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CAS No. : | 924-99-2 | MDL No. : | MFCD00144269 |
Formula : | C7H13NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MVUMJYQUKKUOHO-AATRIKPKSA-N |
M.W : | 143.18 | Pubchem ID : | 5369162 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.57 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 39.47 |
TPSA : | 29.54 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) : | -6.57 cm/s |
Log Po/w (iLOGP) : | 1.9 |
Log Po/w (XLOGP3) : | 0.85 |
Log Po/w (WLOGP) : | 0.62 |
Log Po/w (MLOGP) : | 0.64 |
Log Po/w (SILICOS-IT) : | 0.19 |
Consensus Log Po/w : | 0.84 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.0 |
Solubility : | 14.3 mg/ml ; 0.1 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.05 |
Solubility : | 12.7 mg/ml ; 0.0884 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.54 |
Solubility : | 41.5 mg/ml ; 0.29 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.23 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H317-H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
0.7 g | With triethylamine; In toluene; at 90℃; for 4h; | (a) 2-(4,6-Dichloronicotinoyl)-3-(dimethylamino)acrylic acid ethyl ester A mixture of 4,6-dichloronicotinic acid (0.8 g, 3.9 mmoles) and thionyl chloride (5 ml) was heated at reflux for 2 h. The mixture was concentrated and the residue was dissolved in toluene (10 ml) and added to <strong>[924-99-2]ethyl 3-(dimethylamino)acrylate</strong> (0.84 g, 5.85 mmoles) and triethyl amine (0.6 g, 5.85 mmoles). The mixture was heated at 90 C. for 4 h, cooled, filtered and concentrated. Purification by chromatography gave the sub-tile compound (0.7 g, 54%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In toluene; at 90℃; for 1.5h;Product distribution / selectivity; | a) Ethyl 3-dimethylamino-2-(2-fluoro-5-iodobenzoyl)-2-propenoate; A stirred suspension of 2-fluoro-5-iodobenzoic acid (28.1 g) in DCM (300 mL) at 2O0C was treated with oxalyl chloride (13.9 mL) and DMF (5 drops). After 3 h the clear solution was evaporated and re-evaporated from toluene (2x). The acid chloride was re-dissolved in toluene (500 mL) and treated with triethylamine (22.5 mL) and ethyl 3- dimethylaminopropenoate (19.95 g); After stirring for 1.5 h at 900C the mixture was filtered and the solution purified by flash chromatography (silica gel, 40-70% EtOAc in petroleum ether [b.p. 40-600C]) to give the title compound as a yellow solid (30.8 g); APCI m/z 392.1 [M+H]+.; a) Ethyl 3-dimethylamino-2-(2-fluoro-5-iodobenzoyl)-2-propenoate A stirred suspension of 2-fluoro-5-iodobenzoic acid (28.1 g) in DCM (300 mL) at 20C was treated with oxalyl chloride (13.9 mL) and DMF (5 drops). After 3 h the clear solution was evaporated and re-evaporated from toluene (2x). The acid chloride was re-dissolved in toluene (500 mL) and treated with triethylamine (22.5 mL) and ethyl 3- dimethylaminopropenoate (19.95 g). After stirring for 1.5 h at 900C the mixture was filtered EPO <DP n="47"/>and the solution flash chromatographed on silica gel eluting with 40 to 70% EtOAc in petroleum ether [b.p. 40-600C] to give the title compound as a yellow solid (30.8 g); APCI m/z 392.1 [M+H]+. | |
With triethylamine; In toluene; at 90℃; for 1.5h; | A stirred suspension of 2-fluoro-5-iodobenzoic acid (28.1 g) in DCM (300 mL) at 200C was treated with oxalyl chloride (13.9 mL) and DMF (5 drops). After 1.5 h the clear solution was evaporated and re-evaporated from toluene (2x) under reduced pressure. The acid chloride was re-dissolved in toluene (500 mL) and treated with triethylamine (22.5 mL) 20 and ethyl 3-(dimethylamino)acrylate (19.95 g). After stirring for 1.5 h at 900C the mixture was filtered and the solution flash chromatographed on silica gel eluting with 40 to 70% EtOAc in light petroleum 40-6O0C to give the title compound (30.8 g); APCI m/z 392.1 [M+H]+. | |
With triethylamine; In toluene; at 90℃; for 2.5h; | A stirred suspension of 2-fluoro-5-iodobenzoic acid (99.7 g) in DCM (1 L) at 20 C. was treated with oxalyl chloride (49.8 mL) and DMF (0.3 mL). After 3 h further DMF (0.1 mL) was added. After a further 2 h the clear solution was evaporated and re-evaporated from toluene (3×200 mL). The acid chloride was re-dissolved in toluene (1.5 L) and treated with triethylamine (79.2 mL) and ethyl 3-(dimethylamino)acrylate (65.3 g). After stirring for 2.5 h at 90 C. the mixture was filtered and evaporated. The residue was redissolved in EtOAc, washed with saturated sodium hydrogen carbonate solution (2×), water, saturated brine, dried (MgSO4) and treated with decolourising charcoal for 0.5 h. The mixture was filtered, evaporated, redissolved in diethyl ether and allowed to crystallise. The solid was filtered off, washed with diethyl ether and dried to give the title compound (91.2 g). On concentration and seeding a second crop was obtained (9.0 g); ESMS m/z 391.9 [M+H]+. |
With N-ethyl-N,N-diisopropylamine; In toluene; at 60 - 100℃; for 16.0833h; | Example 51; Step 1; To a suspension of 2-fluoro-5-iodobenzoic acid (4.79 g, 18.0 mmol) and dimethylformamide (69 mul, 0.90 mmol) in toluene (20 ml) was added thionyl chloride (1.57 ml, 21.6 mmol), and the mixture was stirred under heating at 110 C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and subjected to azeotropic distillation with toluene twice. The obtained residue was dissolved in toluene (15 ml), and the solution was added to a solution of ethyl 3-(dimethylamino)acrylate (2.83 g, 19.8 mmol) and diisopropylethylamine (4.07 ml, 23.4 mmol) in toluene (15 ml) at 60 C. over 5 min, and the mixture was stirred under heating at 100 C. for 16 hr. Water and ethyl acetate were added to the reaction mixture, the mixture was stirred, and the layers were separated. The obtained organic layer was washed with water and saturated brine in this order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=3:2 to 1:2) to give the object compound (6.48 g, yield 85%) as a brown oil.1H NMR (CDCl3 400 MHz) (delta) ppm: 0.95 (3H, t, J=7.1 Hz), 2.89 (3H, br s), 3.32 (3H, br s), 3.99 (2H, q, J=7.1 Hz), 6.79 (1H, dd, J=10.0, 8.5 Hz), 7.66 (1H, ddd, J=8.5, 4.6, 2.4 Hz), 7.78 (1H, s), 7.87 (1H, dd, J=6.6, 2.4 Hz) | |
With triethylamine; In toluene; at 90℃; for 2.5h; | A stirred suspension of 2-fluoro-5-iodobenzoic acid (99.7 g) in DCM (1 L) at 200C was treated with oxalyl chloride (49.8 mL) and DMF (0.3 mL). After 3 h further DMF (0.1 mL) was added. After a further 2 h the clear solution was evaporated and re-evaporated from toluene (3 x 200 mL). The acid chloride was re-dissolved in toluene (1.5 L) and treated with triethylamine (79.2 mL) and ethyl 3-(dimethylamino)acrylate (65.3 g). After stirring for 2.5 h at 900C the mixture was filtered and evaporated. The residue was redissolved in EtOAc, washed with saturated sodium hydrogen carbonate solution (2x), water, saturated brine, dried (MgSO4) and treated with decolourising charcoal for 0.5 h. The mixture was filtered, evaporated, redissolved in diethyl ether and allowed to crystallise. The solid was filtered off, washed with diethyl ether and dried to give the title compound (91.2 g). On concentration and seeding a second crop was obtained (9.0 g); ESMS m/z 391.9 [M+H]+. | |
With triethylamine; In toluene; at 90℃; for 1.5 - 2.5h;Product distribution / selectivity; | a) Ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)-2-propenoate; A stirred suspension of 2-fluoro-5-iodobenzoic acid (28.1 g) in DCM (300 mL) at 200C was treated with oxalyl chloride (13.9 mL) and DMF (5 drops). After 3 h the clear solution was evaporated and re-evaporated from toluene (2x) under reduced pressure. The acid chloride was re-dissolved in toluene (500 mL) and treated with triethylamine (22.5 mL) and ethyl 3-(dimethylamino)acrylate (19.95 g). After stirring for 1.5 h at 900C the mixture was filtered and the solution flash chromatographed on silica gel eluting with 40 to 70% EtOAc in light petroleum 40-600C to give the title compound (30.8 g); APCI m/z 392.1 [M+H]+.a) Ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)-2-propenoateA stirred suspension of 2-fluoro-5-iodobenzoic acid (99.7 g) in DCM (1 L) at 200C was treated with oxalyl chloride (49.8 mL) and DMF (0.5 mL). After 3h further DMF (0.1 mL) was added. After a further 2 h the clear solution was evaporated and re-evaporated from toluene (3 x 200 mL). The acid chloride was re-dissolved in toluene (1.5L) and treated with triethylamine (79.2 mL) and ethyl 3-(dimethylamino)acrylate (65.3 g). After stirring for 2.5 h at 900C the mixture was filtered and evaporated. The residue was redissolved in EtOAc, washed with saturated sodium hydrogen carbonate solution (2x), water, saturated brine, dried (MgSO4) and treated with decolourising charcoal for 0.5 h. The mixture was filtered, evaporated, redissolved in diethyl ether and allowed to crystallise. The solid was filtered off washed with diethyl ether and dried to give the title compound (91.2 g). On concentration and seeding a second crop was obtained (9.0 g); APCl m/z 391.9 [M+H]+. | |
