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Structure of 50712-69-1
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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. : | 50712-69-1 |
Formula : | C8H5BrClN |
M.W : | 230.49 |
SMILES Code : | N#CC1=CC(Cl)=CC=C1CBr |
MDL No. : | MFCD09909826 |
InChI Key : | CYBMZAPDOKDQJF-UHFFFAOYSA-N |
Pubchem ID : | 12668052 |
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 | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 49.0 |
TPSA ? Topological Polar Surface Area: Calculated from |
23.79 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.17 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.83 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.95 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.82 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.44 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.84 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.39 |
Solubility | 0.094 mg/ml ; 0.000408 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.99 |
Solubility | 0.237 mg/ml ; 0.00103 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.36 |
Solubility | 0.00997 mg/ml ; 0.0000433 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 |
-5.7 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 |
1.0 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) |
2.05 |
* 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 |
---|---|---|
77.1% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 4h;Reflux; | 2-(bromomethyl)-5-chlorobenzonitrile; 5-chloro-2-methylbenzonitrile (3.02 g, 20 mmol) was dissolved in 70 mL carbon tetrachloride. NBS (N-bromosuccinimide) (3.916 g, 22 mmol) and BPO (benzoyl peroxide) (0.194 g) were added, and refluxed for 4 h. The hot solution was subjected to filtration. The filtrate was spinned to dryness, and then dissolved in 20 mL chloroform, washed with saturated sodium carbonate solution and water, dried with Na2SO4, spinned to dryness, and subjected to column chromatography eluted with petroleum ether to afford 3.532 g white solid with a yield of 77.1%. |
77.1% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 4h;Reflux; | Example 10 The preparation of (R)-2-[[7-(3-aminopiperidin-1-yl)-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl]methyl]-5-chlorobenzonitrile (Compound 10) trifluoroacetate 5-chloro-2-methylbenzonitrile (3.02 g, 20 mmol) was dissolved in 70 mL carbon tetrachloride. NBS (N-bromosuccinimide) (3.916 g, 22 mmol) and BPO (benzoyl peroxide) (0.194 g) were added, and refluxed for 4 h. The hot solution was subjected to filtration. The filtrate was spinned to dryness, and then dissolved in 20 mL chloroform, washed with saturated sodium carbonate solution and water, dried with Na2SO4, spinned to dryness, and subjected to column chromatography eluted with petroleum ether to afford 3.532 g white solid with a yield of 77.1 %. |
54% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 4h;Reflux; | 5-chloro-2-methylbenzonitrile (2.5 g, 16.5 mmol) was dissolved in carbon tetrachloride (40 mL), and N-bromosuccinimide (2.94 g, 16.5 mmol) was added, followed by benzoyl peroxide (0.107 g, 0.33 mmol). The mixture was refluxed for 4 h, and the white succinimide residue was filtered off. The solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel eluting with Hexanes:EtOAc (1:0 to 9:1). One pure fraction was collected (2.05 g, 54 % yield) as a white crystalline solid. [0137] 1H NMR (400 MHz, CDCl3) delta 7.65 (1H, d), 7.57 (1H, dd), 7.50 (1H, d), 4.60 (2H, s). |
54% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 4h;Reflux; | a) 2-(Bromomethyl)-5-chlorobenzonitrile5-chloro-2-methylbenzonitrile (2.5 g, 16.5 mmol) was dissolved in carbon tetrachloride (40 ml_), and N-bromosuccinimide (2.94 g, 16.5 mmol) was added, followed by benzoyl peroxide (0.107 g, 0.33 mmol). The mixture was refluxed for 4 h, and the white succinimide residue was filtered off. The solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel eluting with Hexanes:EtAcO (1 :0 to 9:1 ). One pure fraction was collected (2.05 g, 54 % yield) as a white crystalline solid.1 H NMR (400 MHz, CDCI3) ? 7.65 (1 H, d), 7.57 (1 H, dd), 7.50 (1 H, d), 4.60(2H, s). |
