Structure of 1314324-00-9
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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. : | 1314324-00-9 |
Formula : | C9H11ClFN |
M.W : | 187.64 |
SMILES Code : | N[C@H]1[C@H](C2=CC=C(F)C=C2)C1.[H]Cl |
MDL No. : | MFCD28118781 |
InChI Key : | ZQPBZLHQLCAFOQ-OULXEKPRSA-N |
Pubchem ID : | 56666982 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.33 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 48.54 |
TPSA ? Topological Polar Surface Area: Calculated from |
26.02 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 |
2.39 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.86 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.51 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.19 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.99 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.81 |
Solubility | 0.289 mg/ml ; 0.00154 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.58 |
Solubility | 0.496 mg/ml ; 0.00264 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.67 |
Solubility | 0.403 mg/ml ; 0.00215 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 |
-5.75 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) |
1.97 |
* 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 |
---|---|---|
35% | With hydrogenchloride; In ethyl acetate; at 0℃; | General procedure: Carbamate derivative 3 was taken up in anhydrous EtOAc cooled at 0 C and HCl(g) was bubbled into the solution for 40-90 min. The reaction was monitored by TLC. The resulting HCl salt was filtered and washed with diethyl ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
N,N-Diisopropylethylamine (35 μL, 0.20 mmol) was added to a mixture of (1R,2S)-2-(4-fluorophenyl)cyclopropanamine hydrochloride (Enamine, catNo.EN300-189082: 19 mg, 0.10 mmol) in methylene chloride (0.7 mL), followed by the addition of methyl 1-[4-formyl-4-(methoxymethyl)piperidin-1-yl]methyl}cyclobutanecarboxylate (42 mg, 0.15 mmol). The resulting mixture was stirred at room temperature for 1 h, then sodium triacetoxyborohydride (69 mg, 0.33 mmol) was added. The mixture was stirred at room temperature overnight then diluted with methylene chloride, washed with 1N NaOH, water and brine. Layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The intermediate methyl 1-((4-((((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)-4-(methoxymethyl)piperidin-1-yl)methyl)cyclobutanecarboxylate was dissolved in MeOH/THF (0.1 mL/0.2 mL) then 6N NaOH (0.5 mL) was added. The mixture was stirred at 30 C. overnight, cooled to room temperature and purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C23H34FN2O3 [M+H]+: m/z=405.3. found 405.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 1.0h; | Into a 100-mL round-bottom flask, was placed a solution of N-[(2S)-1-(4-methanesulfonylpiperazin-1-yl)-1,6-dioxohexan-2-yl]-N-methylbenzamide (150 mg, 0.37 mmol, 1.00 equiv) in dichloromethane (60 mL), <strong>[1314324-00-9](1R,2S)-2-(4-fluorophenyl)cyclopropan-1-amine hydrochloride</strong> (100 mg, 0.53 mmol, 1.45 equiv), Na(OAc)3BH (100 mg). The resulting solution was stirred for 1 h at room temperature. After the reaction was complete, the reaction was then quenched by the addition of water (100 mL). The resulting mixture was extracted with ethyl acetate (4×50 mL) and the organic layers were combined. The resulting mixture was washed with brine (3×50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The obtained residue was purified by silica gel column chromatography using ethyl acetate/petroleum ether (1/3). This resulted in 67 mg (34%) of N-[(2S)-6-[[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino]-1-(4-methanesulfonylpiperazin-1-yl)-1-oxohexan-2-yl]-N-methylbenzamide as an off-white solid. 1H NMR (400 MHz, CDCL3, ppm): 7.30-7.45 (m, 5H), 6.90-7.10 (m, 4H), 5.55-5.59 (m, 1H), 3.75-3.85 (m, 4H), 3.25-3.35 (m, 4H), 2.83-2.94 (m, 8H), 2.40-2.48 (m, 1H), 1.71-2.25 (m, 5H), 1.25-1.51 (m, 3H), 1.02-1.14 (m, 1H). LC/MS (ES, m/z): 545 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With triethylamine; In acetonitrile; at 80℃; for 16.0h; | Methyl 3-[[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino]-2-[[4-(1H-1,2,3-triazol-1-yl)phenyl]formamido]propanoate (0322) In a 50-mL round-bottom flask were combined the compound produced in the previous step (1.5 g, 5.51 mmol, 1.00 equiv), CH3CN (20 mL), (1S,2R)-2-(4-fluorophenyl)cyclopropan-1-amine hydrochloride (2.6 g, 13.86 mmol, 2.50 equiv) and Et3N (1.4 g, 13.84 mmol, 2.48 equiv). The resulting solution was stirred for 16 h at 80 C. in an oil bath, then diluted with 50 ml of EtOAc, washed with 1×30 mL of water and 1×30 mL of brine, dried over Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column with EtOAc/petroleum ether (2:1), affording 1 g (43%) of PH-IMA-2013-003-362-11 as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | (S)-methyl 2-[4-(1H-pyrazol-1-yl)benzamido]-3-[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}propanoate [7] (0576) To a solution of 5 (450 mg, 1.66 mmol) in acetonitrile (10 mL) was added 6 (776 mg, 4.15 mmol) followed by triethylamine (0.6 mL, 4.15 mmol). The reaction mixture was stirred under nitrogen atmosphere at 80 C. for 16 h. After this time, the reaction mixture was cooled and diluted with water (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by MS-triggered preparative HPLC to afford 7.TFA (100 mg, 14%) as a brown red gum. MS-triggered Preparative HPLC purifications were performed using a Sunfire C18 column, OBD, 10μ (30×250 mm) with UV detection at 220 nm using a solvent gradient program (15% to 55% acetonitrile/water with 0.1% trifluoroacetic acid). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In dichloromethane; water;Inert atmosphere; | A 12-L, glass round bottom flask was equipped with a N2 bleed. The flask was charged with DCM (2510 mL), (li?,25)-2-(4-fluorophenyl)cyclopropan-l-amine (0625) hydrochloride (505.00 g) and 2 N NaOH solution (NaOH, 224.10 g and purified water, 2810 mL). The contents of the flask were allowed to stir 15 minutes and dissolution was confirmed. The layers were allowed to separate and the aqueous phase was extracted with DCM (1280 mL). The combined organic phase appeared as an opaque liquid, which was transferred to a rotary evaporator bulb and concentrated to a residue at < 40 C under vacuum. The bulb was dried at 25 ± 5 C under vacuum to afford Compound 9 (413 g, 101%) as an orange oil. |
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