With triethylamine; In toluene; at 90℃; | The thirteenth compound obtained in the above reaction was added to 50 mL of toluene, triethylamine (7.300mL, 52.629 mmol), and ethyl 3-(N,N-dimethylamino)acrylate (5.382 g, 37.592 mmol) was dissolved in 20 mL oftoluene. , added dropwise to the reaction system. 90Stir at C for 4-5 h, and the progress of the reaction wasmonitored by thin layer chromatography. After completion of the reaction, the mixture was filtered undersuction, and the filtrate was spun-dried and replaced with ethanol for 2-3 times to obtain a fourteenth compoundof an oily liquid. | |
With triethylamine; In toluene; at 90℃; | The ninth compound obtained in the step a1 is added with 50 mL of toluene.Triethylamine (7.300 mL, 52.629 mmol),Ethyl 3-(N,N-dimethylamino)acrylate (5.382 g, 37.592 mmol) was dissolved in 20 mL of toluene and added dropwise to the reaction system. Stir at 90 C for 4-5 h, and the progress of the reaction was monitored by thin layer chromatography.After the reaction was completed, it was suction filtered, and the filtrate was spun dry and replaced with ethanol for 2-3 times.Obtain an oily liquid compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Step 1: 3-dimethylamino-2-(5-methyl-isoxazole-3-carbonyl)-acrylic acid ethyl ester A solution of 5-methyl-isoxazole-3-carboxylic acid (3.5 g, 27.53 mmol) in dichloromethane (27.53 mL, 1.0M) cooled to 0 C. was treated with oxalyl chloride (5.63 mL, 63.33 mmol, 98%) followed by a few drops of N,N-dimethylformamide. The reaction was stirred at 0 C. for 30 min. At this time, it was allowed to gradually warm to 25 C. The reaction was stirred at 25 C. overnight. At this time, the reaction was concentrated in vacuo and then was dried under high vacuum for 1.5 h. The resulting solid was then slurried with toluene (21.2 mL, 1.3M) at 25 C. and then was treated dropwise with a solution of ethyl-(3-dimethylamino)acrylate (3.98 g, 27.81 mmol) in triethylamine (8.02 mL, 57.55 mmol). The resulting black reaction mixture was heated to 120 C. overnight. At this time, the reaction was cooled to 25 C. and then was partitioned between water (150 mL) and dichloromethane (3*100 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 3-dimethylamino-2-(5-methyl-isoxazole-3-carbonyl)-acrylic acid ethyl ester (assume quantitative yield, 27.53 mmol) as a black oil. The material was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | Step 1: 2-(5-chloro-isoxazole-3-carbonyl)-3-dimethylamino-acrylic acid ethyl ester A solution of 5-chloro-isoxazole-3-carboxylic acid (791 mg, 5.43 mmol) (preparation described in WO03093250 A2) in dichloromethane (27.2 mL, 0.2M) cooled to 0 C. was treated with oxalyl chloride (0.71 mL, 8.15 mmol, 98%) followed by a few drops of N,N-dimethylformamide. The reaction was allowed to gradually warm up to 25 C. The reaction was stirred at 25 C. overnight. At this time, the reaction was concentrated in vacuo. The resulting residue was dissolved in dichloromethane and re-concentrated twice to remove residual oxalyl chloride. The residue was then dissolved in dichloromethane (16 mL, 0.34M) and treated dropwise with a solution of ethyl-3-(dimethylamino)acrylate (0.79 g, 5.51 mmol) in triethylamine (1.6 mL, 11.47 mmol). The resulting red/orange reaction solution was heated to 60 C. overnight. At this time, the reaction was cooled to 25 C. and then partitioned between water (50 mL) and dichloromethane (100 mL). The organics were then washed with water (50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Biotage chromatography (40M column, 50-60% ethyl acetate/hexanes) afforded 2-(5-chloroisoxazole-3-carbonyl)-3-dimethylamino-acrylic acid ethyl ester (300.6 mg, 20%) as a red oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.1% | With triethylamine; In benzene; at 5 - 90℃; for 1.5h; | General procedure: A solution of ethyl 3-(N,N-dimethyl-amino) acrylate (15.7 g, 44 mmol) and dry triethylamine (27 ml) in dry benzene (75 ml) was added drop-wise to the crude acid chloride (compound 27, scheme A)with continuous stirring at 5-10 C. After the whole materials were added together, the solution was heated at 90C for 90 minutes. The reaction mixture was then washed with (2 X 30 ml) of water, and the benzene layer was then dried with anhydrous MgSO4. The solvent, benzene, was then evaporated to dryness under reduced pressure. The residual product was soaked in methanol (10 ml) whereby the title compound (compound 28, scheme A)was precipitated as yellowish crystals that were collected by suction filtration and dried at room temperature. Yield ? 34.2 g (94.1 %); R f value in system (1) = 0.89; mp = 139-141 C (decomposition);1H- NMR (300 MHz, CDCl3): delta 0.95 (t, J = 7.1 Hz, 3H, CH3), 2.97 (s, 3H) and 3.37 (s, 3H) [N (CH3)2], 3.94 (q, J = 7.1 Hz, 2H, CH2Me), 7.27 (d, 3JH-F = 8.2 Hz, 1H, H-6), 7.91 (br s, 1H, N-C(3??)-H); 13C NMR (75 MHz, CDCl3): delta 13.8 (CH3CH2), 43.3, 48.4 [N (CH3)2], 60.2 (CH2Me), 100.9 (C-2??), 114.5 (d, 2JC-F = 23.3 Hz, C-4), 116.9 (d, 2JC-F = 23.1 Hz, C-6), 118.2 (d, 3JC-F = 4.5 Hz, C-1), 144.2 (d, 3JC-F = 6 Hz, C-3), 148.8 (br d, 4JC-F = 1.3 Hz, C-2), 156.6 (d, 1JC-F = 254 Hz, C-5), 160.5 (N-C-3??), 166.5 (CO2Et), 185.1 (C = O); HRMS (ESI, +ve): m/z [M+H] +379.02638 C14H14Cl2FN2O5, requires: 379.02591. |
With triethylamine; In benzene; for 2h;Reflux; | A mixture of 2,4-dichloro-5-fluoro-3-nitrobenzoic acid (10.2 g, 40 mmol) and thionyl chloride (19.0 g, 160 mmol) in dry benzene (120 ml) was refluxed for 3 - 4 h under anhydrous conditions. The solvent and excess thionyl chloride were then distilled off under reduced pressure, and dry benzene (20 ml) was then introduced into the reaction vessel and re-distilled so as to remove traces of thionyl chloride. The resulting 2,4-dichloro-5-fluoro-3-nitrobenzoyl chloride, formed as thick oil, was used as such for the next step without further purification. To a stirred and cooled (5-10 C) solution of ethyl 3-(N,N-dimethylamino)acrylate (6.3 g, 44 mmol) and triethylamine (8.1 g, 80 mmol) in dry benzene (50 ml) was added dropwise a solution of the crude acid chloride (prepared above) in dry benzene (25 ml). The resulting mixture was refluxed for 2 h, then cooled to rt and washed with water (2 x 30 ml). The organic layer was separated, dried (anhydrous MgSO4) and the solvent benzene was then evaporated to dryness under reduced pressure. The residual product was soaked in methanol (10 ml) whereby the title compound 5 was produced as yellowish powder which was collected by suction filtration and dried. Yield = 13.8 g (91%). IR (KBr): v 3074, 3037, 2988, 2928, 2873, 1689, 1619, 1554, 1454, 1397, 1375, 1344, 1321, 1278, 1206, 1177, 1129, 1030 cm-1; 1H NMR (300 MHz, CDCl3): delta 0.95 (t, J = 7.1 Hz, 3H, CH3), 2.97 (s, 3H) and 3.37 (s, 3H) [N (CH3)2], 3.94 (q, J = 7.1 Hz, 2H, CH2Me), 7.27 (d, 3JH-F = 8.2 Hz, 1H, H-6), 7.91 (br s, 1 H, N-C(3")-H); 13C NMR (75 MHz, CDCl3): delta 13.8 (CH3CH2), 43.3, 48.4 [N (CH3)2], 60.2 (CH2Me), 100.9 (C-2"), 114.5 (d, 2JC-F = 23.3 Hz, C-4), 116.9 (d, 2JC-F = 23.1 Hz, C-6), 118.2 (d, 3JC-F = 4.5 Hz, C-1), 144.2 (d, 3JC-F = 6 Hz, C-3), 148.8 (br d, 4JC-F = 1.3 Hz, C-2), 156.6 (d, 1JC-F = 254 Hz, C-5), 160.5 (N-C-3"), 166.5 (CO2Et), 185.1 (C = O). | |
13.8 g | With triethylamine; In benzene; at 5 - 90℃; for 3.5h; | This compound was prepared by refluxing a mixture of 2,4-dichloro-5-fluoro-3-nitrobenzoic acid (I), (10.2 g, 40 mmol), and thionyl chloride (SOCl2) (19.0 g, 160 mmol), dissolved in dry benzene (120 ml) at 75-80 C for 3-4 h under anhydrous conditions. The mixture was then distilled off under reduced pressure to remove solvent and excess thionyl chloride. Dry benzene was then added twice (2 x 20 ml) into the reaction vessel and the mixture was re-distilled so as to remove traces of thionyl chloride. The resulting 2,4-dichloro-5-fluoro-3-nitrobenzoyl chloride (II), formed as thick oil, was used as such for the next step without further purification. To a stirred and cooled (5-10 C) solution of ethyl 3-(N,N-dimethylamino)acrylate (6.3 g, 44 mmol) and triethylamine (4 ml, 8.1 g, 80 mmol) in dry benzene (50 ml), a solution of the crude acid chloride (prepared above) in dry benzene (25 ml) was added drop by drop. The resulting mixture was stirred continuously for 2 h at room temperature under anhydrous conditions. Then, the solution was refluxed at 90 C for 90 minutes. This crude product was evaporated to dryness, redissolved in chloroform; the chloroform was extracted with water (30 ml) and dried (with anhydrous MgSO4). The solvent, chloroform, was then evaporated to dryness under reduced pressure. The residual product (about 20 ml) was soaked in methanol (10 ml) whereby the title compound III was obtained as a yellowish powder that was collected by suction filtration and dried, mp = 140-141 C (decomposition), yield 13.8 g (91 %), Rf value in system (1) = 0.89 and in system (2) = 0.850. 1H NMR(500 MHz, CDCl3): delta 0.95 (t, J= 7.1 Hz, 3H, OCH2CH3), 2.97 (s, 3H) and 3.37 (s, 3H) [N (CH3)2], 3.94 (q, J= 7.1 Hz, 2H, OCH2Me), 7.27 (d,3JH-F= 8.2 Hz, 1H, H-6?), 7.91 (br s, 1H, N-C(3)-H). 13C NMR (75 MHz, CDCl3): delta 13.8 (CH3CH2), 43.3, 48.4 [N (CH3)2], 60.2 (CH2Me), 100.9 (C-2), 114.5 (d,2JC-F= 23.3 Hz, C-4?), 116.9 (d, 2JC-F= 23.1 Hz, C-6?), 118.2 (d, 3JC-F= 4.5 Hz, C-1?), 144.2 (d, 3JC-F= 6 Hz, C-3?), 148.8 (br d, 4JC-F= 1.3 Hz, C-2?), 156.6 (d, 1JC-F= 254 Hz, C-5?), 160.5 (N-C-3), 166.5 (CO2Et), 185.1 (C = O). HRMS ((+ve)-ESI): m/z calculated for C14H14Cl2FN2O5[M+H]+: 379.02638, found: 379.02591. Calculated for C14H13Cl2FN2O5(379.17): C, 44.35; H, 3.46; N, 7.39. Found: C, 44.30; H, 3.38; N, 7.62. