There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type | HazMat fee for 500 gram (Estimated) |
Excepted Quantity | USD 0.00 |
Limited Quantity | USD 15-60 |
Inaccessible (Haz class 6.1), Domestic | USD 80+ |
Inaccessible (Haz class 6.1), International | USD 150+ |
Accessible (Haz class 3, 4, 5 or 8), Domestic | USD 100+ |
Accessible (Haz class 3, 4, 5 or 8), International | USD 200+ |
Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 36282-26-5 | MDL No. : | MFCD00672924 |
Formula : | C7H3BrFN | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MNNDREXLRLDWEY-UHFFFAOYSA-N |
M.W : | 200.01 | Pubchem ID : | 118939 |
Synonyms : |
|
Num. heavy atoms : | 10 |
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 : | 38.81 |
TPSA : | 23.79 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.79 cm/s |
Log Po/w (iLOGP) : | 1.89 |
Log Po/w (XLOGP3) : | 2.43 |
Log Po/w (WLOGP) : | 2.88 |
Log Po/w (MLOGP) : | 2.63 |
Log Po/w (SILICOS-IT) : | 2.9 |
Consensus Log Po/w : | 2.55 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.05 |
Solubility : | 0.176 mg/ml ; 0.000881 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.57 |
Solubility : | 0.535 mg/ml ; 0.00268 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.62 |
Solubility : | 0.0481 mg/ml ; 0.00024 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.64 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P501-P261-P270-P271-P264-P280-P337+P313-P305+P351+P338-P361+P364-P332+P313-P301+P310+P330-P302+P352+P312-P304+P340+P311-P403+P233-P405 | UN#: | 3439 |
Hazard Statements: | H301+H311+H331-H315-H319 | Packing Group: | Ⅲ |
GHS Pictogram: |
* 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 |
---|---|---|
60% | With pyridine; ammonium peroxydisulfate; tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; 4-acetylamino-2,2,6,6-tetramethyl-1-piperidinoxy In acetonitrile at 0.5℃; for 24 h; Molecular sieve; Sealed tube; Irradiation | General procedure: To an oven-dried 2 ml reaction vial equipped with a stir bar wasadded the aldehyde 3a (0.136 g, 1 mmol, 1 equiv) and pyridine(0.474 g, 6.0 mmol, 6 equiv), followed by acetonitrile (2 ml, 0.5M in 3a). The vial was then charged with Ru(bpy)3(PF6)2 (0.017g, 0.02 mmol, 0.02 equiv), 2 (0.043 g, 0.20 mmol, 0.20 equiv),(NH4)2S2O8(0.501 g, 2.2 mmol, 2.2 equiv), and activated 3 Åmolecular sieves (ca. 0.2 g), sealed with a cap, and irradiated inblue LED reactor for 24 h. In the absence of fan cooling, the temperatureof the reaction mixture plateaued at approximately 50°C . After the irradiation was complete, the reaction mixturewas quenched with EtOAc and transferred to a separatoryfunnel. Further EtOAc (30 ml) was added, followed by 0.5 MHCl(aq) (30 ml). The layers were separated, and the aqueous layerwas extracted with EtOAc (3 × 20 ml). The organic layers werethen combined and washed with 0.5 M 0.5 M HCl(aq) (2 × 20 ml),saturated aqueous sodium bicarbonate (2 × 20 ml), and finallybrine (20 ml). The organic layer was then dried over sodiumsulfate and the solvent removed in vacuo to afford the crudeproduct. The resulting crude mixture was adhered to silica gelusing 1.5 weight equivalents of SiO2(relative to the theoreticalyield). The dry-packed material was gently added on top of asilica gel plug. The plug was washed with an excess of hexanes(ca. 5 column volumes). The desired product was eluted off theplug via a 90:10 by volume mixture of hexanes/EtOAc (3–4column volumes). The solvent was removed in vacuo by rotaryevaporation affording the pure nitrile 3c (0.066 g, 50percent) as awhite solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With hydrazine In tetrahydrofuran at 20℃; for 24 h; | Example 4a Preparation of 2-Bromo-4-hydrazino-benzonitrile To a solution of 2-bromo-4-fluorobenzonitrile (5.00 g, 25.00 mmol) in THF (10 mL) is added anhydrous hydrazine (10 mL) through an addition funnel. After addition, the resulting mixture is stirred at room temperature for 24 h. Water (20 mL) is added to the reaction mixture. A white precipitate is collected by filtration, washed with water, and dried in a vacuum oven at 40° C. to afford 2-Bromo-4-hydrazino-benzonitrile (4.92 g, 93percent) as a white solid: 1H NMR (300 MHz, CDCl3) δ8.05 (br s, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 6.72 (dd, J=8.7, 2.0 Hz, 1H), 4.37 (br s, 2H); ESI MS m/z 212 [M+H]+. |
87.2% | With hydrazine In tetrahydrofuran at 20℃; for 16 h; | In a clean, dry 250-mL round-bottom flask, 2-bromo-4- fluorobenzonitrile (25.34 g) was dissolved in tetrahydrofuran(50 itiL) under N2. To this was slowly added anhydrous hydrazine (50 mli) . The solution color changed from yellow to red- orange. The reaction was allowed to stir at room temperature for 16 hours. A yellow-white crystalline solid precipitated from the solution. The mixture was then diluted with THF (50 iriL) to dissolve the solids. The organic layer was then washed with saturated sodium bicarbonate solution until the pH of the organic layer was approximately 8.5. The organic layer was isolated and the solvent was removed under reduced pressure to give a white solid. This was place in a fritted glass funnel and washed with 1.5 L of water, followed by of diethyl ether (ca. 200 mli) . The ether wash was then combined with the white solid and dried under reduced pressure. The title compound was isolated as a fluffy, white or off-white solid (23.43 g, 87.2percent yield). LCMS m/z: calculated = 212.05; observed = 252.98 (M+H+ acetonitrile) |
87.2% | With hydrazine In tetrahydrofuran at 20℃; for 16 h; | Example 4; 3-bromo-4-cyanophenylhydrazine; In a clean, dry 250-mL round-bottom flask, 2-bromo-4-fluorobenzonitrile (25.34 g) was dissolved in tetrahydrofuran (50 mL) under N2. To this was slowly added anhydrous hydrazine (50 mL). The solution color changed from yellow to red-orange. The reaction was allowed to stir at room temperature for 16 hours. A yellow-white crystalline solid precipitated from the solution. The mixture was then diluted with THF (50 mL) to dissolve the solids. The organic layer was then washed with saturated sodium bicarbonate solution until the pH of the organic layer was approximately 8.5. The organic layer was isolated and the solvent was removed under reduced pressure to give a white solid. This was place in a fritted glass funnel and washed with 1.5 L of water, followed by of diethyl ether (ca. 200 mL). The ether wash was then combined with the white solid and dried under reduced pressure. The title compound was isolated as a fluffy, white or off-white solid (23.43 g, 87.20percent yield). MS m/z: calculated=212.05; m/z observed=252.98 (M+41). |
87.2% | With hydrazine In tetrahydrofuran at 20℃; for 16 h; Inert atmosphere | Example 6 3-bromo-4-cyanophenylhydrazine (Intermediate 6) In a clean, dry 250-mL round-bottom flask, 2-bromo-4-fluorobenzonitrile (25.34 g) is dissolved in tetrahydrofuran (50 mL) under N2. To this is slowly added anhydrous hydrazine (50 mL). The solution color changed from yellow to red-orange. The reaction is allowed to stir at room temperature for 16 hours. A yellow-white crystalline solid precipitated from the solution. The mixture is then diluted with THF (50 mL) to dissolve the solids. The organic layer is then washed with saturated sodium bicarbonate solution until the pH of the organic layer is approximately 8.5. The organic layer is isolated and the solvent is removed under reduced pressure to give a white solid. This is placed in a fritted glass funnel and washed with 1.5 L of water, followed by of diethyl ether (ca. 200 mL). The ether wash is then combined with the white solid and dried under reduced pressure. The title compound is isolated as a fluffy, white or off-white solid (23.43 g, 87.2percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at -30℃; for 3 h; Stage #2: at -30 - 20℃; Stage #3: With hydrogenchloride In tetrahydrofuran; water at -10℃; for 0.333333 h; |
To a solution of 2-bromo-4-fluorobenzonitrile (5.0 g, 25.0 mmol) in anhydrous THF (20 mL) is added PrMgCl 2.0M in THF (15.0 mL, 30.0 mmol) at -30°C. The solution is stirred at -30 °C for 3 hours and DMF (5.80 mL, 75.0 mmol) is added. The reaction mixture is allowed to warm to room temperature and is stirred for 1 hour. The solution is cooled to -10°C, 2M hydrochloric acid (37 mL) is added and the solution is stirred for 20 minutes. The solution is concentrated in vacuo to -1/3 original volume and extracted into EtOAc (3x). The combined organics are then dried (Na2S04), filtered and concentrated to afford 4-fluoro-2-formyl benzonitrile (3.9 g, 71percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Stage #1: at 140℃; for 1 h; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 24 h; |
To a 40 mL reaction vial with a stir bar are added 2-bromo-4-fluorobenzonitrile (6.00 g, 30.0 mmol) and 3,4,5-trimethoxybenzylamine (5.4 mL, 32 mmol). The reaction is sealed and stirred at 140° C. for 1 hour. The reaction is cooled to room temperature, and CH2Cl2 (15 mL) and trifluoroacetic acid (15 mL) are added. The vial is sealed and the mixture is allowed to stir at room temperature for 24 hours. The reaction is concentrated, diluted with EtOAc (100 mL), washed with saturated aqueous NaHCO3 (2*100 mL), and dried over Na2SO4. The compound is purified by gradient flash chromatography, eluding with 0percent to 40percent EtOAc in hexanes to yield 4-amino-2-bromobenzonitrile as a tan solid (2.88 g, 49percent yield) (LC/MS m/z=197 [M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With sodium hydride In dimethyl sulfoxide at 20℃; for 3h; | 4.4b Example 4bPreparation of 2-Bromo-4- (7, 7-dimethyl-5-oxo-3, 4 , 5, 6, 7, 8- hexahydro-2H-quinolin-l-yl) -benzonitrileSodium hydride (60% in mineral oil, 0.012 g, 0.30 mmol) is added to a stirred solution of compound 7, 7-Dimethyl- 2, 3, 4, 6, 7, 8-hexahydro-lH-quinolin-5-one (0.030 g, 0.17 mmol) and 2-bromo-4-fluorobenzonitrile (0.060 g, 0.030 mmol) in DMSO(5 mL) . The mixture is stirred at room temperature for 3 h, then quenched by addition to saturated NH4Cl. The aqueous mixture is then extracted with ethyl acetate (3 x 15 mL) . The organic layers are combined, washed with brine, dried over sodium sulfate, filtered and concentrated at reduced pressure. The crude product obtained is combined with a smaller batch of crude material for chromatography (silica gel preparative TLC, 1:1 hexanes/ethyl acetate) to afford 2-Bromo-4- (7, 7-dimethyl- 5-OXO-3, 4,5,6,7, 8-hexahydro-2H-quinolin-l-yl) -benzonitrile(0.034 g, 44%) as a colorless glass: ESI MS m/z 359 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine In toluene at 100℃; for 24h; | 21 Example 21 1-amino-6-fluoro-isoquinoline-4-carbonitrile; Palladium acetate (II) (0.556 g, 2.5 mmol) is added to a degassed solution of 2-bromo-4-fluoro-benzonitrile (10 g, 50 mmol), 3-ethoxyacrylonitrile (10.3 mL, 100 mmol) and triethylamine (14 mL, 100 mmol) in toluene (75 mL). The reaction mixture is stirred in an oil bath at 100° C. for 1 day. The reaction mixture is cooled to RT, filtered through a pad of Celite, and the filter cake is rinsed with EtOAc. After evaporation of the solvent, the residue is purified using a Biotage column eluted with 0-50% EtOAc/hexanes (20 CV) to afford 8.77 g (94%) of 2-(1-cyano-2-ethoxy-vinyl)-4-fluoro-benzonitrile. LC/MS: RT=3.38 min, no ionization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | To a 40 mL reaction vial with a stir bar are added 2-bromo-4-fluorobenzonitrile (6.00 g, 30.0 mmol) and 3,4,5-trimethoxybenzylamine (5.4 mL, 32 mmol). The reaction is sealed and stirred at 140 C. for 1 hour. The reaction is cooled to room temperature, and CH2Cl2 (15 mL) and trifluoroacetic acid (15 mL) are added. The vial is sealed and the mixture is allowed to stir at room temperature for 24 hours. The reaction is concentrated, diluted with EtOAc (100 mL), washed with saturated aqueous NaHCO3 (2*100 mL), and dried over Na2SO4. The compound is purified by gradient flash chromatography, eluding with 0% to 40% EtOAc in hexanes to yield 4-amino-2-bromobenzonitrile as a tan solid (2.88 g, 49% yield) (LC/MS m/z=197 [M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With sodium hydride In N,N-dimethyl-formamide at 60℃; for 3h; | 4; 9 Sodium hydride (60% suspension in mineral oil, 0.031 g, 0.77 mmol) is added to a solution of 2-bromo-4- fluorobenzonitϖle (0.128 g, 0.64 mmol) and 3,4,5- tϖmethoxyphaneyl acetic acid methyl ester (0.1854 g, 0.77 mmol) in DMF (2 mL) . The reaction mixture is stirred at 60 0C for 3 h. After addition of water (3 mL) , the aqueous phase is extracted with EtOAc (3 x) . The combined organic layers are washed with brine, dried over MgSO4, and evaporated to dryness. The residue is purified by column chromatography (SiO2, 20%-50% EtOAc/hexanes) to yield 0.1363 g (51%) of (3-Bromo-4-cyano- phenyl) - (3, 4 , 5-trimethoxy-phenyl) -acetic acid methyl ester. LC/MS Calculated for Ci9Hi8BrNO5: m/z = 420.26. Found: m/z = 421.8 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium acetate In 1,4-dioxane; dimethyl sulfoxide at 85℃; for 20h; | 4 EXAMPLE 4 4-Fluoro-2-{6-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyridin- [3-YLLPYRIDIN-2-YLTBENZONITRILE] A mixture of 4-fluoro-2-bromobenzonitrile (10.0 g, 50.0 mmol), potassium acetate (9.82 g, 100 mmol), bis [(PINACOLATO)] diboron (14.0 g, 55.0 mmol) and dichloro [[L,] [1'-BIS] (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (0.82 g, 1.0 mmol) in 1, 4-dioxane (150 ml containing 3 ml dimethylsulfoxide) was degassed with nitrogen for 1 h then heated at [85°C] for 20 h. The reaction was cooled to ambient temperature and then concentrated [I71] uacuo. The residue was stirred with 2N sodium hydroxide (250 ml) for 10 min then filtered. The filtrate was extracted with diethyl ether (300 ml) and the organics discarded. The aqueous component was cooled to [0°C] then treated with 5N hydrochloric acid added dropwise over 15 min until pH 8. The aqueous phase was extracted with ethyl acetate (2 x 200 ml), the combined organics were dried over anhydrous sodium sulfate, filtered and evaporated to afford 4- [FLUORO-2- (4,] 4,5, 5-tetramethyl- [1,3, 2] dioxaborolan-2-yl) benzonitrile (10.9 g, [88%)] as a pale brown solid: [ON] (360 MHz, CDCl3) 1. 38 (12H, s), 7.15-7. 25 [(1H,] m), 7.53-7. 60 [(1H,] m), 7.67-7. 75 [(1H,] m). 2,6-Dibromopyridine (0.94 g, 4.0 mmol), [4-FLUORO-2- (4,] 4,5, [5-] tetramethyl- [1, 3,2] dioxaborolan-2-yl) benzonitrile (1.48 g, 6.0 mmol) and potassium phosphate (1.70 g, 8. 0 mmol) were dissolved in [N, N-] dimethylformamide (12 ml) and degassed with nitrogen for 15 min. Tetrakis (triphenylphosphine) palladium (0) (230 mg, 0.2 mmol) was added then the mixture heated at [80°C] for 16 h. The mixture was allowed to cool to ambient temperature, diluted with water (150 ml) and extracted into ethyl acetate (2 x 150 ml). The combined organics were washed with brine (100 ml), dried over anhydrous sodium sulfate and evaporated to give a yellow oil. Purification by flash column chromatography on silica eluting with isohexane on a gradient of ethyl acetate (10-15%) gave 4-fluoro-2- (6- [BROMOPYRIDIN-2-YL) BENZONITRILE] (0.42 g, 38%) as a waxy solid: [SN] (360 MHz, CDCl3) 7.21-7. 25 [(1H,] m), 7.59 [(1H,] d, J 8), 7.67 [(1H,] dd, [J 9.] 3,2. 6), 7.72 [(1H,] t, J 7.7), 7.78-7. 87 (2H, m). A mixture [OF 2-(8-FLUOROIMIDAZO [1, 2-A] PYRIDIN-7-YL)] propan-2-ol (97 mg, 0.5 mmol), [4-FLUORO-2-(6-BROMOPYRIDIN-2-YL)] benzonitrile (166 mg, 0.6 mmol) and [CS2CO3] [(538] mg, 1.65 mmol) in 1,4-dioxane (4 ml) was degassed with nitrogen for 30 min. Tetrakis (triphenylphosphine)- palladium [(0)] (29 mg, 0.03 mmol) was added and the mixture heated under reflux for 56 h. On cooling, the mixture was partitioned between ethyl acetate (100 ml) and water (100 ml). The organics were washed with water (100 [ML)] and brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give an orange oil. The oil was purified by flash column chromatography on silica, eluting with dichloromethane (+1% 0. 880 ammonia solution) on a gradient of methanol (2-3%). Collecting appropriate fractions followed by trituration with diethyl ether (5 ml) gave the title imidazopyridine as a white amorphous solid (131 mg, 67%): [SN] (400 MHz, [CD13)] 1.74 (6H, d, J 1.2), 2.07 [(1H,] s), 7.26-7. 30 (2H, m), 7.56-7. 63 (2H, m), 7. [85-7.] 94 (3H, m), 8.22 [(1H,] [S),] 9.74 [(1H,] d, [J 7.] 4); [IN/Z] (ES+) 391 (100%, [MH] +). |
