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. : | 88419-56-1 | MDL No. : | MFCD00061204 |
Formula : | C7H2ClF3O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | STBGCAUUOPNJBH-UHFFFAOYSA-N |
M.W : | 194.54 | Pubchem ID : | 145164 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 36.5 |
TPSA : | 17.07 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.55 cm/s |
Log Po/w (iLOGP) : | 1.66 |
Log Po/w (XLOGP3) : | 2.73 |
Log Po/w (WLOGP) : | 3.74 |
Log Po/w (MLOGP) : | 3.32 |
Log Po/w (SILICOS-IT) : | 3.62 |
Consensus Log Po/w : | 3.01 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.07 |
Solubility : | 0.166 mg/ml ; 0.000851 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.74 |
Solubility : | 0.352 mg/ml ; 0.00181 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.8 |
Solubility : | 0.0306 mg/ml ; 0.000157 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.62 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P260-P264-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P321-P363-P405-P501 | UN#: | 3265 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
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 |
---|---|---|
89% | Stage #1: With n-butyllithium In tetrahydrofuran at -75 - -5℃; for 0.0333333 h; Stage #2: at -75 - 20℃; Stage #3: With hydrogenchloride; water In tetrahydrofuran; ethyl acetate |
Step 2. 3-Oxo-3 -(2, 4, 5-tfluoro-phenyl)-propionic acid ethyl ester (B).[0185] Intermediate A is used to prepare B as described previously [Wierenga, W.; Skulnick, H. I. J. Org. Chem. 1979, 44, 310-311].[0186] A mixture of ethyl hydrogen malonate (0.18mL, 1.50mmole) and dipyridyl ( 1 crystal ) is dissolved in THF (1OmL) and cooled to -750C under argon. n-BuLi (2.8 mL, 4.48 mmole, 5.9 equiv.) is added slowly at -750C to the reaction mixture. The mixture is warmed to - 50C for about two minutes until there is no further disappearance of pink color (to be sure the amount of BuLi is adequate to form the dianion), cooled to -750C, and added slowly to a solution of 2,4,5-trifluorobenzoyl chloride (0.75 mmole) in THF (2-3mL). The resulting reaction mixture is warmed up to room temperature, diluted with ethyl acetate (5OmL), acidified with IN HCl with stirring. The organics were washed with 5percent NaHCO3 (30mLx2), brine (50mLx2), dried over Na2SO4, and concentrated. The resulting oil is purified by SiO2 column (4Og SiO2 column, 20percent EtOAc in hexanes, 40 min. gradient) to give 185mg (89percent) of B as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.4 g | Stage #1: With lithium hexamethyldisilazane In toluene at -78℃; for 0.5 h; Inert atmosphere Stage #2: at 20℃; for 1 h; Inert atmosphere |
A three necked, dried round bottom flask equipped with a stirring bar and 70 mL of toluene under argon was charged with lithium bis(trimethylsilyl)amide (32.25 mmoles in toluene) and cooled to -78 °C followed by a slow addition of the acrylate (3) ( 12.9 mmoles). The resulting bright yellow solution was stirred for 30 mins followed by the dropwise addition of 2,4-dichloro-5-fluorobenzoyl chloride ( 1 5.48 mmoles). The mixture was allowed to warm to room temperature and stirred for 1 h. Upon complete consumption of the starting material, the reaction mixture was cooled to room temperature, quenched with saturated aqueous NH4Cl ( 10 mL), extracted with dichloromethane (3 x 25), washed with brine (25 mL) and dried over Na2SO4. The filtrate was concentrated under pressure and purified by flash chromatography on a silica gel column using a mixture of hexanes/EtOAc as eluent to afford the product (3.4 g) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Step 2. 3-Oxo-3 -(2, 4, 5-tfluoro-phenyl)-propionic acid ethyl ester (B).[0185] Intermediate A is used to prepare B as described previously [Wierenga, W.; Skulnick, H. I. J. Org. Chem. 1979, 44, 310-311].[0186] A mixture of ethyl hydrogen malonate (0.18mL, 1.50mmole) and dipyridyl ( 1 crystal ) is dissolved in THF (1OmL) and cooled to -750C under argon. n-BuLi (2.8 mL, 4.48 mmole, 5.9 equiv.) is added slowly at -750C to the reaction mixture. The mixture is warmed to - 50C for about two minutes until there is no further disappearance of pink color (to be sure the amount of BuLi is adequate to form the dianion), cooled to -750C, and added slowly to a solution of 2,4,5-trifluorobenzoyl chloride (0.75 mmole) in THF (2-3mL). The resulting reaction mixture is warmed up to room temperature, diluted with ethyl acetate (5OmL), acidified with IN HCl with stirring. The organics were washed with 5% NaHCO3 (30mLx2), brine (50mLx2), dried over Na2SO4, and concentrated. The resulting oil is purified by SiO2 column (4Og SiO2 column, 20% EtOAc in hexanes, 40 min. gradient) to give 185mg (89%) of B as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | EXAMPLE 2 2,4,5-Trifluorobenzoyl chloride To a solution of 5.24 g of <strong>[446-17-3]2,4,5-trifluorobenzoic acid</strong> in 50 ml of ether containing two drops of N,N-dimethylformamide was added, under argon, oxalyl chloride dropwise over 30 minutes. Stirring was continued for an additional 30 minutes when gas evolution ceased. The ether was removed in vacuo and the residue vacuum distilled to give 5.07 g of the desired compound, bp 26-27 C./0.75 mm. | |
With thionyl chloride; In N,N-dimethyl-formamide; toluene; at 60℃; for 3.5h; | A solution of <strong>[446-17-3]2,4,5-trifluorobenzoic acid</strong> (139.5Kg) in DMF (8.4Kg) and toluene(613Kg) was treated with thionyl chloride (139.4Kg), stirred at 60C for 3.5 hours, cooled to25C, concentrated to 20% of its original volume, treated with toluene (600Kg), distilled andstored at ambient temperature. | |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h; | To a solution of <strong>[446-17-3]2,4,5-trifluorobenzoic acid</strong> (Aldrich, 704 mg, 4.0 mmol) in dichloromethane (20 mL), was added oxalyl chloride (Aldrich, 0.70 mL, 8.0 mmol) dropwise, followed by two drops of DMF. The reaction mixture was stirred at room temperature for 2 h, and concentrated in vacuo. Toluene (20 mL) was added and the reaction mixture was evaporated in vacuo to remove the excess oxalyl chloride. The residue was dissolved in dichloromethane (20 mL). Half of this acid chloride solution was added to a mixture of 3-amino-l-(4-fluorophenyl)pyridin-2(lH)-one (306 mg, 1.5 mmol) in dichloromethane (5 mL) and TEA (0.5 mL, Aldrich) at 0 0C. The reaction mixture was stirred at room temperature for 1 h. The precipitate that formed was collected by filtration, and washed with methanol, to afford the desired product (363 mg, 67% yield) as a solid. MS(ESI+) m/z 363.25 (M + H)+. |
With thionyl chloride; In toluene;Heating / reflux; | Example 3; 1 - ( 3 - F2-oxo-3 -( 1 H-p yrrol-2- ylmethylene)-2.3 -dihvdro- 1 H-indol-6- ylaminol phenyl 1-3-(2A5-trifluorophenyl)urea; [00107] Synthesis of 2,4,5-trifluorobenzoyl azide (10); [00108] To a solution of <strong>[446-17-3]2,4,5-trifluorobenzoic acid</strong> (10.0 g, 0.057 mol) in toluene(150 mL) is added SOCl2 (12.5 mL, 0.171 mol). The mixture is heated at reflux overnight. All the solvent is removed and the crude is dried in vacuo for an hour to remove residual SOCl2. The crude is then dissolved in acetone (100 ml) and cooled to 00C. A solution of NaN3 (4.5 g, 0.0684 mol) in water (20 mL) is added slowly. The resulting mixture is warmed to room temperature and stirred for 2 hr. Acetone is removed. The mixture is extracted with EtOAc (3x150 mL). The combined organic layer is dried over Na2SO4, filtered and concentrated. The crude is purified by column chromatography (EtOAc/Hexane, gradient, 0-20%) to give the desired product as oil. 1H NMR (400 MHz, CDCl3) delta 7.90-7.70 (m, 1 H), 7.10-7.00 (m, 1 H). | |
With oxalyl dichloride; | <strong>[446-17-3]2, 4, 5-trifluorobenzoic acid</strong> (20 g, 113.6 mmol) was dissolved in thionyl chloride (15ml, 170.4 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated to reflux for 4 h and then thionyl chloride was removed under reduced pressure to provide 2, 4, 5-trifluorobenzoyl chloride 2b.2 (20 g, 103.8 mmol). The acid chloride 2b.2 was dissolved in DCM, cooled to 00C, and triethyl amine(17.2 ml, 126.2mmol) followed by 3- dimethyl amino acrylonitrile 2b.3 (1 1.3 ml, 103.8 mmol) were added. The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was portioned between water and DCM. The organic layer was separated and dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography eluting with 30% ethyl acetate in n-hexane to provide compound 2b.4 (12.2 g, 46.4%). 1H-NMR (DMSO-ct°delta 7.81 (IH, s, -CH), 7.78-7.56 (2H, m, Ar-H), 3.31 (3H, s, - CH3), 3.27 (3H, s, -CH3). EIMS (m/z): 255.21 (M + H)+ | |
With thionyl chloride; for 4h;Heating / reflux; | 2,4,5-trifluorobenzoyl chloride (2) is prepared from <strong>[446-17-3]2,4,5-trifluorobenzoic acid</strong> as described previously. [Reuman, M.; et. al, J. Med. Chem. (1995) 38, 2531-2540]. Thionyl chloride (8 ml) is added to a solid 2,4,5-trifluoro-3-methoxy-benzoic acid (154 mg, 0.75 mmole ). The reaction mixture is refluxed for 4 hours. It is distilled to remove excess thionyl chloride and further dried under vacuum at rt for the further reaction. | |
With thionyl chloride; at 55℃; for 18h; | Thionyl chloride (50 mL, 680 mmol) was added to <strong>[446-17-3]2,4,5-trifluorobenzoic acid</strong> (10 g, 57 mmol) and the mixture stirred at 55 C for 18 hours. After cooling, the excess thionyl chloride was removed in vacuo. The resulting crude oil was azeotroped twice with DCM (30 mL) and toluene (20 mL) and the residue redissolved in DCM (50 mL), then cooled to 0 C. A mixture of 4-methylphenol (6.4 g, 59 mmol) and triethylamine (10 mL, 71 mmol) in DCM (20 mL) was added over 30 minutes. The reaction was allowed to warm up to room temperature over 1 hour. The crude reaction mixture was partitioned between EtOAc (200 mL) and saturated sodium bicarbonate solution (70 mL). The aqueous layer was further extracted with EtOAc (100 mL). The combined organic extracts were combined, washed with saturated sodium bicarbonate solution (70 mL) and water (100 mL). The organic layer was dried over magnesium sulfate and concentrated to provide a crude solid, which was purified by silica gel chromatography eluting with 5% EtOAc in heptane to provide the title compound (10.08 g, 66%) as a white solid. | |