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In toluene; at 90℃; for 1h; | A solution of 2,6-dichloronicotinoyl chloride (62.5 g), ethyl 3,3-dimethylaminoacrylate (58.8 g) and triethylamine (69 g) in toluene (600 mL) was stirred at 90 C. for 1 hour then cooled and concentrated. The concentrate was dissolved in dichloromethane (60 mL), diluted with diethyl ether, and filtered. The filtrate was concentrated, and the concentrate was crystallized from dichloromethane/diethyl ether/hexanes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 2-Ethylpyridine; In toluene; at 0℃;Molecular sieve;Product distribution / selectivity; | Example 3Reaction with 4 Molecular Sieve245 g (1.71 mole) of N,N-dimethylamino-ethyl-acrylate, 183.3 g (1.71 mole) of 2-ethylpyridine, 1.5 L of toluene and 250 g of 4 molecular sieves (that are UOP type 4 beads purchased from the Fluka Company) were added sequentially to a 5-liter reaction vessel. Then, nitrogen was introduced to the reaction vessel, an operation temperature in the reaction vessel was lowered to -10 C. and N,N-dimethylamino-ethyl-acrylate, 2-ethylpyridine and toluene were stirred for 10 minutes. 252.2 g (1.71 mole) of 2,2-dichloro-acetyl-chloride was dissolved in 500 mL of toluene and titrated into the reaction vessel in 30 minutes and then stirred for 1.5 hours at 0 C. to allow a synthetic reaction to proceed. TLC was used to analyze if N,N-dimethylamino-ethyl-acrylate was consumed to determine if the synthetic reaction had reached an end point. Once the end point was reached, 2 L of deionized water was added to the reaction vessel and contents of the reaction vessel were stirred for 30 minutes. After being stirred, the contents immediately separated into two phases. Then, a water phase and the 4 molecular sieves were removed and toluene was removed by vacuum pump to obtain a crude product. Next, the crude product was stirred, washed twice with 1 L hexane respectively and filtered by centrifuge. After being filtered, the crude product was dried in a vacuum oven for 5 hours to obtain a white product being 4,4-dichloro-2-(dimethylamino)methylene-3-oxy-alkyl butyrate (395.7 g; yield: 91%; purity: 99.8% (as shown in FIG. 3); melting point: 68 C.). The structure of the product was analyzed by 1H-NMR, 13C-NMR and frustrated total internal reflection (FTIR), which are respectively shown in FIGS. 4, 5 and 6.The 4 molecular sieves were soaked in 1 L of isopropanol for 24 hours, then dried at 120 C. for 24 hours to obtain 245 g of 4 molecular sieves (recycling rate: 98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With triethylamine; In toluene; at 90℃; for 3h; | 95 mg (0.27 mmol) of 2,4-dichloro-5-(2-chloro-4,6-difluorophenylamino)benzoic acid were boiled with 0.98 ml of thionyl chloride under reflux for 3 hours. The thionyl chloride was distilled off, and the residue was mixed with 3 ml of toluene and concentrated in vacuo. The residue was taken up in 2 ml of toluene and added to a solution of 39 mg (0.27 mmol) of ethyl 3-dimethylaminoacrylate, 6 mul of triethylamine and 1 ml of toluene. The mixture was heated at 90 C. for 3 hours. The mixture was concentrated and chromatographed on silica gel (heptane:ethyl acetate=75:25 to 0:100 in 45 minutes). 30 mg (23%) of the desired product were obtained. MS: M+H=477/479 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Reference Example 7; Step 1; 2-Fluoro-5-iodobenzoic acid (6.60 g, 24.81 mmol) was dissolved in chloroform (70 ml), oxalyl chloride (4.30 ml, 49.29 mmol) and dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and chloroform (35 ml) was. added to the residue to 'allow dissolution. The obtained solution was added dropwise to a solution of ethyl 3-dimethylaminoacrylate (4.26 g, 29.75 mmol) and triethylamine (5.19 ml, 37.24 mmol) in chloroform (35 ml). The mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture to allow partitioning. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate: hexane=1:2 to 1: 1) to give the object product (6.40 g, yield 66%), which comprises an E form and a Z form in a mixture, as an orange solid. ¹H NMR(CDCI3 400MHz) (8) ppm: 0.94 (3H, t, J=7.2Hz) , 2.88 (3H, brs) , 3.31 (3H, brs) , 3.97 (2H, q) , 6.78 (1H, dd, J=8.4, 10.0Hz), 7.65-7.67 (lH, m) , 7.78 (1H, s.) , 7.85 (lH, brs) MS (ESI) : M+ 392 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 8; The compound (85.17 g, 0.31 mol) obtained in Step 7 was dissolved in toluene (450 ml), thionyl chloride (44.40 ml, 0.61 mol) and dimethylformamide (catalytic amount) were added, and the mixture was stirred at 90C for 1 hr. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in toluene. The mixture was concentrated under reduced pressure, and this operation was repeated several times. The residue was dissolved in tetrahydrofuran (250 ml) and the obtained solution was added dropwise to a solution of ethyl 3-dimethylaminoacrylate (43.60 g, 0.31 mol) and triethylamine (50.90 ml, 0.37 mol) in tetrahydrofuran (200 ml) and the mixture was heated under reflux for 15 hr. After allowing to cool, water (300 ml) and ethyl acetate (500 ml) were added to the reaction mixture and the mixture was stirred and partitioned. The organic layer was washed with water (300 ml) and saturated brine in this order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a crude product (124.80 g) as a brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With N-ethyl-N,N-diisopropylamine; In toluene; at 20 - 90℃; for 3.08333h; | A mixture of ethyl 3,3-dimethylaminoacrylate (4.68 g, 32.7 mmol) and N,N-diisopropylethylamine (12 mL, 8.9 g, 69 mmol) was stirred at rt and a solution of 2-chlorobenzoyl chloride (5.72 g, 32.7 mmol) in 30 mL of toluene was added over 5 mins. The yellow solution that formed was placed in an oil bath at 85-90 C. After 3 h, the mixture that formed was filtered and the solid was washed with toluene (4 x 25 mL). The pooled toluene washes were extracted with water (3 x 50 mL) and brine (1 x 30 mL), dried (Na2SO4), filtered and concentrated. The dark filtrate was concentrated and the oily residue was triturated with hexanes (100 mL). The solid that formed was isolated by filtration and washed with hexanes (25 mL). The crude product was dissolved in a minimum volume of EtOAc and added to 16.5 cm of flash silica gel in a 5 cm dia. column. Elution with 100% EtOAc afforded an oil that solidified after trituration with hexanes. The solid, weight 5.68 g (62%), exhibited mp 70-71.5 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In toluene; at 90℃; for 6.5h; | a) Ethyl 2-[2,5-difluorobenzoyl]-3-dimethylamino-2-propenoate; A solution of 2,5-difluorobenzoyl chloride (5.26 g) in toluene (100 mL) was treated with ethyl-3-dimethylamino-2-propenoate (5.27 g), followed by triethylamine (5.9 mL). The mixture was stirred at 90C for 6.5 h then allowed to cool, and the precipitate removed by filtration. The filtrate was concentrated in vacuo to give a residue which was purified by flash chromatography (silica gel, 50-100% Et2O in petroleum ether [b.p. 40-600C]) to give the title compound as a yellow oil (0.95 g); ESMS m/z 284.2 [M+H]+, 306.1 [M+ Na]+. | |
With triethylamine; In toluene; at 90℃; for 6.5h; | a) Ethyl 2-[(2,5-difluorophenyl)carbonyl]-3-(dimethylamino)-2-propenoateA solution of 2,5-difluorobenzoyl chloride (5.26 g, 29.8 mmol) in toluene (100 mL) was treated with ethyl-3-(dimethylamino)-2-propenoate (5.27 g, 36.8 mmol), followed by triethylamine (5.9 mL, 42.5 mmol). The mixture was stirred at 9O0C for 6.5 h then allowed to cool, and the precipitate removed by filtration. The filtrate was concentrated under reduced pressure to give a residue which was purified by flash chromatography (silica gel,50-100% diethyl ether in petroleum ether [b.p. 40-600C]) to give the title compound as a yellow oil (0.95 g); ESMS m/z 284.4 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In chloroform; at 20℃; for 15h; | 2-Fluoro-5-iodobenzoic acid (6.60 g, 24.81 mmol) was dissolved in chloroform (70 ml) and oxalyl chloride (4.30 ml, 49.29 mmol) and dimethylformamide (catalytic amount) were added. The mixture was stirred at room temperature for 3 hrs. The reaction solution was concentrated under reduced pressure and chloroform (35 ml), was added to dissolve the residue. The obtained solution was added dropwise to a solution of ethyl 3,3-dimethylaminoacrylate (4.26 g, 29.75 mmol) and triethylamine (5.19 ml, 37.24 mmol) in chloroform (35 ml), and the mixture was stirred at room temperature for 15 hrs. Water was added to partition the reaction solution, and the organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:2 to 1:1) to give an object product (6.40 g, yield 66%) of a mixture of E form and Z form as an orange solid.1H NMR(CDCl3 400MHz) (delta) ppm: 0.94 (3H, t, J=7.2Hz), 2.88 (3H, brs), 3.31 (3H, brs), 3.97 (2H, q), 6.78 (1H, dd, J=8.4, 10.0Hz), 7.65-7.67 (1H, m), 7.78(1H, s), 7,85 (1H, brs) MS (ESI) : M+ 392 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In toluene; at 90℃; for 1h; | ) [1-(5-Bromo-2-chloro- 3-pyridin-3-yI)methanoyl]dimethylaminoacrylic acid ethyl esterA stirred suspension of 2-chloro-5-bromo pyridine-3-carboxylic acid (5 g) in DCM (50 mL) at 2O0C was treated with oxalyl chloride (2.8 mL) and DMF (1 drop). After 1 h the clear solution was evaporated and re-evaporated from toluene (2x). The acid chloride was re- dissolved in toluene (80 mL) and treated with triethylamine (4.7 mL) and ethyl 3- dimethylaminopropenoate (3.94 g). After stirring for 1 h at 9O0C the mixture cooled and poured onto ice. Saturated aqueous sodium hydrogen carbonate (50 mL) was added and the organic layer washed with water and brine, dried (MgSO4) evaporated and the residue purified by chromatography (silica gel, 50-100% Et2O in petroleum ether [b.p. 40-600C]) to give the title compound as a colourless gum, (6.45 g); ESMS m/z 361.0, 363.0, 365.0 [M+H] +, 315.0, 317.0, 319.0 [M-OEt] +. | |
