Structure of 2243-82-5
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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. : | 2243-82-5 |
Formula : | C11H9NO |
M.W : | 171.20 |
SMILES Code : | O=C(N)C1=CC=C2C=CC=CC2=C1 |
MDL No. : | MFCD00016812 |
InChI Key : | JVXXKQIRGQDWOJ-UHFFFAOYSA-N |
Pubchem ID : | 75245 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 10 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 52.04 |
TPSA ? Topological Polar Surface Area: Calculated from |
43.09 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.47 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.88 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.94 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.23 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.11 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.93 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.59 |
Solubility | 0.441 mg/ml ; 0.00258 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.41 |
Solubility | 0.671 mg/ml ; 0.00392 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.66 |
Solubility | 0.0377 mg/ml ; 0.00022 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 |
-6.01 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 |
0.0 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) |
1.0 |
* 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 |
---|---|---|
58% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; | Naphthalene-2-carboxylic acid amide (0.8 g, 1 eq, 4.678 mmol) was dissolved in THF (80 mL) and the solution was cooled down to 0-50C. A 1.0 M solution of Lithium Aluminium Hydride (LAH) in THF (1.42 g, 8.0 eq, 37.0 mmol) was added drop-wise at 0-50C. The reaction mixture was stirred at RT overnight. After completion of the reaction (confirmed by TLC), ethyl acetate at 0-50C was slowly added to quench the excess LAH in reaction mixture followed by the addition of saturated sodium sulphate solution (2 mL). The reaction mass was filtered through a hy-flow bed and the filtrate was concentrated in vacuo to afford the crude product.The crude product was purified by column chromatography using neutral silica gel of 60- 120 mesh size. A gradient of 3-4 percent methanol in DCM was used to elute the title compound (0.43 g, 58percent). |
56% | Compound 27 (1.00 g, 5.8 mmol) in THF (20 mL) was added slowly to a solution of LAH (1.76 g, 46.4 mmol) in THF (45 mL) at 0° C. The solution was allowed to warm to room temperature and the reaction was stirred overnight. The reaction was cooled to 0° C. and quenched with H2O. The solids were filtered from the solution through celite and washed with hot THF. The filtrate was concentrated and the residue was dissolved in EtOAc (80 mL) and washed with 1 M HCl (3.x.30 mL). The aqueous layer was basified with 6 M NaOH to a pH of 12 and the precipitate was extracted with EtOAc (3.x.30 mL). The resulting organic solution was washed with brine (40 mL), dried with Na2SO4 and filtered. Concentration afforded a slightly yellow solid (510 mg, 56percent yield). m.p. 55-56° C. 1H NMR (CDCl3) delta 7.80 (3H, ArH), 7.72 (s, 1H, ArH), 7.43 (m, 3H, ArH), 4.00 (s, 2H, ArCH2). 13C NMR (CDCl3) delta 140.6, 133.5, 132.5, 128.2, 127.7, 126.1, 125.8, 125.5, 125.1, 46.6. IR (KBr) vmax cm-1: 3362, 3291, 3050, 2915, 1950, 1596, 1507, 1358, 1273. GC: r.t.=8.97 min. EI-MS m/z (percent) 157 (83, M+), 156 (100), 141 (15), 129 (49), 128 (40), 127 (24), 115 (10). | |
