Structure of 10386-27-3
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CAS No. : | 10386-27-3 |
Formula : | C6H3BrN2 |
M.W : | 183.01 |
SMILES Code : | BrC1=NC=CC(=C1)C#N |
MDL No. : | MFCD07367879 |
InChI Key : | AWSJFEKOXQBDSL-UHFFFAOYSA-N |
Pubchem ID : | 11735544 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 36.65 |
TPSA ? Topological Polar Surface Area: Calculated from |
36.68 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.52 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.6 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.72 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.56 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.02 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.48 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.48 |
Solubility | 0.612 mg/ml ; 0.00334 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.98 |
Solubility | 1.91 mg/ml ; 0.0104 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.96 |
Solubility | 0.199 mg/ml ; 0.00109 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 |
-6.28 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) |
2.03 |
* 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 cesium fluoride;tetrakis(triphenylphosphine)palladium (0); In 2-Methyl-1,2-propanediol; | Preparation 72 2-(4-formylphenyl)-4-pyridyl cyanide Benzaldehyde-4-boronic acid (1.36 g), 2-bromo-4-cyano pyridine (1.5 g), cesium fluoride (2.72 g) and tetrakis(triphenylphosphine)palladium(0) (285 mg) were mixed together in dimethyl ethylene glycol (30 ml). The reaction mixture was refluxed for 16 hrs under a atmosphere of nitrogen after which time the cooled mixture was diluted with diethyl ether (40 ml) and washed with water (40 ml), the organic layer was separated and washed with saturated brine, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography eluding with Dichloromethane/Diethyl ether (97.5/2.5, v/v) to afford the title compound (0.81 g). Rf 0.3 (Dichloromethane/Diethyl ether, 97.5/2.5, v/v). deltaH (400 MHz, CDCl3): 10.15 (1H, s), 8.95 (1H, d), 8.20 (2H, d), 8.05 (3H, m), 7.55 (1H, d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | tetrakis(triphenylphosphine) palladium(0); In toluene; at 80℃;Inert atmosphere; | Example 28i 2-(Trimethylstannyl)isonicotinonitrile 2-Bromo-isoniconinonitrile (1.00 g, 5.46 mmol) was dissolved in toluene (25 mL) and 1,1,1,2,2,2-hexamethyldistannane (2.266 mL, 10.93 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.316 g, 0.27 mmol) were added and the reaction was stirred at 80 C. over night under nitrogen atmosphere. The mixture was cooled to room temperature and filtered through a pad of Celite twice and concentrated. Toluene (20 mL) was added and the mixture was concentrated to give the title compound (1.079 g, 74%), which was used without further purification in the next step. MS (EI+) m/z 268 [M]+. |
51.7% | With tetrakis(triphenylphosphine) palladium(0); In toluene; at 110℃; for 16h;Inert atmosphere; | To a stirred solution of 2-bromoisoniconitrile (2 g, 10.92 mmol) in toluene (20 mL), hexamethylditin (4.6 g, 14.20 mmol), and Pd(PPh3)4 (1.2 g, 1.09 mmol) were added at rt. The resulting solution was degassed with nitrogen for 10 min and heated to 110 C for 16 h. The reaction mixture was evaporated under reduced pressure and the crude compound was purified by flash column chromatography on neutral alumina using 50% EtOAc in petroleum ether to afford the title compound (1 ,5 g, 51.7%). LC-MS (method 1): Rt = 1.93 min; m/z = 269.08 (M+H-) |