With triethylamine; In toluene; at 90℃; for 1h; | a) 2-[1 -(S-Bromo^-chloro-S-pyridin-S-yOmethanoyllS^dimethylaminoJacrylic acid ethyl ester EPO <DP n="61"/>A stirred suspension of 2-chloro-5-bromo pyridine-3-carboxylic acid (5 g) in DCM (50 mL) was treated with oxalyl chloride (2.8 mL) and Lambda/,Lambda/-dimethylformamide (1 drop). After 1 h the clear solution was evaporated and re-evaporated from toluene (2x). The acid chloride was re-dissolved in toluene (80 mL) and treated with triethylamine (4.7 mL) and ethyl 3- (dimethylamino)acrylate (3.94 g). After stirring for 1 h at 900C the mixture was cooled and poured onto ice. Saturated aqueous sodium hydrogen carbonate (50 mL) was added and the organic layer washed with water and brine, dried (MgSO4), evaporated and the residue purified by chromatography (silica gel, 50-100% diethyl ether in petroleum ether [b.p. 40-600C]) to give the title compound as a colourless gum, (6.45 g); ESMS m/z 361.0, 363.0, 365.0 [M+H]+, 315.0, 317.0, 319.0 [M-OEt]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In toluene; at 90℃; for 2h; | b) Ethyl 3-dimethylamino-2-(2-fluoro-4acetoxybenzoyl)-2-propenoateA stirred solution of Intermediate 25a (4.91 g) in DCM (80 mL) at 200C was treated with oxalyl chloride (3.25 mL) and DMF (2 drops). After 2 h the clear solution was evaporated and re-evaporated from DCM (2x). The acid chloride was re-dissolved in toluene (100 mL) and treated with triethylamine (5.17 mL) and ethyl 3-dimethylaminopropenoate (4.13 g). After stirring for 2 h at 900C the mixture was filtered and the solution flash chromatographed (silica gel 40 to 100% EtOAc in petroleum ether [b.p. 40-600C]) to give the title compound as a yellow gum (4.3 g); APCI m/z 324.0 [M+H]+. | |
With triethylamine; In toluene; at 90℃; for 2h; | b) Ethyl 3-(dimethylamino)-2-(2-fluoro-4-acetoxybenzoyl)-2-propenoate A stirred solution of Intermediate 12a (4.91 g) in DCM (80 mL) was treated with oxalyl chloride (3.25 mL) and dimethylformamide (2 drops). After 2 h the clear solution was evaporated and re-evaporated from DCM (2x). The acid chloride was re-dissolved in toluene (100 mL) and treated with triethylamine (5.17 mL) and ethyl 3- (dimethylamino)acrylate (4.13 g). After stirring for 2 h at 9O0C the mixture was cooled, filtered and the solution flash chromatographed (silica gel 40 to 100% EtOAc in petroleum ether [b.p. 40-600C]) to give the title compound as a white solid (4.3 g); APCI m/z 324.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In toluene; at 90℃; for 2h; | a) Ethyl (2Z)-3-dimethylamino-2-[2,3-difluoro-5-iodobenzoyl]-2-propenoateA suspension of 2,3-difluoro-5-iodobenzoic acid (2.84 g) in DCM (50 mL) was treated with oxalyl chloride (1.3 mL). After 1.5 h the resultant solution was evaporated, re-dissolved in toluene (50 mL) and re-evaporated to yield the intermediate acid chloride. This crude material was dissolved in toluene (50 mL) and treated with triethylamine (2.1 mL) and ethyl 3-dimethylaminopropenoate (1.86 g). The mixture was stirred for 2 h at 900C, cooled, filtered and evaporated. The crude product was purified by chromatography over silica gel eluting with 0-70% EtOAc in hexane to give the title compound as a yellow solid (3.05 g); ESMS m/z 410.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2,4-Difluoro-5-iodobenzoic acid (650.57 g, 2.29 mol) was dissolved in toluene (1300 ml), and thionyl chloride (184 ml, 2.52 mol) and dimethylformamide (catalytic amount) were added. The mixture was stirred at 90C for 2 hrs. After allowing the mixture to cool, the reaction solution was concentrated under reduced pressure. The residue was dissolved in toluene (330 ml) followed by concentration under reduced pressure, and repeated again. The residue was dissolved in toluene (690 ml) and the obtained solution was added dropwise to a solution of ethyl 3,3-dimethylaminoacrylate (361.52 g, 2.525 mol) and diisopropylethylamine (480 ml, 2.75 mol) in toluene (690 ml) and the mixture was stirred with heating at 90C for 3 hrs. After allowing the mixture to cool, (S)-(+)-valinol (260.00 g, 2.52 mol) was added to the reaction mixture and the mixture was stirred at room temperature for 1 hr. Water (2600 ml) was added to the reaction mixture and the mixture was partitioned. The aqueous layer was extracted with toluene (680 ml) . The organic layers were combined, washed twice with water (2000 ml), and dried over sodium sulfate. After filtration, concentration under reduced pressure gave a crude product (1180 g) as a brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In toluene; at 90℃; for 1.5h; | ) Ethyl 3-dimethylamino-2-(2,5-dichloroisonicotinoyl)-2-propenoate.; A stirred suspension of 2,5-dichloroisonicotinic acid (1.49 g) in DCM (20 mL) at 200C was treated with oxalyl chloride (1 mL) and DMF (1 drop). After 1.5 h the clear solution was evaporated and re-evaporated from toluene (2x). The acid chloride was re-dissolved in toluene (50 mL) and treated with triethylamine (1.62 mL) and ethyl 3- dimethylaminopropenoate (1.44 g). After stirring for 1.5 h at 9O0C the mixture was filtered and the solution flash chromatographed (silica gel 50 to 70% EtOAc in petroleum ether [b.p. 40-600C]) to give the title compound as a yellow gum (2.3 g); APCI m/z 317.0, 319.0 [M+H]+. | |
With triethylamine; In toluene; at 90℃; for 1.5h; | a) 2-[1-(2,5-Dichloropyridin-4-yl)methanoyl]-3-dimethylaminoacrylic acid ethyl ester; A stirred suspension of 2,5-dichloroisonicotinic acid (1.49 g) in DCM (20 mL) was treated with oxalyl chloride (1 mL) and dimethylformamide (1 drop). After 1 h the clear solution was evaporated and re-evaporated from toluene (2x). The acid chloride was re-dissolved in toluene (50 mL) and treated with triethylamine (1.62 mL) and ethyl 3- (dimethylamino)acrylate (1.44 g). After stirring for 1.5 h at 9O0C the mixture cooled, filtered and purified by chromatography (silica gel, 50-70% EtOAc in petroleum ether [b.p. 40- 6O0C]) to give the title compound as a yellow gum (2.3 g); APCIMS m/z 317.0, 319.0,321.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In toluene; at 90℃; for 3h; | a) 3-(Dimethylamino)-2-[(2,3,5-trifluorophenyl)carbonyl]-2-propenoic acid ethyl ester; DMF (20 drops) and oxalyl chloride (15 mL, 171 mmol) were added to a solution of 2,3,5- triflurobenzoic acid (20.12 g, 114 mmol) in dicholoromethane (500 mL) at 00C under argon. After 15 minutes the reaction was removed from the ice bath and stirring continued at 200C until gas evolution had stopped. The mixture was concentrated and the residue mixed with toluene and reconcentrated. The residue was dissolved in toluene (500 mL), and triethylamine (23.9 mL, 171 mmol) and treated with ethyl 3-(dimethylamino)-2- propenoate (21.27 g, 149 mmol). After heating the resultant mixture at 9O0C under argon for 3 hours the reaction was concentrated and the residue purified by chromatography (silica gel, 50 to 80% diethylether in hexane) to give the title compound (6.02 g); ESMS m/z 324.2 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In toluene; at 90℃; for 2h; | a) Ethyl (2Z)-3-(dimethylamino)-2-[(2,3,5-trifluorophenyl)carbonyl]-2- propenoate.; A suspension of 2,3-difluoro-5-iodobenzoic acid (2.84 g, 10 mmol) in dichloromethane (50 mL) was treated with oxalyl chloride (1.3 ml_, 14.9 mmol). After 1.5 h the resultant solution was evaporated, re-dissolved in toluene (50 mL) and re-evaporated to yield the intermediate acid chloride. This crude material was dissolved in toluene (50 mL) and treated with triethylamine (2.1 mL, 15 mmol) and ethyl 3-dimethylaminopropeneoate (1.86 g, 12.9 mmol). The mixture was stirred for 2 h at 9O0C, cooled, filtered and evaporated. The crude product was purified by chromatography over silica gel eluting with 0-70% ethyl acetate in hexane to give the title compound (3.05 g); ESMS m/z 410.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In toluene; at 90℃; for 2h; | a) Ethyl 3-(dimethylamino)-2-(2,3-difluoro-5-iodobenzoyl)-2-propenoateA stirred suspension of 2,3-difluoro-5-iodobenzoic acid (Pharmacia & Upjohn Company patent WO 02/04445 p90) (2.84 g) in DCM (50 mL) was treated with oxalyl chloride (1.3 mL) and dimethylformamide (2 drops). After 1.5 h the clear solution was evaporated and re-evaporated from toluene (2x). The acid chloride was dissolved in toluene (50 mL) and treated with triethylamine (2.1 mL) and <strong>[924-99-2]ethyl 3-(dimethylamino)acrylate</strong> (1.86 g). After stirring for 2 h at 90C the mixture was cooled, filtered and the solution chromatographed EPO <DP n="55"/>on silica gel eluting with 0% to 70% EtOAc in hexane to give the title compound as a yellow solid (3.05 g); ESMS m/z 410.