With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 60℃; for 3h; | To a solution of the crude amide obtained in the above step (1) inTHF (100 ml), BMS (27.5 ml, 0.2904 mol) was slowly added at 0 °C. Theresulted reaction mixture was heated to 60 °C for 3hrs, quenched with 5percent HCIat 0 °C, extracted with EA and washed with 5percent HCI. The aqueous layerswere combined and basified with 1N NaOH, and again extracted with EA.The organic layers were combined and concentrated to give the title compound(13 g) as white solid.TLC System 1 : MC/MeOH =90:10 v/v Rf=0.231H-NMR (300 MHz, CDCI3) 5 ppm: 4.07(s, 2H), 7.48(m, 3H),7.79(m, 4H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | General procedure: A flame-dried resealable 2-5 mL Pyrex reaction vessel was charged with the solid reactant(s): (hetero)aryl nitriles 1 (1.0 mmol) and Cs2CO3 (1.5 mmol). The reaction vessel was capped with a rubber septum, and pyrrolidinone (2 mL per mmol [0.5 M]) was added through the septum. The septum was replaced with a teflon screwcap. The reaction vessel was sealed and heated at 130 °C for 2 h. The resulting suspension was cooled to room temperature and filtered through a pad of celite eluting with CH2Cl2/MeOH (7:3), and the inorganic salts were removed. The filtrate was concentrated and purification of the residue by silica gel column chromatography gave the desired product. | |
88% | With water; at 110℃; for 6h; | General procedure: Two milli liter water at room temperature was added to astirred mixture of nitrile (1mmol) and catalyst (40mg) thenheated with an oil bath maintained at 110°C, and stirred. After completion of the reaction (monitored by TLC), thecatalyst was removed from the reaction mixture by externalmagnet. Then the mixture was extracted with ethyl acetate,subsequently purified by column chromatography on silicagel to provide the corresponding amide products. |
70%Chromat. | With [Ru(CO)(pyridoxal-4-methyl-thiosemicarbazide hydrochloride)(triphenylphosphine)2]; In methanol; water; at 80℃; for 1h;Catalytic behavior; | General procedure: Organic nitrile (1 mmol) and distilled water (1 mL) were sequentially added to 3 mL methanol solution of the ruthenium catalyst (0.3 molpercent) and the reaction mixture was stirred at 80°C. After completion of reaction, the catalyst was extracted from the reaction mixture by the addition of CH2Cl2/petroleum ether followed by filtration. The filtrate was subjected to GC analysis and the product was identified and determined with authentic samples |
With C40H45ClN3O2PRu; In methanol; water; at 20℃; for 4h;Inert atmosphere; Schlenk technique; Green chemistry;Catalytic behavior; | General procedure: Organic nitrile (1 mmol) and distilled water (1 mL) were sequentially added to 3 mL methanol solution of the [Ru?NHC] catalyst (0.5 molpercent) and the reaction mixture was stirred at room temperature. The progress of the reaction in each case was monitored by TLC analysis. After completion of reaction the catalyst was extracted from the reaction mixture by the addition of CH2Cl2/petroleum ether followed by filtration. The filtrate was subjected to GC analysis and the product was identified with authentic samples. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With oxalyl dichloride; triethylamine; In dimethyl sulfoxide; acetonitrile; at 20℃; for 0.666667h;Inert atmosphere; | Nitrogen protection, in a 100 mL three-necked flask equipped with a thermometer,Add anhydrous acetonitrile (10 mL) in turn, twoJia Ya satire (0·03mmol, 2·5mg, 0·Olequiv),2-naphthylcarboxamide (3mmol, 513mg, 1 · Oequiv)And triethylamine (1 · 04mL, 7 · 5mmol, 2 · 5equiv),Slowly add oxalyl chloride to the constant pressure dropping funnel at room temperature(0.31 mL, 3.6 mmol, 1.2 equiv) in dry acetonitrile (5 mL).After the addition was completed, stirring was continued for 40 min, suction filtration, and the filtrate was spun dry.Distilled water (15 mL) was added and extracted with ethyl acetate (3 chi 10 mL).The combined organic layers were washed with aq.Filtration, rotary distillation to remove the solvent to obtain a crude product.Purified by column chromatography (petroleum ether / ethyl acetate = 9:1),441 mg of 2-naphthonitrile was obtained in a yield of 96%. |
