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CAS No. : | 129714-97-2 | MDL No. : | MFCD00010309 |
Formula : | C7H3ClF2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OYZWEOORLJBPMA-UHFFFAOYSA-N |
M.W : | 176.54 | Pubchem ID : | 145600 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 36.54 |
TPSA : | 17.07 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.51 cm/s |
Log Po/w (iLOGP) : | 1.84 |
Log Po/w (XLOGP3) : | 2.63 |
Log Po/w (WLOGP) : | 3.18 |
Log Po/w (MLOGP) : | 2.9 |
Log Po/w (SILICOS-IT) : | 3.18 |
Consensus Log Po/w : | 2.75 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.93 |
Solubility : | 0.208 mg/ml ; 0.00118 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.64 |
Solubility : | 0.406 mg/ml ; 0.0023 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.52 |
Solubility : | 0.0536 mg/ml ; 0.000303 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.27 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P261-P280-P305+P351+P338-P310 | UN#: | 3265 |
Hazard Statements: | H227-H314-H335 | 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 |
---|---|---|
85.5% | With sodium hydroxide In water at 15 - 20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride; for 5h;Reflux; | 1 l (5.0 g, 31.6 mmol) of <strong>[455-40-3]3,5-difluorobenzoic acid</strong> was dissolved in 50 mL of thionyl chloride and refluxed for 5 hours. Concentration under reduced pressure and removal of thionyl chloride afforded crude 3,5-difluorobenzoyl chloride 11a (5.56 g, yellow oil). Yield: 100%. |
90% | With thionyl chloride; In dichloromethane; at 80℃; for 18h; | To a solution of <strong>[455-40-3]3,5-difluorobenzoic acid</strong> (10 g, 63.2 mmol) in DCM (20 mL) was added thionyl chloride (SOCl2, 10 mL). The mixture was heated to 80 ºC for 18 h. The solution was concentrated to afford 3,5-difluorobenzoyl chloride (10 g, 90%). |
86.6% | With thionyl chloride; In N,N-dimethyl-formamide; toluene; for 4h;Reflux; | <strong>[455-40-3]3,5-difluoro-benzoic acid</strong> 70g, thionyl chloride 105g, toluene and DMF of 250mL was added to the reaction bottle. The mixture was heated to reflux for 4 hours. After cooling, the mixture is vacuum distilled, the compound b2 (pink fluid) was obtained in 86.6% yield. |
82% | With thionyl chloride; | Step 1: <strong>[455-40-3]3,5-difluoro-benzoic acid</strong> chloride 1.63 g (10.00 mmol) <strong>[455-40-3]3,5-difluoro-benzoic acid</strong> were mixed with 20 mL thionyl chloride and boiled for 2 h. The reaction mixture was evaporated to dryness and coevaporated twice with toluene. The residue was reacted further as the crude product. Yield: 1.45 g (82% of theoretical) |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere; | General procedure: Acid chlorides were prepared by treating the parent acids (1 .1 mmol) in CH2CI2 (10 mL) at 0 C with oxalyl chloride (1 .0 mL, 1 1 mmol) followed by DMF (1 drop) and stirred at room temperature for 2 h followed by concentrating under a stream of nitrogen to afford acyl chlorides of general structure (2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium hydroxide In ethyl acetate for 0.166667h; | ||
With ammonium hydroxide In tetrahydrofuran at 0℃; Yield given; | ||
With ammonium hydroxide In dichloromethane at 0 - 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In toluene Ambient temperature; | |
97% | In toluene at 20℃; for 1.5 - 4h; | General Procedure for Synthesis of Morpholine Amides 6a-g.Two equivalents of morpholine were slowly injected via syringe over a 5 min period to a 0.3 M solution of the acid chloride in toluene (under Ar). The reaction mixture was stirred at room temperature until the starting acid chloride was consumed (approx. 1.5-4 h, according to TLC using 3:1 hexane-ethyl acetate). The solution was filtered through a pad of celite to remove morpholine hydrochloride, and the pad washed with toluene. The filtrate was concentrated to an oil that was subjected to flash column chromatography. Concentration of the respective fractions led to the respective amides (Table 1). 6f and 6g were synthesized from the acid chloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 95% 2: 2% | With acetylacetonatodicarbonylrhodium(l); triphenylphosphine In toluene at 140℃; for 6h; | |
1: 23% 2: 9% | With acetylacetonatodicarbonylrhodium(l); diphenyl(methyl)phosphine In toluene at 80℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine In chloroform at 0 - 20℃; for 1.58333h; | |
89% | With pyridine In dichloromethane at 20℃; for 12h; | 11.2 3,5-difluoro-N-methoxy-N-methylbenzamide 5-Fluorobenzoyl chloride 11a (5.56 g, 31.6 mmol), N,O-dimethylhydroxylamine hydrochloride (3.08 g, 31.6 mmol) and pyridine (2.5 g, 31.6 mmol) were dissolved in 50 mL of dichloro In methane, the reaction was carried out for 12 hours at room temperature. The residue was purified by silica gel column chromatography (eluent: A) to give 3,5-difluoro-N-methoxy-N-methylbenzamide 11b (5.6 g, Yellow oil), yield: 89%. |
75% | Stage #1: N,O-dimethylhydroxylamine*hydrochloride With triethylamine In dichloromethane at 0℃; Inert atmosphere; Stage #2: 3,5-difluorobenzoyl chloride In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 4-methyl-morpholine; 1,3-bis[(2,6-diisopropyl)phenyl]imidazolinium chloride In xylene at 120℃; for 3.5h; | |
80% | With 4-methyl-morpholine In para-xylene at 120℃; for 3.5h; | 19 19. Preparation of 3,5,4'-trifluorostilbene A 25 mL round bottom flask was charged with p-xylene (10 mL), Pd(OAc)2 (11.3 mg, 0.05 mmol), 1,3-bis-(2,6-diisopropylphenyl) imidazolinium chloride (21.4 mg, 0.05 mmol), 3,5-difluorobenzoyl chloride (0.89 g, 5 mmol), 4-fluorostyrene (0.74 g, 6 mmol), and N-methyl morpholine (0.69 g, 6 mmol). The mixture was stirred at 120° C. for 3.5 h under nitrogen atmosphere. Then it was cooled to room temperature and EtOAc was added and filtered. The filtrate was washed with brine and dried over Na2SO4. Then it was filtered and purified via flash chromatography and gave the product (0.94 g, 80%) as white solid. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.47 (m, 2H), 7.08-6.88 (m, 6H), 6.70 (tt, 1H); 13C NMR (CDCl3, 75 MHz) δ 163.52 (dd), 162.98 (d), 140.82 (t), 132.77, 130.26, 128.58 (d), 126.53, 116.03 (d), 109.20 (q), 102.98 (t); 19F NMR (CDCl3, 282 MHz) δ-31207.2 (q, 2F), -31965.6 (q, 1F); HRMS (EI+) found 234.0645 M+, calcd 234.0656 for C14H9F3. |
48% | With N-ethylmorpholine;; palladium diacetate In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With 4-methyl-morpholine; 1,3-bis[(2,6-diisopropyl)phenyl]imidazolinium chloride In xylene at 120℃; for 3.5h; | |
74% | With 4-methyl-morpholine In para-xylene at 120℃; for 3.5h; | 20 20. Preparation of 4'-acetoxy-3,5-difluorostilbene A 25 mL round bottom flask was charged with p-xylene (10 mL), Pd(OAc)2 (11.3 mg, 0.05 mmol), 1,3-bis-(2,6-diisopropylphenyl) imidazolinium chloride (21.4 mg, 0.05 mmol), 3,5-difluorobenzoyl chloride (0.89 g, 5 mmol), 4-acetoxystyrene (0.97 g, 6 mmol), and N-methyl morpholine (0.69 g, 6 mmol). The mixture was stirred at 120° C. for 3.5 h under nitrogen atmosphere. Then it was cooled to room temperature and EtOAc was added and filtered. The filtrate was washed with brine and dried over Na2SO4. Then it was filtered and purified via flash chromatography and gave the product (1.02 g, 74%) as white solid. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.51 (d, J=8.4 Hz, 2H), 7.12-6.97 (m, 6H), 6.70 (t, 1H), 2.31 (s, 3H). |