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In toluene; at 20℃; for 3h; | Preparation 21 3-Trifluoromethyl-isoxazole-4-carboxylic acid ethyl ester <n="67"/>To a solution of dimethylamino acrylate (5.0 g, 35 mmol) in toluene (50 ml) was added bromo-oxime (Preparation 20, 6.0 g plus ether, 31 mmol), drop-wise, and the resultant solution was stirred for three hours at room temperature. The reaction mixture was evaporated to dryness, then f-butylmethyl ether (60 ml) and water (20 ml) were added. The layers were separated and the organic layer was washed with dilute hydrochloric acid (20 ml), then water (20 ml) and brine (10 ml). The organic fraction was then dried over anhydrous Na2SO4 (s), filtered and evaporated in vacuo to afford the title compound as an orange/brown oil (4.65 g, 72%). Material was taken on with no further purification.1HNMR (CDCI3): 1.35 (t, 3H), 4.36 (q, 2H), 9.03 (s, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With triethylamine; In tetrahydrofuran; for 5h;Heating / reflux; | Crude 12 was dissolved in THF (185 mL) and the solution was added dropwise to a solution of ethyl 3-dimethylaminoacrylate (41.0 g, 286 mmol) and triethylamine (44 mL, 316 mmol) in THF (185 mL). When addition was complete the mixture was heated to reflux for 5 h. The mixture was cooled to rt and concentrated under reduced pressure to give a brown solid. The crude product was triturated with MTBE to give 65.2 g (61%) of 13 as a gray solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In toluene; at 90℃; for 14h; | Step 16; The crude product (2.84 g) obtained in Step 15 was dissolved in toluene (30 ml), thionyl chloride (1.06 ml, 14.49 mmol) and dimethylformamide (catalytic amount) were added, and the mixture was stirred under heating at 100 C. for 2 hr. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and subjected to azeotropic distillation with toluene twice. The obtained residue was dissolved in toluene (15 ml) and the solution was added dropwise to a solution of <strong>[924-99-2]ethyl 3-(dimethylamino)acrylate</strong> (1.45 g, 10.14 mmol) and diisopropylethylamine (2.19 ml, 12.56 mmol) in toluene (15 ml), and the mixture was stirred under heating at 90 C. for 14 hr. After allowing to cool, water was added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water (twice) and saturated brine in this order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1 to 1:2) to give the object compound (2.85 g, yield 70%, 2 steps) as a yellow-brown oil.1H NMR (CDCl3 400 MHz) (delta) ppm: 0.96 (3H, t, J=7.1 Hz), 1.20 (3H, t, J=7.5 Hz), 2.71 (2H, q, J=7.5 Hz), 2.88 (3H, br s), 3.29 (3H, br s), 4.00 (2H, q, J=7.1 Hz), 6.90 (1H, d, J=11.4 Hz), 7.76 (1H, s), 8.02 (1H, br s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With triethylamine; In toluene; at 90℃; for 4h;Inert atmosphere; | 6.1.1 Ethyl 2-(2,4-difluorobenzoyl)-3-(dimethylamino)acrylate (8) A mixture of substituted 2, 4-difluorobenzoyl chloride (3.19 g, 18.1 mmol), <strong>[924-99-2]ethyl 3-(dimethylamino)acrylate</strong> (2.59 g, 18.1 mmol, 1.0 equiv), and triethylamine (2.74 g, 27.1 mmol, 1.5 equiv) in toluene (30 mL) was stirred at 90 C for 4 h. After cooling, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 2:1 to 1:2, v/v) to give the desired product 8 as yellow oil. Yield 65%; 1H NMR (400 MHz, CDCl3) delta 7.79 (s, 1H), 7.62-7.68 (m, 1H), 6.89-6.93 (m, 1H), 6.74-6.80 (m, 1H), 4.03-3.98 (q, J = 7.2 Hz, 2H), 3.31 (s, 3H), 2.89 (s, 3H), 0.95-0.99 (t, J = 7.2 Hz, 3H). |
65% | With triethylamine; In toluene; at 90℃; for 4h; | General procedure: The substituted benzoyl chloride (18.1 mmol), 3-(N,N-dimethylamino)acrylic acid ethyl ester (18.1 mmol), triethylamine (27.1 mmol) was dissolved in 30 mL of toluene, stirred at 90 C for 4 h, concentrated and column chromatographed to give Intermediate 1. ethyl 2-(2,4-difluorobenzoyl)-3-(dimethylamino)acrylate (R2=H): yield 65% |
65% | With triethylamine; In toluene; at 90℃; for 4h; | 2,4-Difluorobenzoyl chloride (18.1 mmol), ethyl 3-(N,N-dimethylamino)acrylate (18.1 mmol), triethylamine (27.1 mmol), dissolved in 30 mL of toluene, stirred at 90 C for 4 h Concentration, column chromatography gave Intermediate 1. Yield 65%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trimethylamine; In diethyl ether; at 22℃;Cooling in ice; | To an ice-cold solution of ethyl-3-(dimethylamino)acrylate (1.56 g, 10.9 mmol) in diethyl ether (30 mL) was added trimethylamine (1.52 ml, 10.9 mmol) followed by drop wise addition (over 1 h) of 2,4-dimethyl-N-hydroxybenzenecarboximidoyl chloride (2.012 g,10.96 mmol) dissolved in diethyl ether (15 mL). A white precipitate formed and additional <n="21"/>diethyl ether (50 mL) was added. The ice bath was removed and the reaction mixture was allowed to stir at 22 0C overnight. The solids were removed by filtration and the organic phase was washed with 5% aq HOAc solution (3x), dried (MgSO4) and the solvent was evaporated to furnish 2.54 g of the title compound. MS m/z 246 [m+1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step A rZ1-Ethyl 2-f2.5-dibromobenzoyl1-3-(dimethylamino1acrylate [00543] To a solution of 2,5-dibromobenzoic acid (1033 g, 36 90 mmol) and oxalyl chloride (4 0 mL, 45 82 mmol) in DCM (100 mL) was added DMF (0 5 mL) The reaction mixture was stirred at rt for 40 mm and concentrated under reduced pressure The crude material was dissolved m THF (100 mL) and added <strong>[924-99-2]ethyl 3-(dimethylamino)acrylate</strong> (5 80 g, 40 51 mmol) and TEA (10 5 mL, 75 33 mmol) The mixture was heated at reflux over night, diluted with EtOAc (250 mL) and washed with H2O (2x100 mL) The organic layer was dried over Na2SO4 and concentrated Purification on silica gel column gave the desired product as a yellow oil ( 1032 g) NMR (CDC13) delta 7 89 (s, 1H), 748 (d, 1H), 743 (s, 04H), 741 (s, 06H), 735(d, 06H), 732 (d, 04H), 3 96 (q, 2H), 3 39 (br s, 3H), 3 03 (br s, 3H), 091 (t, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 2-bromo-5-(4-fluorobenzyloxy)benzoic acid (1 06 g, 3 25 mmol) and oxalyl chloride (035 mL, 401 mmol) in DCM (40 mL) was added DMF (02 mL) The reaction mixture was stirred at rt for 1 h and concentrated under reduced pressure The crude material was dissolved in THF (50 mL) and added ethyl 3-(dimethylammo)acrylate (047 g, 3 29 mmol) and TEA (0 9 mL, 6 46 mmol) The mixture was heated at reflux over night, diluted with H2O (100 mL) and extracted with EtOAc (2x75 mL) The combined organic layer was washed with brine (100 mL), dried over Na2Stheta4 and concentrated Purification on silica gel column gave the desired product (0 32 g) NMR (CDC13) delta 7 84 (s, 1H), 740 (m, 3H), 708 (m, 2H), 700 (d, 1H), 6 83 (dd, 1H), 5 03 (s, 2H), 3 94 (q, 2H), 3 36 (br s, 3H), 3 01 (br s, 3H), 0 89 (t, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 2,5-dimethoxybenzoic acid (4.60 g, 17.63 mmol) and oxalyl chloride (1.9 mL, 21.78 mmol) in DCM (50 mL) was added DMF (0.1 mL). The reaction mixture was stirred at rt over night and concentrated under reduced pressure. The crude material was dissolved in THF (50 mL) and added <strong>[924-99-2]ethyl 3-(dimethylamino)acrylate</strong> (255 g, 17.81 mmol) and TEA (4.9 mL, 35.15 mmol). The mixture was heated at reflux over night, diluted with EtOAc (150 mL) and washed with H2O (2x100 mL). The organic layer was dried over Na2SO4 and concentrated. Purification on silica gel column gave the desired product as clear oil which solidified over time (1.85 g). NMR (CDC13): delta 7.79 (s, 1H), 7.71 (s, 1H), 6.44 (s, 1H), 4.01 (q, 2H), 3.97 (s, 3H), 3.84 (s, 3H), 3.08 (br s, 6H), 1.00 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Example 1; N-[(2E)-1-(difluoromethyl)-3-(dimethylamino)-2-(ethoxycarbonyl)prop-2-en-1-ylidene]-N-methylmethanaminium tetrafluoroborate; 8.8 g (60 mmol) of N-1,1,2,2-tetrafluoroethyldimethylamine were initially charged in 50 ml of dichloromethane under argon, and 8.2 g (60 mmol) of boron trifluoride-diethyl ether complex were added at RT. The mixture was stirred for 30 min and then admixed with 7.15 g (50 mmol) of ethyl dimethylaminoacrylate. After stirring at RT for 2 h and removing the dichloromethane under reduced pressure, 12.4 g of the product (100% yield) were obtained as a yellow oil.19F NMR (CDCl3) delta=-120.35, (d, 2F, J=51 Hz); -151.2 (s, 4F) ppm.1H NMR (CDCl3) delta=1.25 (t, 3H); 2.8, (s, 6H), 3.45 (m, 6H); 4.2 (qu, CH2); 6.87 (t, 1H); 8.16 (s, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
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95% | Example 2; N-[(2E)-1-(Chlorofluoromethyl)-3-(dimethylamino)-2-(ethoxycarbonyl)-prop-2-en-1-ylidene]-N-methyl-methanaminium tetrafluoroborate; 17.6 g (0.1 mmol) of N-1,1,2-trifluoro-2-chloroethyldimethylamine were initially charged in 100 ml of dichloromethane under argon and admixed at RT with 13.6 g (0.1 mol) of boron trifluoride-diethyl ether complex. After stirring for 30 min, 14.3 g (0.1 mol) of ethyl dimethylaminoacrylate were added and the mixture was stirred at RT for 2 h. After the dichloromethane had been removed under reduced pressure, 25.2 g (95% of theory) of the product were obtained. |
Yield | Reaction Conditions | Operation in experiment |