84% | at 300℃; for 1h; | General procedure: Following the amide intermediate Preparation Example A. The reaction vessel is closed (when the amide intermediate has a boiling point at normal pressure equal to or lower than the reaction temperature TB described below) or the reaction vessel is kept open (when the amide intermediate has a boiling point higher than the normal pressure When the reaction temperature is TB), the stirring is continued (600 r/min), the reaction temperature is changed to TB, and after the reaction temperature TB is maintained for TD hours, the reaction is almost complete. Then, the reaction vessel was sealed and connected to a vacuum pump so that the degree of vacuum in the reaction vessel reached 20-50 mbar (according to the type of nitrile product) and the distillate was used as the nitrile product. The yield of the nitrile product was calculated and sampled for nuclear magnetic proteomics and elemental analysis to characterize the nitrile product obtained. Specific reaction conditions and characterization results are shown in Tables A-7, A-8, A-9, A-10 and A-11 below. These characterization results show that the nitrile product obtained has an extremely high purity (above 99%).In these nitrile product preparation examples, 10 g of diphosphorus pentoxide was optionally added to the reaction vessel as a catalyst at the start of the reaction. |
61% | With triethylamine; ethanaminium,N-(difluoro-lambda4-sulfanylidene)-N-ethyl-,tetrafluoroborate; In toluene; at 20℃; for 4h;Inert atmosphere; | General procedure: To a solution of the aldoxime or the amide (1.0 mmol) and Et3N (1.5mmol) in EtOAc (1 mL, 1 M) at r.t. was added XtalFluor-E8 (1.1 mmol)portionwise over ca. 2 min. The resulting solution was stirred at r.t.for 1 h. The reaction mixture was quenched with sat. aq Na2CO3 and extracted with CH2Cl2 (2 × 10 mL). The combined organic layers were washed with H2O and brine, dried (MgSO4), and concentrated under vacuum to afford the crude nitrile, which was purified by flash chromatography, if required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Unless otherwise specified, carboxylic acid (0.542 mmol), TCT (0.0400 g, 0.216 mmol) and K2CO3 (0.2247 g, 1.626 mmol) were mixed together and hand ground for one minute using porcelain mortar and pestle. After addition of ammonium thiocyanate (0.0495 g, 0.650 mmol), the mixture was ground manually for further five minute. During the grinding, THF (calculated to be less than 1 L/mg of solids) was added to aid homogeneous mixing. The crude material was then purified by short column chromatography (column diameter 1.5 cm, packed with 3-4 g silica gel ) using 40-50percent ethyl acetate/hexane as an eluent. | |
With ammonium hydroxide;N,N-dimethyl-formamide; In oxalyl dichloride; hexane; water; | (1) PREPARATION OF NAPHTHALENE-2-CARBOXYLIC ACID AMIDE To a solution of 2-naphthoic acid (25 g, 0.145 mol) in MC (200 ml), oxalyl chloride (38 ml, 0.4356 mol) and a catalytic amount of DMF were added and stirred at room temperature for 2 hrs. After the solvent was evaporated, the crude acyl chloride was diluted with MC (200 ml), to which a solution of ammonium hydroxide in water (160 ml) was dropwise added at an ice bath temperature. After stirring for 1 hr, the precipitated product was collected by suction filtration, triturated in hexane and dried to obtain the title compound, which was used next step without further purification. | |
With ammonia; at 195℃; for 0.5h; | General procedure: Into a 1L open reactor was added 500g of carboxylic acid raw material (chemically pure) and stirring was turned on (600 r/min) from the reactorThe bottom is continuously fed with ammonia gas (chemical purity, water content of 5.1percent by weight, flow rate of 100 g/min) to the carboxylic acid feed. After the reaction was allowed to proceed for TC hours at the reaction temperature TA, ammonia gas flow was stopped. The contents of the reactor were sampled and subjected to nuclear magnetic proton and elemental analysis to characterize the amide intermediate. Specific reaction conditions and characterization results are shown in Table A-1, Table A-2, Table A-3, Table A-4, Table A-5 and Table A-6. These characterization