With tetrakis(triphenylphosphine) palladium(0); In toluene; at 110℃; for 16h; | General procedure: To a stirred solution of methyl 2-chloro isonicotinate (2 g, 12 mmol) in toluene (20 mL), hexamethylditin (4.5 g, 14 mmol) was added. The reaction mixture was degassed with argon for 10 minutes, then Pd(PPI)4 (1.35 g, 10 mmol) was added, it was degassed again for 5 minutes and the resulting reaction mixture was heated at 110C for 16h. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to RT, filtered through the Celite pad, washed with EtOAc and the filtrate was concentrated to dryness. The crude compound was purified by column chromatography using neutral alumina and eluted with 5%EtOAc/pet ether to afford the title compound (1.5 g, 42%) as a colorless liquid. LC-MS (method 1): R, = 1.20 min; m/z = 301.99 (M+H+) |
With tetrakis(triphenylphosphine) palladium(0); In toluene; at 110℃; for 16h;Inert atmosphere; | General procedure: To a stirred solution of methyl 2-chloro isonicotinate (2 g, 0.0116 mol) in toluene (20 mL) was added hexamethylditin (4.5 g, 0.0140 mol). the mixture was degassed with argon for 10 minutes, then Pd(PPhs)i (1.35 g, 0.00116 mol) was added and the mixture was degassed again for 5 minutes. The resulting reaction mixture was heated at 110C for 16h. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to RT, filtered through a Celite pad, washed with EtOAc, the filtrate was concentrated to get crude compound. The crude compound was purified by column chromatography using neutral alumina and eluted with 5%EtOAc/pet ether to afford the title compound (1.5 g, 42%) as a colorless liquid. (0533) LC-MS (method 1): R, = 1.20 min; m/z = 301.99 (Mu+Eta'). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 80℃; for 17h;Inert atmosphere; | In a screw cap vial (2-cyclopropyl-8-methoxy-[l,2,4]triazolo[l,5-a]pyridin-5- yl)boronic acid, compound 303, (26mg, 0.1 mmol) was dissolved in DME (0.6 mL) and 1 M K2CO3 (0.2 ml_) under argon. 2-Bromo-isonicotinonitrile (18mg, 0.1 mmol) and Pd(PPh3)4 (6mg, 0.005 mmol) were added. The suspension was shaken at 800C for 17 h after which brine was added, and the aqueous phase was extracted with DCM (x 3). The combined organic phases were dried, filtered and concentrated. The crude product was purified by flash chromatography, eluent TBME : heptane 4: 1 -> 9: 1. This afforded the title compound as a solid IH NMR (300 MHz, DMSO) delta 9.23 - 9.09 (m, IH), 9.00 (dd, J = 4.9, 0.8 Hz, IH), 7.95 (dd, J = 4.9, 1.5 Hz, IH), 7.90 (d, J = 8.3 Hz, IH), 7.24 (d, J = 8.4 Hz, IH), 4.03 (s, 3H), 2.29 (tt, J = 8.1, 5.0 Hz, IH), 1.18 - 0.87 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 16h; | To a solution of 2-(pyridin-2-yl)-4,5,6,7-tetrahydrooxazolo[4,5-c] pyridine (I- 23.4) (40 mg, 0.2 mmol) in DMF (2 mL) was added <strong>[10386-27-3]2-bromoisonicotinonitrile</strong> (54 mg, 0.3 mmol), DIEA (52 mg, 0.4 mmol). The mixture was heated to 1000C and stirred for 16 h. The mixture was cooled to room temperature and poured into water. The mixture was extracted with EtOAc. The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC to afford 2-(2- (pyridin-2-yl)-6,7-dihydrooxazolo[4,5-c]pyridin-5(4H)-yl)isonicotinonitrile (10 mg, 17percent) as a yellow solid. 