With oxalyl dichloride; In N,N-dimethyl-formamide; acetonitrile; for 1.5h; | To a solution of <strong>[446-17-3]2,4,5-trifluorobenzoic acid</strong> (5.00 g, 28.4 mmol) in acetonitrile (50 mL) was added N,N-dimethylformamide (40 muL) followed by addition of oxalyl chloride (3.60 mL, 42.6 mmol). After 90 min, the volatiles were removed under reduced pressure. The residue was co-evaporated with acetonitrile (50 mL). The residue was then dissolved in methylene chloride (50 mL). This solution was added drop-wise into a cooled (ice bath) mixture of (2S)-1,1,1-trifluoropropan-2-amine hydrochloride (5.52 g, 36.9 mmol) (from Synquest, 98% ee) in toluene (100 mL) and 0.5 M sodium hydroxide aqueous solution (142 mL, 71.0 mmol). After addition, the ice bath was removed, and the reaction was allowed to warm to rt. The reaction was stirred overnight. The organic layer was separated. The aqueous layer was extracted with methylene chloride (50 mL). The combined organic layers were washed with 20% brine (75 mL) and water (2×75 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (6.49 g, 84%) which was directly used in the next step without further purification. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In acetonitrile; for 1.5h; | Step 1: 2,4, 5-Trifluoro-N-[(JS)-2, 2, 2-trifluoro-1-methylethylJbenzamideTo a solution of <strong>[446-17-3]2,4,5-trifluorobenzoic acid</strong> (5.00 g, 28.4 mmol) in acetonitrile (50 mL) was added N,N-dimethylformamide (40 .iL) followed by addition of oxalyl chloride (3.60 mL, 42.6 mmol). After 90 mm, the volatiles were removed under reduced pressure. The residue was co-evaporated with acetonitrile (50 mL). The residue was then dissolved in methylene chloride (50 mL). This solution was addeddrop-wise into a cooled (ice bath) mixture of (2S)-i, 1,1 -trifluoropropan-2-amine hydrochloride (5.52 g, 36.9 mmol) (from Synquest, 98% ee) in toluene (100 mL) and 0.5 M sodium hydroxide aqueous solution (142 mL, 71.0 mmol). After addition, the ice bath was removed, and the reaction was allowed to warm to rt. The reaction was stirred overnight. The organic layer was separated. The aqueous layer was extracted with methylene chloride (50 mL). The combined organic layers were washed with 20% brine (75 mL) and water (2 x 75 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (6.49 g, 84%) which was directly used in the next step without further purification. ?H NMR (300MHz, DMSO-d6) oe 9.01 (d, J= 7.6 Hz, 1H), 7.92-7.50 (m, 2H), 4.76 (m, 1H), 1.31 (d, J= 7.0 Hz, 3H) ppm. LCMS cacid. for C,0H8F6N0 (M+1): mlz = 272.0; Found:272.0. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In acetonitrile; for 1.5h; | To a solution of <strong>[446-17-3]2,4,5-trifluorobenzoic acid</strong> (5.00 g, 28.4 mmol) in acetonitrile (50 mL) was added N,N-dimethylformamide (40 followed by addition of oxalyl chloride (3.60 mL, 42.6 mmol). After 90 min, the volatiles were removed under reduced pressure. The residue was co-evaporated with acetonitrile (50 mL). The residue was then dissolved in methylene chloride (50 mL). This solution was added drop-wise into a cooled (ice bath) mixture of (2S)-l,l,l-trifluoropropan-2-amine hydrochloride (5.52 g, 36.9 mmol) (from Synquest, 98%> ee) in toluene (100 mL) and 0.5 M sodium hydroxide aqueous solution (142 mL, 71.0 mmol). After addition, the ice bath was removed, and the reaction was allowed to warm to rt. The reaction was stirred overnight. The organic layer was separated. The aqueous layer was extracted with methylene chloride (50 mL). The combined organic layers were washed with 20% brine (75 mL) and water (2 x 75 mL), dried over MgS04, filtered and concentrated under reduced pressure to afford the desired product (6.49 g, 84%) which was directly used in the next step without further purification. lU NMR (300 MHz, DMSO-de) delta 9.01 (d, J= 7.6 Hz, 1H), 7.92 - 7.50 (m, 2H), 4.76 (m, 1H), 1.31 (d, J = 7.0 Hz, 3H) ppm. LCMS cacld. for CioHsFeNO (M+l)+: m/z = 272.0; Found: 272.0. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; | (a) 2,4,5-trifluorobenzoyl chloride A suspension of <strong>[446-17-3]2,4,5-trifluorobenzoic acid</strong> (5 g, 28.4 mmol) in DCM (60 mL) was cooled to0CC. Oxalyl chloride (3.72 mL, 42.59 mmol) was added followed by 3 drops of DMF and thereaction allowed to warm to room temperature. Effervescence commenced on warming.The mixture was stirred at room temperature for 2 h then evaporated (co-evaporated fromDCM x 3) and used without further purification | |
With oxalyl dichloride; N,N-dimethyl-formamide; In acetonitrile; for 1.5h; | To a solution of <strong>[446-17-3]2,4,5-trifluorobenzoic acid</strong> (5.00 g, 28.4 mmol) in acetonitrile (50 mL) was added N,N-dimethylformamide (40 muL) followed by addition of oxalyl chloride (3.60 mL, 42.6 mmol). After 90 min, the volatiles were removed under reduced pressure. The residue was co-evaporated with acetonitrile (50 mL). The residue was then dissolved in methylene chloride (50 mL). This solution was added drop-wise into a cooled (ice bath) mixture of (2S)-1,1,1-trifluoropropan-2-amine hydrochloride (5.52 g, 36.9 mmol) (from Synquest, 98% ee) in toluene (100 mL) and 0.5 M sodium hydroxide aqueous solution (142 mL, 71.0 mmol). After addition, the ice bath was removed, and the reaction was allowed to warm to rt. The reaction was stirred overnight. The organic layer was separated. The aqueous layer was extracted with methylene chloride (50 mL). The combined organic layers were washed with 20% brine (75 mL) and water (2×75 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (6.49 g, 84%) which was directly used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) delta 9.01 (d, J=7.6 Hz, 1H), 7.92-7.50 (m, 2H), 4.76 (m, 1H), 1.31 (d, J=7.0 Hz, 3H) ppm. LCMS cacld. for C10H8F6NO (M+1)+: m/z=272.0. Found: 272.0. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 2h; | A suspension of <strong>[446-17-3]2,4,5-trifluorobenzoic acid</strong> (5 g, 28.4 mmol) in DCM (60 mL) was cooled to 0C. Oxalyl chloride (3.72 mL, 42.59 mmol) was added followed by 3 drops of DMF and the reaction allowed to warm to room temperature. Effervescence commenced on warming. The mixture was stirred at room temperature for 2 h then evaporated (co-evaporated from DCM x 3) and used without further purification. | |
With thionyl chloride; In chloroform; at 20 - 70℃; | General procedure: In a 100 mL round bottom flask equipped with mechanical stirrer and a water bath, taken 2-methyl-3-nitrobenzoic acid (15 g, 0.00 mmol), chloroform (200 mL) and then freshly distilled thionyl chloride (30 mL) was added drop wise at room temperature. The reaction mass stirred for 10 min at ambient temperature and slowly heated to 70 C,maintain the same temperature for 1-2 h. After completion ofthe TLC removed the excess thionyl chloride and once stripped off with chloroform to get desired substituted benzoyl chlorides. | |
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere; | General procedure: Commercially available <strong>[446-17-3]2,4,5-trifluorobenzoic acid</strong> (1a) (10.1 g,57.4 mmol) was dissolved in 100 mL of distilled DCM and stirred underargon atmosphere. Oxalyl chloride (5.0 mL, 58.300 mmol) was thenadded to the stirring mixture, the solution was allowed to stir for 5 minat room temperature. Anhydrous DMF (0.45 mL, 5.8 mmol) was added,dropwise, to the stirring solution over 35 s, the resulting solution wasallowed to stir at room temperature for 2 h. The DCM was removedfrom the reaction mixture by rotary evaporation, the resulting oil wasreconstituted in 100 mL of DCM and placed in an ice bath to coolto ~ 0 C. Ammonium hydroxide (40 mL, 28-30% ammonia) wasadded, dropwise, to the cool stirring solution over 2 min, the resultingmixture was allowed to stir for 2.5 h, gradually warming up to roomtemperature. The product was extracted by washing the aqueous layerwith 100 mL of DCM and then 150 mL of ethyl acetate. The organiclayers were pooled and concentrated by rotary evaporation, the resultingsolid was triturated with 9:1 hexanes:ethyl acetate and subjectedto vacuum filtration, which yielded UIAA-I-061 (2a) as a pureyellow solid. 84% yield. 1H NMR (300 MHz, CDCl3) delta = 8.01 (ddd,J = 7.17, 8.94, 10.62 Hz, 1H), 7.05 (ddd, J = 6.05, 9.51, 10.83 Hz,1H), 6.66 (bs, 1H), 6.03 (bs, 1H). 19F NMR (282 MHz, CDCl3)delta = -113.67 (m, 1F), -125.90 (ddd, J = 9.08, 17.12, 21.57 Hz, 1F),-140.15 (m, 1F). HRMS (ESI) calculated for (M + H+) 176.0318,found 176.0323. Retention time (analytical HPLC) = 12.3 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Carbon tetrachloride; ethanol; magnesium 1.) ethanol, toluene, 1 h, 60-70 deg C; 2.) toluene, 0 to -5 deg C; 12 h, room temperature; Yield given. Multistep reaction; | ||
With magnesium In Carbon tetrachloride; ethanol | 130 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid A reaction mixture of 2.4 g of magnesium turnings, 360 ml of anhydrous ethanol and 5 ml of carbon tetrachloride was first evacuated, then purged with argon. A 16 g portion of diethyl malonate was added dropwise through an addition funnel. The mixture was stirred for one hour with a condenser because of an exotherm. The mixture was then heated at reflux for 2 hours followed by cooling to -10° C. A -10° C. solution of 19.45 g of 2,4,5-trifluorobenzoyl chloride in 20 ml of ether was added through an addition funnel. The mixture was stirred at -10° C. for one hour, then overnight at room temperature and then poured into 300 ml of ice/water. The pH was adjusted to 2.5 with concentrated sulfuric acid. The resulting suspension was concentrated to about 250 ml and extracted with chloroform. The extract was washed with water, dried, evaporated to an oil and distilled, giving 24.94 g of (2,4,5-trifluorobenzoyl)propanedioic acid, diethyl ester. | |
83 g | With triethylamine; magnesium(II) chloride In toluene at 20℃; for 1h; | Preparation of compound 3 In a 1000ml reaction flask, add 500ml of toluene as a solvent, its volume dosage is 7-8 times the weight of compound 2, 122ml of triethylamine as an acid binding agent, 64ml of diethyl malonate, and 24g of catalyst magnesium chloride is added after stirring. Stir at room temperature for 1 hour, cool down to 0°C in an ice-salt bath, dropwise add 70 g of compound 2 prepared above, compound 2: diethyl malonate: acid binding agent: catalyst=1:1.1-1.2:2.0-2.5:0.5- 1.0 The temperature is controlled at 0-5°C during the dropwise addition. After the dropwise addition, the ice-salt bath was withdrawn, and the mixture was stirred naturally for 1 hour. Slowly add 200 ml of hydrochloric acid to quench the reaction. The volume of hydrochloric acid is 2.5-3.0 times the weight of compound 2. The reaction solution is poured into a separatory funnel, the toluene layer is separated, washed with water and extracted with toluene three times. The toluene layers were combined, washed with water and saturated brine, and dried over night. The next day, the desiccant was filtered off, and toluene was recovered by vacuum distillation to obtain 83 g of an oily substance, namely the crude product of compound 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 100℃; for 2h; Yield given; | ||
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 2.25h; | Intermediate 1.A tert-Butyl [(2R,3S)-5-oxo-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate; Step A: Phenyl 2,4,5-trifluorobenzoate; A solution of phenol (13.3 g, 141 mmol) in dry dichloromethane (370 mL) was cooled in ice bath and treated with N,N-diisopropylethylamine (34 mL, 193 mmol) followed by dropwise addition of 2,4,5-trifluorobenzoyl chloride (25 g, 129 mmol) over a period of 15 minutes. The ice bath was removed, stirring was continued for two hours at room temperature and the solution was then transferred to a separatory funnel and the organic layer was washed successively with hydrochloric acid solution (2N, 150 mL), saturated aqueous sodium bicarbonate solution (150 mL), and brine (150 mL), dried over anhydrous sodium sulfate, filtered, evaporated and the resulting solid product was purified on silica in portions by eluting successively with hexane, and then 0-5% ether in hexane in a gradient fashion to yield phenyl 2,4,5-trifluorobenzoate as white solid. | |
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 2h; | Intermediate 4.A INTERMEDIATE 4; tert-Butvi r(2i?.35)-5-oxo-2-r2.4.5-trifluorophenyl')tetrahvdro-2H-pyran-3-yllcarbamate; Step A: Phenyl 2,4,5-trifluorobenzoate; A solution of phenol (13.3 g, 141 mmol) in dry dichloromethane (370 mL) was cooled in ice bath and treated with N,7V-diisopropylethylamine (34 mL, 193 mmol) followed by dropwise addition of 2,4,5-trifluorobenzoyl chloride (25g, 129 mmol) over a period of 15 minutes. The ice bath was removed, stirring was continued for two hours at room temperature and the solution was then transferred to a separatory funnel and the organic layer was washed successively with hydrochloric acid solution (2N, 150 mL), saturated aqueous sodium bicarbonate solution (150 mL), and brine (150 mL), dried over anhydrous sodium sulfate, filtered, evaporated and the resulting solid product was purified on silica in portions by eluting successively with hexane, and then 0-5% ether in hexane in a gradient fashion to yield phenyl 2,4,5-trifluorobenzoate as white solid. |
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2.25h; Cooling with ice; | 1.A Intermediate 1; tert-Butyl[(2R,3S)-5-oxo-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate; Step A: Phenyl 2,4,5-trifluorobenzoate; A solution of phenol (13.3 g, 141 mmol) in dry dichloromethane (370 mL) was cooled in ice bath and treated with N,N-diisopropylethylamine (34 mL, 193 mmol) followed by dropwise addition of 2,4,5-trifluorobenzoyl chloride (25 g, 129 mmol) over a period of 15 minutes. The ice bath was removed, stirring was continued for two hours at room temperature and the solution was then transferred to a separatory funnel and the organic layer was washed successively with hydrochloric acid solution (2N, 150 mL), saturated aqueous sodium bicarbonate solution (150 mL), and brine (150 mL), dried over anhydrous sodium sulfate, filtered, evaporated and the resulting solid product was purified on silica in portions by eluting successively with hexane, and then 0-5% ether in hexane in a gradient fashion to yield phenyl 2,4,5-trifluorobenzoate as white solid. | |
