Structure of 914612-23-0
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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. : | 914612-23-0 |
Formula : | C14H14ClN3 |
M.W : | 259.73 |
SMILES Code : | ClC1=C(CN(CC2=CC=CC=C2)CC3)C3=NC=N1 |
MDL No. : | MFCD08273929 |
InChI Key : | RPJAAZOTUXKSEV-UHFFFAOYSA-N |
Pubchem ID : | 25324046 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 18 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.29 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 75.77 |
TPSA ? Topological Polar Surface Area: Calculated from |
29.02 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.66 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.56 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.0 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.07 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.28 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.52 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.42 |
Solubility | 0.0977 mg/ml ; 0.000376 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.82 |
Solubility | 0.396 mg/ml ; 0.00152 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-5.36 |
Solubility | 0.00113 mg/ml ; 0.00000437 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) |
Yes |
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) |
Yes |
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) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.07 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 |
0.0 |
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<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.18 |
* 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 |
---|---|---|
79% | With N,N-dimethyl-formamide; trichlorophosphate; In acetonitrile; at 70℃; for 16.0h; | To a solution of the product from the previous step (100 mg, 0.414 mmol) in acetonitrile (1.7 mL) was added POCb (68 mu, 0.72 mmol) and DMF (13 mu, 0.17 mmol) and the resulting mixture was stirred at 70 C for 4 h. Additional POCI3 (113 mu, 1.2 mmol) was added and the mixture was stirred at 70 C for 12 h. The mixture was concentrated and the residue was taken up in CH2CI2 (10 mL) and partitioned with aqueous sat. NaHC03 (2 mL). The aqueous layer was extracted with CH2CI2 (3 x 3 mL) and the combined organic layers were washed with NaHC03 (1 mL), brine (1 mL), dried over Na2S04, filtered and concentrated. The residue was purified via silica gel chromatography (0 - 10 % MeOH in CH2CI2) to afford the title compound (85 mg, 79 % yield) as a brown liquid.MS (ES+) C14H14CIN3 requires: 259, found: 260 [M+H]+. |
57.8% | 6-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine A mixture of <strong>[109229-22-3]6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one</strong> (5.0 g, 0.02 mol), phosphoryl chloride (3.30 mL, 0.035 mol) and acetonitrile (80 mL) and DMF (catalytic amount) was heated to at 70 C. for 1 hour. The mixture was reduced in vacuo and the remaining black residue was taken up in dichloromethane (250 ml) and poured over ice. The mixture was carefully neutralized with the addition of solid sodium bicarbonate. The layers were separated and the organic dried over sodium sulfate and reduced in vacuo. The mixture was chromatographed using an ethyl acetate:hexanes (0-100%) gradient on an isco flash chromatography system. The combined pure fractions were reduced in vacuo to yield the title compound as a yellow oil (3 g, 57.8%). MS: M+H=260. 1H NMR (DMSO-d6): delta 8.80 (s, 1H). 7.40-7.24 (m, 5H), 3.76 (s, 2H), 3.57 (s, 2H), 2.92 (t, 2H), 2.80 (t, 2H). | |
57.8% | Intermediate 26-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine A mixture of <strong>[109229-22-3]6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one</strong> (5.0 g, 0.02 mol), phosphoryl chloride (3.30 mL, 0.035 mol) and acetonitrile (80 mL) and DMF (catalytic amount) was heated at 70 C. for 1 hour. The mixture was concentrated in vacuo and the remaining black residue was taken up in dichloromethane (250 mL) and poured over ice. The mixture was carefully neutralized with the addition of solid sodium bicarbonate. The organic layer was separated and dried over sodium sulfate and concentrated in vacuo. The mixture was purified by silica gel column with EtOAc/hexane (0-100%) to yield the title compound as a yellow oil (3 g, 57.8%). LC-MS: 260 [M+1]+; 1H NMR (400 MHz, DMSO-d6): delta 8.80 (s, 1H), 7.40-7.24 (m, 5H), 3.76 (s, 2H), 3.57 (s, 2H), 2.92 (t, 2H), 2.80 (t, 2H). |
57.8% | INTERMEDIATE 26-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine[00274] A mixture of <strong>[109229-22-3]6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one</strong> (5.0 g,0.02 mol), phosphoryl chloride (3.30 mL, 0.035 mol) and acetonitrile (80 mL) and DMF (catalytic amount) was heated at 70 0C for 1 hour. The mixture was concentrated in vacuo and the remaining black residue was taken up in dichloroniethane (250 mL) and poured over ice. The mixture was carefully neutralized with the addition of solid sodium bicarbonate. The organic layer was separated and dried over sodium sulfate and concentrated in vacuo. The mixture was purified by silica gel column with EtOAc/hexane (0-100%) to yield the title compound as a yellow oil (3 g, 57.8%). MS: 260 [M+l]+; 1H NMR (400 MHz, DMSO-d6): 8.80 (s, IH), 7.40-7.24 (m, 5H), 3.76 (s, 2H), 3.57 (s, 2H), 2.92 (t, 2H), 2.80 (t, 2H). | |
With trichlorophosphate;N,N-dimethyl-formamide; In acetonitrile; for 3.0h;Reflux; | A mixture of <strong>[109229-22-3]6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one</strong> 1 from Intermediate I, step A(5.0 g, 0.02 mol), phosphorous oxychloride (3.30 mL, 0.035 mol) and acetonitrile (80 mL) and DMF (catalytic amount) was heated at reflux for 3 hours. Then the solvents were reduced in vacuum and the remaining black residue was taken up in dichloromethane (250 mL) and poured over ice. The mixture was carefully neutralized with the addition of solid sodium bicarbonate to pH~8. The layers were separated and the organic was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography to yield compound 2 as a yellow oil (3 g). MS (ESEI): 242.1 [M+l]+ ] NMR (DMSO-d6): delta 8.80 (s, 1Eta).7.40-7.24 (m, 5H), 3.76 (s, 2H), 3.57 (s, 2H), 2.92 (t, 2H), 2.80 (t, 2H). | |
A mixture of 6-benzyl-5f6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one 1 from Intermediate I, step A (5.0 g, 0.02 mol), phosphorous oxychloride (3.30 mL, 0.035 mol) and acetonitrile (80 mL) and DMF (catalytic amount) was heated at reflux for 3 hours. Then the solvents were reduced in vacuum and the remaining black residue was taken up in dichloromethane (250 mL) and poured over ice. The mixture was carefully neutralized with the addition of solid sodium bicarbonate to pH~8. The layers were separated and the organic was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography to yield compound 2 as a yellow oil (3 g). MS (ESEI): 242.1 [M+lf ¾ NMR (DMSO-d6): 8 8.80 (s, 1Eta).7.40-7.24 (m, 5H), 3.76 (s, 2H), 3.57 (s, 2H), 2.92 (t, 2H), 2.80 (t, 2H). |
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