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85% | 71.6 g (0.5 mol) of ethyl dimethylaminoacrylate are dissolved in 150 ml of toluene. After cooling the mixture to 0 C., 50 g (0.5 mol) of difluoroacetyl fluoride are introduced into the solution with stirring at 0-3 C. within 30-40 min. Thereafter, the mixture is stirred at 0-3 C. for 3 h, then cooled to -20 C. At this temperature, 26.4 g of methylhydrazine are slowly added dropwise. Subsequently, the mixture is stirred at 0 C. for a further 3 h, warmed to room temperature and finally stirred at 20-25 C. for 1 h.After adding 500 ml of water, the toluene phase is removed and the water phase is extracted twice more with 100 ml of toluene each time. After the combined toluene phases have been concentrated, ethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (yield: 89% of theory) is obtained in a mixture with the undesired isomer [ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate] in a ratio of 91:9 (GC-MS analysis). Washing with hexane allows the undesired isomer to be removed fully. Yield: 85% |
Yield | Reaction Conditions | Operation in experiment |
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90% | In toluene; at 0 - 3℃; | Example 3 71.6 g (0.5 mol) of ethyl dimethylaminoacrylate are dissolved in 150 ml of toluene and added dropwise with stirring at 0-3 C. to a solution of 73.7 g (0.5 mol) of dichloroacetyl fluoride. After stirring at 0-3 C. for 3 h, the reaction mixture is warmed to room temperature. After complete removal of the solvent under reduced pressure (10 mbar), 114 g (90% of theory) of ethyl 2-(dichloroacetyl)-3-(dimethylamino)acrylate are obtained (m.p. 71-72 C.). |
Yield | Reaction Conditions | Operation in experiment |
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72% | b) 3-(5-Fluoro-pyridin-2-yl)-isoxazole-4-carboxylic acid ethyl esterTo a solution of N-chlorosuccinimide (17.34 g, 130 mmol) in DMF (128 mL) was added 5-fluoro-pyridine-2-carbaldehyde oxime (18.2 g, 130 mmol) portionwise over 2 h at room temperature and as the reaction warmed up to 60 0C the mixture was cooeld back to room temperature with an ice-water bath and the resulting mixture was then stirred for 64 h at room temperature. To this solution was then added ethyl 3-(N5N- dimethylamino)acrylate (18.6 g, 130 mmol) and triethylamine (36.2 mL, 260 mmol) in chloroform (64 mL) and the resulting mixture was then stirred for 1 h at room temperature and poured onto a mixture of ice water and HCl (4 N, 1 L) and extracted with ethylacetate. The organic extract was then washed with water, saturated aqueous sodium hydrogen carbonate solution, brine, dried with sodium sulfate, filtered and evaporated. Purification by chromatography (silica, heptane: ethylacetate = 100:0 to 1 :1) afforded the title product (21.96 g, 72%), which was obtained as a yellow solid. MS: m/e = 237.1 [M+H]+. | |
72% | b) 3-(5-Fluoro-pyridin-2-yl)-isoxazole-4-carboxylic acid ethyl esterTo a solution of N-chlorosuccinimide (17.34 g, 130 mmol) in DMF (128 mL) was added 5-fluoro-pyridine-2-carbaldehyde oxime (18.2 g, 130 mmol) portionwise over 2 h at room temperature and as the reaction warmed up to 600C the mixture was cooled back to room temperature with an ice-water bath and the resulting mixture was then stirred for 64 h at room temperature. To this solution was then added ethyl 3-(N,N-dimethylamino)acrylate (18.6 g, 130 mmol) and triethylamine (36.2 mL, 260 mmol) in chloroform (64 mL) and the resulting mixture was then stirred for 1 h at room temperature and poured onto a mixture of ice water and HCl (4N, 1 L) and extracted with ethylacetate. The organic extract was then washed with water, saturated aqueous sodium hydrogen carbonate solution, brine, dried with sodium sulfate, filtered and evaporated. Purification by chromatography (silica, heptane: ethylacetate = 100:0 to 1 :1) afforded the title product (21.96 g, 72%) which was obtained as a yellow solid. MS: m/e = 237.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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66% | Example 194-Methyl-2- [2-(3-pyridin-2-yl-isoxazol-4-yl)-ethyl] -thiazole-5-carboxylic acid (tetra- hydro-pyran-4-yl)-amidea) 3-Pyridin-2-yl-isoxazole-4-carboxylic acid ethyl esterTo a solution of N-chlorosuccinimide (54.7 g, 409 mmol) in DMF (1 L) was added pyridine-2-carbaldoxime (50 g, 409 mmol) portionwise and the resulting mixture was then stirred for 64 h at room temperature. To this solution was then added ethyl 3-(N5N- dimethylamino)acrylate (58.6 g, 409 mmol) and triethylamine (82.9 mL, 819 mmol) in chloroform (10 mL) and the resulting mixture was then stirred for 14 h at room temperature and poured onto a mixture of ice water and HCl (4 N, 100 mL) and extracted with ethylacetate. The organic extract was then washed with water, saturated aqueous sodium hydrogen carbonate solution, brine, dried with sodium sulfate, filtered and evaporated. Purification by distillation afforded the title product (58.9 g, 66%) which was obtained as a light brown liquid. Bp 125-127C at 0.4 mbar. MS: m/e = 219.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With pivaloyl chloride; triethylamine; In toluene; at 20℃; for 6h; | Example 2To a solution of 17.8 g of triethylamine in 50 ml of toluene are added, at room temperature, first 5.7 g of trifluoroacetic acid and then 7.23 g of ethyl dimethylaminoacrylate. 14 g of trimethylacetyl chloride are metered into this solution which is stirred at room temperature for 6 h. The reaction mixture is poured onto 20 ml of water, the organic phase is removed, the organic phase is washed with 20 ml of water, and the combined aqueous phases are extracted once again with 10 ml of toluene. The combined organic phases are concentrated under reduced pressure. This affords 10.7 g (90% of theory) of ethyl 2-(trifluoroacetyl)-3-(dimethylamino)acrylate. |
85% | (Example 2] Synthesis of Compound (II) using phosgene as a halogenating agent To 65 g of toluene containing 6.28 g of Compound (I) and 8.87 g of triethylamine was cooled with ice, 5.00 g of trifluoroacetic acid was added dropwise. Subsequently, 10.0 g of phosgene was allowed to pass through the reaction mixture, the temperature of the resultant was allowed to increase to room temperature from ice cooling, followed by stirring for 2 hours. Nitrogen was then allowed to pass through the reaction mixture for 1.5 hours. Then, water was added to the reaction mixture for liquid separation. The separated organic layer was washed with saturated sodium bicarbonate solution, and then dried over sodium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure, and hexane was added to the residue, followed by sufficient stirring. The precipitate was filtered to afford 8.89 g (yield: 85%) of Compound (II) as a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | ffl-ethyl 2-(2,6-difluoro-5-iodonicotinoyl)-3-(l-hvdroxy-3J-dimethylbutan-2- ylamino)acrylate.To a solution of 2,6-difluoro-5-iodonicotinic acid (4 g, 14.04 mmol, 1 equiv.) in toluene (30 mL) was added thionyl chloride (5.12 mL, 70.18 mmol, 5 equiv.) followed by DMF (0.5 mL). The reaction was stirred at 110 0C for 1 h. The reaction was concentrated. The residue was re-suspended in THF (15 mL) and added dropwise to a solution of ethyl-3- (dimethylamine)acrylate (2.1 mL, 14.04, 1,1 equiv.) and triethylamine (2.15 mL, 15.44 mmol, 1.1 equiv.) in THF (15 mL). The reaction was stirred at 67 0C for 2 h and cooled to 23 C. (5)-2-amino-3,3-dimethylbutan-l-ol (1.81 g, 15.44 mmol, 1.1 equiv.) was subsequently added and stirred at 23 0C for 30 min. The reaction was quenched with water (40 mL) and ethyl acetate (40 mL). The aqueous layer was extracted with ethyl acetate (2x40 mL), and the organics were dried and concentrated. The compound was purified via silica gel chromatography and concentrated to provide (5)-ethyl 2-(2,6-difluoro-5-iodonicotinoyl)-3-(l- hydroxy-3,3-dimethylbutan-2-ylamino)acrylate Intermediate 80 (4.49 g, 66 %). Calcd for C17H21F2IN2O4 [M + H]+: 482.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | To a solution of 2,6-dichloropyrazine-3-carboxylic acid (9 g, 46.6 mmol) in dichloromethane (250 mL) at room temperature (RT) was added oxalyl chloride (5.2 mL, 61.5 mmol) dropwise followed by careful addition of DMF (3 drops) and then the reaction mixture was stirred at RT for 3 hr. Then it was concentrated in a rotavap and the residue was taken in toluene (150 mL) and added dropwise to a mixture of 3-dimethylaminoacrylic acid ethyl ester (8.5 g, 59.4 mmol) and triethylamine (9.7 mL, 69.5 mmol) and the resulting reaction mixture was stirred at 90 C. for 16 hr. Then the reaction mixture was cooled, filtered, and the filtrate was concentrated. The residue obtained was purified by column chromatography (silica gel 60-120 mesh) eluting with 0-40% EtOAc in petroleum ether to obtain the product as pale yellow solid.Yield: 6.7 g (45%).1H NMR (300 MHz, DMSO-d6): 8.8 (s, 1H), 8.0 (s, 1H), 3.8 (q, 5 Hz, 2H), 3.4 (s, 3H), 3.0 (s, 3H), 0.9 (t, 5 Hz, 3H). LC/MS (M+H)+ 318, 320 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; at 1 - 15℃; for 2.33333h; | First StepA solution of Compound 11A (12.8 g, 89.4 mmol) and pyridine (8.50 g, 107 mmol) in dichloromethane (90 mL) was cooled to 1 to 3 C., and a solution of benzyloxyacetyl chloride (19.8 g, 107 mmol) in dichloromethane (90 mL) was added dropwise over 50 minutes while the same temperature was retained. After the reaction solution was stirred at the same temperature for 30 minutes, a temperature was gradually raised to 15 C. over 60 minutes, and ice water was added. The dichloromethane layer was separated, and the aqueous layer was extracted with dichloromethane once. The combined extracts were washed with water three times, washed with saturated sodium chloride water, and then dried. The solvent was distilled off, and the resulting oil product was purified by subjecting it to silica gel column chromatography. First, the oil product was eluted first with n-hexane and, then, with n-hexane-ethyl acetate (1:1, v/v). The objective fraction was concentrated to obtain 22.2 g of Compound 11B as an oil product.1H-NMR (CDCl3) delta: 1.25 (3H, t, J=7.2 Hz), 2.90 (3H, brs), 3.24 (3H, brs), 4.15 (2H, q, J=7.2 Hz), 4.45 (2H, s), 4.58 (2H, s), 7.25-7.38 (5H, m), 7.72 (1H, s). | |