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 2.25h; | 1.A A solution of phenol (13.3 g, 141 mmol) in dry dichloromethane (370 mL) was cooled in ice bath and treated with /V.N-diisopropylethylamine (34 mL, 129 mmol) followed by dropwise addition of 2,4,5-txifluorobenzoyl chloride over a period of 15 minutes. The ice bath was removed, stirring was continued for two hours at room temperature and the solution was then transferred to a separatory funnel and the organic layer was washed successively with hydrochloric acid solution (2iV, 150 mL), saturated aqueous sodium bicarbonate solution, and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was triturated with hexane to yield an off-white solid product upon evaporation, and the hot hexane-soluble fraction of the resulting solid product was purified on silica in portions by eluting successively with hexane, and then 0-5% ether in hexane in a gradient fashion to yield phenyl 2,4,5-trifluorobenzoate as white solid. | |
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h; Cooling with ice; | A A solution of phenol (13.3 g, 141 mmol) in dry dichloromethane (370 mL) was cooled in ice bath and treated with N,N-diisopropylethylamine (34 mL, 193 mmol) followed by dropwise addition of 2,4,5-trifluorobenzoyl chloride (25g, 129 mmol) over a period of 15 min. The ice bath was removed, stirring was continued for two h at room temperature and the solution was then transferred to a separatory funnel and the organic layer was washed successively with hydrochloric acid solution (2N, 150 mL), saturated aqueous sodium bicarbonate solution (150 mL), and brine (150 mL), dried over anhydrous sodium sulfate, filtered, evaporated and the resulting solid product was purified on silica gel in portions by eluting successively with hexane, and then 0-5% ether in hexane in a gradient fashion to yield phenyl 2,4,5-trifluorobenzoate as a white solid. | |
With N-ethyl-N,N-diisopropylamine | ||
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 2.25h; | 1 A solution of phenol (13.3 g, 141 mmol) in dry dichloromethane (370 mL) was cooled in ice bath and treated with N,iV-diisopropylethylamine (34 mL, 193 mmol) followed by dropwise addition of 2,4,5-trifluorobenzoyl chloride (25g, 129 mmol) over a period of 15 minutes. The ice bath was removed, stirring was continued for two hours at room temperature and the solution was then transferred to a separatory funnel and the organic layer was washed successively with hydrochloric acid solution (2N, 150 mL), saturated aqueous sodium bicarbonate solution (150 mL), and brine (150 mL), dried over anhydrous sodium sulfate, filtered, evaporated and the resulting solid product was purified on silica in portions by eluting successively with hexane, and then 0-5% ether in hexane in a gradient fashion to yield phenyl 2,4,5-trifluorobenzoate as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With [2,2]bipyridinyl; n-butyllithium In tetrahydrofuran; hexane at -78℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; magnesium chloride; triethylamine; In toluene; acetonitrile; | Step (f) Preparation of 3-oxo-3-(2,4,5-trifluoro-phenyl)-propionic acid ethyl ester, 7 To an oven-dried flask was added potassium ethyl malonate (3.66 g, 21.5 mmol) and freshly distilled acetonitrile (70 mL). The mixture was cooled to 10 C. to 15 C. and stirred under an atmosphere of nitrogen and to it added anhydrous magnesium chloride (2.44 g, 25.7 mmol) and triethylamine (2.05 g, 20.3 mmol). The mixture was then stirred at room temperature under nitrogen for 2.5 hours. The resultant white slurry was recooled to 0 C. and 2,4,5-trifluorobenzoyl chloride was added over a period of 15 minutes, followed by more triethylamine (0.23 g, 2.3 mmol). The mixture was then stirred at room temperature overnight under nitrogen. Acetonitrile was then removed in vacuo and toluene (30 mL) was added. The mixture was reconcentrated and more toluene (60 mL) then added. Hydrochloric acid (1.5 M, 40 mL) was cautiously added, ensuring that the temperature did not exceed 25 C., and the aqueous layer separated. The organic fraction was washed with 1.5 M HCl (2*25 mL) and water (2*25 mL), dried over MgSO4, and solvent removed in vacuo to afford 3-oxo-3-(2,4,5-trifluoro-phenyl)-propionic acid ethyl ester as a pale orange solid (2.35 g, 9.55 mmol, 94%). Rf 0.55 (CH2 Cl2), mp 57-59 C. FTIR, numax /cm-1 3088, 2990, 1735, 1687, 1514, 1429, 1321, 1205, 1140, 1055, 897, 807. 1 H NMR (CDCl3, 250 MHz), delta/ppm [12.69 (s), 5.81 (s) and 3.92 (d, J=3.9 Hz)] (2H, keto-enol tautomers); 7.74 (1H, m, Ar H); 6.98 (1H, m, Ar H); 4.24 and 4.17 (2H, both q, 3 J=7.1 Hz); 1.31 and 1.24 (3H, both t, 3 J=7.1 Hz). 13 C{1 H}NMR (CDCl3, 63 MHz), delta/ppm 187.8 (C=O); 173.0 (--HC=C); 166.9 (CO2 Et); 163.7, 159.8, 155.9, 151.8, 149.0, 145.3, 120.9 (quat. Ar C); 118.7, 106.6 (Ar C--H); 92.9 (HC=C); 61.4 and 60.6 (--OCH2); 49.4 (--OCCH2 CO--); 14.0 (--CH3). 19 FNMR (CDCl3, 235 MHz) delta/ppm -110.6 and -111.7 (m, Ar F); -123.5 and -129.0 (m, Ar F); -140.5 and -141.7 (m, Ar F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | Stage #1: 1-benzoyl-2-(N-phenylamino)-1-propene; 2,4,5-trifluorobenzoyl chloride With triethylamine In toluene for 3h; Heating; Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene for 3h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: 2,4,5-trifluorobenzoyl chloride; (E)-4-Propylamino-pent-3-en-2-one With triethylamine In toluene for 3h; Heating; Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene for 3h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In tetrahydrofuran at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With hydrazine hydrate In tetrahydrofuran at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With copper(l) iodide; triethylamine In tetrahydrofuran at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; triethylamine In tetrahydrofuran at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With pyridine In various solvent(s) at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 0 - 20℃; | 2.b 2, 4, 5-trifluorobenzoic acid (20 g, 113.6 mmol) was dissolved in thionyl chloride (15ml, 170.4 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was heated to reflux for 4 h and then thionyl chloride was removed under reduced pressure to provide 2, 4, 5-trifluorobenzoyl chloride 2b.2 (20 g, 103.8 mmol). The acid chloride 2b.2 was dissolved in DCM, cooled to 00C, and triethyl amine(17.2 ml, 126.2mmol) followed by 3- dimethyl amino acrylonitrile 2b.3 (1 1.3 ml, 103.8 mmol) were added. The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was portioned between water and DCM. The organic layer was separated and dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography eluting with 30% ethyl acetate in n-hexane to provide compound 2b.4 (12.2 g, 46.4%). 1H-NMR (DMSO-ctøδ 7.81 (IH, s, -CH), 7.78-7.56 (2H, m, Ar-H), 3.31 (3H, s, - CH3), 3.27 (3H, s, -CH3). EIMS (m/z): 255.21 (M + H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 92 percent / CuI; Et3N / PdCl2(PPh3)2 / tetrahydrofuran / 2 h / 20 °C 2: 75 percent / aq. Na2CO3 / acetonitrile / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: CuI; Et3N / PdCl2(PPh3)2 / tetrahydrofuran / 2 h / 20 °C 2: 75 percent / aq. Na2CO3 / acetonitrile / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: MgCl2; Et3N / acetonitrile / 2.5 h / 20 - 25 °C 1.2: 90 percent / Et3N / acetonitrile / 18 h / 20 °C 2.1: Ac2O / 4 h / Heating 3.1: dimethylsulfoxide / 18 h / 20 °C | ||
Multi-step reaction with 3 steps 1.1: Ph3CH; n-BuLi / tetrahydrofuran 1.2: 100 percent / tetrahydrofuran / 1 h / 20 °C 2.1: Ac2O / 2 h / 130 °C 3.1: CH2Cl2 / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: MgCl2; Et3N / acetonitrile / 2.5 h / 20 - 25 °C 1.2: 90 percent / Et3N / acetonitrile / 18 h / 20 °C 2.1: Ac2O / 4 h / Heating 3.1: dimethylsulfoxide / 18 h / 20 °C 4.1: K2CO3 / dimethylsulfoxide / 1.17 h / 95 °C 5.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / dimethylformamide; tetrahydrofuran / 0.17 h 5.2: 45 percent / dimethylformamide; tetrahydrofuran; benzene / 18 h / 20 °C 6.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / dimethylformamide; tetrahydrofuran / 0.17 h / 0 °C 6.2: 30 percent / dimethylformamide; tetrahydrofuran; benzene / 18 h / 20 °C 7.1: 81 percent / aq. LiOH / methanol / 5 h 8.1: H2 / Pd/C / methanol; H2O / 18 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: Ph3CH; n-BuLi / tetrahydrofuran 1.2: 100 percent / tetrahydrofuran / 1 h / 20 °C 2.1: Ac2O / 2 h / 130 °C | ||
Multi-step reaction with 3 steps 1: 1.) Mg/ethanol, CCl4 / 1.) ethanol, toluene, 1 h, 60-70 deg C; 2.) toluene, 0 to -5 deg C; 12 h, room temperature 2: p-toluenesulfonic acid / H2O / 5 h / Heating 3: acetic anhydride / 2 h / Heating | ||
Multi-step reaction with 2 steps 1.1: magnesium(II) chloride; triethylamine / toluene; tetrahydrofuran / 1 h / 0 - 50 °C / Large scale 2.1: 0.5 h / 140 °C 2.2: 12 h / 140 °C |
Multi-step reaction with 3 steps 1: magnesium / Carbon tetrachloride; ethanol 2: 1,4-dioxane; water monomer 3: acetic anhydride | ||
Multi-step reaction with 2 steps 1: triethylamine; magnesium(II) oxide / toluene; tetrahydrofuran / 80 °C / Cooling with ice 2: acetic anhydride / Reflux | ||
Multi-step reaction with 3 steps 1: triethylamine; magnesium(II) chloride / toluene / 1 h / 20 °C 2: toluene-4-sulfonic acid; sulfuric acid / water monomer / 12 h / Reflux 3: acetic anhydride / 3 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 1.) Mg/ethanol, CCl4 / 1.) ethanol, toluene, 1 h, 60-70 deg C; 2.) toluene, 0 to -5 deg C; 12 h, room temperature 2: p-toluenesulfonic acid / H2O / 5 h / Heating 3: acetic anhydride / 2 h / Heating 4: 94 percent / ethanol / 1 h / Ambient temperature 5: 84 percent / potassium carbonate / dimethylformamide / 2 h / 140 - 150 °C | ||
Multi-step reaction with 3 steps 1: triethylamine / toluene / 5 h / 90 °C 2: diethyl ether; ethanol / 3 h / 25 °C 3: potassium carbonate / N,N-dimethyl-formamide / 5 h / 90 °C | ||
Multi-step reaction with 2 steps 1.1: triethylamine / toluene / 18 h / 90 °C 2.1: ethanol; diethyl ether / 3 h / 20 °C 2.2: 16 h / 100 °C |
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 0.03 h / 180 °C / 9050.33 Torr / Flow reactor; Inert atmosphere 2.1: acetonitrile / 0.02 h / 25 °C / Flow reactor; Inert atmosphere 3.1: acetyl chloride; N-ethyl-N,N-diisopropylamine / acetonitrile / 0.02 h / 25 °C / Flow reactor; Inert atmosphere 3.2: 0.03 h / Flow reactor; Inert atmosphere | ||
Multi-step reaction with 2 steps 1.1: triethylamine / toluene / 3 h / 90 °C / Inert atmosphere 2.1: diethyl ether; ethanol / 2 h / 20 °C / Inert atmosphere 2.2: 2 h / 100 °C / Inert atmosphere | ||
Multi-step reaction with 5 steps 1: magnesium / Carbon tetrachloride; ethanol 2: 1,4-dioxane; water monomer 3: acetic anhydride 5: potassium carbonate / <i>N</i>-methyl-acetamide; chloroform | ||
Multi-step reaction with 3 steps 1: triethylamine / toluene / 5 h / 90 °C / Inert atmosphere 2: ethanol; diethyl ether / 3 h / 20 °C 3: potassium carbonate / N,N-dimethyl-formamide / 5 h / 100 °C | ||
Multi-step reaction with 5 steps 1: triethylamine; magnesium(II) chloride / toluene / 1 h / 20 °C 2: toluene-4-sulfonic acid; sulfuric acid / water monomer / 12 h / Reflux 3: acetic anhydride / 3 h / Reflux 4: ethanol; methanol; isopropanol / 3 h / 0 °C 5: potassium carbonate / N,N-dimethyl-formamide; dimethyl sulfoxide; N,N-dimethyl acetamide / 3 h / 75 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 1.) Mg/ethanol, CCl4 / 1.) ethanol, toluene, 1 h, 60-70 deg C; 2.) toluene, 0 to -5 deg C; 12 h, room temperature 2: p-toluenesulfonic acid / H2O / 5 h / Heating 3: acetic anhydride / 2 h / Heating 4: 94 percent / ethanol / 1 h / Ambient temperature | ||