58% | With N-ethylmorpholine;; palladium diacetate In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With aluminum (III) chloride In 1,2-dichloro-ethane at 20℃; | 59 A round-bottomed flask was charged with 330 mg (0.99 mmol) of 3-chloro-(2,4-dichlorobenzenesulfonamido)benzene (58.1), 397 mg (2.97 mmol, Aldrich Chemical Co.) of anhydrous aluminum trichloride, and 2 mL of dry dichloroethane. Then 210 mg (1.19 mmol, Aldrich Chemical Co.) of 3,5-difluorobenzoyl chloride was added dropwise and the deep red solution was allowed to stir at room temperature overnight. The reaction was then diluted with 30 mL of methylene chloride, washed consecutively with 2N HCl and brine, dried over MgSO4, and concentrated to a dark oil. This was further purified by silica gel flash chromatography (eluting with 1:24 ethyl acetate:methylene chloride). The resulting clear glaze was recrystallized from ether/hexanes to yield 273 mg (58%) of a white solid. 1H NMR (400 MHz) (d6-DMSO) δ 8.15 (1H, d, J=8.5 Hz); 7.91 (1H, d, J=2.1 Hz); 7.68 (1H, dd, J=8.6 Hz, 2.1 Hz); 7.63 (1H, t, J=8.6 Hz); 7.46 (1H, d, J=8.4 Hz); 7.31 (2H, dd, J=7.8 Hz, 2.1 Hz); 7.23 (1H, d, J=1.9 Hz); 7.17 (1H, dd, J=8.4 Hz, 2.2 Hz). MS ESI m/e: 473.9 (M-H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.7% | With triethylamine In dichloromethane at 0 - 20℃; for 1.5h; | 2 Preparation of N-[4-((1R)-1-methyl-2-[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide, Method B Scheme I, step H: To a 0 C. solution of [(2R)-2-(4-aminophenyl)propyl][(methylethyl)sulfonyl]amine (21.5 g, 0.0838 mol) and triethylamine (9.75 g, 13.4 mL, 0.0964 mol) in CH2Cl2 (86 mL) was added 3,5-difluorobenzoyl chloride (16.3 g, 0.0922 mol) dropwise over 30 min. After the addition was complete, the reaction mixture was stirred at 20 C. for 1 hour. The reaction mixture was washed with deionized water (2100 mL) and 0.1 N HCl (2100 mL). The organic phase was diluted with acetone (50 mL) to ensure complete dissolution of the product and the organic phase was washed with saturated K2CO3 (100 mL), 0.1 N HCl (100 mL), dried (MgSO4, 3 g), filtered and co-evaporated with EtOAc to afford an oil. This oil was diluted with diethyl ether (125 mL), which induced crystallization. The solids were collected by filtration, washed with diethyl ether (220 mL), and dried under reduced pressure at room temperature overnight to afford N-[4-((1R)-1-methyl-2-[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide (31.8 g, 95.7%) as a white crystalline powder. An analytical sample was prepared via recrystallization from EtOAc. Thus, a clear solution of N-[4-((1R)-1-methyl-2-[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide (28 g) was achieved in refluxing EtOAc (90 mL, minimum amount). This solution was allowed to cool over 2 hour to room temperature without stirring. The resulting dense mass was pulvarized with a glass rod and recovered by filtration. The collected solids were reslurried in diethyl ether, filtered and dried under reduced pressure to afford N-[4-((1R)-1-methyl-2-[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide (22.2 g, 79% recovery) as a white crystalline powder. In addition, the final title compound, N-[4-((1R)-1-methyl-2-[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide, can be jet milled by one of ordinary skill in the art, for example, with a Model 4 SDM Micronizer by Sturtevant Inc. to provide compound with a mean particle size of about 5.5 microns. |
79% | In dichloromethane; water at -10 - 20℃; | 2 Preparation of N-[4-((1R)-1-methyl-2-[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide, Method A Scheme I, step H: [(2R)-2-(4-aminophenyl)propyl][(methylethyl)sulfonyl]amine p-toluenesulfonate (60.0 g, 0.140 mol), suspended in dichloromethane (375 mL), was treated with saturated aqueous NaHCO3 in an amount sufficient to bring the salt into solution. The organic phase was separated and washed twice with aqueous NaHCO3. HPLC analysis showed complete removal of p-toluenesulfonate from the organic phase. The organic phase was dried (MgSO4), filtered, and chilled to -10 C. 3,5-difluorobenzoyl chloride (27.2 g, 0.154 mol) was added dropwise over 10 min and the mixture was allowed to warm to room temperature with stirring overnight. After completion of reaction, the mixture was diluted with water (100 mL) and acetone (75 mL). The phases were separated, and the organic phase was washed with 0.1N HCl (2100 mL), 0.01N NaOH (3100 mL), and 0.1 N HCl (1100 mL). The organic phase was separated and concentrated to a solid. The solid was resuspended in ethyl acetate and co-evaporated twice with ethyl acetate (260 mL) to remove traces of dichloromethane. The residue was transferred to a 500 mL flask with ethyl acetate (150 mL) and this mixture was heated to reflux to afford a clear solution. The solution was allowed to cool to room temperature over 5 hours, and the suspension was left to stir slowly overnight. The suspension was cooled to 0 C. and stirred for 1 hour. The product was collected by filtration and was vacuum dried to afford N-[4-((1R)-1-methyl-2-[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide (43.9 g, 79.0%) as a white crystalline solid. 1H NMR (CDCl3, 300 MHz) ? 7.80 (s, 1H), 7.59 (d, 2H, J=8.4), 7.40 (m, 2H), 7.23 (d, 2H, J=8.7), 7.01 (tt, 1H, J=2.1, 8.7), 3.87 (dd, 1H, J=5.1, 7.5), 3.36 (m, 1H), 3.21 (m, 1H), 3.09 (m, 1H), 2.98 (m, 1H), 1.32 (d, 3H, J=6.6), 1.30 (d, 3H, J=7.2), 1.28 (d, 3H, J=6.6). |
79% | With triethylamine In dichloromethane at 0 - 20℃; for 1.5h; | 2 Preparation of N-[4-((1R)-1-methyl-2-[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide, Method B Scheme I, step H: To a 0 C. solution of [(2R)-2-(4-aminophenyl)propyl][(methylethyl)sulfonyl]amine (21.5 g, 0.0838 mol) and triethylamine (9.75 g, 13.4 mL, 0.0964 mol) in CH2Cl2 (86 mL) was added 3,5-difluorobenzoyl chloride (16.3 g, 0.0922 mol) dropwise over 30 min. After the addition was complete, the reaction mixture was stirred at 20 C. for 1 hour. The reaction mixture was washed with deionized water (2100 mL) and 0.1 N HCl (2100 mL). The organic phase was diluted with acetone (50 mL) to ensure complete dissolution of the product and the organic phase was washed with saturated K2CO3 (100 mL), 0.1 N HCl (100 mL), dried (MgSO4, 3 g), filtered and co-evaporated with EtOAc to afford an oil. This oil was diluted with diethyl ether (125 mL), which induced crystallization. The solids were collected by filtration, washed with diethyl ether (220 mL), and dried under reduced pressure at room temperature overnight to afford N-[4-((1R)-1-methyl-2-[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide (31.8 g, 95.7%) as a white crystalline powder. An analytical sample was prepared via recrystallization from EtOAc. Thus, a clear solution of N-[4-((1R)-1-methyl-2-[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide (28 g) was achieved in refluxing EtOAc (90 mL, minimum amount). This solution was allowed to cool over 2 hour to room temperature without stirring. The resulting dense mass was pulvarized with a glass rod and recovered by filtration. The collected solids were reslurried in diethyl ether, filtered and dried under reduced pressure to afford N-[4-((1R)-1-methyl-2-[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide (22.2 g, 79% recovery) as a white crystalline powder. In addition, the final title compound, N-[4-((1R)-1-methyl-2-[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide, can be jet milled by one of ordinary skill in the art, for example, with a Model 4 SDM Micronizer by Sturtevant Inc. to provide compound with a mean particle size of about 5.5 microns. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triethylamine In dichloromethane at 20℃; for 1h; | 1 The title compound is prepared in a manner analogous to the procedure described at Example 196 in International Patent Application Publication WO 98/33496 published Aug. 6, 1998 from 3,5-difluorobenzoyl chloride. Alternatively, the title compound can be prepared in a manner analogous to the procedures described generally in Schemes I and II, and more specifically as described in examples 2 and 3 below without employing the resolution steps as would be appreciated by one of ordinary skill in the art. More specifically, into a 500 mL 3-neck flask fitted with a stirrer and thermometer, 3,5-difluorobenzoyl chloride (1.13 g) was added dropwise to a stirred solution of [2-(4-aminophenyl)propyl][(methylethyl)sulfonyl]amine (1.50 g) and triethylamine (625 mg) in methylene chloride (200 mL) at room temperature and under a nitrogen atmosphere. After stirring one hour at this temperature, TLC showed that the starting aniline had been consumed. The organic layer was washed once with water, dried over potassium carbonate, and concentrated under reduced vacuum to yield the crude material (2.61 g) as a solid. This crude material was purified by recrystallization from hexane/ethyl acetate 1:1 to yield the title compound (1.64 g, 71%)) as yellow crystals. M.P. 158 C.-160 C. Ion spray M.S. 397.1 (M*+1). Calculated for C19H22N2O2SF2H2O: Theory: C, 55.03, H, 5.83, N, 6.76. Found: C, 54.63, H, 5.84, N, 6.61. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.9% | With triethylamine In dichloromethane at 20℃; | 3 Scheme II, step H: A 500 mL three necked round bottom flask equipped with a magnetic stirrer, thermometer, addition funnel and a positive nitrogen was charged with [(2R)-2-(4-nitrophenyl)propyl][(methylethyl)sulfonyl]amine (12.02 g, 46.85 mmol) and methylene chloride (200.0 mL). To this solution was added triethylamine (6.53 mL, 46.85 mmol) all at once. The solution was stirred for 10 minutes then added dropwise, neat 3,5-difluorobenzoyl chloride (5.9 mL, 46.85 mmol) over a period of 20 minutes. The reaction exothermed to reflux by the end of addition. Stirred to room temperature over the weekend for convenience. Quenched reaction with 1N HCl (100.0 mL) and separated lower organic layer. Washed the organic layer with 25% brine (70.0 mL) and dried with anhydrous magnesium sulfate. Filtered precipitates and concentrated filtrate to a tan oil (20.0 g). To this oil was added 1:1 ethyl acetate/hexane (125.0 mL) with stirring. A massive off white precipitate formed. The precipitate was then filtered and the cake washed with 1:1 ethyl acetate/hexane (50.0 mL). Precipitate was then dried in a house vacuum oven at 40° C. to provide N-[4-((1R)-1-methyl-2-[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide (15.02 g, 80.9%); 1H NMR (CDCl3, 300 MHz) δ 1.26-1.27 (d, 6H), 1.29-1.30 (d, 2H), 2.92 (m, 1H), 3.10 (m, 1H), 3.20 (1H), 3.3-3.4 (m, 1H), 7.0 (triplet, 1H), 7.20 (d, 2H), 7.40 (d, 2H), 7.60 (m, 2H), 8.19 (s, 1H); 13C NMR (CDCl3, 300 MHz) δ 17.19, 17.30, 19.75, 41.03, 50.99, 54.15, 107.68, 107.86, 108.08, 111.12, 111.33, 121.81, 128.59, 136.97, 138.77, 140.51, 162.62, 162.71, 164.12, 164.61, 164.71. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In dichloromethane; water; methoxybenzene; 1,2-dichloro-ethane | 1.1 Stage 1. Stage 1. Synthesis of 3,5-difluoro-4-methoxybenzophenone A 3-necked flask was charged with 30 ml of 1,2-dichloroethane, 7.6 g (70.0 mmol) of anisole, and 9.7 g (73.0 mmol) of aluminum chloride (AlCl3), a catalyst for Friedel-Crafts acylation reaction. While purging the flask at room temperature with an argon gas, a solution containing 10.0 g (56.6 mmol) of 3,5-difluorobenzoylchloride dissolved in 15 ml of 1,2-dichloroethane was added dropwise to the flask and left for 14 hours for reaction. Subsequently, 20 ml of deionized water was added to the flask and stirred for 15 hours. The reaction product was poured into 200 ml of deionized water and washed three times, each time with 100 ml of methylene chloride, to extract 3,5-difluoro-4-methoxybenzophenone. The solvent was evaporated from the reaction product to give the 3,5-difluoro-4-methoxybenzophenone in a yield of 97%. |
97% | In dichloromethane; water; methoxybenzene; 1,2-dichloro-ethane | 2.1 Stage 1. Stage 1. Synthesis of 3,5-difluoro-4-methoxybenzophenone A 3-necked flask was charged with 30 ml of 1,2-dichloroethane, 7.6 g (70.0 mmol) of anisole, and 9.7 g (73.0 mmol) of AlCl3, a catalyst for Friedel-Crafts acylation reaction. While purging the flask at room temperature with an argon gas, a solution containing 10.0 g (56.6 mmol) of 3,5-difluorobenzoylchloride dissolved in 15 ml of 1,2-dichloroethane was added dropwise to the flask and left for 4 hours for reaction. Subsequently, 20 ml of deionized water was added to the flask and stirred for 15 hours. The reaction product was poured into 200 ml of deionized water and washed three times, each time with 100 ml of methylene chloride, to extract 3,5-difluoro-4-methoxybenzophenone. The solvent was evaporated from the reaction product to give the 3,5-difluoro-4-methoxybenzophenone in a yield of 97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With pyridine at 20℃; for 3h; | 26.3 [0191] (3) To a mixture of 3,5-difluorobenzoyl chloride (1.67 g) and pyridine (8.5 ml) was added portionwise the compound (1.01 g) obtained in the above (2), followed by 3 hours of stirring at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The obtained organic layer was washed with water, saturated ammonium chloride aqueous solution and saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain 2-[1-(3,5-difluorobenzoyl)-1H-benzimidazol-2-yl]-1-phenylvinyl 3,5-difluorobenzoate (1.45 g, 65%) as yellowish white powdery crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 20h; | 51 EXAMPLE 51; Methyl ({4-[4-(3,5-difluorobenzoyl)piperazin-1-yl]-6-ethylthieno[2,3-d]pyrimidin-2-yl}thio)acetateTo a mixture of the hydrochloride salt of Example 34 (0.075 g) in DMF (2.5 m L) in a 2 dram screw cap vial was added diisopropylethylamine (0.104 g) and 3,5-difluorobenzoyl chloride (0.042 g). The mixture was placed in a Lab-Line MAX Q2000 orbital shaker for 20 hours at which time the mixture was partitioned between brine and ethyl acetate. The layers were separated and the organic layer washed four times with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel using 65% ethyl acetate in hexanes as eluent to give 0.063 g (66%) of the title compound: MS (ESI+) for C22 H22 F2 N403 S2 m/z 493.12 (M+H)+. 