88% | With potassium acetate In 1,4-dioxane; dimethyl sulfoxide at 85℃; for 20h; | 4.a 4-Fluoro-2- {6-[8-fluoro-7-(1-hydroxy-1-methylethyl) imidazo [L, 2-C]-PYRIMIDIN-3-YL] PYRIDIN-2-YL} BENZONITRILE a) 4-Fluoro-2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzonitrile A mixture of 4-fluoro-2-bromobenzonitrile (10.0 g, 50.0 mmol), potassium acetate (9.82 g, 100 MMOL), bis (pinacolato) diboron (14.0 g, 55.0 mmol) and dichloro [L, L'-BIS (diphenylphosphino) FERROCENE] PALLADIUM (II) CH2CL2 adduct (0.82 g, 1.0 mmol) in 1,4-dioxane (150 ml) and dimethylsulfoxide (3 ml) was degassed with nitrogen for 1 h then heated at 85C for 20 h. The reaction was cooled to ambient temperature and then concentrated in vacuo. The residue was stirred with 2 N sodium hydroxide (250 ml) for 10 min then filtered. The filtrate was extracted with diethyl ether (300 ml) and the organics discarded. The aqueous component was cooled to 0C then treated with 5 N hydrochloric acid, added dropwise over 15 min until the pH was 8. The aqueous phase was extracted with EtOAc (2 x 200 ML), THE COMBINED organics were dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound (10.9 g, 88%) as a pale brown solid: BA (360 MHz, CDCL3) 1.38 (12 H, s), 7.15-7. 25 (1 H, M), 7.53-7. 60 (1 H, m), 7.67-7. 75 (1 H, m). |
70% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate In 1,4-dioxane at 80℃; for 24h; Inert atmosphere; |
64.8% | Stage #1: 2-bromo-4-fluorobenzonitrile; bis(pinacol)diborane With potassium acetate In 1,4-dioxane for 0.0833333h; Inert atmosphere; Stage #2: With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In 1,4-dioxane at 94℃; for 14h; | 89.89A 89A. 4-fluoro-2-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)benzonitrile To a stirred solution of 2-bromo-4-fluorobenzonitrile (5 g, 25.00 mmol), bis(pinacolato)diboron (9.52 g, 37.5 mmol), potassium acetate (7.36 g, 75.0 mmol), in dioxane (50 mL) argon was purged for 5 mins. PdCl2(dppf)-CH2Cl2 adduct (12.25 g, 15.00 mmol) was added and argon was bubbled through the reaction mixture and heated at 94 °C (silicon oil bath) for 14 h. The reaction mixture was cooled to RT, filtered through celite pad, washed with ethyl acetate (200 mL). The organic layer was washed with water (100 mL) and the aq. layer was separated and re-extracted with ethyl acetate (2 x 100 mL). Combined organic extracts were washed with brine, dried over sodium sulfate and solvent was removed under reduced pressure to give the brown colored crude product. The product was purified by silica gel column chromatography using ethyl acetate in pet ether as an eluant to afford 89A (4 g, 16.19 mmol, 64.8 % yield) as a off- white semi solid. NMR (400 MHz, CDC13) d 7.89-7.93 (m, 1H), 7.54-7.59 (m, 1H), 7.39-7.50 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium carbonate In 1,4-dioxane at 70℃; for 18.25h; | A 48 mL pressure vessel containing 2-bromo-4-fluorobenzonitrile (1.00 g, 5.00 mmol), 2-oxazolidone (0.390 g, 4.50 mmol), K2CO3 (0.970 g, 7.0 mmol) and xantphos (0.231 g, 0.40 mmol) in dioxane (10 mL) was degassed with argon for 15 min. Pd2 dba3 (0.140 g, 0.15 mmol) was introduced and then the reaction mixture was heated at 70 C. for 18 h. The mixture was cooled, diluted with dioxane, and then filtered through Celite. The resulting mixture was concentrated in vacuo and subjected to column chromatography on silica gel with hexanes:ethyl acetate (1:1) to (3:7) gradient as the eluent to afford the title compound as a white solid (0.460 g, 50% yield): 1H NMR (400 MHz, CDCl3) ? ppm: 7.73 (1H, dd, J=5.8, 8.6 Hz), 7.43 (1H, dd, J=2.5, 9.6 Hz), 7.11 (1H, ddd, J=2.5, 7.5, 8.7 Hz), 4.60 (2H, t, J=7.1 Hz), 4.29 (2H, t, J=7.1 HJz); LCMS (+ESI, M+H+) m/z 207. |
50% | With potassium carbonate In 1,4-dioxane at 70℃; for 18h; | A 48 mL pressure vessel containing 2-bromo-4-fluorobenzonitrile (1.00 g, 5.00 mmol), 2-oxazolidone (0.390 g, 4.50 mmol), K2CO3 (0.970 g, 7.0 mmol) and xantphos (0.231 g, 0.40 mmol) in dioxane (10 mL) was degassed with argon for 15 min. Pd2dba3 (0.140 g, 0.15 mmol) was introduced and then the reaction mixture was heated at 70° C. for 18 h. The mixture was cooled, diluted with dioxane, and then filtered through Celite. The resulting mixture was concentrated in vacuo and subjected to column chromatography on silica gel with hexanes:ethyl acetate (1:1) to (3:7) gradient as the eluent to afford the title compound as a white solid (0.460 g, 50% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 7.73 (1H, dd, J=5.8, 8.6 Hz), 7.43 (1H, dd, J=2.5, 9.6 Hz), 7.11 (1H, ddd, J=2.5, 7.5, 8.7Hz), 4.60 (2H, t, J=7.1 Hz), 4.29 (2H, t, J=7.1 HJz); LCMS (+ESI, M+H+) m/z 207. |
50% | With potassium carbonate In 1,4-dioxane at 70℃; for 18h; | 4-Fluoro-2-(2-oxooxazolidin-3-yl)benzonitrile. A 48 mL pressure vessel containing 2-bromo-4-fluorobenzonitrile (1.00 g, 5.00 mmol), 2-oxazolidone (0.390 g, 4.50 mmol), K2CO3 (0.970 g, 7.0 mmol) and xantphos (0.231 g, 0.40 mmol) in dioxane (10 mL) was degassed with argon for 15 inn. Pd2 dba3 (0.140 g, 0.15 mmol) was introduced and then the reaction mixture was heated at 70° C. for 18 h. The mixture was cooled, diluted with dioxane, and then filtered through Celite. The resulting mixture was concentrated in vacuo and subjected to column chromatography on silica gel with hexanes:ethyl acetate (1:1) to (3:7) gradient as the eluent to afford the title compound as a white solid (0.460 g, 50% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 7.73 (1H, dd, J=5.8, 8.6 Hz), 7.43 (1H, dd, J=2.5, 9.6 Hz), 7.11 (1H, ddd, J=2.5, 7.5, 8.7 Hz), 4.60 (2H, t, J=7.1 Hz), 4.29 (2H, t, J=7.1 HJz); LCMS (+EST, M+H+) m/z 207. |
50% | Stage #1: dimethylenecyclourethane; 2-bromo-4-fluorobenzonitrile With 3-(benzyloxy)-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid; potassium carbonate for 0.25h; Stage #2: at 70℃; for 18h; | 4-Fluoro-2-(2-oxooxazolidin-3-yl)bejizonitrile. A 48 mL pressure vessel containing 2-bromo-4-fluorobenzonitrile (1.00 g, 5.00 mmol), 2-oxazolidone (0.390 g, 4.50 mmol), K2CO3 (0.970 g, 7.0 mmol) and xantphos (0.231 g, 0.40 mmol) in dioxane (10 mL) was degassed with argon for 15 min. Pd2dba3 (0.140 g, 0.15 mmol) was introduced and then the reaction mixture was heated at 70 0C for 18 h. The mixture was cooled, diluted with dioxane, and then filtered through Celite. The resulting mixture was concentrated in vacuo and subjected to column chromatography on silica gel with hexanes-.ethyl acetate (1:1) to (3:7) gradient as the eluent to afford the title compound as a white solid (0.460 g, 50% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 7.73 (IH, dd, J = 5.8, 8.6 Hz), 7.43 (IH, dd, J = 2.5, 9.6 Hz), 7.11 (IH, ddd, J = 2.5, 7.5, 8.7 Hz), 4.60 (2H, t, J = 7.1 Hz), 4.29 (2H, t, J = 7.1 HJz); LCMS f ESI, M+H*) m/z 207. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 2-pyrrolidinon; 2-bromo-4-fluorobenzonitrile With caesium carbonate In 1,4-dioxane for 0.25h; Stage #2: In 1,4-dioxane at 105℃; for 48h; | A 48 mL pressure vessel containing 2-bromo-4-fluorobenzonitrile (1.00 g, 5.00 mmol), 2-pyrrolidinone (0.46 mL, 6.00 mmol), Cs2CO3 (2.28 g, 7.0 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos) (0.231 g, 0.40 mmol) in dioxane (6 mL) was degassed with argon for 15 min. Pd2 dba3 was introduced and the reaction mixture heated at 105 C. for 48 h. The mixture was cooled, diluted with ethyl acetate or dioxane, and then filtered through Celite. The resulting mixture was concentrated in vacuo and subjected to column chromatography on silica gel with hexanes:ethyl acetate (3:7) gradient as the eluent to afford the title compound as a white solid (0.887 g, 87% yield): 1H NMR (400 MHz, CDCl3) ? ppm: 7.69 (1H, dd, J=5.8, 8.6 Hz), 7.22 (1H, dd, J=2.5, 9.6 Hz), 7.07 (1H, ddd, J 2.5, 7.6, 8.6 Hz), 3.96 (2H, t, J=7.0 Hz), 2.62 (2H, t, J=8.1 Hz), 2.30-2.22 (2H, m); LCMS (+ESI, M+H+) m/z 205. |
87% | With caesium carbonate In 1,4-dioxane at 105℃; for 48h; | A 48 mL pressure vessel containing 2-bromo-4-fluorobenzonitrile (1.00 g, 5.00 mmol), 2-pyrrolidinone (0.46 mL, 6.00 mmol), Cs2CO3 (2.28 g, 7.0 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos) (0.231 g, 0.40 mmol) in dioxane (6 mL) was degassed with argon for 15 min. Pd2dba3 was introduced and the reaction mixture heated at 105° C. for 48 h. The mixture was cooled, diluted with ethyl acetate or dioxane, and then filtered through Celite. The resulting mixture was concentrated in vacuo and subjected to column chromatography on silica gel with hexanes:ethyl acetate (3:7) gradient as the eluent to afford the title compound as a white solid (0.887 g, 87% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 7.69 (1H, dd, J=5.8, 8.6 Hz), 7.22 (1H, dd, J=2.5, 9.6 Hz), 7.07 (1H, ddd, J=2.5, 7.6, 8.6 Hz), 3.96 (2H, t,. J=7.0 Hz), 2.62 (2H, t, J=8.1 Hz), 2.30-2.22 (2H, m); LCMS (+ESI, M+H+) m/z 205. |
87% | With caesium carbonate In 1,4-dioxane at 105℃; for 48h; | 4-Fluoro-2-(2-oxopyrrolidin-1-yl)benzonitrile. A 48 mL pressure vessel containing 2-bromo-4-fluorobenzonitrile (1.00 g, 5.00 mmol), 2-pyrrolidinone (0.46 mL, 6.00 mmol), Cs2CO3 (2.28 g, 7.0 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos) (0.231 g, 0.40 mmol) in dioxane (6 mL) was degassed with argon for 15 min. Pd2 dba3 was introduced and the reaction mixture heated at 105° C. for 48 h. The mixture was cooled, diluted with ethyl acetate or dioxane, and then filtered through Celite. The resulting mixture was concentrated in vacuo and subjected to column chromatography on silica gel with hexanes:ethyl acetate (3:7) gradient as the eluent to afford the title compound as a white solid (0.887 g, 87% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 7.69 (1H, dd, J=5.8, 8.6 Hz), 7.22 (1H, dd, J=2.5, 9.6 Hz), 7.07 (1H, ddd, J=2.5, 7.6, 8.6 Hz), 3.96 (2H, t, J=7.0 Hz), 2.62 (2H, t, J=8.1 Hz), 2.30-2.22 (2H, m); LCMS (+ESI, M+H+) m/z 205. |
87% | Stage #1: 2-pyrrolidinon; 2-bromo-4-fluorobenzonitrile With caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane for 0.25h; Stage #2: at 105℃; for 48h; | 4-Fluoro-2-(2-oxopyrrolidin-l-yl)benzonitrile. A 48 mL pressure vessel containing 2-bromo-4-fluorobenzonitrile (1.00 g, 5.00 mmol), 2-pyrrolidinone (0.46 mL, 6.00 mmol), Cs2CO3 (2.28 g, 7.0 mmol) and 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (xantphos) (0.231 g, 0.40 mmol) in dioxane (6 mL) was degassed with argon for 15 min. Pd2dba3 was introduced and the reaction mixture heated at 105 °C for 48 h. The mixture was cooled, diluted with ethyl acetate or dioxane, and then filtered through Celite. The resulting mixture was concentrated in vacuo and subjected to column chromatography on silica gel with hexanes: ethyl acetate (3:7) gradient as the eluent to afford the title compound as a white solid (0.887 g, 87% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 7.69 (IH, dd, J = 5.8, 8.6 Hz), 7.22 (IH, dd, J = 2.5, 9.6 Hz), 7.07 (IH, ddd, J = 2.5, 7.6, 8.6 Hz), 3.96 (2H, t,. J = 7.0 Hz), 2.62 (2H, t, J = 8.1 Hz), 2.30-2.22 (2H, m); LCMS C ESI, M+H+) m/z 205. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride;tris-(dibenzylideneacetone)dipalladium(0); In tetrahydrofuran; 1,4-dioxane; | a 5,2'-Difluoro-5'-nitrobiphenyl-2-carbonitrile A suspension of 2-bromo-4-fluorobenzonitrile (2.50 g, 12.5 mmol), potassium fluoride (2.40 g, 41.3 mmol) and <strong>[425378-68-3]2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane</strong> (4.67 g, 17.5 mmol) in tetrahydrofuran (50 ml) was degassed with nitrogen for 30 min. Tris(dibenzylideneacetone)dipalladium(0) and tri-tert-butylphosphine (0.2 M solution in 1,4-dioxane, 3.7 ml) were added and the mixture stirred at ambient temperature for 15 min then at 50 C. for 18 h. After cooling to ambient temperature, the resulting dark suspension was poured onto 0.5 M sodium hydroxide solution (500 ml) and stirred vigorously for 2 h. The dark solid was collected by filtration, washed with water (100 ml) and isohexane (50 ml) and left to air dry which gave the title compound as a brown/black solid: 1H NMR (360 MHz, CDCl3) delta 7.25-7.33 (2H, m), 7.40-7.44 (1H, m), 7.86 (1H, dd, J 9, 6 Hz), 8.35-8.42 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With hydrazine; In tetrahydrofuran; at 20℃; for 24.0h; | Example 4a Preparation of 2-Bromo-4-hydrazino-benzonitrile To a solution of 2-bromo-4-fluorobenzonitrile (5.00 g, 25.00 mmol) in THF (10 mL) is added anhydrous hydrazine (10 mL) through an addition funnel. After addition, the resulting mixture is stirred at room temperature for 24 h. Water (20 mL) is added to the reaction mixture. A white precipitate is collected by filtration, washed with water, and dried in a vacuum oven at 40 C. to afford 2-Bromo-4-hydrazino-benzonitrile (4.92 g, 93%) as a white solid: 1H NMR (300 MHz, CDCl3) delta8.05 (br s, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 6.72 (dd, J=8.7, 2.0 Hz, 1H), 4.37 (br s, 2H); ESI MS m/z 212 [M+H]+. |
87.2% | With hydrazine; In tetrahydrofuran; at 20℃; for 16.0h; | In a clean, dry 250-mL round-bottom flask, 2-bromo-4- fluorobenzonitrile (25.34 g) was dissolved in tetrahydrofuran(50 itiL) under N2. To this was slowly added anhydrous hydrazine (50 mli) . The solution color changed from yellow to red- orange. The reaction was allowed to stir at room temperature for 16 hours. A yellow-white crystalline solid precipitated from the solution. The mixture was then diluted with THF (50 iriL) to dissolve the solids. The organic layer was then washed with saturated sodium bicarbonate solution until the pH of the organic layer was approximately 8.5. The organic layer was isolated and the solvent was removed under reduced pressure to give a white solid. This was place in a fritted glass funnel and washed with 1.5 L of water, followed by of diethyl ether (ca. 200 mli) . The ether wash was then combined with the white solid and dried under reduced pressure. The title compound was isolated as a fluffy, white or off-white solid (23.43 g, 87.2% yield). LCMS m/z: calculated = 212.05; observed = 252.98 (M+H+ acetonitrile) |
87.20% | With hydrazine; In tetrahydrofuran; at 20℃; for 16.0h; | Example 4; 3-bromo-4-cyanophenylhydrazine; In a clean, dry 250-mL round-bottom flask, 2-bromo-4-fluorobenzonitrile (25.34 g) was dissolved in tetrahydrofuran (50 mL) under N2. To this was slowly added anhydrous hydrazine (50 mL). The solution color changed from yellow to red-orange. The reaction was allowed to stir at room temperature for 16 hours. A yellow-white crystalline solid precipitated from the solution. The mixture was then diluted with THF (50 mL) to dissolve the solids. The organic layer was then washed with saturated sodium bicarbonate solution until the pH of the organic layer was approximately 8.5. The organic layer was isolated and the solvent was removed under reduced pressure to give a white solid. This was place in a fritted glass funnel and washed with 1.5 L of water, followed by of diethyl ether (ca. 200 mL). The ether wash was then combined with the white solid and dried under reduced pressure. The title compound was isolated as a fluffy, white or off-white solid (23.43 g, 87.20% yield). MS m/z: calculated=212.05; m/z observed=252.98 (M+41). |