Multi-step reaction with 2 steps 1: triethylamine / toluene / 5 h / 90 °C 2: diethyl ether; ethanol / 3 h / 25 °C | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / acetonitrile / 0.03 h / 180 °C / 9050.33 Torr / Flow reactor; Inert atmosphere 2: acetonitrile / 0.02 h / 25 °C / Flow reactor; Inert atmosphere |
Multi-step reaction with 4 steps 1: magnesium / Carbon tetrachloride; ethanol 2: 1,4-dioxane; water monomer 3: acetic anhydride | ||
Multi-step reaction with 2 steps 1: triethylamine / toluene / 5 h / 90 °C / Inert atmosphere 2: ethanol; diethyl ether / 3 h / 20 °C | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 0.03 h / 150 °C / Flow reactor 2: 0.02 h / 20 °C / 9050.33 Torr / Flow reactor | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / acetonitrile / 0.03 h / 150 °C / Flow reactor 2: acetonitrile / 0.01 h / 20 °C / Flow reactor | ||
Multi-step reaction with 4 steps 1: triethylamine; magnesium(II) chloride / toluene / 1 h / 20 °C 2: toluene-4-sulfonic acid; sulfuric acid / water monomer / 12 h / Reflux 3: acetic anhydride / 3 h / Reflux 4: ethanol; methanol; isopropanol / 3 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 1) lithium bis(trimethylsilyl)amide / 1) THF, 2 h, -5 deg C; 2) THF, 1 h, -5 deg C to room temp. 2: 79 percent / dimethylformamide / 2 h / 110 °C 3: 91 percent / H2 / 10percent Pd/C / trifluoroacetic acid / 18 h / 2068.6 Torr 4: 27 percent / aq. NaOH / ethanol / 18 h / 100 °C | ||
Multi-step reaction with 4 steps 1: 1) lithium bis(trimethylsilyl)amide / 1) THF, 2 h, -5 deg C; 2) THF, 1 h, -5 deg C to room temp. 2: 89 percent / H2 / 10percent Pd/C / trifluoroacetic acid / 2 h / 2068.6 Torr 3: 66 percent / pyridine / 96 h / 120 °C 4: 27 percent / aq. NaOH / ethanol / 18 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 1) lithium bis(trimethylsilyl)amide / 1) THF, 2 h, -5 deg C; 2) THF, 1 h, -5 deg C to room temp. 2: 79 percent / dimethylformamide / 2 h / 110 °C 3: 91 percent / H2 / 10percent Pd/C / trifluoroacetic acid / 18 h / 2068.6 Torr | ||
Multi-step reaction with 3 steps 1: 1) lithium bis(trimethylsilyl)amide / 1) THF, 2 h, -5 deg C; 2) THF, 1 h, -5 deg C to room temp. 2: 89 percent / H2 / 10percent Pd/C / trifluoroacetic acid / 2 h / 2068.6 Torr 3: 66 percent / pyridine / 96 h / 120 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In 1,4-dioxane at 20 - 65℃; for 1.5h; | 107 Reference Example 107; Under ice cooling, triethylamine and 2,4,5-trifluorobenzoyl chloride were added to a solution of ethyl 3-(cyclopentylamino)buta-2-enoate in dioxane, for stirring at ambient temperature for 30 minutes and at 65°C for one hour, to obtain ethyl 3-(cyclopentylamino)-2-(2,4,5-trifluorobenzoyl)buta-2-enoate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | 66 N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,4,5-trifluorobenzamide EXAMPLE 66 N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,4,5-trifluorobenzamide Beginning with 0.027 mMol of 2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035 mMol of 2,4,5-trifluorobenzoyl chloride, the title compound was prepared in 81% yield. | |
81% | C.66 N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,4,5-trifluorobenzamide EXAMPLE C-66 N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,4,5-trifluorobenzamide Beginning with 0.027 mMol of 2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035 mMol of 2,4,5-trifluorobenzoyl chloride, the title compound was prepared in 81% yield. | |
81% | C.66 N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,4,5-trifluorobenzamide EXAMPLE C-66 N-[2-methyl-3-(2-[N',N'-dimethylamino]ethyl)-1H-indol-5-yl]-2,4,5-trifluorobenzamide Beginning with 0.027 mMol of 2-methyl-5-amino-3-(2-(N',N'-dimethylamino)ethyl)-1H-indole and 0.035 mMol of 2,4,5-trifluorobenzoyl chloride, the title compound was prepared in 81% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In acetic acid; toluene | Synthesis of 1-cyclopropyl-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (XXXIVa) STR25 Synthesis of 1-cyclopropyl-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (XXXIVa) STR25 35.8 g (0.25 mol) of ethyl dimethylaminoacrylate and 27.3 g (0.27 mol) of triethylamine are initially introduced in 50 ml of toluene, and a mixture of 24.3 g (0.125 mol) of 2,4,5-trifluorobenzoyl chloride (XXVIa) and 26.3 g (0.125 mol) of 2-chloro-4,5-difluorobenzoyl chloride (XXVIb) are added dropwise at 50° C. within 30 minutes. The mixture is subsequently stirred at from 50° to 55° C. for 1 hour and 17.3 g (0.28 mol) of glacial acetic acid and 15.5 g (0.27 mol) of cyclopropylamine are then added dropwise at from 30° to 36° C. After 1 hour, the salts are extracted with 100 ml of water. The organic phase is concentrated by evaporation in water pump vacuum at 40° C. 81.5 g of (XXXIIa/b) are obtained as an oily residue. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; p-toluenesulfonic acid monohydrate In tetrahydrofuran; methanol | 15 Methyl 3-((2,4-difluorophenyl)amino)-2-(2,4,5-trifluorobenzoyl)acrylate EXAMPLE 15 Methyl 3-((2,4-difluorophenyl)amino)-2-(2,4,5-trifluorobenzoyl)acrylate 26.92 g of a 55% strength dispersion of sodium hydride in white oil were suspended in 200 ml of absolute tetrahydrofuran, the suspension was cooled to 5° C. and a solution of 32.06 g of methyl cyanoacetate in 60 ml of absolute tetrahydrofuran was added dropwise so that a temperature interval of 10°-15° C. was maintained. When the addition had ended, the mixture was subsequently stirred at about 10° C. for 20 minutes and a solution of 60 g of 2,4,5-trifluorobenzoyl chloride in 60 ml of absolute tetrahydrofuran was then added dropwise so that 15° C. was not exceeded. The mixture was then subsequently stirred at about 5° C. for a further hour and thereafter poured onto 400 ml of 4N HCl/400 g of ice and the product was extracted with methylene chloride. The organic phase was dried over sodium sulphate and the volatile constituents were stripped off on a rotary evaporator. The evaporation residue was dissolved in methanol, 3 g of 10% strength palladium-on-active charcoal were added, the mixture was degassed and hydrogenation was carried out under normal pressure at room temperature for three hours. The catalyst was filtered off, 70.22 g of p-toluenesulphonic acid monohydrate and 100 g of 2,4-difluoroaniline were added to the filtrate and the mixture was heated under reflux for one hour. The mixture was then concentrated on a rotary evaporator and the residue was partitioned between 1N HCl and ethyl acetate. The organic phase was washed with sodium chloride solution, dried over sodium sulphate and evaporated. The evaporation residue was recrystallized from ether. 68 g (60% of theory) of colourless crystals. Melting point 116°-119° C. (ether). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In tetrahydrofuran | 1 Methyl 2-cyano-3-hydroxy-3-(2,4,5-trifluorophenyl)-acrylate EXAMPLE 1 Methyl 2-cyano-3-hydroxy-3-(2,4,5-trifluorophenyl)-acrylate 26.92 g of a 55% dispersion of sodium hydride in white oil was suspended in 200 ml of absolute tetrahydrofuran, the suspension was cooled to 5° C. and a solution of 32.06 g of methyl cyanoacetate in 60 ml of absolute tetrahydrofuran was added dropwise so that a temperature interval of 10°-15° C. was maintained. When the addition had ended, the mixture was subsequently stirred at about 10° C. for 20 minutes and a solution of 60 g of 2,4,5-trifluorobenzoyl chloride in 60 ml of absolute tetrahydrofuran was then added dropwise so that 15° C. was not exceeded. The mixture was then subsequently stirred at about 5° C. for a further hour and thereafter poured onto 400 ml of 4N HCl/400 g of ice and the product was extracted with methylene chloride. The organic phase was dried over sodium sulphate and the volatile constituents were stripped off on a rotary evaporator. The crystalline evaporation residue was recrystallized from methanol/ethyl acetate. 75 g (94.2% of theory) of colourless crystals, Melting point: 125°-127° C. (MeOH/ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 24h; | Ethyl alpha(Z)-[(diethylamino)methylene]-2,4,5-trifluoro-beta-oxo-benzenepropanoate An anhydrous CH2Cl2 solution (50 mL) of <strong>[446-17-3]2,4,5-trifluorobenzoic acid</strong> (3.49 g, 19.81 mmol), oxalyl chloride (2.18 mL, 25.75 mmol) and five drops of DMF was stirred for 24 h at room temperature. The reaction mixture was then subjected to concentrated evaporation under reduced pressure, solubilized in toluene (30 mL) and added dropwise to a toluene solution (20 mL) of triethylamine (8.26 mL, 59.43 mmol) and ethyl 3-(diethylamino)-2E-propenoate (4.40 g, 25.75 mmol). After 18 h of stirring at 90C, the cooled reaction mixture was washed with water. The organic layer was dried over Na2SO4, filtered and evaporated. The crude residue was purified by flash chromatography on silica gel (95:5 to 60:40 hexane/AcOEt) to give Ethyl alpha(Z)-[(diethylamino)methylene]-2,4,5-trifluoro-beta-oxo-benzenepropanoate (4.180 g, 12.7 mmol, 64% for the two steps) as a colourless oil. | |
In N-methyl-acetamide; | EXAMPLE 130 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid A solution of 32 g of <strong>[446-17-3]2,4,5-trifluorobenzoic acid</strong> in 305 ml of ether, containing 5 drops of dimethylformamide was first evacuated and then purged with argon. A 27 ml portion of oxalyl chloride was added dropwise, using an addition funnel over a period of 30 minutes, while keeping the reaction under argon. When addition was complete, the mixture was stirred under argon for 30 minutes, then the ether was removed and the residual oil distilled at 0.2-1.0 mm, 28-33 C., giving 30.9 g of 2,4,5-trifluorobenzoyl chloride as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; ammonia; In tetrahydrofuran; | EXAMPLE 4 2,4,5-Trifluorobenzovlacetic acid ethvl ester 7.2 g (0.025 mol) of acetoacetic acid ethyl ester magnesium enolate in 100 ml of tetrahydrofuran was suspended under nitrogen, 3.1 g (0.03 mol) of triethylamine was added and 10.0 g (0.05 mol) of 2,4,5-trifluorobenzoyl chloride was instilled in 10 minutes. The reaction mixture was refluxed for 2 hours, cooled with ice water and hydrolyzed with 40 ml of 1 N HCl. The phases were separated and the water phase was extracted with tert-butyl methyl ether. The organic phases were combined and 20 ml of 10 percent ammonia solution was added with vigorous stirring within 10 minutes. After 1 hour, the phases were separated, dried with sodium sulfate and concentrated by evaporation. The residue was distilled in a vacuum (0.08 mbar). There was a yield of 10.6 g of 2,4,5-trifluorobenzoylacetic acid ethyl ester with a purity of 98.0 percent, corresponding to 84 percent of theory. The boiling point of the product was 90 C./0.08 mbar. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; diethyl ether; ethanol; acetic acid; | EXAMPLE 7 2,4,5-Trifluoro-acetophenone 194.5 g (1 mole) of 2,4,5-trifluoro-benzoyl chloride were initially introduced into 100 ml of diethyl ether and the mixture was heated to boiling under reflux. 1.1 mole of ethoxymagnesium ethyl malonate dissolved in 100 ml of ethanol and 125 ml of diethyl ether were then allowed to drip in in the course of 30 minutes and the mixture was stirred under reflux for a further 1 hour. After cooling, the reaction mixture was stirred into 500 ml of ice water and adjusted to a pH of 1 using concentrated sulphuric acid, and the organic material (345 g) was separated off. This organic material was dissolved in 300 ml of acetic acid and, after the addition of 37.5 ml of concentrated sulphuric acid, heated to reflux until the end of CO2 evolution, which took 6 hours. The reaction mixture was then cooled and poured into water, and the organic phase was separated off and distilled. 83 g of product having a boiling point at 10 mbar of 63 to 64 C. were obtained. This corresponds to a yield of 47% of theory. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; diethyl ether; ethanol; acetic acid; | Example 112 2,4,5-Trifluoroacetophenone 194.5 g (1 mol) of 2,4,5-trifluorobenzoyl chloride were initially introduced into 100 ml of diethyl ether and heated to boiling under reflux. 1.1 mol of ethoxymagnesium malonic ester dissolved in 100 ml of ethanol and 125 ml of diethyl ether were then allowed to drop in in the course of 30 minutes and the mixture was stirred for 1 hour under reflux. After cooling, the reaction mixture was stirred into 500 ml of ice water and adjusted to a pH of 1 with concentrated sulphuric acid, and the organic material (345 g) was separated off. This organic material was dissolved in 300 ml of acetic acid and, after adding 37.5 ml of concentrated sulphuric acid, heated to reflux until evolution of CO2 had ended, which took 6 hours. The reaction mixture was then cooled and poured into water, and the organic phase was separated off and distilled. 83 g of product having a boiling point at 10 mbar of 63 to 64 C. were obtained. This corresponds to a yield of 47% of theory. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In 1-methyl-pyrrolidin-2-one; | (1) To a solution of 2,4,5-trifluorobenzoyl chloride (1.0g, 5.1mmol) in 1-methyl-2-pyrrolidone (10ml), sodium hydroxide (powder) (1.0g, 25mmol) was added, and the resulting mixture was stirred at 130 ØC for 3 hours. After cooling, icewater was added to the reaction mixture, and the resulting mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give 4,5-difluoro-2-hydroxybenzoic acid (0.8g). 1H-NMR(CDCl3) delta:6.75-6.84(1H, m), 7.66-7.75(1H, m), 10.66(1H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In dichloromethane; water at 0 - 20℃; for 3h; | 22 2,4,5-Trifluorobenzoyl chloride (540 mg, 2.78 mmol) was added to a stirred solution of 2- methylarninoethanol (0.185 niL, 3.06 mmol) in DCM (5 mL) and 10% aqueous sodium hydroxide solution (5 mL) at 0°C. After addition was complete the icebath was removed and the reraction was allowed to warm up to RT and stirred for 3 hours. The phases were then separated and the aqueous phase extracted with DCM (3 x 30 mL). The combined organic layers were dried (MgSO4), filtered and evaporated to give the desired compound as a colourless oil (686 mg). This material was used without further purification. 1H ΝMR δ (CDCl3): 2.48 (t, IH), 2.95 (s, 2H), 3.07 (s, IH), 3.31 (t, IH), 3.65 (t, 2H), 3.84 (q, IH), 6.86 - 6.95 (m, IH), 7.14 - 7.24 (m, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A suspension of potassium ethyl malonate (50.8Kg) and magnesium chloride(34.5Kg) in toluene (130Kg) below 0C was treated with THF (265L), cooled to 0C, treatedwith triethylamine (75Kg), warmed to 50C, stirred for 1-5 hours, cooled to 0C, treated with22% (w/w) of EXAMPLE 5 in toluene (163Kg), warmed to ambient temperature, stirred for2 hours, added to 2M HC1 (407Kg), stirred for 30 minutes, separated from the water layer andwashed with water. This procedure was repeated, and the organic layers were combined,concentrated with an ethanol (150L) azeotrope, treated with water (30% by weight of theorganic layer), stirred for 3 hours at 0C, and filtered. The andfiltrant was washed with 3:1ethanol/water and dried under vacuum at 35-45C to provide 86Kg of product. H NMR(CDC13) (keto) 8 7.75 (ddd, J=10.8, 10.8, 6.0Hz, 1H), 7.02 (ddd, 1H), 4.27 (q, J=7.2Hz, 2H),3.95 (d, 4.2Hz, 2H), 1.35 (t, J=7.3Hz, 3H); (enol) 6 12.72 (s, 1H), 7.85 (ddd, J=10.5, 9.6,6.6Hz, 1H), 6.96 (ddd, J=10.5,10.5, 6.6Hz, 1H), 5.84 (s, 1H), 4.23 (q, J=7.2Hz, 2H), 1.27 (t,J=7.4Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 0 - 20℃; for 1h; | 1.C To a solution of 2,4,5-trifluorobenzoic acid (Aldrich, 704 mg, 4.0 mmol) in dichloromethane (20 mL), was added oxalyl chloride (Aldrich, 0.70 mL, 8.0 mmol) dropwise, followed by two drops of DMF. The reaction mixture was stirred at room temperature for 2 h, and concentrated in vacuo. Toluene (20 mL) was added and the reaction mixture was evaporated in vacuo to remove the excess oxalyl chloride. The residue was dissolved in dichloromethane (20 mL). Half of this acid chloride solution was added to a mixture of 3-amino-l-(4-fluorophenyl)pyridin-2(lH)-one (306 mg, 1.5 mmol) in dichloromethane (5 mL) and TEA (0.5 mL, Aldrich) at 0 0C. The reaction mixture was stirred at room temperature for 1 h. The precipitate that formed was collected by filtration, and washed with methanol, to afford the desired product (363 mg, 67% yield) as a solid. MS(ESI+) m/z 363.25 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In acetonitrile | 12 Example 12 1,3-Bis-(2,4,5-trifluorobenzyl)imidazolidin-2-ylideneamine (Compound 12)The title compound was prepared in three steps as described in Procedure D. In the first step, ethylenediamine was reacted in acetonitrile with 2,4,5- trifluorobenzoylchloride (2 eq) in the presence of TEA to give the N,N'-dibenzoylated ethylenediamine upon aqueous work-up. After the last step (reaction with cyanogen bromide, performed at 2000C for 60 min using MW heating), the precipitated solid was filtered off and recrystallized to give the title compound as the hydrogen bromide salt. MS(ES+) m/z 374 ([M + I]+, 100); HR-MS: 374.1086 ([M+1]+, Ci7H14F6N3; calc. 374.10919). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium azide In water; acetone at 0 - 20℃; for 2h; | 3 Example 3; 1 - ( 3 - F2-oxo-3 -( 1 H-p yrrol-2- ylmethylene)-2.3 -dihvdro- 1 H-indol-6- ylaminol phenyl 1-3-(2A5-trifluorophenyl)urea; [00107] Synthesis of 2,4,5-trifluorobenzoyl azide (10); [00108] To a solution of 2,4,5-trifluorobenzoic acid (10.0 g, 0.057 mol) in toluene(150 mL) is added SOCl2 (12.5 mL, 0.171 mol). The mixture is heated at reflux overnight. All the solvent is removed and the crude is dried in vacuo for an hour to remove residual SOCl2. The crude is then dissolved in acetone (100 ml) and cooled to 00C. A solution of NaN3 (4.5 g, 0.0684 mol) in water (20 mL) is added slowly. The resulting mixture is warmed to room temperature and stirred for 2 hr. Acetone is removed. The mixture is extracted with EtOAc (3x150 mL). The combined organic layer is dried over Na2SO4, filtered and concentrated. The crude is purified by column chromatography (EtOAc/Hexane, gradient, 0-20%) to give the desired product as oil. 1H NMR (400 MHz, CDCl3) δ 7.90-7.70 (m, 1 H), 7.10-7.00 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: 2,4,5-trifluorobenzoyl chloride; ethyl 2-(6-chlorobenzo[d]thiazol-2-yl)acetate With N-ethyl-N,N-diisopropylamine In acetonitrile at 5 - 20℃; Stage #2: With potassium carbonate In N,N-dimethyl-formamide; acetonitrile Heating; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.2% | <Example 14> Synthesis of 4-isopropyl-3-methylphenyl 2 ,4,5-trifluoro benzoate0.5 g (3.32 mmol) of 4-isopropyl-3-methylphenol were completely dissolved in 30 ml of acetonitrile, to obtain a reaction solution, which was then added with 1.1 ml of triethylamine and stirred for 30 min. Subsequently, the reaction temperature was controlled to 0C, and 0.72 ml (5.65 mmol) of 2, 4, 5-trichlorobenzoyl chloride were slowly added in droplets at 0C or lower. The reaction temperature was increased to room temperature, and the reaction solution was allowed to react for 3 hr. The resultant reaction solution was added with 20 ml of EPO <DP n="34"/>distilled water and 30 ml of methylene chloride and stirred for 20 min, after which the organic layer was separated. The separated organic layer was added with 20 ml of water, and it was washed with water for 30 min. The separated organic layer was added with 1 g of anhydrous magnesium sulfate (MgSO4) and then filtered. The filtrate was concentrated under reduced pressure at 50 C or lower and purified using silica gel column chromatography, thus yielding 0.92 g (90.2%) of 4- isopropyl-3-methylphenyl 2, 4, 5-trifluoro benzoate as a title compound.IR(KBr, cm"1) : 1744(C=O), 1254 (C-O) GC/MS(m/e) : 308(M+), 159 (base peak) RT (min) : 15.8 1H-NMR (CDCl3, ppm) : 1.29 (m, 6H, isopropyl CH(CH3)2), 2.35 (s, 3H, aromatic-CH3) , 3.12 (m, IH, -CH (CH3) 2) , 6.94(d, 2H, aromatic H), 7.02 (m, 3H, aromatic) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With triethylamine In dichloromethane at 0℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-oxo-piperidine-1-carboxylic acid tert-butyl ester With lithium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.0833333h; Stage #2: 2,4,5-trifluorobenzoyl chloride In tetrahydrofuran for 0.0833333h; | 63 Example 63Preparation of tert-butyl 3-(2,4,5-trifluorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-b]pyridine-4(5H)-carboxylate (intermediate 20) and tert-butyl 3-(2,4,5-trifluorophenyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (intermediate 21) To a solution of 3-N(Boc)-piperidone (615 mg, 3.1 mmol) in THF (8 mL) was add LHMDS (1.0 M in THF, 3.1 mL) at 0° C. After stirring for 5 min, 2,4,5-trifluorobenzoyl chloride was added and stirred for additional 5 min. Acetic acid (1 mL) was added followed by addition of hydrazine monohydrate (1 mL). The reaction was stirred for 10 min and evaporated under vacuum. The crude mixture was extracted between EtOAc and aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude product was purified with 20% to 60% EtOAc/Hex to give intermediate 20 (slow eluting component, 0.32 g) and intermediate 21 (fast eluting component, 0.18 g). LCMS (+ESI) m/z=354 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-oxo-piperidine-1-carboxylic acid tert-butyl ester With lithium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.0833333h; Stage #2: 2,4,5-trifluorobenzoyl chloride In tetrahydrofuran for 0.0833333h; Stage #3: With hydrazine hydrate; acetic acid In tetrahydrofuran for 0.166667h; | 63 Example 63Preparation of tert-butyl 3-(2,4,5-trifluorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-b]pyridine-4(5H)-carboxylate (intermediate 20) and tert-butyl 3-(2,4,5-trifluorophenyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (intermediate 21) To a solution of 3-N(Boc)-piperidone (615 mg, 3.1 mmol) in THF (8 mL) was add LHMDS (1.0 M in THF, 3.1 mL) at 0° C. After stirring for 5 min, 2,4,5-trifluorobenzoyl chloride was added and stirred for additional 5 min. Acetic acid (1 mL) was added followed by addition of hydrazine monohydrate (1 mL). The reaction was stirred for 10 min and evaporated under vacuum. The crude mixture was extracted between EtOAc and aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude product was purified with 20% to 60% EtOAc/Hex to give intermediate 20 (slow eluting component, 0.32 g) and intermediate 21 (fast eluting component, 0.18 g). LCMS (+ESI) m/z=354 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With pyridine at 20℃; for 66h; | General Procedure for the preparation of N-(Pyridin-3-yl)benzamides 3d - u : The corresponding acid chloride 4 (1.0 - 1.1 eq.) was added carefully to a stirred solution of 3-aminopyridine 5 (1.0 eq.) in pyridine (2-3 mL / mmol 5) at room temperature. The resulting mixture was either kept at 100-120°C for 1-2 hours or stirred at room temperature for the indicated period of time. The reaction mixture was poured into water (50 - 200 mL). In most cases, a suspension formed immediately, which was stirred at room temperature (10 min - 2 h) to complete precipitation. The precipitate was filtered off with suction, washed with water (50 mL in three portions) and dried on the filter. The resulting solid was dissolved in CH2Cl2 (150 - 300 mL). Drying over Na2SO4 and subsequent removal of the solvent afforded compounds 3 as solids. In most of the cases, the obtained products were of sufficient purity; however, in rare cases further purification via column chromatography was required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 20 °C / Cooling with ice 2.1: sodium hydride / N,N-dimethyl-formamide; hexane; mineral oil / 2.5 h / 20 °C / Inert atmosphere 2.2: 0 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2.5 h / 60 °C 4.1: sodium tetrahydroborate / isopropyl alcohol; chloroform / 0.5 h / 20 °C 4.2: 1.75 h 5.1: ChiralCel OD / isopropyl alcohol; n-heptane / Resolution of racemate 6.1: hydrogenchloride; zinc / ethanol / 1 h 7.1: dichloromethane / 2.5 h / 20 °C 8.1: osmium(VIII) oxide / water; <i>tert</i>-butyl alcohol; acetone / 0.17 h / 20 °C 8.2: 48 h | ||