1H NMR (400 MHz, CDCl3): delta 8.67 (d, IH), 8.25 (d, IH), 8.03 (d, IH), 7.75 (t, IH), 7.30 (t, IH), 6.81 (s, IH), 6.75 (d, IH), 4.52 (s, 2H), 4.07 (t, 2H), 2.91 (t, 2H); LC/MS: m/e = 304 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol;Reflux; | Description for D35 2-brorno-A/-hydroxy-4-pyridinecarboximidamide (D35)A mixture of <strong>[10386-27-3]2-bromo-4-pyridinecarbonitrile</strong> (0.7 g), sodium bicarbonate (0.65 g) and hydroxylamine hydrochloride (0.53 g) in ethanol (50 ml) was heated at reflux for overnight. The inorganic precipitate was filtered off. The solid was washed thoroughly with ethanol. The filtrate was concentrated. The obtained solid was dried in vacuo to afford 2-bromo-Lambda/-hydroxy-4-pyridinecarboximidamide (0.78 g). MS (ES): C6H6BrN3O requires 215; found 216.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;palladium diacetate; triphenylphosphine; In 1,4-dioxane; at 85℃; for 4h;Inert atmosphere; | Example A3. General experimental for the Suzuki coupling of aryl bromides or chlorides with boronic acidsGeneral Scheme:K2C03, Pd(OAc)2 Ph3P, dioxaneRepresentative SchePh3P, dioxaneA solution of the aryl bromide or aryl chloride (e.g., 6-bromonicotinonitrile, 1 equiv), 4,4,5,5-tetramethyl -2-vinyl-l,3,2- dioxaborolane (2 equiv), K2C03 (2 equiv), Pd(AcO)2 (0.4 equiv) and PI13P (0.8 equiv) in 1,4-dioxane was stirred under N2 at 85 °C until the reaction was complete (approximately 4 h). After cooling to room temperature, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over Na2S04 and concentrated under reduced pressure. The crude vinyl-containing product (e.g., 2-vinylisonicotinonitrile) was purified by silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; at 85℃; for 3h;Inert atmosphere; | General procedure: To a solution of 2-ethynylquinoline 9 (50 mg, 0.33 mmol) in triethylamine (0.4 mL) was added PdCl2(PPh3)2 (12 mg, 0.02 mmol), copper(I) iodide 98percent (6 mg, 0.03 mmol) and 2- bromo-3-trifluoromethylpyridine (110 mg, 0.5 mmol). After the reaction was stirred at 85 °C for 3 h, it was allowed to cool to room temperature and filtered through a pad of Celite by the aid of EtOAc. The filtrate was treated with water and extracted with EtOAc (3 x 10 mL). The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude oil was purified by column chromatography on silica gel (EtOAc/hexane = 1:1) to give 2-((3-(trifluoromethyl)pyridin-2-yl)ethynyl) quinoline 6a (48 mg, 49percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); | Step E. (2S)-4-(tert-Butyldimethylsilyloxy)-N-(1-(2-chlorophenyl)-2-(3,3-difluorocyclobutyl-amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-4-methyl-5-oxopyrrolidine-2-carboxamide A mixture consisting of (2S)-4-(tert-butyldimethylsilyloxy)-N-(1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)-N-(3-fluorophenyl)-4-methyl-5-oxopyrrolidine-2-carboxamide (200 mg, 0.32 mmol), <strong>[10386-27-3]2-bromoisonicotinonitrile</strong> (88 mg, 0.48 mmol), Cs2CO3 (146 mg, 0.45 mmol), Pd2(dba)3 (29 mg, 0.032 mmol), Xant-Phos (19 mg, 0.032 mmol) and 1,4-dioxane (5 mL) was stirred under N2 at 80° C. overnight. After filtration, the filtrate was concentrated in vacuo and the residue was purified by a standard method to give desired product. MS: 726 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); | Step D: (4S)-tert-Butyl 4-((1-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)(3-fluorophenyl)carbamoyl)-3-(4-cyanopyridin-2-yl)-2-oxoimidazolidine-1-carboxylate To a 25 mL flask charged with 1,4-dioxane (4.5 mL) were added (4S)-tert-butyl 4-((1-(2-chlorophenyl)-2-(3,3-difluoro cyclo butylamino)-2-oxoethyl)(3-fluoro-phenyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (250 mg, 0.43 mmol), <strong>[10386-27-3]2-bromoisonicotinonitrile</strong> (122 mg, 0.65 mmol), Cs2CO3 (281 mg, 0.862 mmol), Xant-Phos (25 mg, 0.043 mmol) and Pd2(dba)3 (40 mg, 0.043 mmol). The mixture was degassed and refilled with nitrogen, and then heated to 100° C. for 3 hr. The resulting mixture was cooled and filtered. The filtrate was concentrated in vacuo and the residue was purified by a standard method to give both epimers. The epimers were further separated by a standard method to give the desired product. 1H NMR (400 MHz, CDCl3): delta 8.58 (s, 1H), 8.48 (t, J=5.9 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.37-7.16 (m, 4H), 7.15-6.76 (m, 4H), 6.56-6.31 (m, 2H), 4.95-4.75 (m, 1H), 4.31 (s, 1H), 3.86 (dd, J=10.8, 5.1 Hz, 1H), 3.66 (m, 1H), 2.99 (m, 2H), 2.61-2.27 (m, 2H), 1.56 (s, 9H). MS: 683 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; | Step E. (2S)-4-(tert-Butyldimethylsilyloxy)-N-(l-(2-chlorophenyl)-2-(3,3-M amino)-2-oxoethyl)-l-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-4-methyl-5-o carboxamide. A mixture consisting of (2S)-4-(tert-butyldimethylsilyloxy)-N-(l-(2- chlorophenyl)-2-(3,3-difluorocyclobutylamino)-2-oxoethyl)-N-(3-fluorophenyl)-4-methyl-5- oxopyrrolidine-2-carboxamide (200 mg, 0.32 mmol), <strong>[10386-27-3]2-bromoisonicotinonitrile</strong> (88 mg, 0.48 mmol), Cs2C03 (146 mg, 0.45 mmol), Pd2(dba)3 (29 mg, 0.032 mmol), Xant-Phos (19 mg, 0.032 mmol) and 1 ,4-dioxane (5 mL) was stirred under N2 at 80 °C overnight. After filtration, the filtrate was concentrated in vacuo and the residue was purified by a standard method to give desired product. MS: 726 (M+l)+ . | |
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃;Inert atmosphere; | A mixture consisting of (2 S)-4-(tert-butyldimethylsilyloxy)-N-( 1 -(2- chlorophenyl)-2-(3 ,3 -difluorocyclobutylamino)-2-oxoethyl)-N-(3 -fluorophenyl)-4-methyl-5 - oxopyrrolidine-2-carboxamide (200 mg, 0.32 mmol), <strong>[10386-27-3]2-bromoisonicotinonitrile</strong> (88 mg, 0.48 mmol), Cs2CO3 (146 mg, 0.45 mmol), Pd2(dba)3 (29 mg, 0.032 mmol), Xant-Phos (19 mg, 0.032 mmol) and 1 ,4-dioxane (5 mL) was stirred under N2 at 80 °C overnight. After filtration, the filtrate was concentrated in vacuo and the residue was purified by a standard method to give desired product. MS: 726 (M+1). | |