Product distribution / selectivity; | Preparative Example 67. Preparation of Table 1 Compound No. 236; Bromide 88, prepared from 5-chloro-2-methylbenzonitrile (Matrix Scientific) was combined with amine salt 6 according to the method of Preparative Example 13 to give 89. Nitrile 89 (377 mg, 0.75 mmol) was then dissolved in absolute ethanol (3 ml_). Hydroxylamine hydrochloride (150 mg, 1.5 mmol) and diisopropylethylamine (261 mul_, 194 mg, 1.5 mmol) were added. The reaction mixture was stirred at reflux for 16 hours. The reaction mixture was cooled to room temperature, neutralized with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic solution was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 90 as a yellow solid. Purification by silica gel chromatography (8% (7 M ammonia in methanol) in dichloromethane) gave 90 (167 mg, 42% yield). MS: [M + H]+ = 536. EPO <DP n="146"/>The nitro compound 90 was converted to 91 following procedures given in Preparative Examples 5 and 19, substituting methylamine for cyclopropylamine in the final step. MS: [M + H]+ = 651. | |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;Heating / reflux; | Reference example 71; (1); To 5-chloro-2-methylbenzonitrile (7.8g) in carbon tetrachloride (50ml) were added N-bromosuccinimide (9.26g) and benzoylperoxide (515mg), and the mixture was stirred under reflux overnight. The reaction mixture was cooled and purified with silica gel column chromatography (hexane:ethyl acetate=30:1) to give compound (2) (8.87g) as a yellow transparent oil. 1HNMR(400MHz/CDCl3)delta(ppm):4.60(s,2H),7.50(d,1H,J=8.5Hz),7.57(dd,1H,J=2.3, 8.5Hz),7.65(d,1H,J=2.3Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium hydride; In tetrahydrofuran; at 20℃; for 28h; | To a suspension of sodium hydride (1.91 g, 47.72 mmol) in anhydrous tetrahydrofuran (30 [ML)] at room temperature under nitrogen, was added a solution [OF 2-] [BROMOMETHYL-5-CHLORO-BENZONITRILE11] (10 g, 43.39 mmol) in anhydrous tetrahydrofuran (35 [ML),] followed by the dropwise addition of [DI-TERT] butyl imino dicarboxylate (10.37 g, 47.72 [MMOL)] in anhydrous tetrahydrofuran (30 [ML).] The reaction mixture was stirred at room temperature for 28 hours under nitrogen. The reaction was quenched with water (50 ml) and the solvent removed under reduced pressure. The aqueous layer was extracted with diethyl ether (3 x 100 ml), the combined organics washed with brine (50 [ML),] dried with magnesium sulfate, filtered and the solvent removed by evaporation under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a solvent gradient of heptane: ethyl acetate (4: 1) to give the title compound (13.45 g, 84 [%)] as a pale yellow solid. [1H-NMR] (400 MHz, [CDCI3)] : [9] = 1.46 (s, 18H), 4.98 (s, 2H), 7.28 (d, 1H), 7.53 (d, 1H), 7.61 (d, [1H).] LRMS [(APCI)] : m/z [M + H] [+] [389.] Microanalysis : Found: C, 59.37 ; H, 6.47 ; N, 7.09. [C18H23N204CI] requires C, 58. 93; H, 6.32 ; N, 7.64%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With triethylamine; sodium iodide; In N,N-dimethyl-formamide; at 25℃; for 3h; | A mixture of Ei (hydrochloride salt form, 100 mg, 0.25 mmol) and sodium iodide (4 mg, 0.025 mmol) in DMF (1 mL) was treated with triethylamine (0.1 ml, 0.75 mmol) and <strong>[50712-69-1]2-cyano-4-chlorobenzyl bromide</strong> (0.11 ml, 0.5 mmol) at 250C. The reaction mixture was stirred for 3 hours at the temperature and diluted in CH2CI2. The organic solution was washed with saturated aqueous NaHCO3 solution, brine solution, dried over sodium sulfate, and concentrated in vacuo. The residual material was purified by EPO <DP n="71"/>preparative TLC (10% MeOH in CH2CI2) to afford the desired product F2 (45 mg, 35%). MS: M+H = 517 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; | Step 1. DEEA (3.57 mL, 20.50 mmol) was added to a stirred mixture of 3-hydroxyazetidine hydrochloride (1.00 g, 9.11 mmol) and <strong>[50712-69-1]2-bromomethyl-5-chlorobenzonitrile</strong> (2.10 g, 9.11 mmol) in CH2Cl2 (75 mL). After 16 h the reaction mixture was concentrated and the residue was partitioned between ether and 1N HCl. The aqueous layer was washed with ether, made neutral with NaHCO3, saturated with NaCl and extracted into CH2Cl2. The organic layer was dried (Na2SO4) and evaporated to give 5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzonitrile (1.67 g) as a gum: 1H NMR (CDCl3, 400 MHz) delta 3.03 (m, 2H), 3.68 (m, 2H), 4.49 (t, J=6.2 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.53 (d,d, J=2.2, 6.2 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; | Step 1 DIEA (0.196 mL, 1.12 mmol) was added to a stirred mixture of 3,3-difluoroazetidine hydrochloride (64.8 mg, 0.50 mmol) and <strong>[50712-69-1]2-bromomethyl-5-chlorobenzonitrile</strong> (121.0 mg, 0.52 mmol) in CH2Cl2 (7 mL). After 16 h the reaction was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated. The residue was partitioned