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Structure of 70258-18-3
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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. : | 70258-18-3 |
Formula : | C6H5Cl2N |
M.W : | 162.02 |
SMILES Code : | ClCC1=CN=C(Cl)C=C1 |
MDL No. : | MFCD00125366 |
InChI Key : | SKCNYHLTRZIINA-UHFFFAOYSA-N |
Pubchem ID : | 155479 |
GHS Pictogram: |
![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H302-H314 |
Precautionary Statements: | P260-P264-P270-P280-P301+P312+P330-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P363-P405-P501 |
Class: | 8 |
UN#: | 3261 |
Packing Group: | Ⅱ |
Num. heavy atoms | 9 |
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 | 39.01 |
TPSA ? Topological Polar Surface Area: Calculated from |
12.89 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.83 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.2 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.32 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.75 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.97 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.21 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.66 |
Solubility | 0.356 mg/ml ; 0.0022 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.1 |
Solubility | 1.27 mg/ml ; 0.00786 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.65 |
Solubility | 0.0362 mg/ml ; 0.000223 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) |
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 |
-5.73 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 |
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) |
1.6 |
* 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 |
---|---|---|
With thionyl chloride; In chloroform; | (b) Preparation of 2-chloro-5-chloromethylpyridine Thionyl chloride (14.6 ml, 0.2 mol) was added extremely carefully in dropwise manner to a rapidly stirred mixture of 2-chloro-5-hydroxymethylpyridine (18.6 g, 0.13 mol) and chloroform (150 ml) at ambient temperature (20 C.). After addition was complete the resulting mixture was heated under reflux for 12 hours. The reaction mixture was then allowed to cool to ambient temperature (20 C.) and chloroform was evaporated off under reduced pressure to give a brown oil. The product, 2-chloro-5-chloromethyl-pyridine was isolated from this brown oil by flash chromatography using silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm), with dichloromethane as eluent, as a yellow oil which solidified on standing (17.45 g, 82.9%). | |
With pyridine; thionyl chloride; | (1.2) 2-Chloro-5-chloromethyl-pyridine 85 ml of thionyl chloride are added cautiously to 14.4 g (0.1 mol) of 6-chloro-pyridine-3-methanol. 8.1 g (0.1 mol) of pyridine are then added dropwise and the mixture is heated under reflux until gas evolution is complete. Excess thionyl chloride is removed in vacuo and the residue is poured onto ice. The precipitate is filtered off with suction and dried. Yield 10.6 g (65.5% of theory), m.p.: 38-40 C. The crude product can be used further without purification. | |
With thionyl chloride; In dichloromethane; for 1h;Reflux; | 2-Ch-oropyridinyI-4-mcthylcncdicthylphbsphonatc. 2-Chloronicotinic acid (3.00 g, 19.0 mmol) was dissolved in dry THF (60 mL) and cooled to 0C. Lithium aluminiumhydride (870 mg, 23.0 mmol) was charged into the stirred reaction (CAUTION: gas evolution) followed by gradual warming to reflux for 4 hours. The reaction was quenched with sequential addition of wet THF (5 mL) and water (50 ml.., cautiously) before filtration through celite and removal of volatilcs in vacuo gave yellow oil that was purified by flash chromatography (Si02, CH2CI2 followed by F,t()Ac). The crystalline alcohol was dissolved in CH2C12 (20 mL) and excess thionylchloride (5-10 mL) before refluxing for 1 hour. On cooling to room temperature, volatiles were removed in vacuo and the residue was neutralised with sat. NallCO before extraction with CH2CI2 (3 x 40 mL). Organics were combined, dried over MgSO^, filtered and concentrated to 3-5 mL before purification through a silica plug (eluting with CH2CI2). Removal of volatiles in vacuo gave yellow oil as the desired 2-chloropyridyl-5-methylcnechloride. The alky chloride was dissolved in triethylphosphite ( 10 mL) and heated to 140C for 2 hours. On cooling to room temperature, volatiles were removed in vacuo and the residue purified by flash chromatography (Si02, CFLC^ followed by EtOAc) to give a light yellow oil (). NMR (500 MHz; CDCI3): S/ppm 8.28-8.26 (m, I II, Vy-H), 7.64 (dl. 1 H, 3./„„ - 8.2, 4Jm = 2.5, Py-//), 7.28 (d, 1 H, 3J,„i - 8.2, Py-H), 4.09-4.02 (m, 4H, 0-C//j), 3.09 (d, 211. 3JHi> = 21.6, 0=?