87.2% | With hydrazine; In tetrahydrofuran; at 20℃; for 16.0h;Inert atmosphere; | Example 6 3-bromo-4-cyanophenylhydrazine (Intermediate 6) In a clean, dry 250-mL round-bottom flask, 2-bromo-4-fluorobenzonitrile (25.34 g) is dissolved in tetrahydrofuran (50 mL) under N2. To this is slowly added anhydrous hydrazine (50 mL). The solution color changed from yellow to red-orange. The reaction is allowed to stir at room temperature for 16 hours. A yellow-white crystalline solid precipitated from the solution. The mixture is then diluted with THF (50 mL) to dissolve the solids. The organic layer is then washed with saturated sodium bicarbonate solution until the pH of the organic layer is approximately 8.5. The organic layer is isolated and the solvent is removed under reduced pressure to give a white solid. This is placed in a fritted glass funnel and washed with 1.5 L of water, followed by of diethyl ether (ca. 200 mL). The ether wash is then combined with the white solid and dried under reduced pressure. The title compound is isolated as a fluffy, white or off-white solid (23.43 g, 87.2% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: 6,6-dimethyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indazol-4-one With sodium hydride In dimethyl sulfoxide for 0.25h; Stage #2: 2-bromo-4-fluorobenzonitrile In dimethyl sulfoxide at 45℃; for 23h; | 17 Sodium hydride (168 mg, 7.02 mmol, 1.0 eq. ) was added to a solution of 6, 6-dimethyl-3-trifluoromethyl-1, 5, 6, 7- tetrahydro-indazol-4-one (1.63 g, 7.02 mmol, 1.0 eq. ) in 35 mL of anhydrous dimethyl sulfoxide. After 15 min 2-bromo-4- fluorobenzonitrile (2.25 g, 11.23 mmol, 1.6 eq. ) was added as a solid. The reaction mixture was heated at 45 0C. After 23 h the reaction mixture was cooled to ambient temperature and quenched with 10 mL of saturated aqueous ammonium chloride. The mixture was diluted with water and extracted with ethyl acetate (4x) . The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified on a Biotage (SiO2, hexanes-ethyl acetate) to afford 2-bromo-4- (6, 6-dimethyl-4- oxo-3-trifluoromethyl-4, 5,6, 7-tetrahydro-indazol-l-yl) - benzonitrile (1.83 g, 63%) as an off-white powder, LC/MS: (M+H) = 412.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.2% | Stage #1: 3-difluoromethyl-6,6-dimethyl-1,5,6,7-tetrahydro-indazol-4-one With sodium hydride In dimethyl sulfoxide at 20℃; for 0.333333h; Stage #2: 2-bromo-4-fluorobenzonitrile In dimethyl sulfoxide at 45℃; | 25 NaH (350 mg) was added to a solution of 3-difluoromethyl-6, 6- dimethyl-1,5, 6,7-tetrahydro-indazol-4-one (3.12 g) in DMSO (75 mL) at room temperature. After 20 minutes of stirring, 2- bromo-4-fluorobenzonitrile (4.67 g) was added and stirred at 45 °C overnight. The reaction was diluted with saturated aqueous NH4Cl (100 mL) , H2O (100 mL) . The mixture was extracted with ethyl acetate (4x150 mL) , dried over Na2SO4, filtered, concentrated, purified by column chromatography eluting with a 1:2 mixture of ethyl acetate/hexanes . The concentrate of desired fractions was made into a slurry in ether, stirred for 2 h, filtered, washed by hexane to give pure solid 2-bromo-4- ( 6, β-dimethyl-4-oxo-3-difluoromethyl-4, 5,6, 7-tetrahydro- indazol-1-yl) -benzonitrile (2.82 g, 49.2%). LCMS m/z: (M+H) = 395.65, (MW: 394) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium hydride; In N,N-dimethyl-formamide; at 55℃; for 1h; | The title compound of Example 1 (9.8 g, 55.3 itimol) and 2- bromo-4-fluorobenzonitrile (13.27 g, 66.4 mmol) were dissolved in anhydrous dimethylformamide (DMF, 300 mL) . To this was added sodium hydride (95%, 2.79 g, 111 mmol) and the reaction was stirred at 55 0C for 1 hour. The reaction mixture was cooled to room temperature and water was added. A tan solid precipitated which was filtered, washed with water and ether and then dried in vacuo (16.5 g, 84%). LCMS m/z: (M+H) = 358.1 |
84% | With sodium hydride; In N,N-dimethyl-formamide; at 55℃; for 1h; | Example 2; 2-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrile; The title compound of Example 1 (9.8 g, 55.3 mmol) and 2-bromo-4-fluorobenzonitrile (13.27 g, 66.4 mmol) were dissolved in anhydrous dimethylformamide (DMF, 300 mL). To this was added sodium hydride (NaH, 95%, 2.79 g, 111 mmol) and the reaction was stirred at 55 C. for 1 hour. The reaction mixture was cooled to room temperature and water was added. A tan solid precipitated which was filtered, washed with water and ether and then dried in vacuo (16.5 g, 84%). MS m/z: (M+H)=358.1. |
With sodium hydride; In N,N-dimethyl-formamide; at 55℃; for 1h; | 10235] Thetitle compound of Example 1 (9.8g, 55.3 mmol) and 2-bromo-4-fluorobenzonitrile (13.27 g, 66.4 mmol) are dissolved in anhydrous dimethylformamide (DMF, 300 mL). To this is added sodium hydride (95%, 2.79 g, 111 mmol) and the reaction is stirred at 550 C. for 1 hour. The reaction mixture is cooled to room temperature and water is added. A tan solid precipitated which is filtered, washed with water and ether and then dried in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium hydride In N,N-dimethyl-formamide at 50℃; for 1h; | 39 Pyrrole (2, 6, 6-trimethyltetrahydroindol-4-one) (1.5 g, 8.5 mmol) and 2-bromo-4-fluorobenzonitrile (1.69 g, 8.5 mmol) were dissolved in anhydrous DMF (50 mL) . To this NaH (95%, 408 mg, 17.0 mmol) was added and stirred at 50 0C for 1 h. The reaction mixture was cooled to RT and H2O was added. Product crashed out of solution and was filtered and dried under vacuo (2.4 g, 79%). (100% clean by LCMS, product M+H = 357). |
79% | With sodium hydride In N,N-dimethyl-formamide at 50℃; for 1h; | 16 2-bromo-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile (Intermediate 16) Example 16 2-bromo-4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile (Intermediate 16) Pyrrole (2,6,6-trimethyltetrahydroindol-4-one) (1.5 g, 8.5 mmol) and 2-bromo-4-fluorobenzonitrile (1.69 g, 8.5 mmol) are dissolved in anhydrous DMF (50 mL). To this NaH (95%, 408 mg, 17.0 mmol) is added and stirred at 50° C. for 1 h. The reaction mixture is cooled to RT and H2O is added. Product crashed out of solution and is filtered and dried under vacuo (2.4 g, 79%). |
62% | With sodium hydride In N,N-dimethyl-formamide at 100℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With potassium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 9h; | A high pressure reaction vessel containing 2-bromo-4-fluorobenzonitrile (0.250 g, 1.25 mmol), 2-(methyl)-1,2,5-thiadiazolidine 1,1-dioxide (0.204 g, 1.5 mmol), K2CO3 (0.242 g, 1.4 mmol) and xantphos (0.058 g, 0.1 mmol) in dioxane (6 mL) was degassed with argon for 15 min. Pd2dba3 (0.034 g, 0.08 mmol) was introduced and the reaction mixture was heated at 100 C. for 9 h. The mixture was cooled, diluted with dioxane, and then filtered through Celite. The resulting mixture was concentrated in vacuo and the residue was purified with a Biotage column chromatography system on silica gel with hexanes:ethyl acetate (7:3) gradient as the eluent to afford the title compound as a white solid (0.152 g, 48%): 1H NMR (400 MHz, CDCl3) delta 7.69 (2 H, dd, J=8.6, 5.8 Hz), 7.52 (2 H, dd, J=9.5, 2.4 Hz), 7.09 (2 H, ddd, J=8.7, 7.4, 2.4 Hz), 4.06 (3 H, t, J=6.4 Hz), 3.56 (3 H, t, J=6.6 Hz), 2.90 (3 H, s); LCMS (+ESI, M+H+) m/z 256. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Stage #1: 2,4-dimethyl-3-acetylpyrrole With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: 2-bromo-4-fluorobenzonitrile In N,N-dimethyl-formamide at 60℃; for 1h; | 30.A Part A Preparation of 4-(3-Acetyl-2,4-dimethyl-pyrrol-1-yl)-2-bromo-benzonitrile 60% Sodium Hydride in oil (0.40 g, 10 mmol) is triturated with hexane. N,N-dimethylformamide (4 mL) is added and the flask is chilled to 0 degrees Celsius. 3-acetyl-2,4-dimethylpyrrole (685 mg, 5 mmol) is added. After 5 min, 2-bromo-4-fluorobenzonitrile (1.2 g, 6 mmol) is added. The reaction is stirred for 1 h at 60 degrees Celsius, then cooled and taken up in ethyl acetate (200 ml)/water (100 mL). The organic layer is dried over magnesium sulfate, filtered, concentrated, and subjected to chromatography, to afford 4-(3-Acetyl-2,4-dimethyl-pyrrol-1-yl)-2-bromo-benzonitrile as a tan solid 741 mg (47%). LC/MC m/z=317 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium hydride In N,N-dimethyl-formamide at 100℃; for 1h; | 261 6,6-dimethyl-3-trifluoromethyl-1,5,6,7-tetrahydro-indol-4-one (700 mg, 3.0 mmol) and 2-bromo-4-fluorobenzonitrile (900 mg, 4.5 mmol) are dissolved in anhydrous dimethylformamide (DMF, 20 mL). To this is added sodium hydride (60%, 70 mg, 3.0 mmol) and the reaction is stirred at 100° C. for 1 hour. The reaction mixture is cooled to room temperature and poured into water. The aqueous layer is extracted with EtOAc (3×60 mL), the organic layers are combined and washed H2O (2×30 mL) and brine (30 mL), and dried over Na2SO4. The crude mixture is concentrated and the oil is purified using 40 mm Biotage column (gradient 0-60%, 80 mL/min flow rate for 20 CV). Pure fractions are combined and concentrated to give a tan solid. (1.02 g, 83%). LC/MS: m/z=411 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.1% | Stage #1: 2-bromo-4-fluorobenzonitrile; ethylmagnesium bromide With titanium(IV) isopropylate In diethyl ether at -78 - 20℃; for 4h; Inert atmosphere; Stage #2: With boron trifluoride diethyl etherate In diethyl ether at 20℃; for 4h; Inert atmosphere; | |
52.2% | Stage #1: 2-bromo-4-fluorobenzonitrile; ethylmagnesium bromide With titanium(IV) isopropylate In diethyl ether at -78 - 20℃; for 1h; Inert atmosphere; Stage #2: With boron trifluoride diethyl etherate In diethyl ether at 20℃; for 1h; Inert atmosphere; | A [A] 1 -(2-Bromo-4-fluorophenyl)cyclopropanamine To a stirred solution of 2-bromo-4-fluorobenzonitrile (5 g, 25 mmol) and Ti(Oi-Pr)4 (9.05 mL, 27.5 mmol) in ether (100 mL) at -78 °C was added EtMgBr (18.3 mL,55 mmol) drop wise. The solution was allowed to warm to room temperature and stirred for 1 hour before BF3-Et20 (6.25 mL) was added and stirring continued at room temperature for another 1 hour. The reaction solution was quenched with 1 N HC1 solution, and washed with EtOAc. The aqueous layer was adjusted to pH~10 with aq. NaOH (2 N) solution and then exacted with EtOAc (3 x). The combined organic layers were dried over anhy.Na2S04, filtered, and concentrated in vacuo. The residue was then purified by column chromatography to give title compound (3.0 g, yield 52.2%) as yellowish oil. |
44% | Stage #1: 2-bromo-4-fluorobenzonitrile; ethylmagnesium bromide With titanium(IV) isopropylate In diethyl ether at -70 - 20℃; for 1.16667h; Stage #2: With boron trifluoride diethyl etherate In diethyl ether for 1h; Stage #3: With hydrogenchloride; sodium hydroxide more than 3 stages; | 37 Add ethylmagnesium bromide (3 N, 53.9 mL, 74.9 mmol) to a solution of 2- bromo-4-fluorobenzonitrile(15 g, 73.5 mmol) and tetraisopropoxytitanium (23 mL, 162 mmol) in ether (25 mL) at -70 0C under N2. After stirring at the temperature for 10 min, let it warm-up to RT and stir for one hour. Add boron trifluoride etherate (BF3OEt2) (16.8 mL, 147 mmol) to the solution slowly and stir for another hour. After adding 1 N HCl (200 mL) and ether (150 mL), separate the ether layer. Add 10 % NaOH (150 mL) to the aqueous solution and extract it with ether. Separate the organic layer and dry over magnesium sulfate. Filter and concentrate in vacuo to give a residue. Purify the residue by column chromatography (diethylether) to give the title compound (7.5 g, 44 %). MS (ES) m/z 230 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: 2-bromo-4-fluorobenzonitrile With diisobutylaluminium hydride; magnesium; lithium chloride In tetrahydrofuran at 25℃; for 0.75h; Stage #2: 4-iodoanisol With zinc(II) chloride In tetrahydrofuran for 0.25h; Stage #3: With trifuran-2-yl-phosphane; bis(dibenzylideneacetone)-palladium(0) In tetrahydrofuran at 25℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 90℃; for 30h; Inert atmosphere; | |
91% | Stage #1: 2-bromo-4-fluorobenzonitrile; dimethyl 1H-benzo[d]imidazole-5,6-dicarboxylate In dimethyl sulfoxide for 0.166667h; Inert atmosphere; Stage #2: With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 90℃; for 30h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With hydroxylamine In ethanol; water at 75℃; Inert atmosphere; | |
59% | With hydroxylamine hydrochloride; sodium carbonate In methanol; water at 86℃; for 20h; | 3.1 7.3.1 2-Bromo-4-fluorobenzamidoxime (12)[ 26 ] Methanol (64 mL) was added to a stirred solution of NH2OH·HCl (5.21 g, 75 mmol, 3 eq.) and Na2CO3 (3.98 g, 38 mmol, 1.5 eq.) in water (16 mL). After stirring for 20 min, 2-bromo-4-fluorobenzonitrile (10, 5.00 g, 25 mmol, 1 eq.) was added and the reaction mixture was heated at 86 °C for 20 h. The methanol was removed in vacuo and the aqueous suspension was diluted with ethyl acetate (100 mL). The organic layer was separated from the aqueous layer and washed with water (2 * 20 mL) and brine (20 mL). The combined aqueous layers were washed with ethyl acetate (2 * 50 mL). The combined ethyl acetate layers were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by fc (⌀ = 6.5 cm, l = 15 cm, v = 100 mL, cyclohexane/ethyl acetate 60:40, Rf = 0.34 (cyclohexane/ethyl acetate 5:5)). Colorless solid, mp 120-121 °C, yield 3.43 g (59%). Purity (HPLC): 96.4% (tR = 3.7 and 3.9 min). C7H6BrFN2O (233.0 g/mol). Exact mass (APCI): m/z = 232.9722 (calcd. 232.9720 for C7H779BrFN2O [M + H+]). 1H NMR (600 MHz, DMSO-D6): δ (ppm) = 5.81 (s, 2H, NH2), 7.28 (td, J = 8.5/2.6 Hz, 1H, 5-H), 7.42 (dd, J = 8.5/6.2 Hz, 1H, 6-H), 7.60 (dd, J = 8.7/2.6 Hz, 1H, 3-H), 9.45 (s, 1H, N-OH). 13C NMR (101 MHz, DMSO-D6): δ (ppm) = 114.5 (d, J = 21.1 Hz, 1C, C-5), 119.7 (d, J = 24.7 Hz, 1C, C-3), 122.6 (d, J = 9.9 Hz, 1C, C-2), 132.5 (d, J = 3.5 Hz, 1C, C-1), 132.7 (d, J = 8.9 Hz, 1C, C-6), 150.9 (1C, C=N), 161.7 (d, J = 249.6 Hz, 1C, C-4). FTIR (neat): ṽ (cm-1) = 3483 (m, O-H), 3363 (m, N-H), 1664 (s, C=N), 1029 (m, C-Br, arom). |
39% | With hydroxylamine hydrochloride; sodium hydrogencarbonate In methanol; water at 86℃; |
With hydroxylamine hydrochloride; sodium carbonate In methanol; water at 70℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate In dimethyl sulfoxide at 100℃; for 17.5h; Sealed vial; | 146 K2CO3 (0.691 g, 5.00 mmol) was added to a solution of 2-bromo-4- fluorobenzonitrile (1 g, 5.00 mmol) and pyrrolidine (0.42 mL, 5.08 mmol) in DMSO (10.00 mL) in a vial. The vial was sealed, and the reaction was stirred at 100 0C (bath temp) for 17.5 h. The reaction mixture was diluted with water (50 mL) and EtOAc (25 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over Na2SO4, filtered, concentrated, and dried under high vacuum to afford the title compound (1.21 g, 96%). LC-MS m/z 251 (M)+, 1.11 min (ret time). |
88% | In tetrahydrofuran at 20℃; for 4h; | 83.A; 84.A; 85.A; 86.A Preparation of 2-(2-bromo-4-pyrrolidin-1-ylphenyl)-4,5,6,7-tetrahydro-1 ,3- benzothiazol-7-ol (Example 83), 2-(2-bromo-4-pyrrolidin-1-ylphenyl)-7-isopropoxy-4,5,6,7- tetrahydro-1 ,3- benzothiazole (Example 84), 2-(7-hydroxy-4,5,6,7-tetrahydro-1 ,3-benzothiazol-2- yl)-5-pyrrolidin-1-ylbenzonitrile (Example 85) and 2-[2-(aminomethyl)-4-pyrrolidin-1-ylphenyl]-4,5,6,7-tetrahydro-1 ,3-benzothiazol-7-ol (Example 86) To a solution of 2-bromo-4-fluorobenzonitrile (200 mg, 1.0 mmol) in anhydrous THF (5 ml_) was added pyrrolidine. The reaction mixture was stirred at room temperature for 4 hours. To this was added saturated NaHCO3 solution and H2O, then the mixture was extracted with EtOAc. The combined organic layers were washed with H2O, brine, dried over Na2SO4, filtered and then concentrated to provide 222 mg (88%) of 2-bromo-4-pyrrolidin-1-ylbenzonitrile as a white solid. 2-bromo-4-pyrrolidin-1-ylbenzonitrile, MS: m/z 252 (M + H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With potassium carbonate In 1,4-dioxane at 100℃; for 18h; | 11 4-Fluoro-2-(5-(4-methoxybenzyl)-4,4-dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)benzonitrile. 2-Bromo-4-fluorobenzonitrile, tris(dibenzylideneacetone)dipalladium(0) (0.238 g, 0.26 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.231 g, 0.4 mmol) and potassium carbonate (5.72 g, 41.4 mmol) were stirred together. Added to this was a solution of 2-(4-methoxybenzyl)-3,3-dimethyl-1,2,5-thiadiazolidine 11-dioxide (8.00 g, 29.6 mmol) in dioxane (50 mL) and the resulting mixture stirred at 100° C. for 18 h. The cooled mixture was diluted with CH2Cl2 and the solids were removed by filtration. The solvent was evaporated leaving a yellow oil that was purified by flash chromatography (Biotage flash chromatography system, 5%-100% ethyl acetate/hexane) to give a cream colored solid that was triturated with ethyl acetate/hexane (1:4) to give the title compound as a white powder (4.6048 g, 42% yield). 1H NMR (500 MHz, CDCl3) δ: 7.71-7.65 (2H, m), 7.37 (2H, d, J=8.5 Hz), 7.12-7.08 (1H, m), 6.88 (2H, d, J=8.5 Hz), 4.28 (2H, s), 3.80 (3H, s), 3.78 (2H, s), 1.42 (6H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium hydride In N,N-dimethyl-formamide at 90℃; for 5h; | 6.2.12. 2-Bromo-4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzonitrile (16) To a mixture of 15 (0.100 g, 0.43 mmol) and NaH (15.5 mg, 0.65 mmol) in DMF (8 mL) was added 2-bromo-4-fluorobenzonitrile (86 mg, 0.43 mmol) and heated at 90 °C for 5 h. The reaction mixture was concentrated under reduced pressure and the residue chromatographed (hexane/EtOAc, 10:1-10:2) to give 0.162 g (91%) of 16 as a white solid. 1H NMR (CDCl3) δ 7.97 (d, J = 2.1 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.63 (dd, J = 8.4, 2.1 Hz, 1H), 2.89 (s, 2H), 2.51 (s, 2H), 1.16 (s, 6H); MS (ESI): m/z 410.0/412.0 [M-H]-. |
