Structure of 39895-56-2
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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. : | 39895-56-2 |
Formula : | C8H11NO |
M.W : | 137.18 |
SMILES Code : | NCC1=CC=C(CO)C=C1 |
MDL No. : | MFCD06213766 |
Boiling Point : | No data available |
InChI Key : | WMOUKOAUAFESMR-UHFFFAOYSA-N |
Pubchem ID : | 6496943 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 40.24 |
TPSA ? Topological Polar Surface Area: Calculated from |
46.25 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.53 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.21 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.33 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.94 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.28 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.86 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.13 |
Solubility | 10.1 mg/ml ; 0.0733 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.74 |
Solubility | 24.9 mg/ml ; 0.182 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.24 |
Solubility | 0.784 mg/ml ; 0.00571 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 |
No |
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) |
Yes |
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 |
-6.99 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) |
1.0 |
* 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 |
---|---|---|
99% | In dichloromethane; at 20℃; for 48h; | Boc2O was added in one portion at r.t. to a solution of (4-aminomethyl-phenyl)-methanol Compound 3a (21.2 mmol, 2.9 g) in CH2C12 (100 mL). The resulting solution wasstirred for 48h, then washed with a 10percent citric acid solution (50 mL) followed by brine. Theorganic layer was separated, then dried over Na2SC>4 and filtered. The solvent was removed invacua to obtain (4-hydroxymethyl-benzyl)-carbamic acid tert-butyl ester Compound 3b as awhite solid (5.2 g, 99percent yield), which was used in the next step without further purification.MnO2 (9.6 g) was added to a solution of Compound 3b (21.2 mmol, 5.2 g) inchloroform (60 mL), forming a black suspension that was stirred at r.t. overnight then filteredthrough a pad of celite. The solvent was evaporated in vacua to obtain (4-forinyl-benzyl)-carbamic acid tert-butyl ester Compound 3c as a white solid (4.3 g, 87percent yield), which was usedin the next step without purification.; NaB(OAc)3H (2.8 mmol, 0.58 g) was added to a mixture of Compound 3c (2.6 mmol,0.6 g) and tetrahydro-pyran-4-ylamine Compound 3d (2.6 mmol, 0.26 g) in CH2C12 (25 mL)and the resulting suspension was stirred at r.t. An aliquot of the reaction mixture showed theformation of product (MS m/e 321; 100percent). An aqueous solution of formaldehyde (37percentsolution, 8.6 mmol, 0.7 mL) was added to the reaction mixture, followed by NaB(OAc)3H (2.8mmol, 0.58 g) added in one portion under ice cooling. The reaction mixture was stirred at r.t.for about 2h, then made basic with a 2N NaOH solution and extracted with CH2C12. Theorganic layer was washed with brine, then separated and dried over Na2SO4. The drying agentwas filtered and the solvent was removed in vacua to yield (4-[methyl-(tetrahydro-pyran-4-yl)-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester Compound 3e as a pale yellow oil.MS m/e 235 (M+H, 100percent). The product was purified by column chromatography (4:1CH2Cl2:MeOH) to yield a colorless oil (0.52 g, 59percent yield).; Compound 3e was dissolved in CH2Cl2, then HC1 in dioxane was added and themixture was stirred at r.t. for 12 hrs. The solvent was removed and the gummy residue wasmade basic with 2N NaOH and extracted with EtOAc. The organic layer was