-C/), 1.28- 1.25 (m, 6H, C//3). ,3C{ 'H} NMR (125.7 MHz; CDCIj): S/ppm 150.4 (d, 3Jci> = 7.7, PyCH), 150.3 (d, FontWeight="Bold" FontSize="10" JCP = 4, PyC-Cl), 140.0 (d, 3JCl> - 5.5, PyCH), 127.1 (d, 2Ja> = 9, PyQ, 124.2 (d, VCI> - 2.9, PyCH), 62.6 (d, 2,/a> = 6.8, 0-CH2), 30.5 (d, 'Jcp = 140,0, O-P-CHz), 16.5 (d, = 5.9, CH2-CH3). Λ ,Ρ{} NMR (202.5 MHz; CDCh): S/ppm 24.8 (s, 0=P) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium borohydrid; In water; | Sodium borohydride (24.97 g, 0.66 mol) and ice/water (400 ml) were stirred with ice/salt bath cooling. The 6-chloronicotinyl chloride (31.68 g, 0.18 mol) was added to the resulting mixture at such a rate as to ensure that, with ice/salt bath cooling, the temperature of the mixture did not rise above 15 C. After addition was complete the temperature of the mixture was allowed to rise to ambient temperature (20 C.) and was stirred at this temperature for 12 hours. The mixture was then extracted with dichloromethane (8*200 ml). The combined extracts were dried (Mg SO4) and evaporated under reduced pressure to give a white solid. The product, 2-chloro-5-hydroxymethyl-pyridine, was isolated from this white solid by flash chromatography using silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm), with diethylether as eluent, as a white solid (18.76 g, 72.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate; In tetrahydrofuran; at 70℃; for 2h;Product distribution / selectivity; | EXAMPLE 52 : l-((6-Ethylpyridin-3-yl)methyl)-5-(4-methoxyphenyl)pyridin- 2(1H)-one (Final Compound 4-45)Step I : l-((6-Chloropyridin-3-yl)methyl)-5-(4-methoxyphenyl)pyridin-2(lH)-one 5-(4-Methoxyphenyl)pyridine-2(lH)-one (4.20mmol, 0.85g), 2-chloro-5- (chloromethyl)pyridine (1.5eq, 6.30mmol, 1.02g), K2CO3 (2eq, 8.40mmol, 1.17g) in TEtaF (10mL) were heated at 70C for 2 hours. Then, the reaction was cooled to room temperature. The suspension was filtered off and the filtrate was evaporated under reduced pressure. The residue was puridied by short open column chromatography CEta2Cl2/MeOEta(NEta3)sat. 1% yielding l-((6-chloropyridin-3-yl)methyl)-5-(4- methoxyphenyl)pyridin-2(lH)-one as white solid (1.04g, 75%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphorus pentachloride; sodium carbonate; trichlorophosphate; In ethyl acetate; | STR18 2.0 g (0.016 mol) of 5-hydroxymethyl-2-pyridinone are added to a mixture of 6.7 g (0.032 mol) of phosphorus pentachloride and 2.5 g (0.016 mol) of phosphorus oxychloride, the mixture is stirred at reflux temperature for 7 hours, cooled and taken up in ethyl acetate, ice water is then added, the mixture is rendered neutral using sodium carbonate, the organic phase is separated off and dried over magnesium sulphate, and the solvent is removed under reduced pressure. The residue may be purified by distillation. 2.5 g (96% of theory) of 2-chloro-5-chloromethylpyridine of boiling point 70 C.-80 C. at 1 mbar are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; sodium bicarbonate; In chloroform; water; | REFERENCE EXAMPLE 1 On a water bath at 5-20 C., a mixture of 70.3 g of 2-chloro-5-(hydroxymethyl)pyridine and 50 ml of 1,2-dichloroethane was added dropwise to a mixture of 87.4 g of thionyl chloride and 100 ml of 1,2-dichloroethane over a period of 30 minutes. The whole mixture was stirred at room temperature for 90 minutes and, then, under reflux for 4.5 hours. The reaction mixture was then concentrated and the residue was diluted with 200 ml of chloroform and 60 ml of water. Then, with stirring, 20 g of sodium hydrogen carbonate was added in small portions. Thereafter, the organic layer was separated, treated with activated carbon and concentrated to give 75.9 g of 2-chloro-5-(chloromethyl)pyridine as a yellow brown solid. 1 H NMR (CDCl3): 4.57 (2H, s), 7.34 (1H, d, J=8.5 Hz), 7.72 (1H, dd, J=8.5, 2.5 Hz), 8.40 (1H, d, J=2.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With potassium hydroxide; In acetonitrile; at 45℃; for 5h; | In a 500-ml round-bottom flask, 200 mL of solvent acetonitrile was added, followed by the addition of <strong>[120068-37-3]fipronil</strong> (30.86 mmol, 13.5 g), potassium hydroxide (46.3 mmol, 2.6 g) and stirring until all the <strong>[120068-37-3]fipronil</strong> was dissolved. 2-chloro-5-chloromethyl pyridine, heated to 45 C insulation, 5h <strong>[120068-37-3]fipronil</strong> reaction completely. After the reaction system was cooled, the reaction mixture was extracted twice with saturated sodium chloride, and the aqueous layer was separated and removed. The remaining solution was dried over anhydrous magnesium sulfate and the desiccant was removed by filtration. The filtrate was evaporated to recover 4/5 solvent, Cool to room temperature to give the product. The yield was 63%. |