67.59% | With sodium hydride In dimethyl sulfoxide at 45℃; | |
67.59% | Stage #1: 6,6-dimethyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indazol-4-one With sodium hydride In dimethyl sulfoxide at 20℃; for 0.25h; Stage #2: 2-bromo-4-fluorobenzonitrile In dimethyl sulfoxide at 45℃; |
67.59% | Stage #1: 6,6-dimethyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indazol-4-one With sodium hydride In dimethyl sulfoxide at 20℃; for 0.25h; Stage #2: 2-bromo-4-fluorobenzonitrile In dimethyl sulfoxide at 45℃; | |
63% | Stage #1: 6,6-dimethyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indazol-4-one With sodium hydride In dimethyl sulfoxide for 0.25h; Stage #2: 2-bromo-4-fluorobenzonitrile In dimethyl sulfoxide at 45℃; | |
63% | Stage #1: 6,6-dimethyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indazol-4-one With sodium hydride In dimethyl sulfoxide for 0.25h; Stage #2: 2-bromo-4-fluorobenzonitrile In dimethyl sulfoxide at 45℃; for 23h; | 8 2-bromo-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol- 1 -yl)-benzonitrile (Intermediate 9) 10252] Sodium hydride (168 mg, 7.02 mmol, 1.0 eq.) is added to a solution of 6,6-dimethyl-3-trifluoromethyl-i ,5,6, 7-tetrahydro-indazol-4-one (1.63 g, 7.02 mmol, 1.0 eq.) in 35 mE of anhydrous dimethyl sulfoxide. After 15 mm 2-bromo- 4-fluorobenzonitrile (2.25 g, 11.23 mmol, 1.6 eq.) is added as a solid. The reaction mixture is heated at 45° C. Afier 23 h the reaction mixture is cooled to ambient temperature and quenched with 10 mE of saturated aqueous ammonium chloride. The mixture is diluted with water and extracted with ethyl acetate (4x). The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue is purified on a l3iotage (Si02, hexanes-ethyl acetate) to afford 2-bromo-4-(6,6-dimethyl-4- oxo-3-trifluoromethyl -4,5,6,7-tetrahydro-indazol-1 -yl)benzonitrile (1.83 g, 63%) as an off-white powder. |
With sodium hydride In dimethyl sulfoxide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.2% | Stage #1: 3-difluoromethyl-6,6-dimethyl-1,5,6,7-tetrahydro-indazol-4-one With sodium hydride In dimethyl sulfoxide for 0.25h; Stage #2: 2-bromo-4-fluorobenzonitrile In dimethyl sulfoxide at 45℃; | |
49.2% | Stage #1: 3-difluoromethyl-6,6-dimethyl-1,5,6,7-tetrahydro-indazol-4-one With sodium hydride In dimethyl sulfoxide at 20℃; for 0.333333h; Stage #2: 2-bromo-4-fluorobenzonitrile In dimethyl sulfoxide at 45℃; | 12 2-Bromo-4-(3-difluoromethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (Intermediate 12) Example 12 2-Bromo-4-(3-difluoromethyl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (Intermediate 12) NaH (350 mg) is added to a solution of 3-difluoromethyl-6,6-dimethyl-1,5,6,7-tetrahydro-indazol-4-one (3.12 g) in DMSO (75 mL) at room temperature. After 20 minutes of stirring, 2-bromo-4-fluorobenzonitrile (4.67 g) is added and stirred at 45° C. overnight. The reaction is diluted with saturated aqueous NH4CI (100 mL), H2O (100 mL). The mixture is extracted with ethyl acetate (4*150 mL), dried over Na2SO4, filtered, concentrated, purified by column chromatography eluting with a 1:2 mixture of ethyl acetate/hexanes. The concentrate of desired fractions is made into a slurry in ether, stirred for 2 h, filtered, washed by hexane to give pure solid 2-bromo-4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (2.82 g, 49.2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 2-bromo-4-fluorobenzonitrile With 2-(methylsulfonyl)ethyl alcohol; sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; Stage #2: With hydrogenchloride; water | 10.4 Method 10B: the bromophenol was prepared using the appropriate fluorobromobenzene with methanesulfonylethanol.Under inert atmosphere, to a solution of the fluorinated derivative in dimethylformamide was added methylsulfonylethanol (1.5eq). The mixture was stirred at 0° C. before adding sodium hydride (5eq). The reaction mixture was stirred at room temperature, then acidified with 1M hydrochloric acid solution to pH 2, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed over silica gel.Example 10.4. 2-bromo-4-hydroxybenzonitrile Prepared following the method previously described (Method 10B) using 2-bromo-4-fluorobenzonitrile. The product was chromatographed over silica gel (elution gradient petroleum ether/ethyl acetate 90/10 to 80/20). The product was obtained as a white solid. Yield: 95% Rf (petroleum ether/ethyl acetate 70/30): 0.25 NMR 1H (CDCl3): 5.95 (s, 1H); 6.87 (dd, 1H, J=8.5 Hz, J=2.4 Hz); 7.17 (d, 1H, J=2.4 Hz); 7.54 (d, 1H, J=8.5 Hz). |
With potassium trimethylsilonate In N,N-dimethyl-formamide at 20℃; for 1h; | Intermediate 72-bromo-4-hvdroxybenzonitrileTo a solution of 2-bromo-4-fluoro-benzonitrile (2000mg,9.9995mmol) in DMF (20mL), potassium trimethylsilanolate (2565.7mg,19.999mmol) was added portionwise and the reaction mixture stirred at room temperature for lh. The mixture was diluted with ethyl acetate (100 ml), washed with an aqueous saturated solution of ammonium chloride (100ml) and brine (3x100ml), dried over sodium sulphate and concentrated under vacuum to give the title compound (2000mg) which was used in the next step without purification.LC/MS: QC_3_MIN: t = 1.197 min; m/z 198-200 (Bromine pattern) [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | at 140℃; | |
70% | at 140℃; for 5h; | 4.1.24 2-Bromo-4-(4-methoxybenzylamino)benzonitrile (25) 4-Methoxybenzylamine (5.3 mL, 40.2 mmol) was added to 2-bromo-4-fluorobenzonitrile (24) (5.36 g, 26.8 mmol). The reaction mixture was stirred 5 h at 140 °C in a sealed flask, then the reaction was quenched with H2O and the mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The resulting residue was recrystallized (from hexane/ AcOEt) to afford 25 (5.96 g, 18.8 mmol, 70%) as a pale yellow solid. The mother liquor was concentrated and the residue was purified by silica gel chromatography (hexane/AcOEt = 4/1) to afford 25 (1.76 g, 5.56 mmol, 21%) as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | Stage #1: 3-acetylindole With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: 2-bromo-4-fluorobenzonitrile In N,N-dimethyl-formamide at 50℃; for 0.5h; | 8 Sodium Hydride (60% oil suspension, 20 mmol, 800 mg) is triturated with hexane and suspended in N,N-dimethylformamide (10 mL). 3-Acetylindole (10 mmol, 1.59 g) is added to the ice-cooled suspension. After 5 minutes, 2-bromo, 4-fluorobenzonitrile (14 mmol, 2.8 g) is added. The reaction is stirred at 50 degrees Celsius for 30 minutes. The reaction mixture is allowed to cool and is extracted into ethyl acetate (200 mL) and is washed with water (50 mL). The organic phase is dried over magnesium sulfate. Filtration, followed by concentration, and silica gel chromatography affords the desired 4-(3-Acetyl-indol-1-yl)-2-bromo-benzonitrile as a tan solid (0.92 g, 36%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium carbonate In 1,2-dimethoxyethane; water for 5h; Heating; Reflux; | 5-FIuoro-4'-methoxybIphenyI-2-carbonitrie (CAB06042)A mixture of 2-brorao-4-fluorobenzinitrile (5,0 g, 25.0 mmol), 4-methoxyphenylboronic acid (4.56 g, 30 mmol), dimethoxyethane (25 mL) and 2M Na2CO3 (40 mL) was heated to reflux before Pd2(dba)3 (0.10 g) was added and heating was continued for 5 hours. After cooling to room temperature CHCb (50 ml,) was added to dissolve the product, which crystallised from the organic layer. The mixture was filtered through celite, the organic layer was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography [SiO2, CHCI3] followed by recrystallisation from EtOH to give CAB06042 as a white solid (4,03 g, 71%). Mp. 145- 147 0C; .H NMR (400 MHz, CDCl3) δ 3.87 (s, 3H), 7.02 (AA'BB', 2H), 7.07-7.13 (m, IH), 7.19 (dd, J = 9,4, 2.7 Hz, IH), 7.51 (AA'BB', 2H)5 7.75 (dd, J = 8.6, 5.5 Hz, IH); LRMS (ES+): m/z 228.2 (100%, [M+H]+); HRMS (ES+) calcd for Ci4HnFNO [M+H]+: 228.0819, found 228.0816; Anal. Calcd for CI4HI0FNO: C5 74,00; H, 4.44; N, 6.16. Found C, 73.7; H, 4.40; N, 6.09. |
With bis(dibenzylideneacetone)-palladium(0) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium carbonate In 1,2-dimethoxyethane; water for 5h; Heating; Reflux; | 5-Fluoro-4t-(trifluoromethyl)bipheϖyI-2-carbonitriIe (CAB06081)A mixture of 2-bromo-4-fluorobenzinitrile (4,0 g, 20.0 mmol), 4- (trifluoromethyl)ρhenylboromc acid (4.178 g, 22.0 mmol), dimethoxyethane (30 mL) and 2M Na2CO3 (40 mL) was heated to reflux before Pd2(dba)3 (0.10 g) was added and heating was continued for 5 h. After cooling to room temperature CHCl3 (50 mL) was added to and the mixture was filtered (celite). The organic layer was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography [SiO2, CHCl3] followed by iecrystallisation from CHCb/zi-hexane to give CAB06081 (4,03 g, 71%) as colorless needles. Mp. 106-107 °C; 1H NMR (400 MHz, DMSO-dtf) δ 7.53 (dt, J = 8.6, 2,7 Hz, IH)5 7.62 (dd, J- 9.8, 2 J Hz, IH), 7.84 (d, J= 8.2 Hz, 2H), 7.91 (d, J= 8 2 Hz, 2H), 8.11 (dd, J = 8,6, 5.5 Hz5 IH); LRMS (ES+): m/z 266,1 (100%, [M+H]+); HRMS (ES+) calcd for Ci4H8F4N [M+H]+: 266.0587, found 266.0577; Anal. Calcd for Ci4H8F4N: C, 63.40; H, 2.66; N, 5.28. Found C3 63,5; H, 2.66; N, 5.28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium carbonate In 1,2-dimethoxyethane; water for 5h; Heating; Reflux; | 5,4'-Difluoro-biphenyI-2-carbonitrie (CAB06058)A mixture of 2-bromo-4-fiuorobenzinitrile (5.0 g, 25.0 mmol), 4-fiuorophenylboronic acid (3.85 g,27.5 mmol), dimethoxyethane (30 rtiL) and 2M Na2CO3 (40 mL) was heated to reflux before Pd2(dba)3 (0.10 g) was added and heating was continued for 5 hours. After cooling to room temperature CHCl3 (50 mL) was added to and the mixture was filtered (celite). The organic layer was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography [SiO2, CHCl3] followed by recrystallisation from CHCl3/n-hexane to afford CAB06Θ58 (4.03 g, 71%) as colorless needles. Mp. 111-113 °C; 1H NMR (400 MHz, CDCl3) δ 7,12-7.23 (m, 4H)3 7.50-7.56 (m, 2H), 7,76 (dd, J = 8.6, 5.4 Hz, IH); LRMS (ES+): m/z 416.0 (100%, [M+H]+); HRMS (ES+) calcd for Ci3H8F2N [M+H]+: 216,0619, found 216.0613; Anal, Calcd for Cj3H7F2N: C, 72.56; H3 3.28; N, 6.51. Found C, 72.4; H, 3.28; N3 6.55. |
With bis(dibenzylideneacetone)-palladium(0) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 80℃; for 3h; Inert atmosphere; | 9.9-1 (9-1) Synthesis of 4-Fluoro-2-Phenylbenzonitrile (9-1) Synthesis of 4-Fluoro-2-Phenylbenzonitrile A mixture of 2-bromo-4-fluorobenzonitrile (25.0 g), phenylboronic acid (18.32 g), tetrakis(triphenylphosphine)palladium (0) (2.89 g), a 2 M sodium carbonate aqueous solution (125 mL), and 1,2-dimethoxyethane (DME) (250 mL) was stirred at 80° C. for 3 hours in an argon atmosphere. The resulting reaction mixture was cooled to room temperature, and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4-fluoro-2-phenylbenzonitrile (22.1 g). The yield was 90%. |
78% | With sodium carbonate In 1,2-dimethoxyethane; water for 5h; Heating; Reflux; Inert atmosphere; | 5-FIuoro-biphenyi-2-carbonitrile (CAB06020)A mixture of 2-bromo-4~fiuorobenzinitrile (5.6 g, 28.0 mmol), phenylboronic acid (4.27 g, 35.0 mmol), dimethoxyethane (25 mL) and 2M Na2COs (40 ml.) was heated to reflux before Pdj(dba)3 (0.10 g, 0.11 mmol) was added and heating was continued for 5 h. After cooling to room temperature CHCl3 (50 mL) was added and the mixture was filtered (celite). The mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography [S1O2, CHCl3/hexane (1:10) followed by reciystallisation from hexane to give CABΘ6020 (4,29 g, 78%) as colorless needles. Mp. 79-80 0C; 1H NMR (400 MHz1 CDCl3) δ 7.14 (dt, J= 8.6, 2.7 Hz, IH), 7.22 (dd, J= 9.4, 2.7 Hz, IH), 7.46-7.57 (m, 5H), 7.77 (dd, J= 8,6, 5.5 Hz, IH); LRMS (ES+): m/z 197.9 (100%, [M+H]+); HRMS (ES+) calcd for Ci3H9FN [M+H]+: 198.0714, found 198.0706; Anal. Calcd for Cj3H8FN: C, 79.17; H, 4.09; N, 7,10. Found C, 79.3; H, 4.08; N, 7,04. |
With bis(dibenzylideneacetone)-palladium(0) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With sodium carbonate In 1,2-dimethoxyethane; water for 5h; Heating; Reflux; | 2-(Benzofuran~2-yl)~4-fluorobenzonitriIe (AUPOl 158-1)A mixture of 2-bromo-4-fluorobenzonitrile (5,15 g, 25.65 mmol), benzofuran-2- ylboronic acid (5.0 g, 30,8 mmol), 1 ,2-dimethoxyethane (25 mL) and 2M Na2CO3 (40 niL) was heated to reflux before Pd2(dba)3 (100 mg) was added and heating was continued for 5 h. After cooling to r.t, EtOAc (20 mL) was added to dissolve the product. The mixture was filtered through celite, the organic layer was separated, dried (Na2SO4) and concentrated under reduced pressure, The residue was dissolved in minimum amount of CHCl3 and passed through Silica. Solvent was evaporated and the residue was first purified by crystallisation from a mixture CHCI3/PE (98/2). The filtrate was purified by Combiflash chromatography (40 g column, 13 g Silica, gradient of eluent from PE to PE/EtOac 9/1) to give the title compound as light yellow solid purified by rinsing with PE to give at the end a white solid (5.15 g), This solid had to be purified an ultimate time by drying under vacuum at 80 0C for O/N. Finally, pure expected compound was obtained as a off-white solid in 59% yield (3.6 g); mp 123-124 0C; 1H NMR (270 MHz, CDCl3) .57.13 (IH, td, J = 2.5 and 7.3 Hz, ArH), 730 (IH, X, J = 1.1 Hz5 ArH), 7,40 (IH, X, J = 1.1 Hz, ArH), 7.56 (IH5 d, J = 7.7 Hz, ArH), 7,69 (IH, d, J = 7.7 Hz, ArH), 7.76-7.86 (3H, m, ArH); Anal. Calcd. for Ci5H8FNO: C 75,94, H 3.40, N 5.90. Found: C 75,70, H 3.37, N 5.97 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium carbonate In 1,2-dimethoxyethane; water for 5h; Heating; Reflux; | 4I-(Benzyloxy)-5-fluorobiphenyl-2-carbonitriIe (CAB06048) A mixture of 2-bromo-4-fluorobenzinitrile (4.50 g, 22.5 nimol), 4- benzyloxyphenylboronic acid (5.19 g, 22.76 mmol), dimethoxyethane (25 mL) and 2M Na2CO3 (40 mL) was heated to reflux before Pd2(dba)3 (0,05 g, 0.055 mmol) was added and heating was continued for 5 hours. After cooling to room temperature CHCl3 (ca. 100 mL) was added to dissolve the product, which crystallised from the organic layer. The mixture was filtered through celite, the organic layer was separated, dried (Na2SO4) and concentrated under reduced pressure. The residue was recrystallized from CHCl3/hexane to give CAB06048 (532 g, 78%) as colorless needles. Mp. 94-96 0C; 1H NMR (400 MHz, DMSO-^6) δ 5.12 (s, 2H), 7.06-7.12 (m, 3H), 7.18 (dd, J= 9.4, 2.7 Hz, IH)5 733-7,53 (m, 7H)5 7.74 (dd, J = 8.6, 5,7 Hz, IH); LRMS (ES+): m/z 326.4 (100%, [M+Naf), 3043 (60%, [M+H]+); HRMS (ES+) calcd for C20Hi5FNO [M+H]+: 304.1132, found 304.1125. |