22.2 g | With pyridine; In dichloromethane; at 1 - 15℃; for 2.33333h; | A dichloromethane (90 mL) solution of compound 11A (12.8 g, 89.4 mmol) and pyridine (8.50 g, 107 mmol) was cooled to 1-3C, and a dichloromethane (90 mL) solution of benzyloxy acetyl chloride (19.8 g, 107 mmol) was added dropwise thereto over 50 minutes with the same temperature kept. The reaction solution was stirred at the same temperature for 30 minutes and then gradually heated to 15C over 60 minutes, and ice water was added thereto. The dichloromethane layer was separated, while the aqueous layer was subjected to extraction once with dichloromethane. The combined extracts were washed with water three times, and washed with saturated saline, and then dried. The solvent was distilled off, and the obtained oil was subjected to silica gel column chromatography for purification. Elution was performed first with n-hexane and then with n-hexane-ethyl acetate (1:1, v/v). The fraction of interest was concentrated to obtain 22.2 g of compound 11B as an oil. 1H-NMR (CDCl3) delta: 1.25(3H, t, J=7.2Hz), 2.90(3H,brs), 3.24(3H, brs), 4.15(2H, q, J=7.2Hz), 4.45(2H, s), 4.58(2H, s), 7.25-7.38(5H, m), 7.72(1H, s). |
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 |
---|---|---|
With triethylamine; In toluene; at 40℃; for 3h;Green chemistry; | 29.2 g of N, N dimethylaminoethyl acrylate, 20.2 g of triethylamine and 340 ml of toluene were placed in a three-necked flask and heated with stirring to 40 C. A solution of 45 g of tetrafluorobenzoyl chloride in toluene was slowly added dropwise and added dropwise 1 hour, incubated for 2 hours after dripping, transformed 96%, cooled, filtered triethylamine hydrochloride about 24.8g, a small amount of toluene washing triethylamine hydrochloride filter cake, the filtrate was warmed to 40 C, was added dropwise 16g of L -2-aminopropanol dropwise half an hour, warmed to 90 C, incubated for 0.5 hours, the conversion of 98%, cooled and washed three times, toluene phase delamination, spin dehydration, diluted with DMF to volume to 250ml, liquid phase purity 99.22%. | |
With triethylamine; In toluene; at 60℃; for 6h; | 29.2 g of N, N dimethylaminoethyl acrylate, 24.3 g of triethylamine and 340 ml of toluene were placed in a three-necked flask, and the mixture was stirredHeated to 60 C, a solution of 45 g of tetrafluorobenzoyl chloride / toluene was slowly added dropwise and added dropwise over 2 hours, incubated for 4 hours after the completion of the dropwise addition, converted to 97%, cooled and filtered to give approximately 25.2 g of triethylamine hydrochloride, a small amount of toluene The triethylamine hydrochloride filter cake was washed and the filtrate was warmed to 60 C. 17g L-2-aminopropanol was added dropwise over half an hour until the temperature reached 90 C. The mixture was incubated for 1.5 hours and then transformed into 98%. The mixture was cooled and washed with water Times, toluene phase delamination, spin dry dehydration, add DMF diluted volume to 250ml, liquid phase purity of 99.41%. | |
With triethylamine; In toluene; at 12 - 75℃; for 6.42h; | 220g of toluene, 95g of triethylamine, 200g acid chloride sequentially into the acylation reactor, open stirring, cooling to 13 ;Preparation of the first 98g N, N-dimethylamino ethyl acrylate added to the dropping device, keeping the reaction kettle temperature 12 open stirring dropping,25 minutes to complete all the dropwise addition is completed, slowly heated to 75 C and incubated for 6 hours; step is completed, cooled to20 C, into 60g L-aminopropanol, slowly heated to 45 C, incubated for 3 hours, was added 200g saturated brine,Slowly add dropwise adjust PH5.5, stirring for 20 minutes, retest PH value after stopping stirring Stirred stratification, toluene layer decompression recovery of tolueneNo toluene solution into the reactor, pumped DMF200g stirring dissolved into the ring reactor high tank to be used; to the reaction within the reactorInto DMF1500g, start stirring, cast KF130g, temperature and pressure before recovery fraction to the reactor temperature 160 . Add amineThe reaction solution was heated to maintain refluxing heat 4 hours; end of the insulation, cooling to below 100 , DMF was recovered under reduced pressureWill be dry. After the end of the recovery of high pure water 1200g, stirred for 40 minutes, filtered, washed with water, finally rinsed with methanol, dried, too176g product, 96.8% molar yield. |
With triethylamine; In toluene; at 55℃; for 3h; | 29.2 g of N,N dimethyl amino ethyl acrylate,20.2 g of triethylamine and 340 ml of toluene were added to the three-vial flask.Heat to 55C with stirringIt was slowly added dropwise a solution of 46.8g tetrafluorobenzoyl chloride / toluene,Add 1 hour, after the drop, keep warm for 2 hours.96% conversion, cooling,About 24.8 g of triethylamine hydrochloride was filtered.A small amount of toluene washes the triethylamine hydrochloride filter cake,The filtrate warmed to 40C.16.5 g of L-2-aminopropanol was added dropwise.After half an hour, the temperature rose to 90C.Insulation 0.5 hours, conversion 98%,Cool, wash three times, layer the toluene phase,Spin dry, add DMF diluted to 250ml,The liquid purity is 99.22%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine; In diethyl ether; at 20℃; for 14h; | Step c) 3-(4-Chloro-phenyl)-isoxazole-4-carboxylic acid ethyl ester To a solution of (E)- and/or (Z)-N-hydroxy-4-chloro-benzenecarboximidoyl chloride (58.0 g, 250.3 mmol) in diethylether (1.04 L) was added a solution of ethyl 3-(N,N-dimethylamino)acrylate (90.4 mL, 624 mmol) and triethylamine (50.1 mL, 362 mmol) in diethylether (1.04 L). The resulting mixture was then stirred for 14 h at room temperature and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 4:1) afforded the title product (57 g, 91%) which was obtained as a white solid. MS: m/e=252.1 [M+H]+. |
91% | With triethylamine; In diethyl ether; at 20℃; for 14h; | Step c) 3-(4-Chloro-phenyl)-isoxazole-4-carboxylic acid ethyl ester To a solution of (E)- and/or (Z)-N-hydroxy-4-chloro-benzenecarboximidoyl chloride (58.0 g, 250.3 mmol) in diethylether (1.04 L) was added a solution of ethyl 3-(N,N- dimethylamino)acrylate (90.4 mL, 624 mmol) and triethylamine (50.1 mL, 362 mmol) in diethylether (1.04 L). The resulting mixture was then stirred for 14 h at room temperature and evaporated. Purification by chromatography (Si02, heptane:ethyl acetate = 100:0 to 4: 1) afforded the title product (57 g, 91%) which was obtained as a white solid. MS: m/e = 252.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In acetonitrile; at 10 - 35℃; for 3h; | A solution of 4-bromo-2-nitrobenzoic acid (2.5 g) in thionyl chloride (2.93 mL) was stirred at 80 C. for 3 hours. The reaction mixture was concentrated under reduced pressure. Toluene (3 mL) was added to the residue and the mixture was concentrated again under reduced pressure. A solution of the resulting acid chloride in acetonitrile (8 mL) was added dropwise to a solution of ethyl 3-dimethylaminoacrylate (1.46 g) and TEA (2.83 mL) in acetonitrile (30 mL) at room temperature over 6 minutes. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned by adding ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/heptane, 33 to 66%) to give the title compound (2.55 g). 