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Structure of 240401-22-3
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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. : | 240401-22-3 |
Formula : | C6H11ClN2 |
M.W : | 146.62 |
SMILES Code : | N#CC1CCNCC1.[H]Cl |
MDL No. : | MFCD09037930 |
InChI Key : | PKMPMUHWHIIFBJ-UHFFFAOYSA-N |
Pubchem ID : | 22744637 |
GHS Pictogram: |
![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H301-H319 |
Precautionary Statements: | P264-P270-P280-P301+P310+P330-P305+P351+P338-P337+P313-P405-P501 |
Class: | 6.1 |
UN#: | 2811 |
Packing Group: | Ⅲ |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.83 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 42.27 |
TPSA ? Topological Polar Surface Area: Calculated from |
35.82 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 |
0.81 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.93 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.42 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.08 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.65 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.26 |
Solubility | 8.07 mg/ml ; 0.055 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.14 |
Solubility | 10.5 mg/ml ; 0.0718 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.11 |
Solubility | 11.3 mg/ml ; 0.0773 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) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.62 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) |
1.18 |
* 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 |
---|---|---|
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 0.75h; | Step B: TERT-BUTYL 4-CYANOPIPERIDINE-1-CARBOXYLATE (4.87g, 23. 2MMOL) was dissolved in a solution of 4N HCl/dioxane (30mL) and stirred at rt. After 45min, starting material was no longer present by TLC, and the reaction mixture was concentrated. The product was obtained as an HC1 salt. | |
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 0.75h; | Step B: tert-Butyl 4-cyanopiperidine-1-carboxylate (4.87 g, 23.2 mmol) was dissolved in a solution of 4N HCl/dioxane (30 mL) and stirred at rt. After 45 min, starting material was no longer present by TLC, and the reaction mixture was concentrated. The product was obtained as an HCl salt. | |
2.12 g | With hydrogenchloride; In ethyl acetate; at 20℃; for 1h; | To a solution of N-Boc-4-cyanopiperidine (2.62 g, 12.4 mmol) in EtOAc (10 mL) was carefully added 10 mL HCl/EtOAc. The mixture was stirred at room temperature for 1 h. The solvent was removed by reducing pressure to afford 2.12 g white solid. The filtrate was concnetrated to dryness which was used directly in the next step directly. H NMR (CD3OD) delta 3.40-3.32 (m, 2H), 3.23-3.17 (m, 3H), 2.26-2.21 (m, 2H), 2.10-2.01 (m, 2H). |
With hydrogenchloride; In methanol; isopropyl alcohol; at 20℃; | Intermediate 42Piperidine-4-carbonitrile hydrochloride tert-Butyl 4-cyanopiperidine-l-carboxylate (2.100 g, 9.99 mmol) in methanol (15 ml) was added with HCl in z'-PrOH(3 ml, 5-6N solution). The reaction was stirred at room temperature overnight. Solvent was removed to get 1.56 g product as HCl salt. The material was directly used for the next step reaction without further purification. IH NMR (300 MHz, MeOD) delta ppm 1.82 - 2.03 (m, 2 H) 2.04 - 2.21 (m, 2 H) 3.00 - 3.15 (m, 3 H) 3.17 - 3.32 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate;palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In xylene; at 100℃; for 1h; | A mixture of 1-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]-4-butylpiperazine (50 mg, 0.123 mmol) produced in Example (57b), <strong>[240401-22-3]piperidine-4-carbonitrile hydrochloride</strong> (27 mg, 0.185 mmol), sodium t-butoxide (47 mg, 0.492 mmol), palladium(II) acetate (3 mg, 0.0123 mmol), tri-t-butylphosphonium tetrafluoroborate (11 mg, 0.0369 mmol) and xylene (1 mL) was stirred for 1 hour at an external temperature of 100 C. The reaction mixture was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 32 mg of 1-[4-(4-butylpiperazin-1-yl)-3-(4,4-dimethylcyclohexyl)phenyl]piperidine-4-carbonitrile as a colorless solid. 