With bis(dibenzylideneacetone)-palladium(0) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | 4-(4F-l,2,4-Triazol-4-yamino)-2-broraobenzonitriIe (CAB05094)To a solution of 4H-l,2,4-triazol-4-amine (4 204 gt 50,0 mmol) in DMSO (50 mL) was added KOtBu (5.51 g, 50,0 mmol). The mixture was stirred for 0,5 hours at room temperature before 4-fluoro-2-bromobenzonitrile (5.00 g, 25,0 mmol) was added and stirring was continued for 1 hour. The mixture was poured into crushed ice and neutralized with 2M KHSO4 solution. The precipitate was filtered off and recrystallised from MeOH to give CAB05094 (4.82 g, 73%) as a light yellow crystalline solid. Mp 234-236 0C; 1H NMR (400 MHz5 DMSO^6) delta 6,66 (dd, J= 8,6, 2.4 Hz, IH), 6,79 (d, J= 2,4 Hz, IH)5 7,78 (d, J- 8.6 Hz, IH), 8.86 (s, 2H)5 10.45 (s, IH); 13C NMR (100.6 MHz3 DMSO-rf6) delta 105.0, 1 11.5, 115.4, 117.8, 126.0, 136.2, 143,9, 151.8; LRMS (APCI-): m/z 226611,,88 ((110000%%,, [[CC99HH557799BBrrNN55]]"")),, 226633..88 ((9900%%,, [[CC59H581BiN5]"); HRMS (ES+) calcd for C9H779BrN5 [M+H]+: 263,9879, found 263.9870; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: C12H13NOS With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: 2-bromo-4-fluorobenzonitrile In N,N-dimethyl-formamide at 50℃; | 4.3 NaH (88 mg, 2.18 mmol) was added to a solution of intermediate 4-c (400 mg,1 .82 mmol) in DMF cooled to 0 °C and the mixture was stirred for 5 minutes. 2-Bromo- 4-fluorobenzonitrile (51 1 mg, 2.55 mmol) was added and the reaction was then stirred at 50 °C overnight and then cooled to room temperature. Saturated aqueous ammonium chloride and ethyl acetate were added, the organic layer was separated, washed with brine, dried over anhydrous MgSC>4, filtered and concentrated in vacuo. Purification by silica gel chromatography provided intermediate 4-d as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 7,7-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: 2-bromo-4-fluorobenzonitrile In N,N-dimethyl-formamide at 67℃; for 4h; | 3.3 NaH (54.3 mg, 1 .35 mmol) was added to a solution of intermediate 3-c (291 mg, 1 .35 mmol) in DMF cooled to 0 °C and the mixture was stirred for 5 minutes. 2-bromo- 4-fluorobenzonitrile (380 mg, 1.90 mmol) was added and the reaction was then stirred at 67 °C for 4 hours and then cooled to room temperature. Water and ethyl acetate were added, the organic layer was separated, washed with brine, dried over anhydrous MgSC>4, filtered and concentrated in vacuo. Purification by silica gel chromatography provided intermediate 3-d as a yellow solid. MS (m/z) M+H= 395.8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: 2-bromo-4-fluorobenzonitrile With isopropylmagnesium chloride In tetrahydrofuran at -30℃; for 3h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -30 - 20℃; Stage #3: With hydrogenchloride In tetrahydrofuran; water at -10℃; for 0.333333h; | 56 To a solution of 2-bromo-4-fluorobenzonitrile (5.0 g, 25.0 mmol) in anhydrous THF (20 mL) is added PrMgCl 2.0M in THF (15.0 mL, 30.0 mmol) at -30°C. The solution is stirred at -30 °C for 3 hours and DMF (5.80 mL, 75.0 mmol) is added. The reaction mixture is allowed to warm to room temperature and is stirred for 1 hour. The solution is cooled to -10°C, 2M hydrochloric acid (37 mL) is added and the solution is stirred for 20 minutes. The solution is concentrated in vacuo to -1/3 original volume and extracted into EtOAc (3x). The combined organics are then dried (Na2S04), filtered and concentrated to afford 4-fluoro-2-formyl benzonitrile (3.9 g, 71%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In petroleum jelly; N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 1.3 Stage 3: In a 250 ml round-bottomed flask under argon, 391 mg of a suspension of sodium hydride at 60% in petroleum jelly are added at ambient temperature, in 4 stages, in ½ hour, to a solution of 2.0 g of 9H-carbazole-4-carboxylic acid methyl ester obtained according to the preceding stage and of 1.95 g of 2-bromo-4-fluorobenzonitrile in 50 ml of dimethylformamide. The mixture is stirred at ambient temperature for 3 hours. The reaction medium is evaporated to dryness under vacuum and the residue is chromatographed on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and cyclohexane (50:50). 3.2 g of 9-(3-bromo-4-cyanophenyl)-9H-carbazole-4-carboxylic acid methyl ester are obtained in the form of a white solid, the characteristics of which are the following: 1H NMR spectrum (400 MHz, δ in ppm, DMSO-d6): 4.03 (s, 3H); 7.36 (m, 1H); 7.47 (d, J=7.8 Hz, 1H); 7.50 to 7.60 (m, 2H); 7.72 (d, J=7.8 Hz, 1H); 7.87 (d, J=7.8 Hz, 1H); 7.91 (dd, J=8.3 Hz and 2.0 Hz, 1H); 8.26 (m, 2H); 8.75 (d, J=7.8 Hz, 1H). Mass spectrum (LC/MS; method C): retention time Tr (min)=6.08; m/z=405 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 4h; Inert atmosphere; | 2.2 Stage 2:; In a 20 ml single-necked round-bottomed flask, under argon atmosphere, 80 mg of 4-(quinolin-3-yl)-9H-carbazole, obtained according to the preceding stage, and 60 mg of 2-bromo-4-fluorobenzonitrile are dissolved in 2 ml of anhydrous dimethylformamide (DMF). 16.3 mg of sodium hydride at 60% in oil are then added, and the mixture is stirred at ambient temperature for 4 hours. After the addition of 15 ml of ethyl acetate and 3 ml of water, the organic phase is separated by settling out, washed 3 times with 3 ml of water, dried over magnesium sulphate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (15-40 μm), elution being carried out with dichloromethane, 95 mg of 2-bromo-4-[(4-quinolin-3-yl)-9H-carbazol-9-yl]benzonitrile are obtained in the form of a beige lacquer, the characteristics of which are the following: 1H NMR spectrum (400 MHz, δ ppm, DMSO-d6): 7.08 (m, 1H) 7.24 (d, J=8.1 Hz, 1H) 7.36 (dd, J=6.4, 2.0 Hz, 1H) 7.43 (m, 1H) 7.49 to 7.53 (m, 1H) 7.57-7.67 (m, 2H) 7.74 (m, 1H) 7.89 (m, 1H) 7.96 (dd, J=8.3, 2.0 Hz, 1H) 8.14 (broad d, J=7.9 Hz, 1H) 8.19 (broad d, J=8.2 Hz, 1H) 8.28 (d, J=8.3 Hz, 1H) 8.30 (d, J=2.0 Hz, 1H) 8.63 (d, J=2.2 Hz, 1H) 9.14 (d, J=2.2 Hz, 1H). Mass spectrum (LC/MS method A): retention time Tr (min)=1.22; MH+=474 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In 1,4-dioxane at 80℃; for 2h; Inert atmosphere; Sealed tube; | 10 4-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-4-ylethynyl)benzonitrile Example 10 4-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-4-ylethynyl)benzonitrile Dichloro bis(triphenylphosphine) palladium (II) (29.6 mg, 0.0422 mmol), and triethylamine (742 μl, 534 mg, 5.28 mmol) were added to a solution of intermediate 10.2 (150 mg, 1.06 mmol) and 2-bromo-4-fluorobenzonitrile (1.06 g, 5.28 mmol) in 1,4-dioxane (4 mL), and placed in a sealable tube. Nitrogen gas was bubbled in the reaction mixture for 5 min, before the tube was sealed and the reaction mixture was heated at 80° C. for 2 h. After cooling, the brown solution was filtered through Celite and concentrated under vacuo. The residue was purified by chromatography on a SP1 Biotage system, using hexanes and ethyl acetate as eluents to afford the title compound (33 mg, 12%) as a yellow solid (HPLC: 99%, RT: 6.20 min) 1H NMR (DMSO-d6) δ=12.05 (br s, 1H), 8.31 (d, J=5.1 Hz, 1H), 8.13 (dd, J=8.8, 5.5 Hz, 1H), 7.90 (dd, J=9.3, 2.6 Hz, 1H), 7.69 (dd, J=3.3, 2.6 Hz, 1H), 7.59 (td, J=8.4, 2.6 Hz, 1H), 7.27 (d, J=4.8 Hz, 1H), 6.78 (dd, J=3.7, 1.8 Hz, 1H); MS (m/z) 262 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h; Inert atmosphere; | 1.3 In a 500 ml round-bottomed flask, 695 mg of sodium hydride as a dispersion at 60% in oil are added, in small portions, under argon at ambient temperature, to a mixture of 3.0 g of 3-(3-methyl-1H-indazol-4-yl)quinoline obtained according to the preceding stage and 2.55 g of 2-bromo-4-fluorobenzonitrile in 100 ml of anhydrous dimethylformamide. After stirring at ambient temperature for 1 hour, the reaction mixture is diluted with 500 ml of ethyl acetate and 30 ml of distilled water. The solid in suspension is filtered off and the filtrate is decanted. The organic phase is washed with 100 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and evaporated to dryness under vacuum. The residue combined with the solid previously filtered off is triturated from isopropyl ether and then filtered. The solid is washed with 3 times 80 ml of isopropyl ether and then dried under vacuum. 4.12 g of 2-bromo-4-(3-methyl-4-quinolin-3-ylindazol-1-yl)benzonitrile are obtained in the form of a solid, the characteristics of which are the following: 1H NMR spectrum (400 MHz, δ in ppm, DMSO-d6): 2.15 (s, 3H); 7.38 (d, J=6.8 Hz, 1H); 7.58 to 7.77 (m, 2H); 7.86 (t, J=7.6 Hz, 1H); 8.00 to 8.21 (m, 5H); 8.28 (s, 1H); 8.54 (s, 1H); 9.05 (s, 1H). Mass spectrum (LC/MS method C): Retention time Tr (min)=1.18; [M+H]+: m/z=439. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 1.5h; Inert atmosphere; | 12.2 In a 250 ml round-bottomed flask, 1.05 g of a dispersion of sodium hydride at 60% in oil are added, in small portions under argon at ambient temperature, to a mixture of 3.32 g of 3-methyl-1H-indazole-4-carboxylic acid methyl ester obtained according to the preceding stage and 3.84 g of 2-bromo-4-fluorobenzonitrile in 120 ml of anhydrous dimethylformamide. The reaction medium is left to stir for 1.5 hours and is then diluted with 500 ml of ethyl acetate, and then 20 ml of distilled water are added. After separation by settling out, the aqueous phase is re-extracted with 500 ml of ethyl acetate. The combined organic phases are washed twice with distilled water and then with a saturated solution of sodium chloride, dried over magnesium sulphate and evaporated to dryness under vacuum. The solid obtained is filtered off and washed with four times 100 ml of isopropyl ether and dried under vacuum. 4.4 g of 1-(3-bromo-4-cyanophenyl)-3-methyl-1H-indazole-4-carboxylic acid methyl ester are obtained in the form of a solid, the characteristics of which are the following:1H NMR spectrum (400 MHz, δ in ppm, DMSO-d6): 2.66 (s, 3H); 3.95 (s, 3H); 7.65 (t, J=7.8 Hz, 1H); 7.79 (d, J=7.1 Hz, 1H); 8.02 (d, J=8.3 Hz, 1H); 8.13 (d, J=8.3 Hz, 1H); 8.21 (d, J=8.6 Hz, 1H); 8.25 (s, 1H).Mass spectrum (LC/MS method C): Retention time Tr (min)=1.13; [M+H]+: m/z=370 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Stage #1: 3-{3-(Trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl}quinoline With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Stage #2: 2-bromo-4-fluorobenzonitrile In N,N-dimethyl-formamide; mineral oil at 60℃; for 1h; | 1.1.5 Example 1(5)2-Bromo-4-{4-(quinolin-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile (1e)Sodium hydride (0.183 g, a 55% dispersion in paraffin liquid) was added to a solution of compound (1d) (0.940 g) in N,N-dimethylformamide (hereinafter referred to as DMF, 6 mL) at room temperature, followed by stirring for 30 min. Subsequently, 2-bromo-4-fluorobenzonitrile (0.838 g) was added to the reaction solution, followed by stirring at 60° C. for 1 hr. After cooling, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline in this order and was dried over anhydrous sodium sulfate. After distillation of the solvent, the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (1e) (0.56 g, 38%) as a white solid.1H-NMR (DMSO-d6) δ 9.03-9.01 (2H, m), 8.89 (1H, d, J=1.8 Hz), 8.58-8.54 (2H, m), 8.23 (1H, d, J=8.6 Hz), 8.16 (1H, d, J=8.4 Hz), 8.11 (1H, d, J=8.2 Hz), 7.91 (1H, brt, J=7.0 Hz), 7.76-7.71 (2H, m); LRMS (ESI) m/z 494, 496 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: 3-Methyl-4-(4-phenyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.166667h; Stage #2: 2-bromo-4-fluorobenzonitrile In N,N-dimethyl-formamide; mineral oil at 50℃; for 0.5h; | 97.97.4 Example 97(4)2-Bromo-4-{3-methyl-4-(4-phenyl-1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile (97d)Compound (97c) (0.140 g) was dissolved in DMF (1.7 mL), and sodium hydride (0.024 g, a 55% dispersion in paraffin liquid) was added to the resulting solution at 0° C., followed by stirring for 10 min. Then, 2-bromo-4-fluorobenzonitrile (0.112 g) was added to the reaction solution, followed by stirring at 50° C. for 30 min. Ice water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain compound (97d) (0.160 g, 69%) as a white solid.1H-NMR (DMSO-d6) δ: 8.76 (1H, d, J=2.20 Hz), 8.58 (1H, d, J=5.12 Hz), 8.41 (1H, dd, J=8.66, 2.20 Hz), 8.21-8.19 (4H, m), 7.95 (2H, d, J=8.29 Hz), 7.49 (1H, d, J=5.12 Hz), 7.46 (2H, t, J=7.81 Hz), 7.32 (1H, t, J=7.81 Hz), 2.10 (3H, s); LRMS (ESI) m/z 454 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.1% | With palladium diacetate; potassium carbonate; triphenylphosphine In 1,4-dioxane; water for 4h; Inert atmosphere; Reflux; | 4.42. 5-Fluoro-4'-methylbiphenyl-2-carbonitrile (11) To a solution of 2-bromo-4-fluorobenzonitrile (6.82 g, 34.10 mmol), p-tolylboronic acid (5.75 g, 42.29 mmol), PPh3 (1.76 g, 6.33 mmol) and Pd(OAc)2 (28 mg, 0.13 mmol) in 1,4-dioxane (96 mL) was added K2CO3 (11.67 g, 84.60 mmol) in 24 mL H2O. The mixture was refluxed for 4 h under nitrogen. Then the mixture was diluted with EtOAc, washed with 5% NaOH and brine, dried with MgSO4, and concentrated in vacuo. Chromatographied with petroleum ether/ethyl acetate (150:1) to yield the desired product as white solid (5.84 g, 81.1%). 1HNMR (400 MHz, CDCl3) δ: 7.79 (1H, dd, J1 = 8.4 Hz, J2 = 5.2 Hz, Ph'-H), 7.40 (2H, d, J = 8.4 Hz, Ph-H), 7.29 (2H, d, J = 8.4 Hz, Ph-H), 7.22 (1H, dd, J1 = 9.6 Hz, J2 = 2.8 Hz, Ph'-H), 7.14-7.10 (1H, m, Ph'-H), 2.44 (3H, s, Ph-CH3). ESI-MS (m/z): 211.23[M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 16h; Sealed tube; | 204 Intermediate 204a: 2-Bromo-4-phenoxybenzonitrile To a solution of 2-bromo-4-fluorobenzonitrile (0.400 g, 2.000 mmol) and phenol (0.207 g, 2.200 mmol) in DMF (10 mL) was added potassium carbonate (0.332 g, 2.400 mmol) and the resulting mixture was stirred at 50°C in a sealed vial overnight. After 16 h, LC- MS showed that the reaction was essentially complete (co-injection with starting material), with a single major peak (target mass not observed). The mixture was filtered to remove the potassium salts, the filter-cake was washed with a DMF (2 mL) and the filtrate was evaporated. The residue obtained was partitioned with EtOAc-saturated aqueous NH4Cl and the organic phase was separated, dried (Na2S04) and evaporated. This afforded the essentially pure product (0.466 g, 85% yield) which was used as such in the next step. LC-MS (Method J): 1.330 min, [M + H]+ = no ion observed; lH NMR (400 MHz, DMSO-i) δ ppm 7.90 (d, /= 9.0 Hz, IH), 7.48 (t, /= 8.2 Hz, IH), 7.39 (d, /= 2.3 Hz, IH), 7.29 (t, /= 7.4 Hz, IH), 7.17 (d, /= 7.4 Hz, IH), 7.05 (dd, /= 2.3, 8.6 Hz, IH). |
32% | With potassium carbonate In dimethyl sulfoxide at 20℃; | 21 Preparation 21: 2-bromo-4-phenoxybenzonitrile (P21) To a solution of 2-bromo-4-fluorobenzonitrile (0.5 g, 2.50 mmol) and phenol (0.25 g, 2.62 mmol) in DMSO (2 mL), at RT, K2C03 (0.69 g, 5 mmol) was added and the reaction mixture was stirred at RT overnight. Water and Et20 were added to the reaction mixture, the organic phase was washed withwater and saturated NaHCO3, dried and the solvent removed under reduced pressure. Crude materialwas purified by FC on silica gel (eluent: Cy/EA from 100/0 to 90/10) to give 2-bromo-4-phenoxybenzonitrile (p21, 220 mg, y= 32%).1H NMR (CHLOROFORM-d): 6 ppm 7.60 (d, 1 H) 7.42 - 7.51 (m, 2 H) 7.26 - 7.33 (m, 1 H) 7.23 (d, 1 H)7.09 (d, 2 H) 6.98 (dd, 1 H) |
With potassium carbonate In N,N-dimethyl-formamide at 45℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: 2-bromo-4-fluorobenzonitrile With sodium sulfide In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Stage #2: With hydrogenchloride; zinc In water Cooling with ice; Inert atmosphere; | General Procedure General procedure: Into an oven-dried flask equipped with a magnetic stir bar was added aryl fluoride (1.00 g, 1.0 eq.), Na2S (1.1 eq.) and DMF (5 mL) under argon. The reaction mixture was stirred at room temperature for 1 h. Then 1 M NaOH (50 mL) was added and was washed with CH2Cl2 (2 x 25 mL). The aqueous layer was acidified to pH ~ 1-2 with 6 N HCl and extracted with CH2Cl2 (2 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to provide a crude residue. To the residue was added 10% HCl (40 mL) and cooled with an ice-water bath. Then zinc dust (4 g) was added and the mixture was stirred for 1 h. Then EtOAc (100 mL) was added and the mixture was stirred for an additional 30 minutes. The organic layer was separated and washed with water (40 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated to provide the desired product with satisfactory purity. |