results show that the amide intermediates obtained have an extremely high purity (above 99percent).In this embodiment, the ammonia gas can be directly replaced with waste ammonia gas (from Yangzi Petrochemical Plant, containing approximately50wtpercent of ammonia gas, the rest were toluene, oxygen, nitrogen, steam, carbon monoxide, and carbon dioxide, and the flow rate of this waste ammonia was 130g/min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | EXAMPLE 49 2-Naphthalenecarboxamide, N-(4-decylphenyl)-3-hydroxy A suspension of 1.0 g (0.021 mole) of 50percent sodium hydride/mineral oil in 25 ml of dimethyl sulfoxide under a nitrogen atmosphere is cooled in a cold water bath while 4.7 g (0.020 mole) of 4-(n-decyl)aniline is added. The mixture is stirred at room temperature for one hour, then treated in portions over 15 minutes with 2.0 g (0.0099 mole) of 3-hydroxy-2-naphthalene-carboxylic acid methyl ester. An additional 50 ml of dimethyl sulfoxide is added, and the mixture is stirred at room temperature for 45 hours. The reaction mixture is added to 500 g of ice/water and acidified with 4.0N hydrochloric acid. The gelatinous precipitate is filtered and distributed between the water (300 ml) and dichloromethane (100). The layers are separated and the aqueous layer is washed with fresh dichloromethane (2*150 ml). The combined organic layers are washed with water (1*250 ml), 1.0N hydrochloric acid (2*250 ml), and water again. The organic layer is dried (anhydrous sodium sulfate) and evaporated. Recrystallization of the residue from aqueous 2-propanol yield 1.4 g (35percent yield) of the amide product. An additional recrystallization as above yields an analytically pure sample, mp 171°-173° C. V. Preparation of Compounds of Formula I Wherein y is 2 | |
35% | EXAMPLE 49 2-Naphthalenecarboxamide, N-(4-decylphenyl)-3-hydroxy A suspension of 1.0 g (0.021 mole) of 50percent sodium hydride/mineral oil in 25 ml of dimethyl sulfoxide under a nitrogen atmosphere is cooled in a cold water bath while 4.7 g (0.020 mole) of 4-(n-decyl)aniline is added. The mixture is stirred at room temperature for one hour, then treated in portions over 15 minutes with 2.0 g (0.0099 mole) of 3-hydroxy-2-naphthalene-carboxylic acid methyl ester. An additional 50 ml of dimethyl sulfoxide is added, and the mixture is stirred at room temperature for 45 hours. The reaction mixture is added to 500 g of ice/water and acidified with 4.0 N hydrochloric acid. The gelatinous precipitate is filtered and distributed between water (300 ml) and dichloromethane (100 ml). The layers are separated and the aqueous layer is washed with fresh dichloromethane (2 x 150 ml). The combined organic layers are washed with water (1 x 250 ml), 1.0 N hydrochloric acid (2 x 250 ml), and water again. The organic layer is dried (anhydrous sodium sulfate) and evaporated. Recrystallization of the residue from aqueous 2-propanol yield 1.4 g (35percent yield) of the amide product. An additional recrystallization as above yields an analytically pure sample, mp 171-173°C. | |
STR16 5-Naphthalen-2-yl-3H-[1,3,4]thiadiazole-2-thione To a stirred solution of 1-naphthyl acrylic acid (20.0 g, 0.12 mol) in dry tetrahydrofuran (200 ml) and N,N-dimethylformamide (2 ml) was added dropwise at 0° C. oxalyl chloride (21.5 ml, 0.256 mol). The mixture was stirred for 1 h at room temperature and the solvent was evaporated in vacuo affording crude acid chloride. To a solution of 25percent aqueous ammonium hydroxide (33 ml) in tetrahydrofuran (100 ml) was added dropwise a solution of the acid chloride in dichloromethane (150 ml) at 0° C. The resulting reaction mixture was stirred for 1 h at room temperature. To the reaction mixture was added diethyl ether (200 ml) and water (200 ml). The precipitate was filtered off and washed with water (2*75 ml) and diethyl ether (2*75 ml), dried in vacuo at 50° C. affording 20.0 g (100percent) of naphthalene-2-carboxylic acid amide as a solid. |