Multi-step reaction with 7 steps 1: N-ethyl-N,N-diisopropylamine 2: sodium hydride 3: Heating 4: sodium tetrahydroborate 5: zinc; hydrogenchloride / water 6: ChiralCel AD 7: osmium(VIII) oxide; 4-methylmorpholine N-oxide | ||
Multi-step reaction with 8 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2.25 h / 0 - 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 2.5 h / 20 °C 2.2: 0 - 20 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2.5 h / 60 °C 4.1: sodium tetrahydroborate; silica gel / chloroform; isopropyl alcohol / 0.5 h / 20 °C 4.2: 1.75 h 5.1: tetrahydrofuran / 1.75 h / Resolution of racemate 6.1: hydrogenchloride; zinc / ethanol; water / 1 h 7.1: dichloromethane / 2.5 h / 20 °C 8.1: osmium(VIII) oxide / water; acetone; <i>tert</i>-butyl alcohol / 0.17 h / 20 °C 8.2: 48 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 20 °C / Cooling with ice 2.1: sodium hydride / N,N-dimethyl-formamide; hexane; mineral oil / 2.5 h / 20 °C / Inert atmosphere 2.2: 0 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2.5 h / 60 °C 4.1: sodium tetrahydroborate / isopropyl alcohol; chloroform / 0.5 h / 20 °C 4.2: 1.75 h 5.1: ChiralCel OD / isopropyl alcohol; n-heptane / Resolution of racemate 6.1: hydrogenchloride; zinc / ethanol / 1 h 7.1: dichloromethane / 2.5 h / 20 °C 8.1: osmium(VIII) oxide / water; <i>tert</i>-butyl alcohol; acetone / 0.17 h / 20 °C 8.2: 48 h 9.1: sodium periodate / water; tetrahydrofuran / 3 h | ||
Multi-step reaction with 7 steps 1: N-ethyl-N,N-diisopropylamine 2: sodium hydride 3: Heating 4: sodium tetrahydroborate 5: zinc; hydrogenchloride / water 6: ChiralCel AD 7: rhodium(III) chloride; sodium periodate | ||
Multi-step reaction with 9 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2.25 h / 0 - 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 2.5 h / 20 °C 2.2: 0 - 20 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2.5 h / 60 °C 4.1: sodium tetrahydroborate; silica gel / chloroform; isopropyl alcohol / 0.5 h / 20 °C 4.2: 1.75 h 5.1: tetrahydrofuran / 1.75 h / Resolution of racemate 6.1: hydrogenchloride; zinc / ethanol; water / 1 h 7.1: dichloromethane / 2.5 h / 20 °C 8.1: osmium(VIII) oxide / water; acetone; <i>tert</i>-butyl alcohol / 0.17 h / 20 °C 8.2: 48 h 9.1: sodium periodate / tetrahydrofuran; water / 3 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In toluene; at 90℃; for 3h; | In toluene, A solution of 2,4,5-trifluorobenzoyl chloride (50 g, 257 mmol) was added to a solution of triethylamine (107 mL, 771 mmol) and ethyl 3- (dimethylamino) acrylate (44.2 g, 308 mmol) in toluene (500 mL) . The mixture was stirred at 90 C. for 3 hours. The reaction mixture was cooled, washed with water and extracted with EtOAc. The organic layer was dried over Na 2 SO 4, filtered and concentrated to give compound 149a (75 g, 97% yield) as a brown oil. The crude product was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.23% | With triethylamine In toluene at 90℃; for 5h; Inert atmosphere; | |
With triethylamine In toluene at 90℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10.08 g | With triethylamine In dichloromethane at 0 - 20℃; for 1.5h; | 45 Preparation 45 4-Methylphenyl 2,4,5-trifluorobenzoate Thionyl chloride (50 mL, 680 mmol) was added to 2,4,5-trifluorobenzoic acid (10 g, 57 mmol) and the mixture stirred at 55 °C for 18 hours. After cooling, the excess thionyl chloride was removed in vacuo. The resulting crude oil was azeotroped twice with DCM (30 mL) and toluene (20 mL) and the residue redissolved in DCM (50 mL), then cooled to 0 °C. A mixture of 4-methylphenol (6.4 g, 59 mmol) and triethylamine (10 mL, 71 mmol) in DCM (20 mL) was added over 30 minutes. The reaction was allowed to warm up to room temperature over 1 hour. The crude reaction mixture was partitioned between EtOAc (200 mL) and saturated sodium bicarbonate solution (70 mL). The aqueous layer was further extracted with EtOAc (100 mL). The combined organic extracts were combined, washed with saturated sodium bicarbonate solution (70 mL) and water (100 mL). The organic layer was dried over magnesium sulfate and concentrated to provide a crude solid, which was purified by silica gel chromatography eluting with 5% EtOAc in heptane to provide the title compound (10.08 g, 66%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: triethylamine / chloroform 2: 1-methyl-pyrrolidin-2-one; potassium <i>tert</i>-butylate / <i>tert</i>-butyl alcohol 3: sodium hydroxide | ||
Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane / toluene / 0.5 h / -78 °C 1.2: 2.17 h / -78 - 20 °C 2.1: dimethyl sulfoxide; toluene / 120 °C 3.1: sodium hydroxide / dimethyl sulfoxide; toluene / 1 h / 90 °C | ||
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / 0.03 h / 140 °C / Flow reactor 1.2: 0.02 h / 20 °C / 9050.33 Torr / Flow reactor 2.1: 0.12 h / 180 °C / Flow reactor 2.2: 150 °C / 9050.33 Torr / Flow reactor |
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / 0.03 h / 150 °C / Flow reactor 2.1: 0.02 h / 20 °C / 9050.33 Torr / Flow reactor 3.1: 0.12 h / 180 °C / Flow reactor 3.2: 150 °C / 9050.33 Torr / Flow reactor | ||
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / 0.03 h / 140 °C / Flow reactor 1.2: 0.02 h / 20 °C / 9050.33 Torr / Flow reactor 2.1: tetra(n-butyl)ammonium hydroxide / water / 0.08 h / 150 °C / Flow reactor 3.1: tetra(n-butyl)ammonium hydroxide / water / 0.07 h / 150 °C / 9050.33 Torr / Flow reactor | ||
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / 0.03 h / 150 °C / Flow reactor 2: 0.02 h / 20 °C / 9050.33 Torr / Flow reactor 3: tetra(n-butyl)ammonium hydroxide / water / 0.08 h / 150 °C / Flow reactor 4: tetra(n-butyl)ammonium hydroxide / water / 0.07 h / 150 °C / 9050.33 Torr / Flow reactor | ||
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / acetonitrile / 0.03 h / 150 °C / Flow reactor 2: acetonitrile / 0.01 h / 20 °C / Flow reactor 3: tetra(n-butyl)ammonium hydroxide / dimethyl sulfoxide; 2-methyltetrahydrofuran; water / 0.08 h / 150 °C / Flow reactor 4: tetra(n-butyl)ammonium hydroxide / dimethyl sulfoxide; 2-methyltetrahydrofuran; water / 0.05 h / 150 °C / Flow reactor |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sodium hydroxide / water; toluene / 20 °C 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 2 h / 80 °C | ||
Multi-step reaction with 2 steps 1: sodium hydroxide / dichloromethane; water; toluene / 20 °C / Cooling with ice 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 2 h / 80 °C | ||
Multi-step reaction with 2 steps 1: sodium hydroxide / dichloromethane; toluene; water / 20 °C / Cooling with ice 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 2 h / 80 °C |
Multi-step reaction with 2 steps 1: water; sodium hydroxide / dichloromethane; toluene / 20 °C / Cooling with ice 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 2 h / 80 °C | ||
Multi-step reaction with 2 steps 1: sodium hydroxide 2: 1,8-diazabicyclo[5.4.0]undec-7-ene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium hydroxide In water; toluene at 20℃; | 4.1 2,4,5-Trifluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide To a solution of 2,4,5-trifluorobenzoic acid (5.00 g, 28.4 mmol) in acetonitrile (50 mL) was added N,N-dimethylformamide (40 μL) followed by addition of oxalyl chloride (3.60 mL, 42.6 mmol). After 90 min, the volatiles were removed under reduced pressure. The residue was co-evaporated with acetonitrile (50 mL). The residue was then dissolved in methylene chloride (50 mL). This solution was added drop-wise into a cooled (ice bath) mixture of (2S)-1,1,1-trifluoropropan-2-amine hydrochloride (5.52 g, 36.9 mmol) (from Synquest, 98% ee) in toluene (100 mL) and 0.5 M sodium hydroxide aqueous solution (142 mL, 71.0 mmol). After addition, the ice bath was removed, and the reaction was allowed to warm to rt. The reaction was stirred overnight. The organic layer was separated. The aqueous layer was extracted with methylene chloride (50 mL). The combined organic layers were washed with 20% brine (75 mL) and water (2×75 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (6.49 g, 84%) which was directly used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 9.01 (d, J=7.6 Hz, 1H), 7.92-7.50 (m, 2H), 4.76 (m, 1H), 1.31 (d, J=7.0 Hz, 3H) ppm. LCMS cacld. for C10H8F6NO (M+1)+: m/z=272.0. Found: 272.0. |
With sodium hydroxide In dichloromethane; water; toluene at 20℃; Cooling with ice; | 2.1 Step 1 : 2, 4, 5-Trifluoro-N-[ ( lS)-2, 2, 2-trifluoro-l-methylethyl]benzamide To a solution of 2,4,5-trifluorobenzoic acid (5.00 g, 28.4 mmol) in acetonitrile (50 mL) was added N,N-dimethylformamide (40 followed by addition of oxalyl chloride (3.60 mL, 42.6 mmol). After 90 min, the volatiles were removed under reduced pressure. The residue was co-evaporated with acetonitrile (50 mL). The residue was then dissolved in methylene chloride (50 mL). This solution was added drop-wise into a cooled (ice bath) mixture of (2S)-l,l,l-trifluoropropan-2-amine hydrochloride (5.52 g, 36.9 mmol) (from Synquest, 98%> ee) in toluene (100 mL) and 0.5 M sodium hydroxide aqueous solution (142 mL, 71.0 mmol). After addition, the ice bath was removed, and the reaction was allowed to warm to rt. The reaction was stirred overnight. The organic layer was separated. The aqueous layer was extracted with methylene chloride (50 mL). The combined organic layers were washed with 20% brine (75 mL) and water (2 x 75 mL), dried over MgS04, filtered and concentrated under reduced pressure to afford the desired product (6.49 g, 84%) which was directly used in the next step without further purification. lU NMR (300 MHz, DMSO-de) δ 9.01 (d, J= 7.6 Hz, 1H), 7.92 - 7.50 (m, 2H), 4.76 (m, 1H), 1.31 (d, J = 7.0 Hz, 3H) ppm. LCMS cacld. for CioHsFeNO (M+l)+: m/z = 272.0; Found: 272.0. | |
With potassium carbonate; sodium sulfate | 2 Step 2. Step 2. (S)-2,4,5-trifluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide (Compound 1a) An aqueous solution (158 L) containing (S)-1,1,1-trifluoropropan-2-amine hydrochloride salt (35 kg) was charged to a 1000 L reactor, and toluene (198 kg) was charged to the reactor followed by portion-wise addition of K2CO3 (82 kg). 2,4,5-trifluorobenzoyl chloride (36.1 kg) was dissolved in toluene (40 kg), and the toluene solution was charged to the reactor with the toluene solution of amine intermediate. The resulting mixture was stirred at 20° C. for 2 hours. The batch was filtered and the filter cake was washed with toluene (117 kg). The filtrate and wash were charged to a 1000 L reactor, and 1N aqueous NaOH solution (125 kg) was charged to the reactor. The mixture was stirred for 2 hours and the phases were allowed to split. The aqueous phase was discarded, and the organic phase was washed twice with water (135 kg) and stored in a clean container (solution 1). A separate portion (portion 2) was treated at the same way to afford solution 2. Solution 1 and solution 2 were charged to a 1000 L reactor, and Na2SO4 (104 kg) was charged to the reactor. The mixture was stirred for 2 hours, filtered, and the filter cake was washed with toluene (90 kg). The filtrate and wash were charged to a 500 L reactor, and the batch was distilled under vacuum at 50° C. Toluene (14 kg) and heptane (166 kg) were charged to the 500 L reactor and the batch was stirred at 80° C. until a solution was obtained. The solution was cooled to 25° C. and stirred for 2 hours. The product was isolated by vacuum filtration, and the filter cake was washed with n-heptane (40 kg). The filter cake was dried under vacuum at ≤50° C. to afford the crude product, (S)-2,4,5-trifluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide (87.0 kg; 79.0 wt % by LOD; net weight: 68.7 kg; 68%; 69.4% by HPLC; 97.1 ee % by chiral HPLC), which was further purified from a mixture of IPA and n-heptane according to the following procedures. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.49 g | With sodium hydroxide In dichloromethane; water; toluene at 20℃; Cooling with ice; | J2.1 Step 1: 2,4, 5-Trifluoro-N-[(JS)-2, 2, 2-trifluoro-1-methylethylJbenzamide Step 1: 2,4, 5-Trifluoro-N-[(JS)-2, 2, 2-trifluoro-1-methylethylJbenzamideTo a solution of 2,4,5-trifluorobenzoic acid (5.00 g, 28.4 mmol) in acetonitrile (50 mL) was added N,N-dimethylformamide (40 .iL) followed by addition of oxalyl chloride (3.60 mL, 42.6 mmol). After 90 mm, the volatiles were removed under reduced pressure. The residue was co-evaporated with acetonitrile (50 mL). The residue was then dissolved in methylene chloride (50 mL). This solution was addeddrop-wise into a cooled (ice bath) mixture of (2S)-i, 1,1 -trifluoropropan-2-amine hydrochloride (5.52 g, 36.9 mmol) (from Synquest, 98% ee) in toluene (100 mL) and 0.5 M sodium hydroxide aqueous solution (142 mL, 71.0 mmol). After addition, the ice bath was removed, and the reaction was allowed to warm to rt. The reaction was stirred overnight. The organic layer was separated. The aqueous layer was extracted with methylene chloride (50 mL). The combined organic layers were washed with 20% brine (75 mL) and water (2 x 75 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (6.49 g, 84%) which was directly used in the next step without further purification. ‘H NMR (300MHz, DMSO-d6) ö 9.01 (d, J= 7.6 Hz, 1H), 7.92-7.50 (m, 2H), 4.76 (m, 1H), 1.31 (d, J= 7.0 Hz, 3H) ppm. LCMS cacid. for C,0H8F6N0 (M+1): mlz = 272.0; Found:272.0. |
