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel, eluents CH/AcOEt (100:0 to 0:100) to give the title compound (2.86 g, 24% yield).HPLC-MS (Method A): Ret, 2.26 mm; ESl-MS m/z, 289 (M÷1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
132 mg | First, sodium bis(trimethylsilyl) amide (1.0 M tetrahydrofuran solution) (1.6 mL) was added dropwise to a solution of <strong>[500912-18-5]2-<strong>[500912-18-5](2-fluoro-6-methoxyphenyl)acetonitrile</strong></strong> (86 mg) in tetrahydrofuran (2.4 mL) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. N-benzyl-bis(2-chloroethyl)amine hydrochloride (140 mg) was added to the resultant solution, followed by reflux for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then was dried with anhydrous magnesium sulfate. the solvent was removed by evaporation under reduced pressure. The obtained residue was purified by silica gel column chromatography (diethylether/n-hexane = 50/50) to obtain 1-benzyl-4-(2-fluoro-6-methoxyphenyl)piperidine-4-carbonitr ile (132 mg). 1H-NMR (400MHz, CDCl3) delta: 2.28-2.37(m,2H),2.43-2.50(m,2H),2.50-2.59(m,2H),2.89-2.98(m ,2H),3.58(s,2H),3.91(s,3H),6.67(ddd,J=12.9,8.4,1.2Hz,1H),6. 74(d,J=8.3Hz,1H),7.21-7.29(m,3H),7.29-7.36(m,4H). |
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