between 1N HCl and ether. The aqueous layer was made neutral with NaHCO3 and was extracted with CH2Cl2. The organic layer was dried with Na2SO4 and then evaporated to give 5-chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]benzonitrile (67.8 mg) as a glass: 1H NMR (CDCl3, 400 MHz) delta 3.68 (t, J=11.9 Hz. 4H), 3.93 (s, 2H), 7.54 (m, 2H), 7.63 (d, J=2.2 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 20. Preparation of Table 1 Compound No. 1 EPO <DP n="114"/>Compound No. 1 of Table 1 , was prepared by alkylation of Compound A14 with 2-cyano benzyl bromide as in Preparative Example 14. Further treatment of the intermediate ester with hydroxylamine hydrochloride ( 13 mg, 300 mole%) in sodium carbonate and reflux for 16 h afforded Compound No 1. (11 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 187 5-chloro-1-(4-chloro-2-cyanobenzyl)-2-imino-1,2-dihydropyridine-3-carboxamide hydrochloride To a solution of 2-amino-5-chloronicotinamide (0.16 g) in N,N-dimethylformamide (3 ml) was added <strong>[50712-69-1]2-(bromomethyl)-5-chlorobenzonitrile</strong> (0.32 g), and the mixture was stirred at 100C for 14 hr. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=3:2 - 4:1). 2N Hydrochloric acid-methanol solution (1 ml) was added to the obtained yellow oil at room temperature, and the obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (3 mg). 1H-NMR (DMSO-d6) d ppm 5.75 (2H, s), 7.24 (1H, d, J=2.0 Hz), 7.68 (1H, dd, J=8.3, 2.0 Hz), 8.05 (1H, d, J=8.3 Hz), 8.23 (1H, s), 8.60-8.78 (3H, m), 9.38-9.81 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In toluene; at 140℃; for 4h; | A solution of <strong>[50712-69-1]2-(bromomethyl)-5-chlorobenzonitrile</strong> (1.95 g, 8.46 mmol) and P(OEt)3 (3.63 mL, 21.15 mmol) in toluene were heated to 140 ºC for 4 hours. Excess of P(OEt)3 was removed in vacuo, and the product was extracted with ethyl acetate. Combined organic extracts were dried over MgSO4. Column chromatography on silica gel gave the desired product as a slightly yellow oil (2.1 g, 86% yield). [0139] 1H NMR (400 MHz, CDCl3) delta 7.65-7.58 (1H, m), 7.51 (2H, m), 4.19-4.00 (4H, m), 3.37 (2H, d), 1.29 (6H, t). |
86% | In toluene; at 140℃; for 4h; | b) Diethyl 4-chloro-2-cyanobenzylphosphonateA solution of <strong>[50712-69-1]2-(bromomethyl)-5-chlorobenzonitrile</strong> (1 .95 g, 8.46 mmol) and P(OEt)3 (3.63 ml_, 21 .15 mmol) in toluene were heated to 140 5C for 4 hours. Excess of P(OEt)3 was removed in vacuo, and the product was extracted with ethyl acetate. Combined organic extracts were dried over MgS04. Column chromatography on silica gel gave the desired product as a slightly yellow oil (2.1 g, 86% yield).1 H NMR (400 MHz, CDCI3) ? 7.65 - 7.58 (1 H, m), 7.51 (2H, m), 4.19 - 4.00 (4H, m), 3.37 (2H, d), 1 .29 (6H, t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In methanol; 2,2,2-trifluoroethanol; at 20℃; for 6h; | Solid <strong>[50712-69-1]2-(bromomethyl)-5-chlorobenzonitrile</strong> (500 mgs, 2.17 mmol) was added in two portions to a stirred solution of morpholine (0.2 mL, 2.3 mmol) and triethylamine (0.3 mL, 2.17 mmol) in methanol (1 mL). After 6 hr at rt, the solvent was removed and the residue was dissolved in ethylacetate and washed with 1 N NaOH, water, saturated aqueous sodium chloride solution and dried (MgSO4). Filtration and concentration gave 5-chloro-2-(morpholinomethyl)benzonitrile which was used without purification for next step. LCMS-ESI+ (m/z): [M+H]+ calcd for C12H13N20 as (M+H)+ 237.7 found: 237.2. 1H NM (400 MHz, Chloroform-c ) delta 8.61 (d, J = 8.7 Hz, 1 H), 7.80 - 7.67 (m, 2H), 4.37 (s, 2H), 4.33 - 4.23 (m, 2H), 3.99 (m, 2H), 3.33 (m, 2H), 3.12 - 2.99 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Sodium hydride (176 mgs, 4.41 mmol) was added to pyrrolidin-2-one (0.31 mL, 4.0 mmol) in DMF (10 mL) at 0C under nitrogen. The resulting solution was stirred at rt for 30 minutes and cooled again to 0C. 5-bromo-2-(chloromethyl)benzonitrile (921 mgs, 4.00 mmol) was added and the reaction stirred at 20 C for 2 hours. The residue was poured onto ice/water and extracted into ethyl acetate and the combined organics washed with saturated brine (100 mL), dried over Na2SO4, filtered and evaporated to give crude product. The crude product was purified by flash silica chromatography (30% EtOAc in hexanes). Pure fractions were evaporated to dryness to give 5-chloro-2-((2- oxopyrrolidin-1 -yl)methyl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C12H11CIN2O as (M+H)+ 235.7 found: 235.2 |
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