With sodium sulfide * 10 H2O In N,N-dimethyl-formamide at 20℃; for 1h; | i48 -bromo-4-mercaptobenzonitrile 2-bromo-4-fluoro-benzonitrile (2 g, 10 mmol) was dissolved in DMF (5 mL). Na2S 10H2O (2.58 g, 10 mmol) was added. The mixture was stirred at rt 1 h. Then 1M NaOH (100 mL) was added. The mixture was extracted by DCM (100 mL*2). Then the water phase was acided by 6 M HC1 to pH=2. The mixture was extracted by DCM (200 mL*2). The organic phase was washed by brine, dried over Na2S04, filtered and concentrated. The crude material was used for next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 18h; | A solution of 2-bromo-4-fluorobenzonitrile (200 mg, 1.OOmmol), <strong>[71810-97-4]D-alanine amide hydrochloride</strong> (148 mg, 1.19 mmol) and DIEA (0.620 mL, 3.56 mmol) in DMSO (3 mL) was stirred at 100 C for 18 h. EtOAc and water were added. The organic phase was separated, dried over Na2S04, concentrated in vacuo. The residue was purified by a silicsa gel column, eluted first with 30percent EtOAc in hexane, then with 100percent EtOAc to give (R)-2-(3-bromo-4- cyanophenylamino)propanamide (185 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 18h; | Example 1. 4-((lR,2S)-2-aminocyclohexylamino)-2-(m-tolylamino)benzamideScheme 1 Cs2C03, toluene100 CH202 K2C03 DMSO100 C[0307] A solution of 2-bromo-4-fluorobenzonitrile (0.761 g, 3.80 mmol), tert-butyl (lS,2R)-2-aminocyclohexylcarbamate (l .OOg, 0.808 mmol) and DIEA (1.00 mL, 5.76 mmol) in DMSO (6 mL) was stirred at 100 C for 18 h. EtOAc and water were added. The organic phase was separated, washed with IN HC1, then with 5% NaHC03, dried over Na2S04, concentrated in vacuo to give tert-butyl (lS,2R)-2-(3-bromo-4- cyanophenylamino)cyclohexylcarbamate (1.48 g) as an off- white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 18h; | A solution of 2-bromo-4-fluorobenzonitrile (255 mg, 1.27 mmol), D -phenylalanine amide (220 mg, 1.34 mmol) and DIEA (0.466 mL, 2.68 mmol) in DMSO (3 mL) was stirred at 100 C for 18 h. The mixture was then purified by HPLC to give (R)-2-(3-bromo-4- cyanophenylamino)-3-phenylpropanamide (102 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate In N,N-dimethyl-formamide at 20 - 80℃; | |
60.5% | Stage #1: 3,6,6-trimethyl-1(2),5,6,7-tetrahydro-4H-indazole-4-one With sodium hydride In dimethyl sulfoxide Stage #2: 2-bromo-4-fluorobenzonitrile In dimethyl sulfoxide at 45℃; | 29 2-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indazol-1 -yl)benzonitrile: 3,6,6-Trimethyl-6,7-dihydro-1 H-indazol-4(5H)-one (0.535 g, 3 mmol) was dissolved in dry DMSO (15 mL). Sodium hydride (0.15 g, 3.75 mmol) was slowly added. After H2 evolution ceased, 2-bromo-4-fluorobenzonitrile (0.900 g, 4.50 mmol) was added. The resulting mixture was heated at 45 °C overnight, cooled, poured into satd. NH4CI solution (50 ml), and extracted with EtOAc three times. The combined organic phases were washed with water/brine, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% - 50% EtOAc in hexanes) to afford the title compound as a white solid (0.65 g, 60.5%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.01 (d, J = 2.15 Hz, 1 H), 7.82 (d, J = 8.61 Hz, 1 H), 7.63 (dd, J = 2.15, 8.42 Hz, 1 H), 2.90 (s, 2H), 2.59 (s, 3H), 2.47 (s, 2H), 1 .18 (s, 6H). LCMS: fR = 0.90 min, 100%. MS (ESI): m/z 358, 360 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: 2-bromo-4-fluorobenzonitrile With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.166667h; Stage #2: carbon dioxide In tetrahydrofuran; hexane at -78 - 20℃; for 17h; | 25.1 A solution of n-butyllithium (1 .6 M in hexanes, 4.4 mL, 7 mmol) was added to a solution of diisopropylamine (1 .05 mL, 7.50 mmol) in tetahydrofuran (20 mL) at -78 °C. The solution was warmed at -10°C for 15 minutes. Then the mixture was cooled at - 78 °C for 30 minutes and a solution of 2-bromo-4-fluorobenzonitrile (1 g, 5.0 mmol) in tetrahydrofuran (15 mL) was added. After stirring at -78 °C for 10 minutes, carbone dioxide (gaz) was bubbled in the mixture with a syringe for 5 minutes. The reaction was stirred at -78°C for 2 hours and was warmed at room temperature for 15 hours. The mixture was then quenched with water stirred for 20 minutes. The mixture was extracted three times with sodium hydroxide (10%). The aqueous layer was acidified with hydrochloric acid (6N) and extracted three times with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to provide 2-bromo-3-cyano-6-fluorobenzoic acid (25a) as a orange powder (700 mg, 2.87 mmol, 63%).1 H NMR (400 MHz, CDCI3) 7.26-7.30 (m, 1 H), 7.78 (dd, J = 5.4 and 8.8 Hz, 1 H). MS m/z ([M-H]-) 242/244. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.7% | Stage #1: 2-bromo-4-fluorobenzonitrile; methylmagnesium bromide In diethyl ether at 20℃; for 0.5h; Inert atmosphere; Stage #2: With titanium(IV) isopropylate In diethyl ether for 6h; Reflux; Inert atmosphere; | A [A] 1 -(2-Bromo-4-fluoro-phenyl)- 1 -methyl-ethylamine To a stirred solution of 2-bromo-4-fluorobenzonitrile (5 g, 25 mmol) in ether (100 mL) was added MeMgBr (25 mL, 75 mmol) at room temperature. The solution was stirred at room temperature for 0.5 hour before Ti(Oi-Pr)4 (41 mL, 25 mmol) was added and the resulting mixture was heated to reflux for 6 hours. Aqueous NaOH (10%, 200 mL) solution was then slowly added to the reaction mixture at 0 °C and the reaction mixture was stirred at room temperature for additional 30 minutes. After dilution with aq. Na2C03 (5%, 400 mL) solution, it was extracted with t-BuOMe (100 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue obtained was diluted with aq. HC1 solution (5%) and the aqueous layer was washed with t-BuOMe (50 mL x 2) and basified with 20% aq. NaOH to pH~ 10. The resulting aqueous layer was further extracted with t-BuOMe (100 mL x 3). The combined organic layers were then dried over anhy. Na2S04, filtered, and concentrated in vacuo to give a crude product, which was purified by column chromatography to give the title product (3.0 g, yield 51.7%) as yellowish oil. MS: 231.7 (M+H+, IBr) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | Stage #1: 2-bromo-4-fluorobenzonitrile With hydroxylamine hydrochloride; sodium carbonate In methanol; water at 86℃; for 17.5h; Stage #2: glutaric anhydride, In N,N-dimethyl-formamide at 148℃; for 0.5h; | 6.2.2. General procedure B for the synthesis of 3-[(3-phenyl)-1,2,4-oxadiazol-5-yl]butanoic acids 11 General procedure: Hydroxylamine hydrochloride (1.0 equiv) was dissolved in H2O (0.4 mL per mmol) and sodium carbonate (0.5 equiv) was added.The mixture was stirred for 25 min at rt. A solution of the respective benzonitrile 8 (1.0 equiv) in CH3OH (1.8 mL per 1 mmol) was added to the solution under vigorous stirring. The reaction mixture was stirred at 86°C until the starting material was converted.Then, CH3OH was removed under reduced pressure and the residue was diluted with brine and extracted with CH2Cl2 until the product was extracted completely. The organic layer was dried (Na2SO4) and removed under reduced pressure. Afterwards, glutaric anhydride (1.0 equiv) and DMF (0.5 mL) were added to the residue and the reaction mixture was stirred for 30 min at 148°C. The solvent was removed in vacuo and the residue was purified by fc(cyclohexane/ethyl acetate/formic acid 50:50:0.01). The product was purified by recrystallization (CH2Cl2/H2O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 90℃; for 4.08333h; Inert atmosphere; | 30.1 Example 30 4-((lR,2S)-2-Amino-cyclohexylamino)-2-(6-methyl-pyridin-2-ylamino)-benzamide Step 1 4-Fluoro-2-(6-methyl-pyridin-2-ylamino)-benzonitrile 2-Bromo-4-fluoro-benzonitrile (1.0 g, 5.0 mmol), 6-methyl-pyridin-2-ylamine (540 mg, 5.0 mmol) and Cs2C03 (4.88 g, 15.0 mmol) were dissolved in dioxane (30 mL), then the reaction mixture was de-gassed with nitrogen (purged through the solution for 5 min). Pd2dba3 (229 mg, 0.25 mmol) and Xantphos (289 mg, 0.5 mmol) were added under nitrogen and the mixture heated to 90 °C for 4 h. The reaction mixture was cooled, filtered and the filter cake washed with EtOAc (20 mL). The combined filtrates were concentrated under reduced pressure to give a crude residue that was purified by chromatography (silica, 10% to hexane to 15 % EtOAc in hexanes) to give 4-fuoro-2-(6-methyl-pyridin-2-ylamino)-benzonitrile (470 mg, 41 %) as white solid. MS (EI/CI) m/z: 228.2 [M + H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: 2-bromo-4-fluorobenzonitrile With isopropylmagnesium chloride In tetrahydrofuran; diethyl ether at -40℃; for 3h; Inert atmosphere; Stage #2: dibromodifluoromethane In tetrahydrofuran; diethyl ether at -78 - 20℃; for 8h; Inert atmosphere; | The optimized procedure for the bromodifluoromethylation of aryl Grignard reagents with CF2Br2 General procedure: To a stirred solution of Ar-X 9 (1.0 mmol) in THF(4.5 ml) was added dropwise a solution of i-PrMgCl in Et2O (2.0 M, 0.53 ml, 1.06 mmol) at -40 °C under Ar and the resulting mixture was stirred at -40 °C for 3 h and cooled to -78 °C. To a stirred solution of dibromodifluoromethane in THF (2.46 M, 0.49 ml, 1.2 mmol) was added dropwise the prepared solution of Ar-MgCl 10 in THF via cannula at -78 °C and the resulting mixture was gradually warmed to room temperature over 8 h. The reaction was quenched with saturated aqueous NH4Cl (10 ml) and extracted with EtOAc (10 ml x 3). The combined extracts were dried over Na2SO4. Concentration of the solvent in vacuo afforded a residue, which was purified by silica gel column chromatography and recycle GPC to give Ar-CF2Br 11. |
58% | Stage #1: 2-bromo-4-fluorobenzonitrile With isopropylmagnesium chloride In tetrahydrofuran; diethyl ether at -40 - 20℃; for 3.33333h; Inert atmosphere; Stage #2: dibromodifluoromethane In tetrahydrofuran; diethyl ether at -78 - 20℃; for 8h; Inert atmosphere; | 4 Under an argon atmosphere,2-Bromo-4-fluorobenzonitrile (200.0 mg, 1.0 mmol) was added to THF (4.5 ml) and cooled to -40 ° C.A diethyl ether solution (2 M, 525 μl, 1.05 mmol) of isopropyl magnesium chloride was added to the resulting mixture,And the mixture was stirred for 20 minutes.after that,The reaction solution was warmed to room temperature and stirred for 3 hours,A THF-diethyl ether solution of 2-cyano-5-fluorophenylmagnesium chloride was prepared.A solution of the prepared 2-cyano-5-fluorophenyl magnesium chloride in THF-diethyl etherWas added dropwise to a THF solution (2.46 M, 490 μl, 1.2 mmol) of dibromodifluoromethane cooled to -78 ° C.,The temperature was raised to room temperature and stirred for 8 hours.Saturated ammonium chloride aqueous solution (2.0 ml) was added to the reaction solution,And extracted with ethyl acetate.Combine the organic layers,Washed with water and saturated aqueous sodium chloride solution,After drying,The filtrate was concentrated under reduced pressure.The obtained crude product was purified by silica gel column chromatography (ethyl acetate-hexane) and recycle GPC (chloroform)To obtain 2- (bromodifluoromethyl) -4-fluorobenzonitrile (144.9 mg, 58%) as a yellow oily substance. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | Stage #1: 1-aminobenzimidazole With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 25℃; for 0.5h; Stage #2: 2-bromo-4-fluorobenzonitrile In dimethyl sulfoxide at 25℃; | 2.b Step B. 4-(1 H-Benzo[dlimidazol-1-ylamino)-2-bromobenzonitrile. To a solution of t-BuOK (6.21 g, 55 mmol) in DMSO (50 mL) at 25°C was added dry 1 H- benzo[d]imidazol-1 -amine (7.32 g, 55 mmol). After stirring for 30 minutes, 2-bromo- 4-fluorobenzonitrile (2 g, 10 mmol) was slowly added and the mixture further stirred at 25°C for 2 hours. The reaction mixture was quenched with water, filtered, concentrated under reduced pressure to afford the title compound as a white solid (3 g, 19%). MS (ESI) m/z: 313 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11%; 62% | [00134] A stirred solution of <strong>[674792-04-2](R)-tert-butyl 2-isopropylpiperazine-1-carboxylate</strong> (360 mg, 1.58 mmol), 2-bromo-4-fluorobenzonitrile (316 mg, 1.58 mmol), i-Pr2NEt (0.6 mL, 3.3 mmol) and DMSO (4 mL) was heated at 120 C for 2 h. The mixture was cooled to rt and used directly in the next step.[00135] Step 2[00136] NaSO2Me (1.61 g, 15.8 mmol) and proline (55 mg, 0.47 mmol) were added to the mixture. The mixture was sparged with N2 for 10 mm and CuT (54 mg, 0.28 mmol) was added. The mixture was heated at 110 C under N2 for 16 h. The mixture was cooled, diluted with EtOAc (100 mL), washed with water (2 x 10 mL) and brine (10 mL), and dried over Na2504. Removal of the solvent left an orange oil (677 mg). Chromatography on a 40- g silica cartridge eluted with a 0-100% EtOAc in hexanes gradient afforded (R)-tert-butyl 4- (3-bromo-4-cyanophenyl)-2-isopropylpiperazine- 1 -carboxylate (403 mg, 62%) and the title compound (75 mg, 11%). LC-MS Method 4 tR = 0.96 mm, mlz = 408, 352, 308. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sulfuric acid; potassium nitrate at 0 - 18℃; for 1.5h; | |
98% | With sulfuric acid; potassium nitrate at 0 - 25℃; for 2h; Inert atmosphere; | 159 Preparation 159: 2-bromo-4-fluoro-5-nitrobenzonitrile To a solution of 2-bromo-4-fluorobenzonitrile (1.0 g, 5.0 mmol) in conc. H2SO4 (5.0 ml_) was added KNO3 (556 mg, 5.50 mmol) in portions at 0 °C, and then stirred at 25 °C for 2 h. The reaction mixture was poured into ice water and the mixture was extracted with ethyl acetate (3 x 10 ml_). The combined organic layers were washed with brine (10 ml_) dried (Na2SO4) and concentrated to give the title compound (1.2 g, 98%).1H NMR (400 MHz, CDCl3) d 8.45 (d, J = 7.3 Hz, 1 H), 7.75 (d, J = 9.5 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With potassium carbonate In dimethyl sulfoxide at 125℃; for 0.416667h; Microwave irradiation; | 44.4 Synthesis of 2-bromo-4-(4-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)benzonitrile The compound obtained in Step 3 (20mg),2-bromo-4-fluorobenzonitrile (21 mg),Potassium carbonate (15mg) was dissolved in DMSO (0.2mL), It was stirred for 25 min under microwave irradiation under 125 ° C. The reaction mixture was HPLC column chromatography reverse phase preparative purification, The resulting fraction was concentrated in vacuum, The title compound was obtained as a white amorphous (15mg, 46%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | General procedure: The first reaction, the formation of imidazo[1,2-a]pyridine-2-carboxylic acid, was carried out in a 1000 muL reactor (glasschip) at 100 C. The acid exiting the first reactor was combinedwith EDC/HOBt/DIPEA (1:1:1, 0.5 M, DMA) in a T-mixer.The synthesis of amidoxime (ArCN/NH2OH·HCl/DIPEA(1.1:1:3), 0.4 M, DMA) was achieved by placing a secondreactor (250 muL glass chip) in a heated silicone oil bath at100 C. This stream was next introduced into a third reactor andmixed with the stream exiting from the T-mixer at 150 C. Thestream exiting the third chip was collected after passing throughthe back pressure regulator. This reaction was carried out with aback pressure of 4.0 bar. The reaction mixture was mixed withexcess water and extracted three times with dichloromethane.The combined organic layers were washed with brine, driedover magnesium sulfate, filtered, and concentrated and the residue was purified via automated flash chromatography(SiO2) to afford the desired product (CombiFlash Rf, 12g flashcolumn). The solvent gradient was 90% hexane to 50% ethylacetate over 15 min at a flow rate of 15 mL/min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With [1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) chloride-dichlormethane complex; potassium carbonate In 1,4-dioxane at 100℃; Inert atmosphere; | 34.1A 2-(2,5-Dimethoxypyridin-4-yl)-4-fluorobenzonitrile [0972] 1.11 g (4.17 mmol) of diisopropyl (2,5-dimethoxy- pyridin-4-yl)borate, 1.73 g (12.50 mmol, 3 eq.) of potassium carbonate and 0.340 mg (0.417 mmol, 0.1 eq.) of [1,1-bis (diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct were initially charged in a flask, which was then evacuated and filled with argon three times. 