1H NMR (CDCI3) δ 1.33 (t, 3 H), 2.86 (q, 2 H), 3.58 (m, 2 H), 3.72 (s, 3 H), 3.8-3.97 (m, 8 H), 6.84 (s, 1 H), 6.91 (m, 1 H), 6.98 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | 5.130 5.130 N-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1,3-DIOXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLMETHYL]-3,5-DIFLUORO-BENZAMIDE To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml) was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 3,5-difluorobenzoyl chloride (0.5 g, 2.8 mmol). The reaction mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was then quenched with MeOH (1 mL) and washed with H2O (40 mL), 1N HCl (40 mL) and brine (40 mL). The organic layer was dried over MgSO4 and concentrated in vacuo, and the resulting mixture was purified by ISCO silica gel flash chromatography (eluent: 3% MeOH in CH2Cl2 for 10 min, then 5% MeOH in CH2Cl2 for 10 min) to afford N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3,5-difluoro-benzamide as a white solid (0.5 g, 54%): mp, 218-220° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.4 min. (99%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.53-2.65 (m, 2H), 2.85-2.93 (m, 1H), 4.96 (d, J=5.8 Hz, 2H), 5.15-5.21(dd, J=5, 12 Hz, 1H), 7.46-7.84 (m, 6H), 9.33 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.96, 30.92, 38.49, 48.86, 106.93, 110.58, 110.69, 110.82, 110.93, 121.99, 127.21, 131.54, 133.20, 134.83, 137.42, 138.62, 160.51, 160.67, 163.78, 163.95, 164.10, 166.92, 167.48, 169.81, 172.73. Anal Calcd for C21H15F2N3O5: C, 59.02; H, 3.54; N, 9.83. Found: C, 58.90; H, 3.15; N, 9.73. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine In dichloromethane at 0℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydroxide In dichloromethane; water at 0℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
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77% | Stage #1: 5-(4-azidophenyl)-2-(di-tert-butoxycarbonylamino)imidazole-1-carboxylic acid tert-butyl ester With hydrogen In tetrahydrofuran at 20℃; for 12h; Stage #2: 3,5-difluorobenzoyl chloride With triethylamine In tetrahydrofuran; dichloromethane at -78℃; for 0.5h; | 4 To a solution of anhydrous THF (5 mL) and 10% Pd/C (0.010 g) was charged 5-(4-azido-phenyl)-2,2-tert-butoxycarbonylaminoimidazole-l -carboxylic acid tert-butyl ester (0.100 g, 0.200 mmol). Air was removed from the system and the reaction was back flushed with hydrogen. This process was repeated three times before setting the reaction under a hydrogen balloon at atmospheric pressure and temperature for 12 h. After that time, the reaction was filtered to remove the catalyst. The filtrate was cooled to -78 °C and triethylamine (0.027 mL, 0.200 mmol) was added prior to the drop-wise addition of 3,5-difiuorobenzoyl chloride (0.035 g, 0.200 mmol) diluted in anhydrous dichloromethane (0.50 mL). The reaction was stirred at -78 0C for 30 mins and then quenched with methanol (1 mL) before being concentrated under reduced pressure and purified by flash column chromatography (10-40% EtOAc/Hexanes) to obtain the title compound 2,2-tert-butoxycarbonylamino-5-[4-(3,5- difluorobenzoylamino)phenyl]imidazole-l-carboxylic acid tert-butyl ester (0.094 g, 77%) as a pale yellow solid: 1H NMR (300 MHz, DMSO-J6) δ 10.42 (s, IH), 8.08 (s, IH), 7.82 (m, 4H), 7.69 (m, 2H), 7.54 (m, IH), 1.57 (s, 9H), 1.38 (s, 18H); 13C NMR (I OO MHZ, CD3OD) δ 165.8, 163.2, 151.0, 147.7, 140.1, 139.6, 130.0, 126.7, 122.4, 114.7, 111.9, 108.1, 88.2, 85.7, 28.3; HRMS (ESI) calcd for C3IH36F2N4O7 (M+) 614.2552, found 614.2554. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With triethylamine In dichloromethane at 20℃; | 6 N-(2-azidoethyl)-3,5-difluorobenzamide: As in the synthesis of N-(2-azidoethyl)tetradecanamide, 3,5-difluorobenzoyl chloride (0.219 g, 1.24 mmol) was reacted with 2-azidoethanamine (0.107 g, 1.24 mmol) and triethylamine (0.251 g, 2.48 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-3,5-difluorobenzamide (0.280 g, 59%). 1H NMR (300 MHz, CDCl3) δ 7.32 (s, 2H), 7.29 (s, 1H), 6.91 (t, 1H), 3.58 (q, 2H), 3.51 (t, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 165.9, 164.7, 161.5, 161.4, 137.6, 110.7, 106.9, 50.7, 39.9 ppm; HRMS (ESI) calcd for C9H8F2N4O2S (M+) 226.0666, found 226.0662. |
59% | With triethylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrazine hydrate In ethanol at 80℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine In tetrahydrofuran at 20℃; | 3.B To a solution of ethyl isocyanoacetate (3.23 g, 28.3 mmol) and triethylamine (Et3N, 8.6 g, 84.9 mmol) in THF (20 mL) was added a solution of 3,5-difluorobenzoyl chloride (5 g, 28.3 mmol) in THF dropwise. After stirring at room temperature for 48 h, the mixture was diluted with water and extracted with EtAOc (50 mL x 2), dried over Na2Sθ4 and concentrated to afford the crude product which was washed with hexanes to obtain ethyl 5-(3,5-difiuorophenyl)-1,3-oxazole-4-carboxylate (5 g, 70 %) as a yellow solid. MS(ES) m/e 254 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With N-ethyl-N,N-diisopropylamine In methanol at 23℃; for 2h; Inert atmosphere; | 41 3,5-Difluorobenzoyl chloride (1.9 μL, 0.013 mmol, 2.0 equiv) was added to a solution of CSa-aminomethylminocycline trifluoroacetate 49 (4.0 mg, 0.0067 mmol, 1 equiv) and N,N-diisopropylethylamine (4.6 μL, 0.027 mmol, 4.0 equiv) in methanol (200 μL) at 23 0C. The reaction mixture was stirred at this temperature for 2 h, then was concentrated. The product was purified by preparatory HPLC on an Agilent Prep C 18 column [10 μm, 250 x 21.2 mm, UV detection at 350 nm, Solvent A: 0.1% trifluoroacetic acid in water, Solvent B: acetonitrile, injection volume: 5.0 mL (4.0 mL 0.1% trifluoroacetic acid in water, 1.0 mL acetonitrile), gradient elution with 5->;40% B over 50 min, flow rate: 7.5 mL/min]. Fractions eluting at 43-45 min were collected and concentrated, affording C5a-Ν-3,5- difluorobenzoylaminomethylrninocycline trifluoroacetate 54 as a yellow solid (1.5 mg, 30%). 1H NMR (600 MHz, CD3OD, trifluoroacetate) δ 7.70 (d, IH, J= 9.0 Hz), 7.37-7.34 (m, 2H), 7.19-7.14 (m, IH), 6.95 (d, IH, J= 9.0 Hz), 3.95 (s, IH), 3.74 (d, IH, J= 14.4 Hz), 3.40-3.33 (m, 2H), 3.26 (d, IH, J= 13.8 Hz), 3.13 (s, 6H), 3.01 (s, 6H), 2.62 (d, IH, J = 16.2 Hz), 2.20 (dd, IH, J= 13.8, 2.4 Hz), 1.75 (t, IH, J= 13.8 Hz); HRMS-ESI (m/z): [M+H]+ calcd for C3]H33F2N4O8, 627.2261 ; found 627.2123. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In tetrahydrofuran at 20℃; for 4h; | 4.1.3. General procedure for synthesis of 8-21 General procedure: To the solution of 7 in THF, various acid chlorides (1.0 equiv) were added. Reaction mixture was allowed to stir for 4 h at room temperature. Solvent was evaporated under vacuum and crude product was washed with n-hexane to yield 8-21 in 74-97% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: 4-amino-5-fluoro-pyrimidin-2-ol With N,O-bis-(trimethylsilyl)-acetamide In acetonitrile at 70℃; for 1h; Stage #2: 3,5-difluorobenzoyl chloride In acetonitrile at 20℃; for 12h; | 4 To an 8 mL screw-cap vial containing 4-amino-5-fluoro-pyrimidin-2-ol* (100 mg, 0.775 mmol) and acetonitrile (CH3CN; 3 mL) was added bis-N,O-trimethylsilylacetamide (BSA; 378 microliters (μL), 1.55 mmol). The mixture was heated to 70° C. for 1 h resulting in a clear solution. After cooling to room temperature, 3,5-difluorobenzoyl chloride (182 μL, 1.55 mmol) was added, and the mixture was stirred at room temperature for 12 h. A white precipitate formed and was collected by vacuum filtration. The solid was washed with Et2O (1×10 mL) and air-dried overnight to yield the final product as a white solid (126 mg, 60%): mp 227-231° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (br s, 1H), 8.27 (br s, 1H), 8.14 (d, J=6.8 Hz, 1H), 7.80-7.35 (m, 3H); ESIMS m/z 270 (M+H), 268 (M-H). *4-Amino-5-fluoro-pyrimidin-2-ol can be purchased commercially. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With aluminum (III) chloride at 125℃; for 1.5h; | 2 Step 2: 6-(3,5-difluoro-benzoyl)-4-methyl-3H-benzoxazol-2-one 1.45 g (8.21 mmol) 3,5-difluorobenzoic acid chloride, 1.22 g (8.21 mmol) 4-methyl-3H-benzoxazol-2-one and 4.40 g (33.0 mmol) aluminium trichloride were heated to 125° C. for 1.5 h with stirring. The mixture was mixed with ice water and the product precipitated as a solid was suction filtered and washed with water. After trituration of the precipitate with MeOH it was suction filtered, washed with MeOH and dried i. vac. Yield: 2.20 g (93% of theoretical) ESI-MS: m/z=290 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(N-hydroxycarbamimidoyl)piperidine-1-carboxylic acid tert-butyl ester; 3,5-difluorobenzoyl chloride With triethylamine In tetrahydrofuran at 20℃; for 2h; Cooling with ice; Stage #2: With tetrabutyl ammonium fluoride In tetrahydrofuran at 50℃; for 0.5h; | 7 Preparation Example 7 To a solution of tert-butyl 4-[amino(hydroxyimino)methyl]piperidine-1-carboxylate (3.0 g) in THF (30 mL) were added 3,5-difluorobenzoyl chloride (2.4 g) and triethylamine (3.44 mL) under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction liquid were added ethyl acetate and water, and the organic phase was separated. The organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue were added THF (25 mL) and a 1 M tetrabutylammonium fluoride/THF solution (12.4 mL), followed by stirring at 50°C for 30 minutes. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform). To the purified product was added diisopropyl ether, and the resulting solid was collected by filtration and dried to obtain tert-butyl 4-[5-(3,5-difluorophenyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxylate (4.22 g) as an orange solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine In dichloromethane at 0 - 20℃; for 12h; | |
75% | With triethylamine In toluene at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: {trans-3-piperazin-1-yl-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile; 3,5-difluorobenzoyl chloride With triethylamine In tetrahydrofuran Stage #2: With trifluoroacetic acid In dichloromethane for 1h; Stage #3: With ethylenediamine In methanol | 8b Example 8b. {trans-3-[4-(3,5-difluorobenzoyl)piperazin-l-yl]-l-[4-(7H-pyrrolo[2,3- d] py r imidin-4-yl)- 1 H-py r azol- 1 -yl] cy clobutyl} acetonitrileTo a solution of {trans-3-piperazin-l-yl-l-[4-(7-[2- (trimethylsilyl)ethoxy]methyl} -7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 1 H-pyrazol- 1 - yl]cy clobutyl} acetonitrile (0.030 g, 0.061 mmol, from Example lb, Step 1) intetrahydrofuran (1 mL) was added triethylamine (0.025 mL, 0.18 mmol) followed by 3,5- difluorobenzoyl chloride (0.012 mL, 0.091 mmol, Aldrich). The reaction was stirred for a few hours, then concentrated via rotary evaporation. The product was then deprotected by first stirring with 1 : 1 TFA:DCM for 1 hour, followed by evaporation and stirring with excess ethylenediamine in methanol until deprotection of SEM was complete. The compound was purified via preparative HPLC-MS (CI 8, eluting with a gradient of H20/MeCN containing 0.15% ΝΗ4ΟΗ). The eluent containing the desired mass was frozen and lyophilized to afford product as the free base (20 mg, 60%). 1H NMR (300 MHz, dg-dmso): δ 12.12 (br s, IH), 8.83 (s, IH), 8.69 (s, IH), 8.42 (s, IH), 7.60 (dd, IH), 7.36 (tt, IH), 7.21-7.12 (m, 2H), 7.07 (dd, IH), 3.72-3.56 (m, 2H), 3.43 (s, 2H), 3.37-3.25 (m, 2H), 3.08-2.94 (m, 2H), 2.83 (tt, IH), 2.46-2.24 (m, 6H); 19F NMR (282 MHz, d6- dmso): δ -109.00 (dd, 2F); LCMS (M+H)+: 503.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.5% | With methyloxirane In tetrahydrofuran at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With N-ethyl-N,N-diisopropylamine In dichloromethane | 9 3,5-Difluorobenzoyl chloride (50 mg, 0.28 mmol, CAS RN 129714-97-2) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (45 mg, 0.23 mmol, example 1, intermediate a) and DIPEA (79 μL, 0.45 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the desired compound as a waxy solid (26 mg, 34%). MS (ESI): m/z=339.1 [M+H]+. |
34% | With N-ethyl-N,N-diisopropylamine In dichloromethane | 9 3,5-Difluorobenzoyl chloride (50 mg, 0.28 mmol, CAS RN 129714-97-2) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (45 mg, 0.23 mmol, example 1, intermediate a) and DIPEA (79 μ, 0.45 mmol) in CH2CI2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the desired compound as a waxy solid (26 mg, 34%). MS (ESI): m/z = 339.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With dmap; triethylamine In dichloromethane at 20℃; Inert atmosphere; | II.I-58 Example 1-58 N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3,5-difluoro-benzamide General procedure: Example 1-58 N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3,5-difluoro-benzamide A 10 mL round bottom flask was charged with 3,5-difluorobenzoyl chloride (78.0 mg, 0.442 mmol) and anhydrous methylene chloride (5 mL) and was treated with 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one (intermediate D) (49.8 mg, 0.175 mmol), triethylamine (87.1 mg, 0.12 mL, 0.861 mmol), and catalytic N,N- (dimethylamino)pyridine (DMAP) ( one spatula tip). The flask was capped with a glass stopper and the reaction stirred at room temperature over the weekend. The reaction was partitioned between methylene chloride (25 mL) and water (25 mL). The organic portions were dried over magnesium sulfate, filtered and rinsed with methylene chloride, concentrated on a rotary evaporator, and briefly dried on a vacuum pump. The material was then purified via Analogix Intelliflash 280 chromatography using a 12 g silica gel column and a l%-5% MeOH/CLbC^ gradient elution. Two columns were required to isolate the desired product from the bis-acylation side product. Fractions containing the two products were separately combined and concentrated. The second product to elute was the desired product N-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3,5-difluoro-benzamide, isolated as an off-white solid (44 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (t, .7=5.14 Hz, 1 H) 8.27 (d, .7=8.66 