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃;Inert atmosphere; | Step E. (2S)-4-(tert-Butyldimethylsilyloxy)-N-(l-(2-chlorophenyl)-2-(3,3-difluorocyclobutyl- amino)-2-oxoethyl)-l-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-4-methyl-5-oxopyrrolidine-2- carboxamide. A mixture consisting of (2S)-4-(tert-butyldimethylsilyloxy)-N-(l-(2- chlorophenyl)-2-(33-difiuorocy clobuty lamino)-2-oxoethyl)-N-(3-fiuorophenyI)-4-methy 1-5- oxopyrrolidine-2-carboxamide (200 mg, 0.32 mmo l), <strong>[10386-27-3]2-bromoisonicotinonitrile</strong> (88 mg 0.48 mmol), Cs2C03 (146 mg, 0.45 mmo l), Pd2(dba)3 (29 mg, 0.032 mmol), Xant-Phos (19 mg, 0.032 mmol) and 1,4-dioxane (5 mL) was stirred under N2 at 80 °C overnight. After filtration, the filtrate was concentrated in vacuo and the residue was purified by a standard method to give desired product. MS: 726 (M+l)+ . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 3h;Inert atmosphere; | Step D: (4S)-tert-Butyl 4-((l-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino) -2-oxoethyl)(3- fluorophenyl)carbamoyl)-3-(4-cyanopyridin-2-yl)-2-oxoimidazolidine-l-carboxylate. To a 25 mL flask charged with 1 ,4-dioxane (4.5 mL) were added (4S)-tert-butyl 4-((l-(2-chlorophenyl)- 2-(3,3-difluoro cyclo butylamino)-2-oxoethyl)(3-fluoro -phenyl)carbamoyl)-2-oxoimidazolidine- 1 - carboxylate (250 mg, 0.43 mmol), <strong>[10386-27-3]2-bromoisonicotinonitrile</strong> (122 mg, 0.65 mmol), CS2CO3 (281 mg, 0.862 mmol), Xant-Phos (25 mg, 0.043 mmol) and Pd2(dba)3 (40 mg, 0.043 mmol). The mixture was degassed and refilled with nitrogen, and then heated to 100 °C for 3 hr. The resulting mixture was cooled and filtered. The filtrate was concentrated in vacuo and the residue was purified by a standard method to give both epimers. The epimers were further separated by a standard method to give the desired product. 1H NMR (400 MHz, CDC13): delta 8.58 (s, 1H), 8.48 (t, J= 5.9 Hz, 1H), 7.71 (d, J= 8.4 Hz, 1H), 7.37 - 7.16 (m, 4H), 7.15 - 6.76 (m, 4H), 6.56 - 6.31 (m, 2H), 4.95 - 4.75 (m, 1H), 4.31 (s, 1H), 3.86 (dd, J= 10.8, 5.1 Hz, 1H), 3.66 (m, 1H), 2.99 (m, 2H), 2.61 - 2.27 (m, 2H), 1.56 (s, 9H). MS : 683 (M+l)+. | |
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 3h;Inert atmosphere; | To a 25mL flask charged with 1 ,4-dioxane (4.5 mL)wereadded (45)-tert-butyl 4-((1 -(2-chlorophenyl)-2-(3 ,3 -difluoro cyclo butylamino)-2-oxoethyl)(3 -fluoro -phenyl)carbamoyl)-2-oxoimidazolidine-1-carboxylate (250 mg, 0.43 mmol), <strong>[10386-27-3]2-bromoisonicotinonitrile</strong> (122 mg, 0.65 mmol), Cs2CO3 (281 mg,0.862 mmol), Xant-Phos (25 mg, 0.043 mmol) and Pd2(dba)3 (40 mg, 0.043 mmol). The mixture was degassed and refilled with nitrogen, and then heated to 100°C for 3hr. The resulting mixture was cooled and filtered. The filtrate was concentrated invacuo and the residue was purified by a standard methodto give both epimers. The epimers were further separated bya standard methodto give the desired product. ?H NMR (400 MHz, CDC13): 8.58 (s, 111), 8.48 (t, J 5.9 Hz, 111), 7.71 (d, J 8.4 Hz, 111), 7.37?7.16 (m, 411), 7.15 ?6.76 (m, 411), 6.56?6.31 (m, 211), 4.95 ?4.75 (m, 111), 4.31 (s, 111), 3.86 (dd,J= 10.8, 5.1 Hz, 111), 3.66 (m, 111), 2.99 (m, 211), 2.61 ?2.27 (m, 211), 1.56 (s, 911). MS : 683(M+1). | |