42.3% | Add 3mmol <strong>[120068-37-3]fipronil</strong> in a 50ml flask [Chemical name:5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole-3-carboxamide],Dry 10 ml of tetrahydrofuran and cool to below 0C in an ice bath.Under nitrogen protection, 3 mmol of NaH was added in batches and after half an hour of reaction,9 mmol of 2-chloro-5-chloromethylpyridine was added dropwise,After the addition is complete, naturally rise to room temperature, continue stirring for 3 hours, and concentrate.Dissolve with 20 ml of methylene chloride and wash 3 times with 40 ml of water.The organic phase is dried over anhydrous sodium sulfate and dissolved.The resulting oil was chromatographed on a column of petroleum ether and ethyl acetate (5:1 by volume) to give structural formulas such asLight yellow oily liquid shown in I-135-(6-chloropyridin-3-ylmethylamino)-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole-3- Nitrile] 0.71 g,The reaction yield was 42.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With manganese(IV) oxide; iron(III) chloride; chlorine; at 120℃; under 760.051 Torr; for 45h; | At 1 atmosphere,20 g of 2-chloro-5-chloromethylpyridine (0.12 mol) and 0.5 g of manganese dioxide 0.5 g of ferric chloride were heated to 120 C, and chlorine gas was introduced into the mixture for 45 hours.Using GC-MS tracking, it was found that 36% of the starting material was converted to 2,3-dichloro-5-trichloromethylpyridine.When the temperature of the reaction system is heated to 170 C, chlorine gas is continuously introduced for 7 hours.GC-MS trace detection revealed that the starting material had reacted completely.The reaction mixture was diluted with n-hexane, washed with aqueous sodium carbonate and the organic layer was separated.Drying over anhydrous sodium sulfate and removing the solvent by distillation.25.4 g of a yellow liquid 2,3-dichloro-5-trichloromethylpyridine was obtained.The yield was 79%. |
562 g | With chlorine; copper(II) oxide; at 275℃; for 60h; | 500 g (3.08 mol) of 2-chloro-5-chloromethylpyridine (molecular weight: 162 g / mol) and 50 g (10% by weight) of copper oxide were charged into a 1 L four-necked flask equipped with a thermometer, a condenser and a mechanical stir And heated to 275 C, and then chlorinated by passing Cl 2 into the above solution, and the reaction was carried out for 60 hours to obtain 562 g (2.12 mol) of 2,3-dichloro-5-trichloromethylpyridine. A solution of 562 g (2.12 mol) of 2,3-dichloro-5-trichloromethylpyridine was heated to 70 C and added with 5 g of catalyst antimony pentachloride followed by 210 g (10.5 mol) of hydrogen fluoride at 200 C, 8.5 MPa pressure for 30 hours to give 421 g (1.95 mol) of 2,3-dichloro-5-trifluoromethylpyridine in a yield of 63.2% from 2-chloro-5-chloromethylpyridine, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; In acetonitrile; at 70℃; for 16h; | A solution of 2,7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester hydrochloride (400 mg, 1.5 mmol)And 2-chloro-5- (chloromethyl) pyridine(243 mg, 1.5 mmol) was dissolved in acetonitrile (50 mL), potassium carbonate (621 mg, 4.5 mmol) was added and reacted at 70 ° C for 16 hours.After cooling to room temperature, ethyl acetate (100 mL) and water (50 mL) were added, the phases were separated and the aqueous phase was extracted with ethyl acetate (150 mL x2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give The title compound was obtained as a yellow oil (480 mg, yield 90percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
144.9 g | With hydrogen bromide; acetic acid; In toluene; at 90 - 100℃; for 10h;Sealed tube; | Take 100g raw material 2-chloro-5-chloromethyl pyridine and 200g of toluene was added to the reaction flask, 25% hydrobromic acidSolution 400g. Heating to 90 ~ 100 . The reaction for 10 hours, desolventizing. The residue was taken up in 200 g of DCM and adjusted to pH = 6-8 with 10% NaOH solution. The solution was separated and the organic phase was obtained. The DCM was removed by desolvation. The residue is 2-bromo-5-bromomethylpyridine, mass 144.9g, content of 93%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; acetonitrile; at 50℃; for 1h;Inert atmosphere; | To a solution of <strong>[854690-87-2](3-(difluoromethyl)phenyl)boronic acid</strong> (0.405 g, 2.5 mmol) and 2-chloro-5-(chloromethyl)pyridine (0.430 g, 2.5 mmol) and potassium carbonate (0.691 g, 5 mmol) in acetonitrile (70 ml_) and water (10 ml_) was added [1 ,1 '-b/s(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane (0.204 g, 0.25 mmol) under argon. The mixture was stirred at 50 C for 1 h. Volatiles were removed under reduced pressure and water (50 ml_) was added. The aqueous layer was extracted with ethyl acetate (80 ml_ x 3), dried with sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 12/1 ) to give 2-chloro-5-(3-(difluoromethyl)benzyl)pyridine (0.397 g, 1 .45 mmol, 58%) as a colorless oil. LCMS (ESI) m/z: 254.1 [M+H]+. |
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