1H-NMR (400 MHz, CDCl3) delta: 0.94 (t, J=7.6 Hz, 3H), 0.97 (s, 3H), 1.01 (s, 3H), 1.24-1.64 (m, 12H), 1.95-2.13 (m, 4H), 2.36-2.46 (m, 2H), 2.59 (brs, 4H), 2.72-2.79 (m, 1H), 2.86 (brs, 4H), 2.91-3.05 (m, 3H), 3.31-3.41 (m, 2H), 6.72 (dd, J=8.8, 2.8 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.0 g of 1-benzyl-4-piperidinecarbonitrile was dissolved in 100 ml 1,2-dichloroethane, 7.1 ml 1-chloroethyl chloroformate was added thereto under ice-cooling. The mixture was stirred at room temperature for 15 min, and then heated under reflux for 1 hr and 20 min. After evaporating, 50 ml methanol was added thereto and it was heated under reflux for 1 hr. The reaction solution was evaporated, and the crystalline residue was washed with ethyl acetate and collected by filtration to give 8.0 g of 4-piperidinecarbonitrile hydrochloride as white crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; | A mixture of 1.2 g of the resulting 4-piperidinecarbonitrile hydrochloride, 1.0 g 1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine, 1.8 g diisopropylethylamine, and 10 ml 1-methyl-2-pyrrolidone was stirred at 170 C. for 2 hr and 30 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In a dry round bottom flask was placed <strong>[240401-22-3]4-cyanopiperidinium chloride</strong> (13, 5g, 45.4 mmol) dichloromethane (150ml) and triethylamine (18.98ml, 136 mmol). To the reaction was added dropwise ethanesulfonyl chloride (4.56 ml, 45.4 mmol) and the solution stirred 1 hour and quenched with water (100 ml). The mixture was extracted with dichloromethane (3x 50 ml) and the combined organic <n="55"/>fractions dried (MgSO4), filtered, and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes to give 1- (ethylsulfonyl)pirhoeridine-4-carbonitrile (14) as a white solid. MS 203 (M+l) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | 2-methylpropyl 2-[4-(2,3,4,5-tetrahydro-l,4-benzoxazepin-7-yl)phenyl]- lH-imidazole-1-carboxylate (361 mg, 0.92 mmol) was taken into dichloromethane (5 mL) followed by addition of DIPEA (0.32 mL, 1.84 mmol). The solution thus obtained was added slowly by syringe over several minutes to a solution of phosgene (20 W% in toluene, 0.49 mL, 0.93 mmol) diluted in dichloromethane (5 mL) and cooled to 0 0C. The resulting mixture was stirred for 5 minutes then allowed to warm to room temperature and concentrated. The residue was taken back into dichloromethane (5 mL) followed by addition of DIPEA (0.48 mL, 2.76 mmol) and <strong>[240401-22-3]4-cyanopiperidine hydrochloride</strong> salt (156 mg, 1.06 mmol) then stirred for 12h. The mixture was concentrated then partitioned with ethyl acetate and 10% aqueous citric acid. The organic solution was washed with brine, dried over anhydrous sodium sulfate then filtered and concentrated. The residue was purified by silica gel chromatography (100% ethyl acetate) to give 2-methylpropyl 2-(4-{4-[(4-cyanopiperidin-l-yl)carbonyl]-2,3,4,5- tetrahydro-l,4-benzoxazepin-7-yl}phenyl)-lH-imidazole-l-carboxylate (296 mg, 61 % yield) as a crystalline solid. MS (EI) for C30H33N5O4: 529 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; | A mixture of N,N'-di-BOC methyl {5-[4-(chlorocarbonyl)-2,3,4,5- tetrahydro-l,4-benzoxazepin-7-yl]-lH-benzimidazol-2-yl}carbamate (40 mg, 0.07 mmol), 4- cyanopiperidine hydrochloride (20 mg, 0.14 mmol), and diisoproylethylamine (0.13 mL, 0.14 mmol), in dichloromethane (2 mL) was stirred at room temperature for one hour. The mixture was concentrated and purified directly by silica gel chromatography (0-15% methanol- dichlomethane) to give N,N'-di-BOC methyl (6-{4-[(4-cyanopiperidin-l-yl)carbonyl]- 2,3 ,4,5-tetrahydro- 1 ,4-benzoxazepin-7-yl} - 1 H-benzimidazol-2-yl)carbamate as an amorphous residue. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.3 g | To a stirred suspension of compound Int 1-5 (2.12g) in 30 mL of dry THF was added compound Int 1-4 (2.7 g, 12.4 mmol), excess Ti(OPr)4, MgS04 andNa2C03. The mixture was stirred at 70C oil bath for 4 h. The mixture was cooled to room temperature, then to the stirring mixture suspension was added excess NaBH(OAc)3 and stirred for 2h. The mixture was filtrated and concentrated. The residue was purified by column to afford 3.3 g yellow solid. H NMR (CDCI3 ) delta 7.65 (s, 1H), 7.01-6.98 (m, 4H), 6.89 (s, 1H), 5.62 (q, J=6.8 Hz, 1H), 2.57-2.49 (m, 4H), 2.23-2.08 (m, 2H), 1.83 (d, J=8.4 Hz, 2H), 1.79 (d, J=7.2 Hz, 3H), 1.76-1.70 (m, 3H). MS (ESI) m/z(M+l): 313. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Example 12-10 l-(2-(l-(4-Fluorobenzyl)-3-(trifluoromethyl)-4,5-dihydro-lH-pyrazolo[3,4-c]pyridin- 6(7H)-yl)-2-oxoethyl)piperidine-4-carbonitrile TFA salt To a solution of 2-chloro-l-(l-(4-fluorobenzyl)-3-(trifluoromethyl)-4,5-dihydro- 1H- pyrazolo[3,4-c]pyridin-6(7H)-yl)ethanone (Example 12-1, step 1) (100 mg, 0.267 mmol) and <strong>[240401-22-3]piperidine-4-carbonitrile hydrochloride</strong> (78 mg, 0.533 mmol) in CH3CN (8 mL) was added Cs2C03 (174 mg, 0.533mmol). The mixture was stirred at rt for 16 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase HPLC (MeCN and H20 with 0.05% TFA as mobile phase) to give l-(2-(l-(4- fluorobenzyl)-3-(trifluoromethyl)-4,5-dihydro-lH-pyrazolo[3,4-c]pyridin-6(7H)-yl)-2- oxoethyl)piperidine-4-carbonitrie trifluoroacetate salt as a yellow solid (60 mg, yield 50%). 