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 3h;Inert atmosphere; | StepD: (4S)-tert-Butyl 4-((l-(2-chlorophenyl)-2-(3,3-difluorocyclobutylamino) -2-oxoethyl){3- fluorophenyl)carbamoyl)-3-(4-cyanopyridin-2-yl)-2-oxoimidazolidine-l-carboxylate. To a 25 mL flask charged with 1,4-dioxane (4.5 mL) were added(4S)-tert-butyl4-((l-(2-chlorophenyI)- 2-(33-difluoro cyclo butylamino)-2-oxoethyl)(3-fiuoro -phenyl)carbamoyl)-2-oxoimidazolidine- 1- carboxylate (250 mg, 0.43 mmol), <strong>[10386-27-3]2-bromoisonicotinonitrile</strong> (122 mg 0.65 mmol), CS2CO3 (281 mg, 0.862 mmol), Xant-Phos (25 mg 0.043 mmol) and Pd2(dba)3 (40 mg, 0.043 mmol). The mixture was degassed and refilled with nitrogen, and then heated to 100 °C for 3 hr. The resulting mixture was cooled and filtered. The filtrate was concentrated in vacuo and the residue was purified by a standard method to give both epimers. The epimers were further separated by a standard method to give the desired product. 'HNMR (400 MHz, CDC13): delta 8.58 (s, 1H), 8.48 (t, J= 5.9 Hz, 1H), 7.71 (d, J= 8.4 Hz, 1H),7.37 - 7.16 (m, 4H), 7.15 - 6.76 (m, 4H), 6.56 - 6.31 (m, 2H), 4.95 - 4.75 (m, 1H), 4.31 (s, 1H), 3.86 (dd,J= 10.8, 5.1 Hz, 1H), 3.66 (m, 1H), 2.99 (m, 2H),2.61 -2.27 (m, 2H), 1.56 (s,9H).MS : 683(M + 1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 3h;Inert atmosphere; | Step D: Ethyl 2-((4S)-4-((l-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(3- fluorophenyl)carbamoyl)-3-(4-cyanopyridin-2-yl)-2-oxoimidazolidin-l-yl)acetate - Compound 94. To a 25 mL-flask were added ethyl 2-((4S)-4-((l-(2-chlorophenyl)-2-(3,3- difluorocyclobutylamino)-2-oxoethyl) (3-fluoro -phenyl)carbamoyl)-2-oxoimidazolidin- 1 - yl)acetate (50 mg, 0.0882 mmol), <strong>[10386-27-3]2-bromoisonicotinonitrile</strong> (21 mg, 0.115 mmol), CS2CO3 (58 mg,0.176 mmol), Xant-Phos (5.2 mg, 0.009mmol), Pd2(dba)3 (8.2 mg, 0.009 mmol) and 1 ,4- dioxane (1 mL). The mixture was degassed and refilled with nitrogen, and then heated to 100 °C for 3 hr. The resulting mixture was cooled and filtered and then the filtrate was concentrated in vacuo. The residue was purified by a standard method to give both epimers. FontWeight="Bold" FontSize="10" H NMR (400 MHz, CDC13): delta 8.63-8.57 (S, 1H), 8.55 - 8.38 (m, 1H), 7.63 (s, 1H), 7.46 - 6.84 (m, 8H), 6.45-6.37 (m, 1H), 6.22 - 5.94 (m,lH), 5.06 - 4.77 (m, 1H), 4.43-4.37 (m, 1H), 4.32-4.20 (m, 1H), 4.21 (q, J= 7.1 Hz, 2H), 3.82 - 3.46 (m, 3H), 3.12 - 2.82 (m, 2H), 2.66 - 2.25 (m, 2H), 1.29 (t, J= 7.1 Hz, 3H). MS : 669 (M+l)+. | |
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 3h;Inert atmosphere; | To a 25 mL-flask were addedethyl 2-((45)-4-((1-(2-chlorophenyl)-2-(3,3- difluorocyclobutylamino)-2-oxoethyl) (3 -fluoro -phenyl)carbamoyl)-2-oxoimidazolidin- 1- yl)acetate (50 mg, 0.0882 mmol), <strong>[10386-27-3]2-bromoisonicotinonitrile</strong> (21 mg, 0.115 mmol), Cs2CO3 (58 mg,0.176 mmol), Xant-Phos (5.2 mg, 0.OO9mmol), Pd2(dba)3 (8.2 mg, 0.009 mmol) and 1,4- dioxane (1 mL). The mixture was degassed and refilled with nitrogen, and then heated to 100°C for 3hr. The resulting mixture was cooled and filtered and then the filtrate was concentrated in vacuo. The residue was purified by a standard method to give both epimers.?H NMR (400 MFTz, CDC13): 8.63-8.57 (5, 1H), 8.55 ? 8.38 (m, 1H), 7.63 (s, 1H), 7.46 ? 6.84 (m, 8H), 6.45-6.37 (m, 1H), 6.22 ? 5.94 (m,1H), 5.06 ? 4.77 (m, 1H), 4.43-4.37 (m, 1H), 4.32-4.20 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.82 ? 3.46 (m, 3H), 3.12 ? 2.82 (m, 2H), 2.66 ? 2.25 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H). MS : 669(M+1). | |