Hz, 1 H) 8.03 (s, 1 H) 7.38 - 7.73 (m, 9 H) 6.90 (d, =1.81 Hz, 1 H) 4.37 (d, .7=5.24 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 1-methyl-2,4-dioxo-1,2-dihydroquinazoline-3(4H)-carbothioamide With triethylamine In N,N-dimethyl-formamide at 0 - 5℃; for 0.5h; Stage #2: 3,5-difluorobenzoyl chloride In N,N-dimethyl-formamide at 20℃; | Synthesis of substituted-N-(1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-carbonothi -oyl)benzamide derivatives(5a-f) General procedure: Compound 4 (0.1 mmol) in dimethylformamide (1 mL)was taken and cooled to 0-5 °C in an ice bath. Triethylamine(0.1 mmol) was added to cold reaction mixture and stirredfor 30 min, then different acid chlorides (0.1 mmol) wereadded, and the reaction mixture was allowed to stir at roomtemperature for 6-8 h. After completion of the reaction(TLC), the reaction mixture was quenched with saturatedsodium bicarbonate solution; the product was extracted withethyl acetate, dried over anhydrous sodium sulfate and thesolvent was evaporated and crystallized from ethanol affordingthe corresponding 5a-f. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With pyridine; dmap In dichloromethane at 20℃; Inert atmosphere; | Typical experimental protocol for synthesis of dimer esters 5: General procedure: To a 2-dram vial,equipped with magnetic stir bar under an atmosphere of argon, were added dimer alcohol 4 (10 mg, 0.017 mmol, 1.0eq)55 and anhydrous dichloromethane (400 mL). Pyridine (4 mL, 0.049 mmol, 3.0 eq), DMAP (2 mg, 0.017 mmol, 1.0 eq), and acid chloride (0.049 mmol, 3.0 eq) were added and the reaction mixture was stirred at rt overnight or until complete consumption of 4 as indicated by analytical TLC. The reaction was quenched with water and extracted with dichloromethane (3 x 5 mL). The organic layers were combined and washed with brine, dried over Na2SO4, vacuum filtered, and concentrated under reduced pressure. The crude residue was purified directly on silica gel; gradient elution (0-30% EtOAc in hexanes) afforded the desired product as a colorless, amorphous solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With aluminum (III) chloride In ethanol; water at 20℃; for 24h; Inert atmosphere; | 3 Synthesis of 3,4',5-trifluorobenzophenone, 1 In a 100 mL RB flask, equipped with an addition funnel, condenser, a stir bar, a nitrogen gas inlet and a CaCl2 drying tube were placed 9.10g (68.0mmol) of AlCl3 and 25mL of fluorobenzene. 3,5-difluorobenzoylchloride (6.5mL, 55.0mmol) was measured under a nitrogen blanket and added to the addition funnel containing 28mL of fluorobenzene. The resulting mixture was added to the flask, drop wise, over 1h at room temperature and maintained with stirring for 24h. The reactant mixture was precipitated into an excess of acidified deionized water (300mL) and extracted into chloroform (150mL). The organic layer was washed three times with DI water, dried over MgSO4 and evaporated to dryness via the rotary evaporator followed by drying in vacuo to obtain 11.82g (91%) of an off-white solid. The crude product was recrystallized from ethanol and then from ethanol/water to afford 8.02g (62%) of white needle-like crystals with a melting point of 65-67°C. 1H-NMR (300MHz, CDCl3, δ): 7.10 (tt, J=8.5, 2.4Hz, 1H), 7.21-7.29 (m, 2H), 7.30-7.38 (m, 2H), 7.87-7.93 (m, 2H). 13C NMR (75.5MHz, CDCl3, δ): 107.7 (t), 112.7 (dd), 115.8 (d), 132.6 (d), 132.6 (d), 140.4 (t), 162.7 (dd), 165.8 (d), 192.4 (t). Elemental Analysis: Calc. Anal. for C13H7F3O: C, 66.11; H, 2.99; Found: C, 66.03; H, 2.87. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.2% | With pyridine; In dichloromethane; at 0 - 20℃; for 8h;Inert atmosphere; | 43g compd. b3 (compd. b3 is compd. a1 produced according to the procedure of manufacture), polypyridine 70g, and dichlomethane 200 ml bottles which are added to the reaction. Next, the mixture is stirred under nitrogen, then 0 °C -5 ° C is cooled. In 100 ml of a solution of the compound b2 dichlomethane 68g of reaction of the drop in the bottle. After completion of the addition, reaction bottle is warmed to room temperature, the stirring time is 8. Next, bottle 100 ml of water is added during the reaction, then a 5 min. The organic layer is collected, 100 ml of the water layer is extracted using dichlomethane 2 times. The organic layer is collected, the pH value of about 7 in order to adjust a 100 ml saline water. Next, the organic layer is collected in the dryer 30 min. 20g anhydrous sodium sulfate, then filtered. Furthermore, the liquid is condensed, the petroleum ether and ethyl acetate (9:1) is purified by using a xerographic chromatography, compd. b4 (corallite fluid) is obtained by the yield 61.2percent. Compd. b4 of purity (gas chromatography (GC) analysis by a) the, 95.799percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With triethylamine In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere; | 61 Synthesis of 4-chloro-N-(3,5-difluorobenzoyl)deacetyl colchicine 4-chlorodeacetyl colchicine (50 mg, 0.128 mmol) was dissolved in dichloromethane (2 mL) under argon atmosphere, and cooled at 0 degree C. Triethylamine (19 mul, 0.128 x 1.1mmol) and 3,5-difluorobenzoylchloride (16 mul, 0.128 x 1 mmol) were added and stirred at room temperature for 1 hour. Water was added and the reaction mixture was quenched, extracted with saturated sodium bicarbonate solution and chloroform. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by Silica gel chromatography(Biotage Isolera One, SNAP 10 g, methanol/chloroform) to obtain title compound (a reddish brown solid, 50 mg, 0.094 mmol, 73%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With triethylamine In dichloromethane at 0 - 20℃; for 1.16h; Inert atmosphere; | 337 Synthesis of N-(3,5-difluorobenzoyl)-4-iodo deacetyl colchicine 4-iodo deacetyl colchicine (50 mg, 0.103 mmol) was dissolved in dichloromethane (2 mL)under argon atmosphere, and cooled at 0 degree C. Triethylamine (16 mul, 0.103 x 1.1mmol) and 3,5-difluorobenzoylchloride (13 mul, 0.103 x 1 mmol) were added, and stirred at 0 degree C for 10 minutes, and room temperature for 1 hour. Water was added and the reaction mixture was quenched, 0.1N hydrochloric acid was added, and extracted with chloroform. The chloroform layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by Silica gel column chromatography (Biotage Isolera One, SNAP 10 g,methanol/chloroform) to obtain title compound (brown solid and 36mg, 0.058 mmol, 56%) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 4-methyl-morpholine In N,N-dimethyl acetamide at 0 - 25℃; for 1.16667h; Inert atmosphere; | Synthesis of substituted carboxamides 12k-12o (generalprocedure) General procedure: To a solution of the compound 11 (1.00 mmol) in 3 cm3 of dimethylacetamide was added N-methylmorpholine (5.00 mmol) followed by drop wise addition of corresponding acid chlorides (1.30 mmol) at 0 °C under nitrogen atmosphere. The reaction medium was stirred atthe same temperature for 10 min and then allowed to stir at room temperature for 1 h under nitrogen atmosphere. After completion of reaction, water was added to the reaction mixture and stirred for 10 min. The solid precipitated outwas filtered, washed with water and dried under vacuum to afford the corresponding carboxamides 12k-12o. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In N,N-dimethyl acetamide at 0℃; Inert atmosphere; | General procedure for the synthesis of 7-[aryl(benzoylamino)-phenyl]-pyrazolo [1, 5-a] pyrimidine-3-carboxylic acid ethyl ester (8 a-h) General procedure: To a solution of the amine (7a-c) (2.49 mmol) in dimethylacetamide(5 vol), the corresponding acid chloride (2.49mmol) was added drop wise at 0 °C under argon atmosphereand then slowly warmed the reaction medium to roomtemperature. The reaction medium was stirred at the sametemperature for 1 h. The reaction conversion was monitoredby TLC. The reaction mixture was poured to ice cold waterand stirred at room temperature for 30 min and the precipitatedsolid was filtered, washed with water, and driedunder vacuum. This crude product was further purified bycolumn chromatography using ethyl acetate and hexane toget the required amide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In N,N-dimethyl acetamide at 0℃; Inert atmosphere; | General procedure for the synthesis of 7-[aryl(benzoylamino)-phenyl]-pyrazolo [1, 5-a] pyrimidine-3-carboxylic acid ethyl ester (8 a-h) General procedure: To a solution of the amine (7a-c) (2.49 mmol) in dimethylacetamide(5 vol), the corresponding acid chloride (2.49mmol) was added drop wise at 0 °C under argon atmosphereand then slowly warmed the reaction medium to roomtemperature. The reaction medium was stirred at the sametemperature for 1 h. The reaction conversion was monitoredby TLC. The reaction mixture was poured to ice cold waterand stirred at room temperature for 30 min and the precipitatedsolid was filtered, washed with water, and driedunder vacuum. This crude product was further purified bycolumn chromatography using ethyl acetate and hexane toget the required amide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With scandium tris(trifluoromethanesulfonate) at 60℃; for 120h; | (3,5-Difluorophenyl)(4-methoxyphenyl)methanone (5) Scandium triflate (0.12 g, 0.25 mmol) was added toa solution of anisole (0.27 g, 0.271 mL, 2.5 mmol) and 3,5-difluorobenzoyl chloride (0.44 g, 2.5 mmol) innitroethane (5 mL). The resultant dark-purple solution was stirred at 60 °C for 5 days at which point TLC showed no remaining starting material. The solution was quenched with saturated NaHCO3(10 mL) and extracted thrice with DCM. The solvent from the combined organic layers was dried overMgSO4, evaporated under vacuum, and the residue was purified on silica gel (hexanes:EtOAc, 90:10)to give 5 (0.36 g, 59%) as white crystals. m.p.: 90-92 °C. 1H-NMR (CDCl3) δ 7.81 (m, 2H), 7.26 (m, 2H),7.00 (m, 3H), 3.90 (s, 3H). 13C-NMR (CDCl3) δ 192.64, 163.80, 162.64 (dd, J1 = 251.0 Hz, J2 = 11.8 Hz),141.35 (t, J1 = 251.0 Hz, J2 = 11.8 Hz), 132.55, 128.98, 113.87, 112.56 (dd, J1 = 25.2 Hz, J2 = 11.2 Hz),107.13 (t, J = 25.3 Hz), 55.58. 19F-NMR (CDCl3) δ 108.41. HRMS ESI: calc’d 249.0722 for C14H11O2F2;found 249.0735. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 28℃; Inert atmosphere; | General procedure for the synthesis of substituted carboxylicacid methyl esters 7a-7h General procedure: 6-Aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acidmethyl ester (5, 0.55 g, 2.86 mmol) was dissolved in5.50 cm3 of N,N-dimethylformamide and 1.10 g of N,Ndiisopropylethylamine(8.58 mmol) and correspondingacid chlorides 6a-6h (3.14 mmol) were added drop wiseunder nitrogen atmosphere. The reaction mixture wasgradually allowed to attain room temperature (28 C) andstirred for 2-3 h. The completion of reaction wasmonitored by TLC. The reaction mixture was poured to60 cm3 of ice cold water, stirred for 1 h and theprecipitate formed was filtered, washed with 5 cm3 ofwater and dried under vacuum at room temperature(28 C) for 12 h to afford the crude product. The crudeproduct was crystallized by digesting in 5 cm3 of ethylacetate and 25 cm3 of n-heptane at room temperature(28 C), stirred for 1 h, filtered, washed with 5 cm3 of nheptaneand dried under vacuum at room temperature(28 C) to afford the corresponding substituted carboxylicacid methyl esters 7a-7h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: trimethylsulfoxonium iodide With potassium <i>tert</i>-butylate In tetrahydrofuran for 2h; Inert atmosphere; Reflux; Stage #2: 3,5-difluorobenzoyl chloride In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere; | |
89% | Stage #1: trimethylsulfoxonium iodide With potassium <i>tert</i>-butylate In tetrahydrofuran for 2h; Inert atmosphere; Reflux; Stage #2: 3,5-difluorobenzoyl chloride In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; | |
Stage #1: trimethylsulfoxonium iodide With potassium <i>tert</i>-butylate In tetrahydrofuran for 2h; Inert atmosphere; Reflux; Stage #2: 3,5-difluorobenzoyl chloride In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With pyridine; at 20.0℃; for 16.0h;Inert atmosphere; | General procedure: Benzoyl chloride (0.062mL, 0.53mmol, 1 equivalent) was added dropwise to 3-amino-5-(pyridin-4-yl)pyridin-2-one (100mg, 0.53mmol, 1 equivalent) in pyridine (3 mL) and the mixture was stirred for 16h at room temperature. The solvent was removed under reduced pressure and the residue taken up in methanol and filtered to give the desired product as a light-yellow solid (41mg, 27percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With triethylamine In dichloromethane at 0 - 20℃; for 4h; | 3 General procedure: A magnetically stirred suspension of 1 (200 mg, 1 mmol) and NEt3 (229 μ, 2 mmol) in CH2CI2 (10 mL) was treated with a solution of the appropriate benzoyl chlorides (1 .1 mmol) in CH2CI2 (10 mL) dropwise at 0 °C. The reaction mixture was then warmed to room temperature and stirring continued for 4 h. The resultant solution was diluted with CH2CI2 (25 mL) and NaHCO3 (25 mL of a sat. aq. solution), the separated organic phase was subsequently washed with NaHCO3 (25 mL of a sat. aq. solution) and brine (50 mL) before being dried (MgSO4), filtered and concentrated under reduced pressure to give crude oils (of compounds of the Formula 1 a). Purification by either trituration (EtOAc) followed by recrystallisation (MeOH/CH2Cl2) or via flash chromatography afforded the required amides |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine In dichloromethane for 24h; | 1.1 Step 1: Synthesis of intermediate 1 3,5-difluorobenzoyl chloride (15.3 g, 90.0 mmol) was dissolved in anhydrous dichloromethane (100 mL). It was then slowly added to a solution of triethylamine (25.4 mL) and N-phenyl-o-phenylenediamine (18.2 g, 99.0 mmol) dissolved in dichloromethane (200 mL). After the reaction mixture was reacted for 24 hours under anaerobic conditions, it was washed with water (100 mL) and aqueous sodium hydrogencarbonate (100 mL), and then neutralized with diluted hydrochloric acid, and the organic phase was extracted, then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography. The eluent was dichloromethane and finally a pure white powder (21.5 g, 76%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | In acetonitrile at 20℃; Reflux; | General procedure: A solution of sulfamethazine drug (0.5 mmol, 0.14 g) in acetonitrile (3.0 mL) was stirred at room temperature for 15-20 minutes. Then the corresponding acid chloride (0.5 mmol) wasadded slowly, and the reaction mixture was refluxed for 3-4 hours. Progress of the reaction was monitored by TLC (Silica gel, hexane: ethyl acetate, 4: 6). After complete consumption of substrate, the reaction mixture was cooled down, and the precipitate was filtered off and washed with hexane, ethyl acetate, and acetone to remove impurities. Structures of all synthetic compounds 3-39 were characterized by different spectroscopic techniques; such as 1H-, and 13C NMR, EI-MS, FAB-MS, HR-FAB-MS, UV and IR spectroscopy. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With pyridine; at 20℃; for 1h; | General procedure: To a solution of ethyl 2-amino-4-methylthiazole-5-carboxylate(0.005 mole) and pyridine (4 mL), substituted benzoylchlorides(1 equivalent) were added and kept at roomtemperature for 1 h. Completion of the reaction was monitoredby TLC. After the completion of reaction, the reactionmixture was poured on crushed ice, solid mass soobtained was filtered and washed with cold water. Thecharacterization data for ethyl 2-(3,5-difluorobenzamido)-4-methylthiazole-5-carboxylate are as follows:Yield: 82%, mp: 98-100 C. 1H NMR (CDCl3,300 MHz, δ, TMS = 0): 7.50 (2H, d, J = 6.0 Hz), 7.05-7.11(1H, m), 4.34 (2H, q, J = 7.2 Hz), 2.59 (3H, s), 1.38 (3H, t,J = 7.2 Hz) (3-jan-2017). 13C NMR (CDCl3, 75 MHz, δ,TMS = 0): 16.81, 19.28, 63.26, 160.04, 165.01, 172.14 (28-10-2016). Anal. Calcd. MS: 326.0537; Found m/z:327.0567 (M+ + 1). Anal. Calcd. For C14H12F2N2O3S: C,51.53; H, 3.71; F, 11.64; N, 8.58; O, 14.71; S, 9.83; Found:C, 51.62; H, 3.66; F, 11.75; N, 8.44; S, 9.99. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium hydroxide In water at 0 - 5℃; for 2h; | General procedure for the synthesis of 2-phenyl/substituted phenyl-N-(9-ethyl-9H-carbazol-3-yl)hydrazinecarboxamides (4) General procedure: An equimolar amount of hydrazinecarboxamide intermediate 3 andsubstituted benzoyl chloride were dissolved in 30% NaOH water solutionand reaction mixture was stirred for additional 2 h at 0-5 °C.Reaction mixture was diluted with water and neutralized with aceticacid. Appeared precipitate was filtered and dried to give crude productswith some impurities. Crude product was purified by column chromatographyusing Chloroform and methanol (95:5) as eluent to achievetarget compounds 4-17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine In dichloromethane at 0℃; for 2h; | (E)-3,5-difluoro-N-(3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)benzamide (15q) To a solutionof 15d (400 mg, 1.2 mmol) and TEA (365 mg, 3.6 mmol) in anhydrousDCM (15 mL) was added 3,5-difluorobenzoyl chloride(318 mg, 1.8 mmol). The reaction mixture was stirred at 0 °C for 2 hunder argon. Then extracted by DCM and washed with H2O followed by brine. The organic layers were dried over anhydrousNa2SO4, filtered and evaporated. The crude materialwas purified bysilica gel column chromatography (25e30% EtOAc in petroleumether) to afford product 15q as yellow solid. (402 mg; yield, 70%;TLC, PE: EA 3:1; Rf ~ 0.2) 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s,1H), 8.66-8.54 (m, 2H), 7.92 (d, J 16.4 Hz, 1H), 7.86-7.70 (m, 6H),7.57 (tt, J 9.2, 2.4 Hz, 1H), 7.51 (d, J 16.4 Hz, 1H), 7.34-7.25 (m,1H), 5.89 (dd, J 9.8, 2.3 Hz, 1H), 3.98-3.86 (m, 1H), 3.83-3.71 (m,1H), 2.48-2.38 (m, 1H), 2.08-1.97 (m, 2H), 1.84-1.70 (m, 1H),1.67-1.54 (m, 2H). MS (ESI), m/z: 461.2 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.4% | In 1-methyl-pyrrolidin-2-one at 20℃; for 1h; Inert atmosphere; | S1.2.14. Synthesis of N-(3-(5-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,1-b]thiazol-6-yl)phenyl)-2-phenylacetamide (18a): General procedure: To a solution of 4-(6-(3-aminophenyl)-2,3-dihydroimidazo[2,1-b]thiazol-5-yl)-N-(4-morpholinophenyl)pyrimidin-2-amine (17) (300 mg, 0.636 mmol), in 2 ml of NMP, added 2-phenylacetyl chloride (128 mg, 0.827 mmol) stirred the reaction mixture for 1 hr rt, The reaction mixture was diluted with diethyl ether, stirred for 5 min and ether was removed. The dilution of the reaction mixture with diethyl ether and removal of ether was repeated twice. The reaction mixture was further diluted with DCM and washed with aqueous saturated NaHCO3. The organic layer was dried over anhydrous Na2SO4, concentrated to yield crude product which was purified by flash column chromatography (silica gel, eluted with 6% MeOH in DCM) to afford the title compound N-(3-(5-(2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-2,3-dihydroimidazo[2,1-b]thiazol-6-yl)phenyl)-2-phenylacetamide (18a) (200 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine With triethylamine In tetrahydrofuran; dichloromethane at 0 - 5℃; for 0.5h; Stage #2: 3,5-difluorobenzoyl chloride In tetrahydrofuran; dichloromethane at 20℃; for 6h; | 4.2. General procedure for the synthesis of pyrazine derivatives (2a-eand 3a-e) General procedure: In an ice bath, compound 1 (0.1 mmol) was cooled to 0-5 °C indichloromethane (10 mL). Triethylamine (0.1 mmol) was added toa cold reaction mixture and stirred for 30 min, after which various acid chlorides/benzyl chlorides (0.1 mmol) were added andreaction mixture was left to stir at room temperature for 6-8 h.The reaction mixture was quenched with saturated NaHCO3 solution after completion of the reaction (TLC); the product was extracted with EtOAc, dried over anhydrous Na2SO4, and the solventwas evaporated and recrystallised from ethanol to yield the corresponding 2a-e and 3a-e compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With pyridine In chloroform at 0 - 20℃; Inert atmosphere; | B11 General procedure: The inside of the 100 ml flask was replaced with nitrogen, 3.0 g (1 equivalent) of a mixture of compound 201 and compound 202 was added, and then 15 ml of dehydrated pyridine and 15 ml of chloroform were added. 4.5 g (2.1 eq) of 3-methylbenzoyl chloride was slowly added dropwise while cooling in an ice bath.After the dropping, the temperature was raised to room temperature and the mixture was stirred overnight. It was cooled again in an ice bath, methanol was added, and quenching was performed. Chloroform and water were added and stirred, and then the organic layer was separated. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over magnesium sulfate. The organic layer was then concentrated to give 6.78 grams of crude product. Purification by silica gel column chromatography gave compound 205 (endo-form: exo-form = 86: 14), which is a mixture of isomers of endo-form and exo-form, in an amount of 5.94 grams (yield 95%). The 1H-NMR data of the obtained compound 205 is shown below. |
Tags: 129714-97-2 synthesis path| 129714-97-2 SDS| 129714-97-2 COA| 129714-97-2 purity| 129714-97-2 application| 129714-97-2 NMR| 129714-97-2 COA| 129714-97-2 structure
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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.
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