1.00 g (5.00 mmol, 1.2 eq) of 2-bromo-4-fluorobenzonitrile and 40 ml of dioxane were added, argon was passed through for 2 mm and the mixture was stirred at 1000 C. overnight. The reaction mixture was cooled down, filtered through kieselguhr and washed with acetonitrile, and the filtrate was concentrated. The crude product was purified by means of normal phase flash chromatography (eluent: cyclohexane/ ethyl acetate, 5-25%). Yield: 0.75 g (67% of theory).10973] LC/MS [Method 1]: R=0.96 mm; MS (ESIpos):mlz=259 (M+H), 10974] ‘H-NMR (400 MHz, DMSO-d5): ö [ppm]=8.10-8.01 (m, 2H), 7.55-7.46 (m, 2H), 6.86 (s, 1H), 3.86 (s, 3H),3.80 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 0.666667h; Microwave irradiation; | 32.1D 2-Bromo-4-(methylamino)benzonitrile [0949] 1.00 g (4.90 mmol) of 2-bromo-4-fluorobenzonitrile, 335 mg (4.96 mmol, 1.012 eq.) of methylamine hydrochloride and 1.71 ml (9.80 mmol, 2 eq.) of N,N-diisopropylethylamine were initially charged in 9.85 ml of 1-methyl-2-pyrrolidone and the mixture was heated in the microwave at 120° C. for 40 min. The cooled reaction mixture was partitioned between ethyl acetate and water, and the aqueous phase was extracted once more with ethyl acetate. The combined organic phases were washed three times with water, then with saturated aqueous sodium chloride solution, dried and concentrated. The crude product was purified by means of normal phase flash chromatography (eluent: cyclohexane/ethyl acetate, 0-40%). Yield: 660 mg (63% of theory). LC/MS [Method 1]: Rt=0.82 min; MS (ESIpos): m/z=211 (M+H)+, 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.50 (d, 1H), 7.06-6.94 (m, 1H), 6.84 (d, 1H), 6.60 (dd, 1H), 2.73 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium hydride In N,N-dimethyl-formamide; mineral oil for 4h; Inert atmosphere; | General procedure for preparation of 4a-j, 7a-r: General procedure: Pyrrole intermediates 3a-j, or 7a-p or 7s (0.7 mmol) and 2-bromo-4-fluorobenzonitrile (0.7 mmol) were dissolved in 0.5 mL of dry dimethyl formamide (DMF) in a round bottom flask. Sodium hydride (60% dispersion in oil) (0.7 mmol) was then added into the stirring reaction mixture under argon. After 4 h 10 mL of water was added to the reaction mixture and extracted using ethyl acetate (2 x 15 mL). The organic layers was washed with brine and dried over sodium sulfate followed by concentration. column chromatography (SiO2) was performed utilizing 20% ethyl acetate in hexanes to obtain products as amorphous solids |
With sodium hydride In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.7% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate In ethanol; water; toluene at 120℃; for 1.5h; Inert atmosphere; Sealed tube; Microwave irradiation; | 323 Intermediate 323a: methyl l-((2'-cyano-5'-fluoro-[l,l'-biphenyl]-4-yl)methyl)-2- ethoxy-lH-benzo[d]imidazole-7-carboxylate To a solution of 1-005 (600 mg, 1.375 mmol) and 2-bromo-4-fluorobenzonitrile (330 mg 1.650 mmol) in 4: 1 toluene/EtOH (12 mL) was added K3P04 (2 M, aq) (2.063 mL, 4.13 mmol) followed by PdCi2(dppf) (101 mg, 0.138 mmol). The resulting mixture was sparged with N2 for 2 min before being sealed and heated at 120 °C for 45 min in the microwave. Additional PdCl2(dppf) (101 mg, 0.138 mmol) was added to the reaction mixture which was then evacuated and backfilled with N2 (3x) and stirred for an additional 45 min in the microwave at 120 °C. The reaction mixture was then concentrated onto celite and purified by ISCO (80 g column 0-100% EtOAc/Hexanes) to afford the title compound (Intermediate 323a, 400 mg, 0.931 mmol, 67.7 % yield). LC- MS: MS (ESI) m/z: 430.1 (M+H)+. H NMR (500 MHz, CDC13) δ 7.77 (d, J=7.9 Hz, 2H), 7.59 (d, J=7.7 Hz, 1H), 7.45 (d, J=8.0 Hz, 2H), 7.23 - 7.09 (m, 5H), 5.73 (s, 2H), 4.73 - 4.67 (m, 2H), 3.78 (s, 3H), 1.51 (t, J=7.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.6% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; toluene at 95℃; for 2h; Inert atmosphere; Sealed tube; | 205 Intermediate 205a: 4'-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3- yl)methyl)-5-fluoro-[l,l'-biphenyl]-2-carbonitrile A mixture of 2-ethyl-5,7-dimethyl-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzyl)-3H-imidazo[4,5-b]pyridine (OOld, 0.262 g, 0.670 mmol), 2-bromo-4- fluorobenzonitrile (0.147 g, 0.736 mmol) and 2 M Na2C03 (0.837 mL, 1.674 mmol) in toluene-ethanol (9:1, 10 mL) was purged with a stream of N2 for 5 min in a sealable vial. To this mixture was added Pd(Ph3P)4 (0.077 g, 0.067 mmol), the vial was sealed and the mixture was stirred at 95 °C (block temperature) for 2 h. The cooled mixture was diluted with EtOAc and the organic phase was separated, dried (Na2S04) and evaporated to give a pale yellow gum. This material was purified by flash chromatography (ISCO/ 0-100% EtOAc-DCM) to give 4'-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)- 5-fluoro-[l,l'-biphenyl]-2-carbonitrile (0.174 g, 67.6% yield) as a colourless gum which solidified on standing in vacuo to give a waxy solid. This material was used as such in the next step. LC-MS (Method J): 1.331 min, [M + H]+ = 385.1; H NMR (400 MHz, DMSO-i) δ ppm 8.03 (dd, /= 5.5, 8.6 Hz, 1H), 7.55 (d, /= 8.2 Hz, 2H), 7.50 (dd, /= 2.7, 9.8 Hz, 1H), 7.43 (dt, J= 2.7, 8.6 Hz, 1H), 7.25 (d, /= 8.2 Hz, 2H), 6.94 (s, 1H), 5.53 (s, 2H), 2.80 (q, /= 7.4 Hz, 2H), 2.50 (s, 3H), 2.49 (s, 3H), 1.23 (t, /= 7.4 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.4% | Stage #1: benzyl alcohol With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: 2-bromo-4-fluorobenzonitrile In N,N-dimethyl-formamide at 20℃; for 3h; | 212 Intermediate 212a: 4-(Benzyloxy)-2-bromobenzonitrile To a solution of benzyl alcohol (0.228 mL, 2.200 mmol) in dry DMF (10 mL) was added 60% sodium hydride (0.096 g, 2.400 mmol) and the resulting mixture was stirred at RT under N2 for 30 min. To the resulting clear solution was added 2-bromo-4- fluorobenzonitrile (0.400 g, 2.000 mmol) all at once and stirring was continued at RT for 3 h. The reaction mixture was then quenched with saturated aqueous NH4CI (2 mL) and then it was poured into ice-saturated aqueous NH4CI and extracted with EtOAc (x2). The combined organic phase was washed (0, brine), dried (Na2S04) and evaporated to give the crude product as an oil which solidified on standing in vacuo. This material was purified by flash chromatography (ISCO/ 0-50% EtOAc-hexane) to give 4-(benzyloxy)-2- bromobenzonitrile (0.394 g, 68.4% yield) as an off-white crystalline solid which was used as such in the next step. LC-MS (Method J): 1.349 min, [M + H]+ = no ion observed; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (d, /= 8.6 Hz, 1H), 7.54 (d, /= 2.3 Hz, 1H), 7.45-7.32 (m, 5H), 7.19 (dd, /= 2.3, 8.6 Hz, 1H), 5.22 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 60% 2: 26.2% | With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 16h; Sealed tube; | 215 Intermediate 215a and 215b: 2-Bromo-4-(lH-indazol-l-yl)benzonitrile and 2-Bromo-4-(2H-indazol-2-yl)benzonitrile A mixture of 2-bromo-4-fluorobenzonitrile (0.200 g, 1.000 mmol), 1H-indazole (0.130 g, 1.100 mmol) and potassium carbonate (0.276 g, 2.000 mmol) in dry DMF (5 mL) was stirred at 120°C (block temperature) in a sealed vial for 16 h. The cooled mixture was filtered through a small plug of cotton wool to remove the potassium salts and the residue was washed with a little DMF. The filtrate was evaporated to give a turbid orange gum which was purified by flash chromatography (ISCO/ 50-100% DCM-hexane) to give 2-bromo-4-(lH-indazol-l-yl)benzonitrile (Intermediate 215a, 0.179 g, 60.0% yield) as a white solid. LC-MS (Method J): 1.402 min, [M + H]+ = 297.9, 299.9; H NMR (400 MHz, DMSO-i) δ ppm 8.53 (s, IH), 8.28 (d, / = 2.0 Hz, IH), 8.12 (d, / = 8.6 Hz, IH), 8.07 (dd, /= 2.0, 8.6 Hz, IH), 8.03 (d, /= 8.6 Hz, IH), 7.94 (d, /= 7.8 Hz, IH), 7.59 (dd, J= 7.4, 8.2 Hz, IH), 7.35 (t, J= 7.4 Hz, IH). Further elution afforded 2-bromo-4-(2H- indazol-2-yl)benzonitrile (Intermediate 215b, 0.078 g, 26.2% yield) as a white solid. LC-MS (Method J): 1.385 min, [M + H]+ = 298.0, 300.0; H NMR (400 MHz, DMSO- ) δ ppm 9.32 (s, IH), 8.64 (d, / = 2.0 Hz, IH), 8.33 (dd, / = 2.0, 8.6 Hz, IH), 8.16 (d, /= 8.6 Hz, IH), 7.76 (d, J= 8.6 Hz, IH), 7.70 (d, J= 9.0 Hz, IH), 7.35 (dd, J= 6.7, 7.8 Hz, IH), 7.12 (dd, J= 6.7, 8.2 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate In ethanol; water; toluene for 24h; Reflux; | 6.1.1-6 2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline is dissolved in toluene and placed in a two-neck flask. Add Tripotassium phosphate, Pd (PPh3) 2Cl2 and Ethanol dissolved in water. After 5 minutes, add 2-bromo-4-fluorobenzonitrile. Allow to reflux for 24 hours. When the reaction is complete, extract with CH2Cl2. Purification by silica gel column (yield: 72%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.8% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 80℃; for 5h; Inert atmosphere; | 60.1 Step 1: (S)-tert-butyl 4-(2-cyano-5-fluorophenyl)-2-methylpiperazine-l-carboxylate To a solution of 2-bromo-4-fluorobenzonitrile (1 g, 5.03 mmol) and (S)-tert-bu y 2- methylpiperazine-l-carboxylate (1.01 g, 5.03 mmol) in toluene (20mL) was added Pd2(dba)3(229 mg, 0.25 mmol), BINAP (313 mg, 0.503mmol), and t-BuONa(986 mg, 10.06 mmol). The mixture was stirred at 80°C for 5 hrs under nitrogen. The resulting reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica to give (S)-fert-butyl-4- (2-cyano-5-fluorophenyl)-2-methylpiperazine-l-carboxylate (125 mg, 0.39 mmol, 7.8%) as a yellow liquid. ESI-MS (EI+, m/z): 342.0 [M+Na]+. |
7.8% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 80℃; for 5h; Inert atmosphere; | 60.1 Step 1: Step 1: (S)-tert-butyl 4-(2-cyano-5-fluorophenyl)-2-methylpiperazine-1-carboxylate To a solution of 2-bromo-4-fluorobenzonitrile (1 g, 5.03 mmol) and (S)-tert-butyl 2-methylpiperazine-1-carboxylate (1.01 g, 5.03 mmol) in toluene (20 mL) was added Pd2(dba)3 (229 mg, 0.25 mmol), BINAP (313 mg, 0.503 mmol), and t-BuONa (986 mg, 10.06 mmol). The mixture was stirred at 80° C. for 5 hrs under nitrogen. The resulting reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica to give (S)-tert-butyl-4-(2-cyano-5-fluorophenyl)-2-methylpiperazine-1-carboxylate (125 mg, 0.39 mmol, 7.8%) as a yellow liquid. ESI-MS (EI+, m/z): 342.0 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With pyridine; tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; ammonium peroxydisulfate; 4-acetylamino-2,2,6,6-tetramethyl-1-piperidinoxy; ammonium carbamate In water; acetonitrile at 20℃; for 24h; Irradiation; Sealed tube; | |
60% | With pyridine; ammonium peroxydisulfate; tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; 4-acetylamino-2,2,6,6-tetramethyl-1-piperidinoxy In acetonitrile at 0.5℃; for 24h; Molecular sieve; Sealed tube; Irradiation; | Representative Procedure - Preparation of 4-Methoxybenzonitrile(4a) General procedure: To an oven-dried 2 ml reaction vial equipped with a stir bar wasadded the aldehyde 3a (0.136 g, 1 mmol, 1 equiv) and pyridine(0.474 g, 6.0 mmol, 6 equiv), followed by acetonitrile (2 ml, 0.5M in 3a). The vial was then charged with Ru(bpy)3(PF6)2 (0.017g, 0.02 mmol, 0.02 equiv), 2 (0.043 g, 0.20 mmol, 0.20 equiv),(NH4)2S2O8(0.501 g, 2.2 mmol, 2.2 equiv), and activated 3 Åmolecular sieves (ca. 0.2 g), sealed with a cap, and irradiated inblue LED reactor for 24 h. In the absence of fan cooling, the temperatureof the reaction mixture plateaued at approximately 50°C . After the irradiation was complete, the reaction mixturewas quenched with EtOAc and transferred to a separatoryfunnel. Further EtOAc (30 ml) was added, followed by 0.5 MHCl(aq) (30 ml). The layers were separated, and the aqueous layerwas extracted with EtOAc (3 × 20 ml). The organic layers werethen combined and washed with 0.5 M 0.5 M HCl(aq) (2 × 20 ml),saturated aqueous sodium bicarbonate (2 × 20 ml), and finallybrine (20 ml). The organic layer was then dried over sodiumsulfate and the solvent removed in vacuo to afford the crudeproduct. The resulting crude mixture was adhered to silica gelusing 1.5 weight equivalents of SiO2(relative to the theoreticalyield). The dry-packed material was gently added on top of asilica gel plug. The plug was washed with an excess of hexanes(ca. 5 column volumes). The desired product was eluted off theplug via a 90:10 by volume mixture of hexanes/EtOAc (3-4column volumes). The solvent was removed in vacuo by rotaryevaporation affording the pure nitrile 3c (0.066 g, 50%) as awhite solid. |
47% | With pyridine; ammonium peroxydisulfate In acetonitrile at 50℃; for 24h; |
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; sodium acetate / water; methanol / 4 h / 20 °C 2: acetic anhydride; potassium carbonate / dimethyl sulfoxide / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.3% | With caesium carbonate; In N,N-dimethyl-formamide; at 25℃; for 4h;Inert atmosphere; | 1) Under a nitrogen atmosphere, 0.30 g (1.50 mmol) of 2-bromo-4-fluorobenzonitrile, 3.0 mL of N,N-dimethylformamide (analytical grade) and <strong>[16545-68-9]cyclopropanol</strong> 0.14 g (2.40 mmol) were put into In a 25 mL single-mouth flask, 0.88 g (2.70 mmol) of cesium carbonate was added in three portions under magnetic stirring, so that the temperature inside the flask did not exceed 25 C. The temperature was controlled at 25 C, and the reaction was magnetically stirred for 4 h.2) After the reaction time is reached, the reaction liquid obtained in the step 1) is quenched with 15 mL of water, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate and filtered, and evaporated. Have a crude product;The crude product is purified by a silica gel column. The purification is specifically: 2.5 g of column chromatography silica gel containing 200-300 mesh sieve in a column, and the crude product is dissolved in 1.0 mL of ethyl acetate and 0.5 g of the above silica gel. After steaming the mixture, the mixture was poured into a silica gel column, and a mixture of ethyl acetate and petroleum ether = 1:10 by volume was used as a detergent, and the amount was 150 mL; the eluate which satisfies the pure point of TLC detection was collected; Concentration treatment gave a white solid which was found to be 2-bromo-4-(cyclopropoxy)benzonitrile in a yield of 80.3%. |
0.29 g | With caesium carbonate; In N,N-dimethyl-formamide; at 25℃; for 4h;Inert atmosphere; | To a solution of 2-bromo-4-fluorobenzonitrile (0.30 g, 1.5 mmol) and <strong>[16545-68-9]cyclopropanol</strong> (0.14 g, 2.4 mmol) in DMF (4 mL) wasadded Cs2CO3 (0.88 g, 2.7 mmol) in a 25 mL single-necked round-bottom flask. After that, themixture was stirred at 25 C under nitrogen. After stirring for 4 h, the resulting mixture was dilutedwith H2O (30 mL) and extracted with MTBE (10 mL×3). Then the combined organic phase waswashed with saturated aqueous NaCl (10 mL×3) and dried over Na2SO4 for 0.5 h. After that, theorganic phase was filtered under reduced pressure and the filtrate was concentrated underreduced pressure to give product as a yellow sticky substance. Then a mixture of 30 mL MTBE and100 mL n-hexane was added to dissolve the yellow sticky substance. Subsequently, the solutionwas cooled for 30 minutes with the mixture of water and ethanol. Lastly, the solution was filteredunder reduced pressure and the filtrate was dried naturally to obtain desired product in 80.3%yield (0.29g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium diacetate; N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 100℃; for 8h; Inert atmosphere; | ||