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 3h;Inert atmosphere; | Step D: Ethyl 2-((4S)-4-((l-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)(3- fluoroph enyl )carbamoyl )-3-( 4-cyan opyridin -2-yl )-2-oxoimidazolidin -1-yl )acetate - Compound 94. To a 25 mL-fiask were added ethyl 2-((4S)-4 (l -(2-chlorophenyl)-2-(3,3- difiuorocyclobutylamino)-2-oxo ethyl) (3-fiuoro -phenyl)carbamoyl)-2-oxoimidazolidin- l- yl)acetate (50 mg, 0.0882 mmol), <strong>[10386-27-3]2-bromoisonicotinonitrile</strong> (21 mg, 0.115 mmol), CS2CO3 (58 mg,0.176 mmol), Xant-Phos (5.2 mg, 0.009 mmol), Pd2(dba)3 (8.2 mg, 0.009 mmo l) and 1 ,4- dioxane (1 mL). The mixture was degassed and refilled with nitrogen, and then heatedto 100 °C for 3 hr. The resulting mixture was cooled and filtered and then the filtrate was concentrated in vacuo. The residue was purified by a standard method to give both ep imers. 'H MR (400 MHz, CDC13): delta 8.63-8.57 (S, 1H), 8.55 - 8.38 (m, 1H), 7.63 (s, 1H), 7.46 - 6.84 (m, 8H), 6.45-6.37 (m, 1H), 6.22 - 5.94 (m, lH), 5.06 - 4.77 (m, 1H), 4.43-4.37 (m, 1H), 4.32-4.20 (m, 1H), 4.21 (q, J= 7.1 Hz, 2H), 3.82 - 3.46 (m, 3H), 3.12 - 2.82 (m, 2H), 2.66 - 2.25 (m, 2H), 1.29 (t, J= 7.1 Hz, 3H). MS : 669 (M + l)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃;Inert atmosphere; | A mixture of amine (0.30 mmol), aryl bromide (0.30 mmol), Cs2C03 (129 mg, 0.39 mmol), Pd2(dba)3 (18 mg, 0.02 mmol) and Xant-Phos (9.4 mg, 0.02 mmol) in 1 ,4-dioxane (10 mL) was stirred under nitrogen atmosphere at 80 °C overnight. After filtration, the filtrate was concentrated in high vacuo and the residue was purified by prep-TLC to give the desired products. The product was prepared followed the general procedure for Buchwald reaction set forth above. 1H NMR (400 MHz, CDC13) : delta 8.51-8.45 (m, 1H), 7.72 - 7.52 (m, 1H), 7.48 - 7.29 (m, 3H), 7.26 - 6.77 (m, 7H), 6.75 - 6.61 (m, 1H), 6.46 - 6.20 (m, 1H), 6.14 - 6.1 1 (m, 1H), 5.04 - 4.88 (m, 1H), 4.20 (s, 1H), 3.35 - 3.08 (m, 2H), 2.89 (s, 2H), 2.31 (s, 2H). MS: 634.2 (M+l)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 14h;Inert atmosphere; Sealed tube; | A solution of 4-(trifluoromethyl)phenylboronic acid (519 mg, 2.73 mmol), <strong>[10386-27-3]2-bromo-isonicotinonitrile</strong> (500 mg, 2.73 mmol) and potassium carbonate (358 mg, 2.73 mmol) in DMF (5 mL) at 25°C was purged with nitrogen gas and evacuated three times. The solution was then treated with tetrakis(triphenylphosphine)palladium(0) (158 mg, 137 tmol) and then sealed and heated to 120°C for 14 h. The reaction mixture was cooled to 25°C, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded 2-(4-trifluoromethyl-phenyl)- isonicotinonitrile (0.38 g, 56percent) as a white solid. MH+ = 