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Structure of 175204-45-2
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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. : | 175204-45-2 |
Formula : | C6H4BrCl2N |
M.W : | 240.91 |
SMILES Code : | ClC1=CC(CBr)=CC(Cl)=N1 |
MDL No. : | MFCD00052637 |
InChI Key : | XDKGMGJZRFOZRV-UHFFFAOYSA-N |
Pubchem ID : | 2781829 |
GHS Pictogram: |
![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H302-H314 |
Precautionary Statements: | P260-P264-P270-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501 |
Class: | 8 |
UN#: | 3261 |
Packing Group: | Ⅱ |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.17 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 47.09 |
TPSA ? Topological Polar Surface Area: Calculated from |
12.89 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.25 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.33 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.13 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.49 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.64 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.97 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.81 |
Solubility | 0.0374 mg/ml ; 0.000155 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.28 |
Solubility | 0.127 mg/ml ; 0.000528 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.52 |
Solubility | 0.00728 mg/ml ; 0.0000302 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) |
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) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.41 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 |
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) |
2.01 |
* 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 |
---|---|---|
23% | 121 mg of sodium hydride as a 60% suspension in oil (3.05 mmol) are introduced at room temperature into a 50 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 20 ml of DMF and 500 mg of 26 (2.03 mmol). The medium is stirred for 1 hour and 489 mg (2.03 mmol) of 4-bromomethyl-2,6-dichloropyridine are then added. The medium is stirred for 3 hours, 50 ml of EtOAc and 50 ml of water are added to the reaction medium and, after separation of the phases by settling, the organic phase is washed once with 50 ml of water. The organic phase is dried, filtered and then evaporated to dryness. 1.5 g of crude product are recovered, which product is chromatographed on a silica cartridge (20 g) with an 80/20 heptane/EtOAc mixture. 190 mg of product 36 are recovered (yield=23%). 1H NMR (300 MHz, DMSO-d6), δ (ppm): 1.39 (s, 9H); from 2.59 to 2.79 (m, 4H); 3.67 (m, 1H); 3.94 (m, 1H); 4.32 (d, J=16.5 Hz, 1H); 4.81 (partially masked m, 1H); 4.87 (d, J=16.5 Hz, 1H); 6.80 (d, J=6.5 Hz, 1H); 7.46 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | EXAMPLE 29 2,6-dichloro-4(((4-phenylpiperidin-4-yl)methoxy)methyl)pyridine. This compound was prepared according to the experimental condition of intermediate 5 from 4-(bromomethyl-2,6-dichloro)pyridine (131 mg, 0.55 mmoL), and and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (145 mg, 0.50 mmol) to afford 50.0 mg (22%) of the desired compound. The resulting residue was taken directly towards deprotection following the procedure outlined in Example 28 to afford 10 mg (5% overall) of the desired compound as the TFA salt. 1H-NMR (CD3OD,400 MHz) δ7.34-7.48 (m, 5H), 7.10 (s, 2H), 4.43 (s, 2H), 3.49 (s, 2H) 3.29-3.40 (m, 2H), 2.89-2.96 (m, 2H), 2.50-2.56 (m, 2H), 2.15-2.19 (m, 2H). Mass spec.: 351.10 (MH)+. EXAMPLE 30 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With hydrogenchloride; caesium carbonate; In dimethyl sulfoxide; | (1f) At rt, cesium carbonate (1.4 g) was added to a solution of the phenol (436 mg) and 2,6-dichloro-4-bromomethylpyridine (1.04 g) in 4 mL of dimethylsulfoxide. After 3 h, the reaction was quenched with 1N aqueous HCl, to pH=7. The mixture was partitioned between ethyl acetate and 1N aqueous HCl then extracted with ethyl acetate (3*). The combined organic extracts were dried (Na2SO4), concentrated and chromatographed to give the product (473 mg, 71% yield). MS (M+H)+=463. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[1(R)]-3-[4-[(2,6-dichloro-4-pyridinyl)methoxy]phenyl]-N1-hydroxy-α1-(1-methylethyl)-2-oxo-N3-(4-pyridinylmethyl)-1,3-pyrrolidinediacetamide Beginning with the phenol from (780e) and 4-bromomethyl-2,6-dichloropyridine, example 781 was prepared in an analogous series of reactions to (780f-i). MS found: (M+H)+ =600. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[1(R)]-α-[3-amino-3-[4-[(2,6-dichloro-4-pyridinyl)methoxyl]phenyl]-2-oxo-1-pyrrolidinyl]-N-hydroxy-4-piperidineacetamide bis(trifluoroacetate) Beginning with the phenol from (501c) and 4-bromomethyl-2,6-dichloropyridine, example 502 was prepared in an analogous series of reactions to (6b), (92d) and example 117. MS found: (M+H)+ =508. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With potassium carbonate; potassium iodide; In acetone; at 60℃; for 3h; | EXAMPLE 21 rac-6-Chloro-3-(2,6-dichloro-pyridin-4-ylmethyl)-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one A mixture of rac-3-(3-methoxy-phenyl)-6-chloro-1,3-dihydro-indol-2-one (82 mg, 0.3 mmol) (from Example 6b supra), 4-bromomethyl-2,6-dichloro-pyridine (85.3 mg, 0.35 mmol) (Maybridge), potassium iodide (59.2 mg, 0.35 mmol) and potassium carbonate (89.2 mg, 0.645 mmol) in acetone (3 mL) was heated at 60 C. for 3 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate and extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(2,6-dichloro-pyridin-4-ylmethyl)-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a light brown solid. (Yield 60 mg, 45%). HRMS(ES+) m/z Calcd for C21H15Cl3N2O2+H [(M+H)+]: 433.0272. Found: 433.0273. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate; potassium iodide; In acetone; at 60℃; for 2h; | EXAMPLE 23 rac-5-[6-Chloro-3-(2,6-dichloro-pyridin-4-ylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester A mixture of 5-[6-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl]-3,4-dihydro-2H-pyridine-carboxylic acid tert-butyl ester (0.32 g, 0.9 mmol) (from Example 20a supra), 4-bromomethyl-2,6-dichloro-pyridine (0.26 g, 1.08 mmol) (Maybridge), potassium iodide (0.18 g, 1.08 mmol) and potassium carbonate (0.27 g, 1.97 mmol) in acetone (30 mL) was heated at 60 C. for 2 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate and washed with water and brine. Aqueous layers were back washed with ethyl acetate. The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by chromatography (ethyl acetate-dichloromethane, 25:75, V/V) to give rac-5-[6-chloro-3-(2,6-dichloro-pyridin-4-ylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a white solid. (Yield 0.28 g, 60%). HRMS(ES+) m/z Calcd for C24H24Cl3N3O3+H [(M+H)+]: 508.0956. Found: 508.0957. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(S)-4-methyl-2-(( 1 -((2-(trimethylsilyl)ethoxy) methyl)- 1H-tetrazol-5 -yl)methyl)pentanoic acid (II’TERMEDL&TE 30, 483 mg, 1.47 mmol) was dissolved in THF (15 ml) and cooled to -78C then LDA (4.38 ml, 3.68 mmol. 0.84 M) was added. The reaction was stirred for 45 mins then <strong>[175204-45-2]4-(bromomethyl)-2,6-dichloropyridine</strong> (425 mg, 1.764 mmol) in THF was added. The reaction mixture was stirred at -78C for 5 hrs, then quenched with saturated NH4C1 solution, extracted with EtOAc (2x) then dried (Na2504), filtered and concentrated. The residuewas purified by reverse phase MPLC with ACN and water buffered with 0.05% TFA to yield (S)-2-((S)-2-(2,6-dichloropyridin-4-yl)- 1 -(1 -((2-(trimethylsilyl)ethoxy) methyl)- 1H-tetrazol-5- yl)ethyl)-4-methylpentanoic acid. LC/MS [M+H]+: 488. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.1 g | With N-Bromosuccinimide; triphenylphosphine; In tetrahydrofuran; at 0℃; for 2h; | To a solution of (2,6-dichloropyridin-4-yl)methanol [0794] in tetrahydrofuran was added triphenylphosphine and N-bromosuccinimide at 0 C. and the reaction mixture was stirred at same temperature. After 2 h, the reaction mixture was diluted with water and extracted with ethyl acetate (3×150 mL). The combined organic layer was washed with brine (2×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford a crude product which was purified by column chromatography to afford 1.1 g of 4-(bromomethyl)-2,6-dichloropyridine [0795] as colorless liquid. MS(M+1)+=241.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | To the suspension of sodium hydride in THF was added 2-Pyrrolidone (1.76 g, 20.75 mmol) at 0 C. under nitrogen atmosphere and stirred at same temperature for 45 mins. The reaction mixture was added slowly to an ice cooled solution of 4-(bromomethyl)-2, 6-dichloropyridine (2.5 g, 10.37 mmol) in THF under nitrogen atmosphere. The reaction mixture was slowly warmed to rt and stirred at rt for 20h. The reaction was quenched with water and extracted in ethyl acetate, washed with water and brine solution. The organic layer was dried over sodium sulphate, filtered and concentrated to afford crude product, which was purified by column chromatography using ethyl acetate in pet-ether as solvent to afford 1-((2, 6-dichloropyridin-4-yl)methyl)pyrrolidin-2-one as yellow solid (1.4 g, 53%). MS (M+1)+=247.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.96 g | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; for 16h; | The procedure is similar to step 2[0720] in example 2 (at 90 C.). 1.1 g of <strong>[175204-45-2]4-(bromomethyl)-2,6-dichloropyridine</strong> [0795] gave 0.96 g of 2,6-dichloro-4-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)pyridine [0796] as brown solid. MS(M+1)+=257.2. |
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