1H NMR (400 MHz, Methanol-d4) delta: 7.32-7.26 (m, 2H), 7.15-7.08 (m, 2H), 5.37- 5.36 (m, 2H), 4.67-4.52 (m, 2H), 4.40-4.32 (m, 2H), 3.87-3.61 (m, 4H), 3.52-3.35 (m, 1H), 3.24-2.91 (m, 2H), 2.83-2.71 (m, 2H), 2.29-2.20 (m, 4H); LCMS (ESI) m/z 450.0 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 60℃; | (1) <strong>[240401-22-3]4-cyanopiperidine hydrochloride</strong> (587mg) to a suspension of N- dimethylformamide, potassium carbonate (1.1g) was added to 2-chloro-5-nitro-nicotinic acid nitrile (609mg) under ice-cooling and, 60 It was stirred in. After the reaction, it cooled to room temperature and, after addition of water, the precipitated solid was collected by filtration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.5% | With thionyl chloride; N,N-dibutylformamide; In toluene; at 20℃; for 18h; | 11.9 g [75.7 mmol] of dibutylformamide (99%) were added to a suspension of 10 g [75.7 mmol] of isonipecotamide (97%) in 50 ml of toluene at 20C over 5 minutes. After 5 minutes, the addition of 18.91 g [158.9 mmol] of thionyl chloride at 20C was initiated. This addition required 45 minutes in which the temperature was maintained constantly at 20C. After the end of the addition, the mixture was stirred at 20C for a further 18 hours. The suspension was filtered and the filter residue was washed with toluene. After drying there remained 9.63 g of a colourless solid. Analysis by GC against a reference standard following silylation gave a 4-cyanopiperidine hydrochloride content of 99.7% (w/w). A yield of 86.5%) of theory is calculated therefrom. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 24h; | General procedure: A solution of 5-bromo-2-chloropyrimidine (CAS: 32779-36-5, 300 mg, 1.55 equiv), 3-cyanopiperidine hydrochloride (CAS:828300-57-8, 250 mg, 1.7 mmol) and DIPEA (567 muL, 3.3 mmol) in acetonitrile (3 mL) was heated at 80 C. for 4 hours. 3-Cyanopiperidine hydrochloride (CAS:828300-57-8, 125 mg, 0.85 mmol) and DIPEA (567 muL, 3.3 mmol) were again added, and the stirring at 80 C. was continued for 20 hours. The reaction mixture was diluted with DCM and washed with water. The organic phase was separated using a phase separator and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with n-heptane/ethyl acetate to give the titled compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With hydrogen sulfide; dibutylamine; In ethanol; at 60℃; under 3000.3 Torr; for 17h; | General procedure: 50 ml of ethanol, 15 g of <strong>[240401-22-3]4-cyanopiperidine hydrochloride</strong> (102.2 mmol) and 0.52 g of triethylamine (5.1 mmol) are heated to 60C in a 250 ml pressure reactor. Subsequently, hydrogen sulphide is introduced into the reactor, such that there is a constant gauge pressure of 4 bar. After 5 hours, no further hydrogen sulphide is introduced, and the reaction mixture is stirred at 60C for a further 12 hours and then cooled down to 20C. Excess hydrogen sulphide is discharged via a chlorine bleach scrubber, then the reaction mixture is cooled down further to 10C and the gas space of the reactor is purged with nitrogen for 15 minutes. The solids present in the reactor are subsequently filtered off with suction using a glass suction filter, washed once more with a little ethanol (25 ml) and dried by suction. On completion of drying at 40C under reduced pressure, 16.8 g (92.9 mmol, 91% of theory) of the desired piperidine-4-carbothioamide hydrochloride (I) are obtained in a purity of 99% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With triethylamine; In methanol; at 150℃; for 3h;Microwave irradiation; Inert atmosphere; | General procedure: A chloro substituted pyridine/pyrimidine/pyrazine (1 equivalent) and a substituted piperidine (1.5-4 equivalents, for example 3 equivalents) or salt thereof were dissolved or slurried in a suitable solvent (for example NMP, DMF or an alcohol (ethanol or methanol)) and subjected to heat either by an oil bath or using the microwave at a temperature between 120 - 160 C for 60 min to overnight (for example 90 min). Where the substituted piperidine is in the form of a HCI salt, an excess of triethylamine (TEA) is added. (0275) The reaction was routinely run in methanol and the product was isolated, upon cooling of the reaction mixture, by cooling the solution and washing with cold methanol. In the cases where the product was impure then chromatography was used to isolate the pure product. |
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