6.49 g | With water; sodium hydroxide In dichloromethane; toluene at 20℃; Cooling with ice; | J2.1 2,4,5-Trifluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide To a solution of 2,4,5-trifluorobenzoic acid (5.00 g, 28.4 mmol) in acetonitrile (50 mL) was added N,N-dimethylformamide (40 μL) followed by addition of oxalyl chloride (3.60 mL, 42.6 mmol). After 90 min, the volatiles were removed under reduced pressure. The residue was co-evaporated with acetonitrile (50 mL). The residue was then dissolved in methylene chloride (50 mL). This solution was added drop-wise into a cooled (ice bath) mixture of (2S)-1,1,1-trifluoropropan-2-amine hydrochloride (5.52 g, 36.9 mmol) (from Synquest, 98% ee) in toluene (100 mL) and 0.5 M sodium hydroxide aqueous solution (142 mL, 71.0 mmol). After addition, the ice bath was removed, and the reaction was allowed to warm to rt. The reaction was stirred overnight. The organic layer was separated. The aqueous layer was extracted with methylene chloride (50 mL). The combined organic layers were washed with 20% brine (75 mL) and water (2×75 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (6.49 g, 84%) which was directly used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 9.01 (d, J=7.6 Hz, 1H), 7.92-7.50 (m, 2H), 4.76 (m, 1H), 1.31 (d, J=7.0 Hz, 3H) ppm. LCMS cacld. for C10H8F6NO (M+1)+: m/z=272.0. Found: 272.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate In acetone at 20℃; for 24h; | General procedure for the synthesis of compounds 3 and 4a-l General procedure: 2 mmol of either amidoxime 1 [30] or 2 [26] were dissolved in acetone (200 mL) in a round-bottomed flask; then, K2CO3 (0.35 g; 2.5 mmol) and the corresponding aroyl chloride (2.5 mmol), were added to the reaction mixture and stirred for 24 h at room temperature. The solvent was removed under vacuum and the residue treated with water and refluxed for 30 min 1,2,4-Oxadiazoles products were obtained by filtration and further purified by chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With triethylamine In tetrahydrofuran at 0 - 20℃; | 49.b (b) ethyl 5-(2,4, 5-trifluorophenyl)-oxazole-4-carboxylate (b) ethyl 5-(2,4, 5-trifluorophenyl)-oxazole-4-carboxylate Ethyl isocyanoacetate (3.72 g, 31.23 mmol) in THF (30 mL) was cooled to 0C Et3N (11.81 mL, 85.19 mmol) was added drop wise followed by the addition of 2,4,5-trifluorobenzoyl chloride (5.52 g, 28.4 mmol) in THF (30 mL) over 5 mm. The reaction was allowed to warm to room temperature and stirred overnight. The mixture was diluted with DCM (100 mL) and washed with saturated aqueous NaHCO3 (3 x 50 mL) and brine (50 mL). The organic phase was separated, dried over Na2SO4. filtered and solvent removed in vacuo to give a brown solid. Purification by flash chromatography eluting with 0-80% EtOAc in Petroleum ether (40-60) gave ethyl 5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylate (3.7 g, 48% yield) as a cream solid.LC-MS (Method 0)272.0 [M+H] RT 1.97 mm |
48% | With triethylamine In tetrahydrofuran at 0 - 20℃; | 49.b (b) ethyl 5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylate Ethyl isocyanoacetate (3.72 g, 31.23 mmol) in THF (30 mL) was cooled to 0°C. Et3N (11.81 mL, 85.19 mmol) was added drop wise followed by the addition of 2,4,5-trifluorobenzoyl chloride (5.52 g, 28.4 mmol) in THF (30 mL) over 5 min. The reaction was allowed to warm to room temperature and stirred overnight. The mixture was diluted with DCM (100 mL) and washed with saturated aqueous NaHC03 (3 χ 50 mL) and brine (50 mL). The organic phase was separated, dried over Na2S04, filtered and solvent removed in vacuo to give a brown solid. Purification by flash chromatography eluting with 0-80% EtOAc in Petroleum ether (40-60) gave ethyl 5-(2,4,5-trifluorophenyl)-oxazole-4-carboxylate (3.7 g, 48% yield) as a cream solid. LC-MS (Method C) 272.0 [M+H]+; RT 1.97 min |
48% | With triethylamine In tetrahydrofuran at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: triethylamine / toluene / 18 h / 90 °C 2.1: ethanol; diethyl ether / 3 h / 20 °C 2.2: 16 h / 100 °C 3.1: acetonitrile / Reflux | ||
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 0.03 h / 180 °C / 9050.33 Torr / Flow reactor; Inert atmosphere 2.1: acetonitrile / 0.02 h / 25 °C / Flow reactor; Inert atmosphere 3.1: acetyl chloride; N-ethyl-N,N-diisopropylamine / acetonitrile / 0.02 h / 25 °C / Flow reactor; Inert atmosphere 3.2: 0.03 h / Flow reactor; Inert atmosphere 4.1: acetonitrile; dimethyl sulfoxide / 150 °C / Flow reactor; Inert atmosphere | ||
Multi-step reaction with 2 steps 1.1: lithium hexamethyldisilazane / toluene / 0.5 h / -78 °C 1.2: 2.17 h / -78 - 20 °C 2.1: dimethyl sulfoxide; toluene / 120 °C |
Multi-step reaction with 4 steps 1: triethylamine / toluene / 5 h / 90 °C / Inert atmosphere 2: ethanol; diethyl ether / 3 h / 20 °C 3: potassium carbonate / N,N-dimethyl-formamide / 5 h / 100 °C 4: triethylamine / acetonitrile / 168 h / Reflux | ||
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / 0.03 h / 140 °C / Flow reactor 1.2: 0.02 h / 20 °C / 9050.33 Torr / Flow reactor 2.1: tetra(n-butyl)ammonium hydroxide / water / 0.08 h / 150 °C / Flow reactor | ||
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / 0.03 h / 150 °C / Flow reactor 2: 0.02 h / 20 °C / 9050.33 Torr / Flow reactor 3: tetra(n-butyl)ammonium hydroxide / water / 0.08 h / 150 °C / Flow reactor | ||
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / acetonitrile / 0.03 h / 150 °C / Flow reactor 2: acetonitrile / 0.01 h / 20 °C / Flow reactor 3: tetra(n-butyl)ammonium hydroxide / dimethyl sulfoxide; 2-methyltetrahydrofuran; water / 0.08 h / 150 °C / Flow reactor |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.18 g | With triethylamine In toluene at 90℃; for 18h; | 1 Ethyl α(Z)-[(diethylamino)methylene]-2,4,5-trifluoro-β-oxo-benzenepropanoate An anhydrous CH2Cl2 solution (50 mL) of 2,4,5-trifluorobenzoic acid (3.49 g, 19.81 mmol), oxalyl chloride (2.18 mL, 25.75 mmol) and five drops of DMF was stirred for 24 h at room temperature. The reaction mixture was then subjected to concentrated evaporation under reduced pressure, solubilized in toluene (30 mL) and added dropwise to a toluene solution (20 mL) of triethylamine (8.26 mL, 59.43 mmol) and ethyl 3-(diethylamino)-2E-propenoate (4.40 g, 25.75 mmol). After 18 h of stirring at 90°C, the cooled reaction mixture was washed with water. The organic layer was dried over Na2SO4, filtered and evaporated. The crude residue was purified by flash chromatography on silica gel (95:5 to 60:40 hexane/AcOEt) to give Ethyl α(Z)-[(diethylamino)methylene]-2,4,5-trifluoro-β-oxo-benzenepropanoate (4.180 g, 12.7 mmol, 64% for the two steps) as a colourless oil.1H NMR (400 MHz, CDCl3, δ): 0.97 (t, 3H, OCH2CH3, 3JH-H = 7.1 Hz), 1.03 (br s, 3H, NCH2CH3), 1.33 (br s, 3H, NCH2CH3), 3.45 (br s, 4H, NCH2CH3), 3.98 (q, 2H, OCH2CH3, 3J = 7.1 Hz), 6.87 (Td, 1H, H5, 3JH-F = 9.7 Hz, 4JH-F = 6.3 Hz), 7.45 (m, 1H, H8), 7.75 (s, 1H); 19F NMR (376 MHz, CDCl3, δ): -115.6 (dd, F2, 5JF-F=15.5 Hz, 4JF-F=5.3 Hz), -130.2 (br s, F4); -142.8 (dd, F5, 3JF-F=21.5 Hz, 5JF-F=15.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.9% | With pyridine; dmap at 0 - 60℃; | General Procedure for Preparation of 18,6'-O-Bisallyl-2'-N-acyl Derivatives of Et 770 (4a-k) General procedure: Compound 3 (15.3 mg,0.018 mmol) and DMAP (1.1 mg) were dissolved in pyridine(1.5 mL), and 15 equimolar quantity of an acid chloride wasadded at 0°C. The reaction mixture was heated at 60°C for2 to 3 h. After the solvent was removed in vacuo, the residuewas diluted with water (10 mL) and extracted with chloroform(15 mL×3). The combined extracts were washed with brine(15 mL), dried, and concentrated in vacuo to give a residue.The residue was purified by silica gel column chromatographyusing an appropriate eluent to give the corresponding purifiedproducts (4a-k). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine In dichloromethane at 25℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In diethyl ether; acetonitrile at 0 - 20℃; for 6.75h; Inert atmosphere; | ||
In diethyl ether; acetonitrile at 0 - 20℃; for 6.75h; Inert atmosphere; | 2 [0137] Synthesis of 2-diazo-1-(2,4,5-trifluorophenyl)ethan-1-one (FIG. 28): Under an atmosphere of argon and anhydrous conditions, the No.59 2,4,5-trifluorobenzoyl chloride (87 mg, 0.45 mmol) was dissolved in No.36 MeCN (5 mL) in a 25 mL round bottom flask. No.37 Trimethylsilyl diazomethane (2M solution in No.38 diethyl ether, 0.67 mL, 1.3 mmoles, 3 equiv) was added dropwise via syringe to reaction mixture at 0°C., over 15 minutes. After stirring at 0°C. for 30 minutes, the yellow solution was allowed to warm to ambient temperature and continued stirring (6 h). The MeCN and resulting residue were then removed under reduced pressure (780 mmHg). The 1-(3-chloro-2,4,5,6-tetrafluorophenyl)-2-diazoethan-1-one intermediate was used in the next step of the reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.5 g | Stage #1: ethyl (Z)-3-(cyclopropylamino)acrylate With lithium hexamethyldisilazane In toluene at -78℃; for 0.5h; Inert atmosphere; Stage #2: 2,4,5-trifluorobenzoyl chloride In toluene at -78 - 20℃; for 1h; | 1; 2.2 Ethyl (Z)-3-(cyclopropylamino)-2-(2,4,5-trifluorobenzoyl)acrylate (5) A three necked, dried round bottom flask equipped with a stirring bar and under argon was charged with lithium bis(trimethylsilyl)amide (6.07 mL, 6.07mmoles in toluene) and cooled to -78 °C followed by a slow addition of the acrylate (3) (5.05 mmoles). The resulting bright yellow solution was stirred for 30 mins followed by the dropwise addition of 2,4,5-trifluorobenzoyl chloride (6.07 mmoles). The mixture was allowed to warm to room temperature and stirred for 1 h. After the completion of the reaction, the reaction mixture was quenched with saturated aqueous NH4Cl (10 mL). The organic layer was washed with brine and dried over Na2SO4. The organic solvent was removed under pressure. The crude mixture was purified by flash chromatography on a silica gel column using a mixture of hexanes/EtOAc as eluent resulting in a yellowish powder ( 1.5g, 96%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With triethylamine In acetonitrile at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane at 20℃; for 2h; | General procedure: A mixture of compound 9 (1 equiv) and TFA (14 equiv) in DCM (10mL) was stirred overnight at room temperature. Then the solvent was evaporated. The residue was washed with a saturated solution of aqueous NaHCO3 mand extracted with DCM The organic layer was collected and purified using