24.2 g | With palladium diacetate; N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 100℃; for 4h; Inert atmosphere; | 13.1 Step one: 2-Bromo-4-fluorobenzonitrile (13-1, 30.0 g) and ethyl acrylate (12-1a, 32 mL) were dissolved in dry DMF (200 mL), added with diisopropylethylamine (44 mL), palladium acetate (494 mg) and tri-o-tolylphosphine (1.0 g), heated to 100 °C and stirred for 4h under nitrogen. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, poured into ice water, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude was purified by silica gel column chromatography to obtain 13-2 (24.2 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: methyl (R)-2-[1-(4-bromophenyl)ethyl](butyl)amino}benzo[d]oxazole-4-carboxylate With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; bis(pinacol)diborane In 1,4-dioxane at 100℃; Inert atmosphere; Stage #2: 2-bromo-4-fluorobenzonitrile With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere; | 5.1.61 Methyl (R)-2-[1-(2′-cyano-5′-methyl-[1,1′-biphenyl]-4-yl)ethyl] (cyclopropylmethyl)amino}benzo[d]oxazole-4-carboxylate (36a) General procedure: A solution of compound 35 (5.54g, 12.9mmol) dissolved in 1,4-dioxane (129mL) was added Pd(dppf)Cl2 (1.89g, 2.58mmol), bis(pinacolato)diboron (8.19g, 32.3mmol) and KOAc (6.33g, 64.5mmol) under argon atmosphere. The reaction mixture was heated at 100°C for 4h. The resulting mixture was concentrated under reduced pressure, and then saturated NH4Cl aq. was added. The mixture was filtered through a celite pad and extracted with AcOEt. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. A solution of this crude material was dissolved in 1,4-dioxane (129mL) and H2O (13mL). To this solution was added 2-bromo-4-methylbenzonitrile (7.59g, 38.7mmol), Pd(PPh3)4 (1.49g, 1.29mmol) and Cs2CO3 (16.8g, 51.6mmol). The reaction mixture was heated at 100°C for 5h, and the resulting mixture was filtered through a celite pad and extracted with AcOEt. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with 33%-55% AcOEt in heptane to afford the titled compound (5.12g, 85%) as a white amorphous |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.6% | Stage #1: 2-bromo-4-fluorobenzonitrile; (R)-N-butyl-N-{1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}benzo[d]oxazol-2-amine With tetrakis(triphenylphosphine) palladium(0); 3K(1+)*O4P(3-)*4H2O In 1,2-dimethoxyethane Inert atmosphere; Reflux; Stage #2: With trimethylsilylazide; di(n-butyl)tin oxide In toluene at 120℃; | 5.1.44 (R)-N-butyl-N-{1-[5′-chloro-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl]ethyl}benzo[d]oxazol-2-amine (33j) General procedure: To a solution of compound 32 (350mg, 0.833mmol), 2-bromo-4-chlorobenzonitrile (269mg, 1.25mmol) and K3PO47H2O (1.13g, 3.33mmol) in DME (30.0mL) was added Pd(PPh3)4 (40.0mg, 0.035mmol) under N2 atmosphere. The reaction mixture was refluxed for 5h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC. The obtained compound was dissolved in toluene (30mL). To this solution was added TMSN3 (195mg, 1.69mmol) and dibutyltin oxide (211mg, 0.846mmol). The mixture was heated at 120°C overnight under N2. The resulting mixture was concentrated under reduced pressure and extracted with CHCl3 and H2O. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified preparative TLC and preparative HPLC to afford the titled compound (39.2mg, 10%) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: methyl (R)-2-[1-(4-bromophenyl)ethyl](cyclopropylmethyl)amino}benzo[d]oxazole-4-carboxylate With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; bis(pinacol)diborane In 1,4-dioxane at 100℃; Inert atmosphere; Stage #2: 2-bromo-4-fluorobenzonitrile With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere; | 5.1.61 Methyl (R)-2-[1-(2′-cyano-5′-methyl-[1,1′-biphenyl]-4-yl)ethyl] (cyclopropylmethyl)amino}benzo[d]oxazole-4-carboxylate (36a) General procedure: A solution of compound 35 (5.54g, 12.9mmol) dissolved in 1,4-dioxane (129mL) was added Pd(dppf)Cl2 (1.89g, 2.58mmol), bis(pinacolato)diboron (8.19g, 32.3mmol) and KOAc (6.33g, 64.5mmol) under argon atmosphere. The reaction mixture was heated at 100°C for 4h. The resulting mixture was concentrated under reduced pressure, and then saturated NH4Cl aq. was added. The mixture was filtered through a celite pad and extracted with AcOEt. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. A solution of this crude material was dissolved in 1,4-dioxane (129mL) and H2O (13mL). To this solution was added 2-bromo-4-methylbenzonitrile (7.59g, 38.7mmol), Pd(PPh3)4 (1.49g, 1.29mmol) and Cs2CO3 (16.8g, 51.6mmol). The reaction mixture was heated at 100°C for 5h, and the resulting mixture was filtered through a celite pad and extracted with AcOEt. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with 33%-55% AcOEt in heptane to afford the titled compound (5.12g, 85%) as a white amorphous |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With fac-tris(2-phenylpyridinato-N,C2')iridium(III); 2,7-di-tertbutylpyrene; <i>N</i>,<i>N</i>-dimethyl-aniline In N,N-dimethyl-formamide at 20℃; for 7h; Inert atmosphere; Irradiation; | |
82 %Spectr. | With C64H22B2F34IrN6(1-)*C16H36N(1+); triethylamine In [D3]acetonitrile for 6h; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With tris-(dibenzylideneacetone)dipalladium(0); N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 100℃; Inert atmosphere; | 33.A Step A: 2- (benzylthio) -4-fluorobenzonitrile A mixture of 2-bromo-4-fluorobenzonitrile (500 mg, 2.5 mmol), Pd 2 (dba) 3 (115 mg, 0.13 mmol), Xant-Phos (72 mg, 0.13 mmol), DIEA (1.2 mL, 7.5 mmol), and BnSH (0.3 mL, 2.75 mmol) in toluene (10 mL) was stirred at 100°C under N 2 temperature overnight. The mixture was washed with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na 2SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 2- (benzylthio) -4-fluorobenzonitrile (469 mg, yield 77%) as a brown solid. LC-MS: 244 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.5 mg | Stage #1: 2-bromo-4-fluorobenzonitrile; 3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-amine With methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II); sodium t-butanolate In toluene at 120℃; for 1h; Microwave irradiation; Stage #2: With tetrabutyl ammonium fluoride In tetrahydrofuran for 16h; Reflux; Stage #3: With ammonia In methanol for 0.5h; | 5.3.10 2-[[3-(4-Pyridyl)-1H-indazol-5-yl]amino]benzonitrile [12] General procedure: Intermediate 74 (375mg, 1.10mmol) was taken up in toluene (4.5mL) and 2-bromobenzonitrile (301mg, 1.65mmol) and sodium tert-butoxide (148mg, 1.54mmol) were added. The solution was then thoroughly degassed with argon before adding RuPhos Pd G3 (92mg, 110μmol) and heating in the microwave to 120°C for 1h. The solution was then filtered through Celite and washed through with EtOAc (30mL) before concentrating the filtrate. The material was then purified by FCC on silica gel (0-100% EtOAc in hexane). The appropriate fractions were pooled and concentrated before being dissolved in THF (5mL) and TBAF (1M in THF) (2.10mL, 2.10mmol) was added and the reaction mixture was stirred at reflux for 16h. The reaction mixture was diluted in EtOAc (20mL), before washing with sat. NH4Cl and brine (20mL). The organic layer was isolated, dried with Na2SO4 and condensed. This oil was then taken up in methanol (10mL), 7M ammonia in methanol (0.5mL) was added and the mixture was stirred for 30min. The reaction mixture was then concentrated to dryness under reduced pressure before the product was purified via trituration with MeOH, collecting 12 as a brown solid (38.5mg, 6.4% over two steps). |
9.5 mg | Stage #1: 2-bromo-4-fluorobenzonitrile; 3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-amine With methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II); sodium t-butanolate In toluene at 120℃; for 1h; Microwave irradiation; Stage #2: With tetrabutyl ammonium fluoride In tetrahydrofuran for 16h; Reflux; Stage #3: With ammonia In methanol for 0.5h; | 5.3.10 2-[[3-(4-Pyridyl)-1H-indazol-5-yl]amino]benzonitrile [12] General procedure: Intermediate 74 (375mg, 1.10mmol) was taken up in toluene (4.5mL) and 2-bromobenzonitrile (301mg, 1.65mmol) and sodium tert-butoxide (148mg, 1.54mmol) were added. The solution was then thoroughly degassed with argon before adding RuPhos Pd G3 (92mg, 110μmol) and heating in the microwave to 120°C for 1h. The solution was then filtered through Celite and washed through with EtOAc (30mL) before concentrating the filtrate. The material was then purified by FCC on silica gel (0-100% EtOAc in hexane). The appropriate fractions were pooled and concentrated before being dissolved in THF (5mL) and TBAF (1M in THF) (2.10mL, 2.10mmol) was added and the reaction mixture was stirred at reflux for 16h. The reaction mixture was diluted in EtOAc (20mL), before washing with sat. NH4Cl and brine (20mL). The organic layer was isolated, dried with Na2SO4 and condensed. This oil was then taken up in methanol (10mL), 7M ammonia in methanol (0.5mL) was added and the mixture was stirred for 30min. The reaction mixture was then concentrated to dryness under reduced pressure before the product was purified via trituration with MeOH, collecting 12 as a brown solid (38.5mg, 6.4% over two steps). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: ((E)-3-fluoro-2-hydroxymethylallyl)carbamic acid tert-butyl ester With sodium hydride In N,N-dimethyl-formamide; paraffin oil at 0 - 20℃; for 0.5h; Stage #2: 2-bromo-4-fluorobenzonitrile In N,N-dimethyl-formamide; paraffin oil at 0 - 20℃; for 2h; | 4.K Procedure K: preparation of tert-butvl (E)-(2-((3-bromo-4-cvanophenoxv1methyl)3-fluoroallyl)carhamate To a stirring solution of Int-5 (573 mg) in DMF (5.0 mL) was added NaH (60% in paraffin oil; 120 mg) at 0 °C and stirred at rt for 30 min. A solution of 2-bromo-4-fluorobenzonitrile (500 mg) in DMF (5.0 mL) was then added dropwise at 0 °C. Stirring at rt was continued for 2 h. The reaction mixture was cooled to 0 °C and quenched with saturated aqueous NH4C1 solution. The product was extracted with ethyl acetate (20 mL x 3), and the combined organic layers were dried over Na2SO4and then concentrated in vacuo to give tert-butyl (E)-(2-((3-bromo-4-cyanophenoxy)methyl)-3-fluoroallyl)carbamate (750 mg, 82%). MS: 385.0 [M+H]+. |
82% | Stage #1: ((E)-3-fluoro-2-hydroxymethylallyl)carbamic acid tert-butyl ester With sodium hydride In N,N-dimethyl-formamide; paraffin oil at 0 - 20℃; for 0.5h; Stage #2: 2-bromo-4-fluorobenzonitrile In N,N-dimethyl-formamide; paraffin oil at 0 - 20℃; for 2h; | 4.K Procedure K: preparation of tert-butvl (E)-(2-((3-bromo-4-cvanophenoxv1methyl)3-fluoroallyl)carhamate To a stirring solution of Int-5 (573 mg) in DMF (5.0 mL) was added NaH (60% in paraffin oil; 120 mg) at 0 °C and stirred at rt for 30 min. A solution of 2-bromo-4-fluorobenzonitrile (500 mg) in DMF (5.0 mL) was then added dropwise at 0 °C. Stirring at rt was continued for 2 h. The reaction mixture was cooled to 0 °C and quenched with saturated aqueous NH4C1 solution. The product was extracted with ethyl acetate (20 mL x 3), and the combined organic layers were dried over Na2SO4and then concentrated in vacuo to give tert-butyl (E)-(2-((3-bromo-4-cyanophenoxy)methyl)-3-fluoroallyl)carbamate (750 mg, 82%). MS: 385.0 [M+H]+. |
82% | Stage #1: ((E)-3-fluoro-2-hydroxymethylallyl)carbamic acid tert-butyl ester With sodium hydride In N,N-dimethyl-formamide; paraffin oil at 0 - 20℃; for 0.5h; Stage #2: 2-bromo-4-fluorobenzonitrile In N,N-dimethyl-formamide; paraffin oil at 0 - 20℃; for 2h; | 4.K Procedure K: preparation of tert-butvl (E)-(2-((3-bromo-4-cvanophenoxv1methyl)3-fluoroallyl)carhamate To a stirring solution of Int-5 (573 mg) in DMF (5.0 mL) was added NaH (60% in paraffin oil; 120 mg) at 0 °C and stirred at rt for 30 min. A solution of 2-bromo-4-fluorobenzonitrile (500 mg) in DMF (5.0 mL) was then added dropwise at 0 °C. Stirring at rt was continued for 2 h. The reaction mixture was cooled to 0 °C and quenched with saturated aqueous NH4C1 solution. The product was extracted with ethyl acetate (20 mL x 3), and the combined organic layers were dried over Na2SO4and then concentrated in vacuo to give tert-butyl (E)-(2-((3-bromo-4-cyanophenoxy)methyl)-3-fluoroallyl)carbamate (750 mg, 82%). MS: 385.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.5 g | Stage #1: 2-bromo-4-fluorobenzonitrile With lithium dipropan-2-ylazanide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -15℃; for 1h; Inert atmosphere; | 3.1 Step 1: Synthesis of Compound 3-1 Under nitrogen protection, 2-bromo-4-p-fluorobenzonitrile (3 g) and THF (20 mL) were added to the reaction flask in turn, cooled to -78°C, LDA (7.5 mL, 2M THF solution) was added, and stirred at low temperature for 1 hour, Then DMF (1.16 mL) was added, and the mixture was stirred at low temperature for 1 hour, and then heated to -15°C and stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, extracted with EA (50 mL*3), the organic phases were combined, washed with brine, dried, concentrated, and purified by column chromatography to obtain 1.5 g of the target compound 3-1. |
1.5 g | Stage #1: 2-bromo-4-fluorobenzonitrile With lithium dipropan-2-ylazanide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -15℃; for 2h; Inert atmosphere; | 1.1 Step 1: Synthesis of Compound 1-1 Under nitrogen protection, 2-bromo-4-p-fluorobenzonitrile (3 g) and THF (20 mL) were added to the reaction flask in turn, cooled to -78°C, LDA (7.5 mL, 2M THF solution) was added, and stirred at low temperature for 1 hour, Then DMF (1.16 mL) was added, and the mixture was stirred at low temperature for 1 hour, and then heated to -15°C and stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, extracted with EA (50 mL*3), the organic phases were combined, washed with brine, dried, concentrated, and purified by column chromatography to obtain 1.5 g of the target compound 1-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: trans-4-hydroxycyclohexylamine hydrochloride With sodium hydride; sodium hydroxide In N,N-dimethyl-formamide at -10 - 0℃; for 0.5h; Stage #2: 2-bromo-4-fluorobenzonitrile In N,N-dimethyl-formamide at -10 - 20℃; for 5h; | 1. Synthesis of compound 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-bromobenzonitrile Compound sodium hydride (60%, 3.50 g, 87.50 mmol) was dissolved in 400 mL of DMF, and then stirred at -10 °C to 0 °C for 10 min, to which was added (1r,4r)-4-hydroxycyclohexylamine hydrochloride (4.17 g, 27.5 mmol). After the reaction solution was stirred for 30 min at -10 °C to 0 °C, the solution of 2-bromo-4-fluorobenzonitrile (5.00 g, 25.00 mmol) in DMF was slowly added, and the resultant solution was stirred at -10 °C to 0 °C for 1h. The reaction solution was naturally warmed to room temperature, and then stirred for additional 4 h. The reaction solution was added with the mixture of ice-water, and then extracted with ethyl acetate. The organic layer was washed three times with saturated brine. The organic phase was adjusted to pH 1 with 1 mol/L dilute hydrochloric acid solution, and extracted three times with ethyl acetate, to which was then added the saturated solution of sodium hydroxide to adjust pH to 12. The resultant solution was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, to provide compound 4-(((1r, 4r)-4-aminocyclohexyl)oxy)-2-bromobenzonitrile (5.20 g, 17.63 mmol), with a yield of 71%. LC/MS (ESI+) calcd for C13H15BrN2O+ [M + H]+ m/z, 295.0; found 295.0. |
Tags: 36282-26-5 synthesis path| 36282-26-5 SDS| 36282-26-5 COA| 36282-26-5 purity| 36282-26-5 application| 36282-26-5 NMR| 36282-26-5 COA| 36282-26-5 structure
[ 64695-82-5 ]
2-Bromo-4,5-difluorobenzonitrile
Similarity: 0.94
[ 64695-82-5 ]
2-Bromo-4,5-difluorobenzonitrile
Similarity: 0.94
[ 64695-82-5 ]
2-Bromo-4,5-difluorobenzonitrile
Similarity: 0.94
[ 64695-82-5 ]
2-Bromo-4,5-difluorobenzonitrile
Similarity: 0.94
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :