Structure of 56032-35-0
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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. : | 56032-35-0 |
Formula : | C6H6ClN3O3S |
M.W : | 235.65 |
SMILES Code : | O=[N+](C1=C(OC)N=C(SC)N=C1Cl)[O-] |
MDL No. : | MFCD29922353 |
InChI Key : | LHFPJGXWWXFDAC-UHFFFAOYSA-N |
Pubchem ID : | 21517683 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.33 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 54.08 |
TPSA ? Topological Polar Surface Area: Calculated from |
106.13 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 |
2.14 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.77 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.74 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.02 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.24 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.77 |
Solubility | 0.402 mg/ml ; 0.0017 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-4.0 |
Solubility | 0.0235 mg/ml ; 0.0000999 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.28 |
Solubility | 1.23 mg/ml ; 0.00522 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) |
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) |
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 |
-6.22 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 |
2.0 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) |
2.46 |
* 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 |
---|---|---|
a. 4-Chloro-6-methoxy-2-methylthio-5-nitro-pyrimidine, m.p. 77.5-79.5C (petroleum ether); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | at 20℃; for 3.0h; | Step 3: A mixture of 4,6-Dichloro-2-methylthio-5-nitropyrimidine (5.25 g, 21.88 mmol) in methanol (40 mL) was treated with sodium methoxide (1.3 g, 24.06 mmol). The mixture was stirred at room temperature for 3 h. At this point the reaction was poured onto ice to give a brown solid which was filtered and washed with water. The solid was dried under vacuo to give 4-Chloro-6-methoxy-2-methylthio-5-nitropyrimidine (4.40 g, 85%) as a brown solid. LRMS for C6H6Cl1N3O3S (M+H)+ at m/z=235. The NMR spectrum obtained on the sample is compatible with its structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With acetic acid; at 85℃; for 6.0h; | Step 4: A mixture of 4-Chloro-6-methoxy-2-methylthio-5-nitropyrimidine (4.40 g, 18.68 mmol) in acetic acid (30 mL) was treated with ammonium thiocyanate (2.84 g, 37.37 mmol). The mixture was stirred at 85 C. for 6h. After partial evaporation the liquid was poured onto ice to give a brown solid which was filtered and washed with water. The solid was dried under vacuo to give 4-Methoxy-2-methylthio-5-nitro-6-thicyanato-pyrimidine (2.20 g, 46%) as a brown solid. LRMS for C7H6N4O3S2 (M+H)+ at m/z=258. The NMR spectrum obtained on the sample is compatible with its structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With triethylamine; In isopropyl alcohol; at 20℃; for 0.75h; | 2,2-Diethoxyethylamine (470 μL, 3.23 mmol) was added to a suspension of pyrimidine 9 (0.63 g, 2.67 mmol) in i-PrOH (30 mL), and the mixture was stirred at r.t. until the starting compound has dissolved. Et3N (560 μL, 4.0 mmol) was then added and the mixture was stirred for a further 45 min. H2O (50 mL) was added and the product was extracted with CH2Cl2 (2 × 50 mL). The organic layers were combined, washed with H2O (2 × 20 mL), dried (Na2SO4), and concentrated. The residue was purified by flash chromatography(silica gel, CH2Cl2; Rf = 0.42) to give a yellow solid; yield: 0.61 g(69%); mp 65.5-67.5 C.IR (KBr): 3380 (NH) cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.27 (t, J = 6.9 Hz, 6 H, 2 × CH3),2.55 (s, 3 H, SCH3), 3.60 (dq, 2J = 9.3 Hz, 3J = 6.9 Hz, 2 H,2 × CHAHBCH3), 3.72-3.83 (m, 4 H, NCH2 and 2 × CHAHBCH3),4.09 (s, 3 H, OCH3), 4.68 (t, J = 5.4 Hz, 1 H, OCH), 8.84 (br s, 1 H,NH).13C NMR (75 MHz, CDCl3): δ = 14.8, 15.6, 44.3, 55.7, 63.2, 100.5,113.5, 156.6, 163.8, 174.6.Anal. Calcd for C12H20N4O5S: C, 43.36; H, 6.07. Found: C, 43.68;H, 6.11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium carbonate; at 20℃; for 6.0h; | Na2CO3 (0.49 g, 4.62 mmol) was added to a soln of pyrimidine 717(1.0 g, 4.16 mmol) in MeOH (30 mL), and the mixture was stirredat r.t. for 6 h. H2O (150 mL) was added and the resulting precipitate was collected by filtration, dried, and crystallized (hexane) to givea colorless solid; yield: 0.63 g (64%); mp 78-79 C (Lit.19 77.5-79.5 C).1H NMR (300 MHz, CDCl3): δ = 2.60 (s, 3 H, SCH3), 4.13 (s, 3 H,OCH3).13C NMR (75 MHz, CDCl3): δ = 14.8, 56.2, 128.8, 151.4, 160.9,173.8.Anal. Calcd for C6H6ClN3O3S: C, 30.58; H, 2.57. Found: C, 30.75;H, 2.54. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.73 g | With lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - 20℃; for 22.0h; | c) 1-(tert-butyl) 3-methyl 3-(6-methoxy-2-(methylthio)-5-nitropyrimidin-4-yl)azetidine-1,3-dicarboxylate (10) To a solution of 4-chloro-6-methoxy-2-methylsulfanyl-5-nitropyrimidine (4.27 g, 17.2 mmol, 1.0 eq.) (9) in tetrahydrofuran (86 ml) is added 1-(tert-butyl) 3-methyl azetidine-1,3-dicarboxylate (3.56 ml, 18.08 mmol, 1.1 eq.). The resulting heterogeneous mixture was cooled to -78 C. and 1M LiHMDS in THF (18.07 ml, 18.08 mmol, 1.1 eq.) was then added dropwise and the reaction mixture was stirred at room temperature for 22 hours. The reaction mixture was poured slowly into water and ethyl acetate. The layers were separated and the aqueous layer was subjected to re-extraction with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using dichloromethane in heptane from 50% to 100% to give the desired compound (1-(tert-butyl) 3-methyl 3-(6-methoxy-2-(methylthio)-5-nitropyrimidin-4-yl)azetidine-1,3-dicarboxylate (10)) in the form of a yellow powder (4.73 g, 66% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium methylate; In methanol; | b) 4-chloro-6-methoxy-2-methylsulfanyl-5-nitropyrimidine (9) 4,6-Dichloro-2-methylsulfanyl-5-nitropyrimidine (10.0 g, 41.6 mmol) in 102 ml of methanol are added slowly (9.49 ml, 41.6 mmol) of sodium methoxide at 30% by weight (a pale yellow precipitate forms). The reaction medium is cooled to 0 C. and the precipitate is filtered off and then rinsed twice with methanol and dried in a vacuum oven at 40 C. to give 4.62 g of a pale yellow powder. The filtrate is concentrated to dryness and then resuspended in water, filtered and dried in a vacuum oven at 40 C. to obtain a further 5.5 g of pale yellow powder. The two fractions obtained contain 70% of the expected product (4-chloro-6-methoxy-2-methylsulfanyl-5-nitropyrimidine-(9)) and 30% of the dimethoxy analog. |
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