248.9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; tert-butyl XPhos; In toluene; at 50℃; for 1.5h;Inert atmosphere; | Preparation 21": 2-({4-[(tert-Butyldimethylsilyl)oxy]phenyl}amino)pyridine-4-carbonitrile A solution composed of <strong>[10386-27-3]2-bromo-4-pyridinecarbonitrile</strong> (5.00 g, 36.1 mmol), 4-[(tert-butyldimethylsilyl)oxy]aniline (8.06 g, 36.1 mmol), sodium tert-butylate (4.50 g, 46.9 mmol) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.458 g, 1.08 mmol) in toluene (50 mL) is purged with nitrogen. Tris(dibenzylideneacetone)-dipalladium(0) (0.99 g, 1.08 mmol) is then added to the reaction mixture, and then the batch is heated at 50° C. for 1.5 hours. The mixture is then allowed to cool to ambient temperature. Water is added and the reaction mixture is extracted with ethyl acetate (3*20 mL). The combined organic phases are washed with brine, and then concentrated under reduced pressure. The crude product is absorbed onto silica gel and purified by chromatography over silica gel using ethyl acetate and heptane as eluants. The product obtained is dissolved in the warm state in heptane and precipitates, with stirring, at ambient temperature, and then at 0° C. After filtration, the expected compound is obtained in the form of a solid. 1H NMR (400 MHz, CDC3) delta ppm: 0.22 (s, 6H), 1.00 (s, 9H), 6.61 (br. s, 1H), 6.81-6.84 (m, 2H), 6.84-6.89 (m, 2H), 7.12-7.17 (m, 2H), 8.26 (dd, J=5.1, 0.9 Hz, 1H) 13C NMR (100 MHz, CDC3) delta ppm: -4.29, 18.31, 25.78, 109.11, 114.73, 117.23, 121.17, 121.74, 124.93, 132.12, 149.79, 153.45, 158.00 MS (ESI+): [M+H]+ 326.19 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃;Inert atmosphere; | (2S)-N-( 1 -(2-chloro -phenyl)-2-(3 ,3 -difluorocyclobutylamino)-2- oxoethyl)-N-(3 -fluoro-5 -(isoxazol-5 -yl)phenyl)-5 -oxopyrrolidine-2-carboxamide (200 mg, 0.37 mmol), 2-bromopyrimidine (102 mg, 0.56 mmol), Cs2CO3 (240 mg, 0.74 mmol), Pd2(dba)3 (37 mg, 0.04 mmol) and Xant-Phos (22 mg, 0.03 mmol) in 1 ,4-dioxane (15 mL) were stirred under N2 at 80 °C overnight and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a standard method to give the desired product. ?H NMR (400 MHz,CDC13): 8.69-8.17 (m, 311), 7.80-7.28 (m, 311), 7.25-6.93 (m, 511), 6.63-6.30 (m, 311), 4.96-4.92 (m, 111), 4.37-4.34 (m, 111), 3.06-2.83 (m, 311), 2.58-2.21(m, 411), 2.08-2.02 (m, 111). MS:649.1 (M+1). | |
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃;Inert atmosphere; | Step G: Compound315. (2S -N-(l-(2-chloro -phenyl)-2-(3,3-difluorocyclobutylamino)-2- oxoethyl)-N-(3-fiuoro-5-(isoxazol-5-yl)phenyl)-5-oxopyrrolidine-2-carboxamide (200 mg, 0.37 mmol), 2-bromopyrimidine (102 mg, 0.56 mmol), Cs2C03 (240 mg, 0.74 mmol), Pd2(dba)3 (37 mg, 0.04 mmol) andXant-Phos (22 mg, 0.03 mmol) in 1,4-dioxane (15 mL) were stirred under N2 at 80 °C overnight and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a standard method to give the desired pro duct. FontWeight="Bold" FontSize="10" H NMR (400 MHz, CDC13): delta 8.69-8.17 (m, 3H), 7.80-7.28 (m, 3H), 7.25-6.93 (m, 5H), 6.63-6.30 (m, 3H), 4.96- 4.92 (m, lH), 4.374.34 (m, 1H), 3.06-2.83 (m, 3H), 2.58-2.21(m, 4H), 2.08-2.02 (m, 1H). M S: 649.1 (M+l)+. |
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