cyclohexane/acetone (0-30%) to get compound 10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: Ethyl 3-(Cyclopropylamino)-2-propenoate With lithium hexamethyldisilazane In toluene at -78℃; for 0.5h; Stage #2: 2,4,5-trifluorobenzoyl chloride In toluene at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: Ethyl 3-(Cyclopropylamino)-2-propenoate With lithium hexamethyldisilazane In toluene at -78℃; for 0.5h; Stage #2: 2,4,5-trifluorobenzoyl chloride In toluene at -78 - 20℃; for 2.16667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: ethyl 3-(propylamino)acrylate With lithium hexamethyldisilazane In toluene at -78℃; for 0.5h; Stage #2: 2,4,5-trifluorobenzoyl chloride In toluene at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: (E/Z)-ethyl 3-(benzylamino)acrylate With lithium hexamethyldisilazane In toluene at -78℃; for 0.5h; Stage #2: 2,4,5-trifluorobenzoyl chloride In toluene at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: ethyl 3-(cyclohexylamino)acrylate With lithium hexamethyldisilazane In toluene at -78℃; for 0.5h; Stage #2: 2,4,5-trifluorobenzoyl chloride In toluene at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide at 20℃; for 4h; | 4 Synthesis of target compound I (No. 010): Add 10 mL of 10% NaOH solution to a 50 mL three-necked flask, add 0.75 g of glycine to dissolve, slowly add 1.95 g of 2,4,5,-trifluorobenzoyl chloride, stir at room temperature for 4 h, adjust the pH to 1-2 with hydrochloric acid. A white solid was precipitated, and tetrahydrofuran was recrystallized and purified to carry out the next condensation reaction.1.0 mmol of compound VII, 1.0 mmol of the prepared carboxylic acid in 20 mL of CH 2 Cl 2 ,The temperature was controlled at about 0 °C, and 1.2 mmol of EDCI, 2.0 mmol of DIPEA, and 1.2 mmol of HOBt were added in sequence, and the reaction was stirred at room temperature overnight. The reaction solution was washed with 10 mL of 5% HCl solution, 10 mL of 5% NaHCO3 solution, and 10 mL of saturated brine.After washing twice, it was dried over anhydrous Na 2 SO 4 and then spun dry, and the product was isolated by column chromatography. White solid, yield 56%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium t-butanolate In neat (no solvent) at 100℃; for 1h; Inert atmosphere; Microwave irradiation; | General procedure: The reaction methods used for all the reactions shown in Tables2-4 are the same except for cholesterol, 1e where 1.0 mL of 1,4-dioxane was added. An oven dry clean microwave vial is loadedwith 1.0 mmol of NaOtBu (100.0 mg), 0.0025 mmol of PdCl2(dtbpf)(2.0 mg), capped with air-tight silicon septa and flushed withargon. Then 0.5 mmol of aroyl chloride was added as limiting reagentvia micro syringe, and tertiary alcohol (1.0 mL) was added via drysyringe. The resulting reaction mixture was then microwaved(CEM Explorer 24, 300 W) at 100 C for 60 min. Crude reaction productin reaction tube was diluted with dichloromethane and transferredinto a separating funnel. Water was then added to the funneland, after standard extraction, excess alcohol was completely misciblewith water. The bottom organic layer was collected in a smallErlenmeyer flask over anhydrous Na2SO4. The dichloromethanelayer was filtered through sintered funnel and filtrate, collectedin a round bottom flask, and completely dried by rotary evaporator and under reduced pressure in vacuo. In case of cholesterol 1e,0.5 mmol of aroyl chloride, 1.0 mmol of cholesterol, and 1.0 mLof 1,4-dioxane were used. The desired ester product was confirmedby 1H NMR, 13C NMR, and 19F NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.3% | With triethylamine In tetrahydrofuran at 20℃; for 4h; Cooling with ice; | 17 Example 17 Synthesis of compound Iq (R = 2,4,5-trifluorophenyl): The intermediate N-2-hydroxyethyl-1-adamantanecarboxamide (0.335 g, 1.5 mmol) and tetrahydrofuran (14 mL) and the acid binding agent triethylamine (2.8 mmol) were mixed, dissolved by stirring, and in an ice bath condition A solution (7 mL) of 2,4,5-trifluorobenzoyl chloride (1.5 mmol) in tetrahydrofuran was slowly added dropwise. After the dropwise addition, the reaction was carried out at room temperature for 4 hours, and then the triethylamine hydrochloride formed by the reaction was filtered off. The filtrate was subjected to rotary evaporation to remove the solvent tetrahydrofuran. The obtained rotary evaporation residue was separated by column chromatography to obtain a pale yellow solid (eluent was 1: 3 volume ratio of ethyl acetate and petroleum ether), which is2- (1-Adamantanecarboxamido) ethyl 2,4,5-trifluorobenzoate, Calculate the yield of 73.3% |
With triethylamine In tetrahydrofuran at 20℃; for 4h; Cooling with ice; | 17 Example 17 Synthesis of compound Iq (R = 2,4,5-trifluorophenyl): The intermediate N-2-hydroxyethyl-1-adamantanecarboxamide (0.335 g, 1.5 mmol),Tetrahydrofuran (14 mL) and acid binding agent triethylamine (2.8 mmol) were mixed, dissolved by stirring,A solution of 2,4,5-trifluorobenzoyl chloride (1.5 mmol) in tetrahydrofuran (7 mL) was slowly added dropwise under ice bath conditions.After the dropwise addition, the reaction was carried out at room temperature for 4 hours, and then the triethylamine hydrochloride formed by the reaction was filtered off.The obtained rotary distillation residue was separated by column chromatography (eluent was a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 1: 3) to obtain a pale yellow solid.That is, 2,4,5-trifluorobenzoic acid-2- (1-adamantylcarboxamido) ethyl ester, and the yield was calculated to be 73.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium hydroxide In dichloromethane at 0 - 20℃; for 2.5h; | 4.3.1. Preparation of 2,4,5-trifluorobenzamide (2a) (UIAA-I-061) General procedure: Commercially available 2,4,5-trifluorobenzoic acid (1a) (10.1 g,57.4 mmol) was dissolved in 100 mL of distilled DCM and stirred underargon atmosphere. Oxalyl chloride (5.0 mL, 58.300 mmol) was thenadded to the stirring mixture, the solution was allowed to stir for 5 minat room temperature. Anhydrous DMF (0.45 mL, 5.8 mmol) was added,dropwise, to the stirring solution over 35 s, the resulting solution wasallowed to stir at room temperature for 2 h. The DCM was removedfrom the reaction mixture by rotary evaporation, the resulting oil wasreconstituted in 100 mL of DCM and placed in an ice bath to coolto ~ 0 °C. Ammonium hydroxide (40 mL, 28-30% ammonia) wasadded, dropwise, to the cool stirring solution over 2 min, the resultingmixture was allowed to stir for 2.5 h, gradually warming up to roomtemperature. The product was extracted by washing the aqueous layerwith 100 mL of DCM and then 150 mL of ethyl acetate. The organiclayers were pooled and concentrated by rotary evaporation, the resultingsolid was triturated with 9:1 hexanes:ethyl acetate and subjectedto vacuum filtration, which yielded UIAA-I-061 (2a) as a pureyellow solid. 84% yield. 1H NMR (300 MHz, CDCl3) δ = 8.01 (ddd,J = 7.17, 8.94, 10.62 Hz, 1H), 7.05 (ddd, J = 6.05, 9.51, 10.83 Hz,1H), 6.66 (bs, 1H), 6.03 (bs, 1H). 19F NMR (282 MHz, CDCl3)δ = -113.67 (m, 1F), -125.90 (ddd, J = 9.08, 17.12, 21.57 Hz, 1F),-140.15 (m, 1F). HRMS (ESI) calculated for (M + H+) 176.0318,found 176.0323. Retention time (analytical HPLC) = 12.3 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.43% | With pyridine In dichloromethane at 25℃; for 16h; Inert atmosphere; | 16.B Step B N-(2-Chloro-6-fluorophenyl)-2.4.5-trifluorobenzamide. To a mixture of 2- chloro-6-fluoro-aniline (3.86 g, 26.53 mmol) and pyridine (8.74 g, 110.53 mmol) in DCM (45 mL) was added a solution of 2,4,5-trifluorobenzoyl chloride (4.30 g, 22.11 mmol) in DCM (5 mL). The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by addition of ThO (70 mL). The mixture was extracted with DCM (60 mL c 2). The combined organic layers were washed with brine (100 mL), dried over NaiSCL, fdtered and concentrated under reduced pressure. The residue was triturated with petroleum ether/ethyl acetate (10: 1,30 mL) to afford the title compound (5.6 g, 18.44 mmol, 83.43% yield) as white solid. MS (ESI): mass calcd. forC13H6CIF4NO, 303.0; m/z found, 304.0 [M+H]+. NMR (400MHz, CDCL) d = 8.06 (ddd, J =12, 8.9, 10.4 Hz, 2H), 7.33 - 7.27 (m, 2H), 7.19 - 7.06 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethyl acetoacetate With sodium carbonate In acetonitrile at 0 - 20℃; for 1h; Stage #2: 2,4,5-trifluorobenzoyl chloride In acetonitrile at 0 - 70℃; for 7h; Overall yield = 98.4 percent; | 3-13 Preparation of a mixture of compound 1 and compound 5 Add 500ml acetonitrile, 12.2g (0.114mol) sodium carbonate to a 1000ml three-necked flask successively, control the temperature in an ice bath to 0-5, add 81.25g (0.625mol) ethyl acetoacetate,After stirring for 1 h, 110.4 g (0.57 mol) of 2,4,5 trifluorobenzoyl chloride prepared according to the method in Example 1 was added dropwise, and the temperature was controlled at 0°C-5°C during the dropping process, and the addition was completed in 30 minutes. Incubate at about 5°C for 2 hours, then warm to room temperature, and hold for 5 hours to obtain compound 4. The reaction system does not undergo any post-treatment, heated at 70°C, reacted for 5 hours, sampled and controlled by TLC, cooled to room temperature, filtered to remove residue, and recovered solvent 138.6 g crude product of compound 1 and compound 5 enol isomer mixture was obtained, with a yield of 98.4%, and the ratio of compound 5: compound 1 was 24:75 by HPLC. The liquid chromatogram of the crude product is shown in Figure 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | Stage #1: 2,4,5-trifluorobenzoyl chloride With selenium; sodium tetrahydroborate In water at 50 - 70℃; for 1.5h; Stage #2: chloroacetone In water at 20 - 50℃; for 2h; Cooling; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide | 1 Step 1. Step 1. (S)-2,4,5-trifluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide (Compound 1a) A mixture of (2S)-1,1,1-trifluoropropan-2-amine (520.96 g, 4.61 mol) in toluene (9.7 L) was cooled to 0° C.-5° C. before a solution of 1.0 M sodium hydroxide aqueous solution (6.92 L, 6.92 mol, 1.5 equiv) was added at 0° C.-8° C. 2,4,5-Trifluorobenzoyl chloride (995.62 g, 5.07 mol, 1.1 equiv) was then added dropwise to the mixture at 0° C.-15° C. over 20 min. The cooling bath was removed and the reaction mixture was warmed to room temperature and stirred at room temperature for an additional 1 h. The two phases of the reaction mixture were then separated. The organic phase was washed with 0.5 M aqueous sodium hydroxide solution (4.6 L) and concentrated under reduced pressure to afford the crude product as a white solid. The solid was then slurried in n-heptane (2.3 L) at 50° C. for 1 h, then cooled to room temperature. The solids were collected by filtration, washed with n-heptane (1 L), and dried under vacuum for 2 days to give (S)-2,4,5-trifluoro-N-(1,1,1-trifluoropropan-2-yl)benzamide (1203.7 g, 93.2%) as a white powder. 1HNMR (300 MHz, DMSO-d6) δ 9.00 (d, J=8.09 Hz, 1H), 7.69 (m, 2H), 4.75 (m, 1H), 1.92 (d, J=7.00 Hz, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With triethylamine In dichloromethane at 20℃; | 12.3 (3) N'-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)-2-methylbenzoyl)-2,4,5-trifluorobenzoylhydrazide: The 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)-2-methylbenzoylhydrazide (0.431g, 1mmol), triethylamine (0.224g, 1.3mmol) was added to a 100mL three-mouth round-bottom flask, 10mL of dichloromethane was added, and 2,4,5-trifluorobenzoyl chloride (0.252g, 1.3mmol) of dichloromethane solution was added dropwise, and the reaction at room temperature was 8 to 12h. After the end of the reaction, the reaction mixture was desolubled under reduced pressure, the silica gel was mixed, and the chromatography column was separated to obtain a yellow solid of 0.295g, and the yield was 50%. |
Tags: 88419-56-1 synthesis path| 88419-56-1 SDS| 88419-56-1 COA| 88419-56-1 purity| 88419-56-1 application| 88419-56-1 NMR| 88419-56-1 COA| 88419-56-1 structure
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 :