washed withbrine, then separated and dried over Na2SO4. The drying agent was filtered and the solvent wasremoved in vacua to obtain (4-aminomethyl-benzyl)-methyl-(tetrahydro-pyran-4-yl)-amineCompound 3f as a pale yellow oil (0.3 g, 83percent yield). MS m/e 235 (M+H, 100percent).; A solution of 3-(3-trifluoromethyl-phenyl)-acryloyl chloride Compound 3g (0.3 mrnol,0.07 g) in THF (2 mL) was added dropwise to a solution of Compound 3f (0.2 mmol, 0.05 g)and Et3N (0.8 mmol, 0.14 mL) in THF (10 mL) at 0°C. The resulting suspension was allowedto warm to r.t. overnight. The reaction mixture was made basic with a 2N NaOH solution andextracted with EtOAc (25 mL). The aqueous layer was extracted with EtOAc (2X10 mL) andthe organic layers were washed with brine, then dried over Na2SO4 and filtered. The solventwas removed in vacua to yield a yellow solid (with methane) as the product. The crude productwas purified by preparative TLC (9:1 EtOAc-.MeOH, Rf = 0.2) to yield N-(4-[methyl-(tetrahydro-pyran-4-yi)-amino]-methyl}-benzyi)-3-(3-trifluoromethyl-phenyl)-acrylamideCompound 3h (0.06 g, 49percent yield). MS m/e 433 (M+H, 100percent).; Mel (0.08 mL, 1.28 mmol) was added dropwise to a solution of Compound 3h (0.07mmol, 0.03 g) in a mixture of acetone:acetonitrile (2 mL). The resulting solution was stirred atr.t. for 24h to provide a residue. The residue was washed with ether (2x 1 mL) and dried undera high vacuum to provide Compound 64 (0.04 g, 93percent yield) as an iodide salt. MS m/e 584(M+H, 100percent). |
99% | In dichloromethane; at 20℃; for 48h; | Boc2O was added in one portion at r.t. to a solution of (4-aminomethyl-phenyl)-methanol Compound 3a (21.2 mmol, 2.9 g) in CH2Cl2 (100 mL). The resulting solution was stirred for 48 h, then washed with a 10percent citric acid solution (50 mL) followed by brine. The organic-layer was separated, then dried over Na2SO4 and filtered. The solvent was removed in vacuo to obtain (4-hydroxymethyl-benzyl)-carbamic acid tert-butyl ester Compound 3b as a white solid (5.2 g, 99percent yield), which was used in the next step without further purification. |
88% | In chloroform;Inert atmosphere; | 1.7 l-'Butoxycarbonylaminomethyl-4-hydroxymethyl benzene, 7.7Amine 6 (1.44g, 10.5 mmol) was dissolved in CHCI3 (50 ml) and Boc20 (2.29 g, 10.5 mmol, 1 eq) was added slowly. The reaction was stirred under nitrogen overnight before the solvent was evaporated and the residue obtained was dissolved in ethyl acetate (50 ml). This solution was washed with a citric acid solution (3 * 50 ml), brine (50 ml), dried over Na2S04, and evaporated to yield 7 as a white solid (2.20 g, 9.2 mmol, 88 percent). Rf = 0.57 (DCM / MeOH sat. N3/4, 8:2); Vmax = cm-1; 'H NMR (300 MHz, CDC13) delta - 7.33 (d, 3J(H,H) = 8.2 Hz, 2H, ArCH a to CH2OH), 7.26 (d, J(H,H) = 8.2 Hz, 2H, ArCH a to CH2NHBoc), 4.86 (bs, 1H, NHBoc), 4.68 (s, 2Eta, CH^OH), 4.30 (d, 3J(H,H) = 5.7 Hz, 2H, CH?NHBoc), 1.96 (bs, 1H, OH), 1.46 (s, 9Eta, C(CH?)3); l 3C NMR (75 MHz, CDC13) delta = 155.9 (CO), 140.0 (ArCCH2OH), 138.3 (ArCCH2NHBoc), 127.6 (ArCH a to CH2NHBoc), 127.2 (ArCH a to CH2OH), 85.2 (C(CH3)3), 65.0 (C3/4OH), 44.4 (CH2NHBoc), 28.4 (C(C3/4)3); HRMS (ESI+): m/z calculated for C,3Hi9N03Na [M + Na]+ : 260.1257, found 260.1253. |
31% | In dichloromethane; at 20℃; | The mixture of (4-(aminomethyl)phenyl)methanol (1 g, 7.29 mmol) and di-tert-butyl dicarbonate (1.59 g, 7.29 mmol) in dichloromethane (30 mL) was stirred at room temperature overnight then concentrated under reduced pressure and the crude product was added to a silica gel column and was eluted with dichloromethane:ethyl acetate (1:1) to give tert-butyl 4-(hydroxymethyl)benzylcarbamate (0.8 g, 2.28 mmol, 31percent yield) as a white solid.1H NMR (400 MHz, DMSO-d6) delta ppm 7.37 (s, 1H), 7.22 (dd, J = 27.8, 8.0 Hz, 4H), 5.13 (t, J = 5.7 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H), 4.10 (d, J = 6.1 Hz, 2H), 1.36 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.87 g | With triethylamine; In dichloromethane; at 0 - 20℃; for 22.0h; | 20.0 g (0328) (132 mmol) of 4-(aminomethyl)benzoic acid was dispersed in 100 mL of anhydrous THF, and 350 mL (2.65 equiv.) of 1M borane-THF in THF was added dropwise. The reaction mixture was heated to reflux for eight hours, and then allowed to cool to room temperature. 100 mL of MeOH was added to quench the remaining borane-THF, and the reaction was stirred for an additional 15 minutes. The reaction solution was then filtered over celite and evaporated in vacuo to give a light yellow solid. 250 mL of DCM was then added to the reaction flask containing the crude intermediate product, followed by 37 mL (2 equiv.) of triethylamine. The reaction was cooled to 0C, 21 mL (1.1 equiv.) of trifluoroacetic anhydride was added dropwise and the reaction was allowed to stir overnight, allowing it to gradually reach room temperature. After 22 hours of reaction time, all of the starting material had been consumed as evidenced by TLC. 250 mL of water was added to the reaction and the organic layer was separated. The aqueous layer was extracted once more with 250 mL of DCM, the combined organics were washed with water (100 mL), and were dried over sodium sulfate, filtered and evaporated in vacuo to give a thick yellow oil. This oil was purified via automated flash chromatography (EPCLC W-Prep 2XY, Yamazen Corp., Yodogawa-Ku Osaka, Japan) using DCM/MeOH as the eluents. The fractions containing the desired product were combined and evaporated to give 15.87 g (51.44% yield for both steps) of 3 as a white solid. lH NMR (300 MHz, CDC13) δ 7.34 (d, J = 8.17 Hz, 2H), 7.26 (d, J = 8.16 Hz, 2H), 6.86 (s, br, 1H), 4.66 (s, 2H), 4.49 (d, J = 5.86 Hz, 2H), 2.02 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; In methanol; at 25℃; for 2.0h;Inert atmosphere; | A solution of 2.55 g of 4-(aminomethyl)benzyl alcohol (18.6 mmol) and 2.64 mL of triethylamine (18.68 mmol) was dissolved in 25 mL of anhydrous methanol, 2.94 mL of ethyl trifluoroacetate (24.6 mmol) was added dropwise under argon atmosphere, and 25 C stirring reaction 2 hours, after the end of the reaction, adding 35mL ethyl acetate and 35mL water extraction,The ethyl acetate layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate overnight. The solvent was removed in vacuo to give crude 4-[(trifluoroacetamido)methyl]benzyl alcohol. The crude product was purified by silica gel column chromatography the eluent was eluted with ethyl acetate / cyclohexane (1: 2, v / v). To give 4-[(trifluoroacetamido)methyl]benzyl alcohol (3.9 g, 20.6 mmol) in 90% yield. |
76% | With triethylamine; In dichloromethane; at 20℃; for 4.0h;Inert atmosphere; | 4-aminomethylbenzyl alcohol (500 mg, 2.89 mmol) was dissolved in 3 ml DCM.TEA (3.0 eq, 1.169 ml, 8.4 mmol) was added dropwise and kept under argon atmosphere. Afterwards, 400 µl (1.2 eq, 3.36 mmol) of EtTFA were added dropwiseand the mixture was stirred in argon atmosphere at room temperature for 4 hr.The reaction was followed up by TLC (DCM:MeOH 5%). The reaction mixture dissolvedin DCM and was washed with brine and the organic phase dried with MgSO4.The organic phase was filtered and evaporated. The crude of the reaction was purified by chromatography (silica gel), eluted with a gradient of 0-5% MeOH inDCM. Yield (1, 500 mg, 76%, white solid). |
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