1H-NMR (400 MHz, CDCl3) delta (ppm): 0.91 (t, J=7.2 Hz, 3H), 3.11 (s, 3H), 3.39 (s, 3H), 3.89 (q, J=7.2 Hz, 2H), 7.25 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0, 1.6 Hz, 1H), 8.00 (s, 1H), 8.19 (d, J=1.6 Hz, 1H). ESI-MS m/z 393 [M+Na]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Methyl 4-amino-2-fluorobenzoate (.) (13.0 g, 76.9 mmol) was suspended in a 3 N aqueous hydrochloric acid solution (108 mL), and an aqueous (25 mL) solution of sodium nitrite (5.57 g, 80.7 mmol) was added to the resulting suspension over 10 minutes under ice cooling. The resulting mixture was stirred at the same temperature for 30 minutes, and then the obtained reaction mixture was added to a mixed water (412 mL) and ethanol (52 mL) suspension of sodium acetate (82.0 g) and 3-dimethylamino ethyl acrylate (14.3 mL) over 5 minutes under ice cooling. The resulting mixture was stirred at the same temperature for 90 minutes. Subsequently, water was added to the reaction mixture, and the resulting mixture was extracted twice with dichloromethane. The organic layer thus obtained was dried over anhydrous sodium sulfate. The resulting mixture was filtered, and then the solvent was distilled off under reduced pressure. The resulting residue was diluted with ethanol (228 mL) and water (114 mL), and then hydroxylamine hydrochloride (6.06 g, 84.5 mmol) and sodium acetate (13.9 g, 169 mmol) were added to the resulting mixture. The mixture was stirred at room temperature for 2.5 hours. Subsequently, water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The organic layer thus obtained was dried over anhydrous sodium sulfate. The resulting mixture was filtered, then the solvent was distilled off under reduced pressure, and the resulting residue was diluted with acetic acid (120 mL) and acetic anhydride (179 mL). The resulting mixture was stirred at 60C for 1 hour, and then the solvent in the reaction mixture was distilled off under reduced pressure. The resulting residue was diluted with tetrahydrofuran (239 mL), and then potassium carbonate (106 g, 0.769 mol) was added to the resulting mixture. The mixture was stirred at room temperature for 1 hour. Subsequently, water was added to the reaction mixture, and the resulting mixture was extracted twice with dichloromethane. The organic layer thus obtained was dried over anhydrous sodium sulfate. The resulting mixture was filtered, then the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane) to give the title compound (15.9 g, yield: 71%). 1H-NMR (400 MHz, CDCl3) delta ppm: 8.27 (1H, s), 8.13-7.98 (3H, m), 4.49 (2H, q, J = 7 Hz), 3.97 (3H, s), 1.45 (3H, t, J = 7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With triethylamine; In diethyl ether; at 20℃; for 19h; | A solution of <strong>[924-99-2]ethyl 3-(dimethylamino)acrylate</strong> (4.33 mL, 30.3 mmol) and triethylamine (2.446 mL, 17.55 mmol) in Et2O (46 mL) was added dropwise to a solution of (Z)-2-chloro-N-hydroxybenzimidoyl chloride (2.3 g, 12.10 mmol) in Et2O (46.0 mL) to give a white suspension which was stirred overnight at 20 C. After 19 h, the salts were filtered and then rinsed with Et2O (30 mL). The filtrate was concentrated to dryness to give 5.86 g of an orange liquid which was purified by flash chromatography using a mixture of hexane/Et2O to afford ethyl 3-(2-chlorophenyl)isoxazole-4-carboxylate 3a (2.36 g, 77% yield) as a colorless oil; 1H NMR (DMSO-d6) was consistent with the desired product; MS m/z 252.1 (MH+); HPLC 100%, Rt=1.96 min, column 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With indium(III) triflate; In acetonitrile; at 20℃; for 6h; | Chromene-3-carbaldehyde 8 and its corresponding [beta] -enamino ester (shown in Table 1) 9 or [beta] -enaminoketone (11 mL) was stirred at room temperature with stirring at room temperature with indium (III) trifluoromethanesulfonate (III) trifluoromethanesulfonate. Synonym: In (OTf) 3, Indium (III) triflate, Trifluoromethanesulfonic acid indium (III) salt, Tris (trifluoromethanesulfonato) indium, Sigma-Aldrich,> 99.0%, 5.0 mol%].The reaction mixture was stirred for 4-12 hours, and after completion of the reaction was confirmed by TLC (hexane-EtOAc, 4: 1, v / v), 10 mL of water was added and the solution was diluted with ethyl acetate (10 mL x 3) .The solvent was evaporated and purified by silica gel column chromatography using hexane-ethyl acetate (4: 1, v / v) to give the following compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With indium(III) triflate; In acetonitrile; at 60℃; for 11h; | Chromene-3-carbaldehyde 8 and its corresponding [beta] -enamino ester (shown in Table 1) 9 or [beta] -enaminoketone (11 mL) was stirred at room temperature with stirring at room temperature with indium (III) trifluoromethanesulfonate (III) trifluoromethanesulfonate. Synonym: In (OTf) 3, Indium (III) triflate, Trifluoromethanesulfonic acid indium (III) salt, Tris (trifluoromethanesulfonato) indium, Sigma-Aldrich,> 99.0%, 5.0 mol%].The reaction mixture was stirred for 4-12 hours, and after completion of the reaction was confirmed by TLC (hexane-EtOAc, 4: 1, v / v), 10 mL of water was added and the solution was diluted with ethyl acetate (10 mL x 3) .The solvent was evaporated and purified by silica gel column chromatography using hexane-ethyl acetate (4: 1, v / v) to give the following compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With indium(III) triflate; In acetonitrile; at 20℃; for 6h; | Chromene-3-carbaldehyde 8 and its corresponding [beta] -enamino ester (shown in Table 1) 9 or [beta] -enaminoketone (11 mL) was stirred at room temperature with stirring at room temperature with indium (III) trifluoromethanesulfonate (III) trifluoromethanesulfonate. Synonym: In (OTf) 3, Indium (III) triflate, Trifluoromethanesulfonic acid indium (III) salt, Tris (trifluoromethanesulfonato) indium, Sigma-Aldrich,> 99.0%, 5.0 mol%].The reaction mixture was stirred for 4-12 hours, and after completion of the reaction was confirmed by TLC (hexane-EtOAc, 4: 1, v / v), 10 mL of water was added and the solution was diluted with ethyl acetate (10 mL x 3) .The solvent was evaporated and purified by silica gel column chromatography using hexane-ethyl acetate (4: 1, v / v) to give the following compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With indium(III) triflate; In acetonitrile; at 20℃; for 3h; | A solution of MeCN (1 mmol) containing chromene diene 13 (0.5 mmol) and the corresponding enamino ester 9 or? -enaminokone 11 (0.6 mmol) shown in Table 1 3.0 mL) was stirred at room temperature while adding indium (III) trifluoromethanesulfonate [Indium (III) trifluoromethanesulfonate].The reaction mixture was stirred for 2-8 hours, and after completion of the reaction was confirmed by TLC (hexane-EtOAc, 4: 1, v / v), 10 mL of water was added and the solution was extracted with ethyl acetate (10 mL x 3) .The solvent was evaporated and the residue was subjected to silica gel column chromatography using hexane-ethyl acetate (4: 1, v / v) to obtain the following compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.2% | In water; at 20 - 25℃; for 3h; | The sodium salt of ethyl formyl Step 1) was added to a concentration of 280g of 35% aqueous solution of dimethylamine hydrochloride, a temperature of 20-25 C during the control, and stirred at 20-25 C at the end of the reaction 3hrs after standing 30mins points to lower water phase, the upper organic phase 143g 3-N, N- dimethylaminoethyl acrylate crude; obtained crude product was distilled under reduced pressure to 20~100mbar, 70~110 C condition 3-N , of N- dimethylaminoethyl acrylate product 130. 5g, a yield of 91.2% (compared to sodium ethoxide meter), gas chromatography content of 99.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.58 g | With pyridine; In toluene; at 20℃; for 2h;Inert atmosphere; | Except that perfluoro(2-methyl-3-oxahexanoyl) fluoride was changed to perfluoro(3,6-dioxaoctanoyl) fluoride (1.74 g), the reaction was conducted under the same conditions as in Synthesis Example 1 for 2 hours to obtain the following compound (2.58 g). 1H-NMR (300 MHz, CDCl3)delta=1.29(t, J=7.2 Hz, 3H), 2.87(s, 3H), 3.31(s, 3H), 4.15(q, J=7.2 Hz, 2H), 7.70(s, 1H). 19F-NMR(300 MHz, CDCl3, CCl3F standard)delta=-74.2 to -74.3(2F), -86.2 to -86.3(3F), -87.6 to -88.1(6F). |
2.58 g | With pyridine; In toluene; at 20℃; for 2h;Inert atmosphere; | In Synthesis Example 1, except that instead of perfluoro(1 -(1 -propoxy)propionic acid) fluoride (perfluoro (2-methyl-3-oxa-hexanoyl) fluoride), perfluoro(3,6-diox- aoctanoyl) fluoride (1 .74 g) was used, the reaction was carried out for 2 hours under the same conditions, to obtain 2.58 g of the following compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.5 g | With pyridine; In toluene; at 20℃; for 10h;Inert atmosphere; | In a nitrogen atmosphere, ethyl beta-dimethylamino acrylate (1.43 g) was dissolved in toluene (10 ml), and pyridine (0.8 g) was added at room temperature. Here, perfluoro(2-methyl-3-oxa-hexanoyl) fluoride (3.2 g) was dropwise added, followed by stirring for 10 hours at the same temperature. To the reaction mixture, water (20 ml) was added, and the organic phase was separated. Further, the aqueous phase was extracted with toluene (10 ml), and the extract was combined with the previous organic phase. This organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, to obtain a compound represented by the following formula (4.5 g). 1H-NMR (300 MHz, CDCl3)delta=1.31(t, J=7.2 Hz, 3H), 3.07(s, 3H), 3.31(s, 3H), 4.17(q, J=7.2 Hz, 2H), 7.67(s, 1H). |
4.5 g | With pyridine; In toluene; at 20℃; for 10h;Inert atmosphere; | Under a nitrogen atmosphere, ethyl 3-dimethylam- inoethyl acrylate (1.43 g) was dissolved in toluene (10 ml), and pyridine (0.8 g) was added at room temperature. Perfluoro(1 -(1 -propoxy) propionic acid) fluoride (perfluoro(2- methyl-3-oxa-hexanoyl) fluoride) (3.2 g) was dropwise added thereto, followed by stirring for 10 hours at the same temperature. Water (20 ml) was added to the reaction mixture, and the organic phase was separated. Further, the aqueous phase was extracted with toluene (10 ml), and the extract was combined with the previous organic phase. This organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled oil to obtain 4.5 g of a compound represented by the following formula. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | The compound 2,4-difluorobenzoic acid (950 mg, 6 mmol) was dissolved in 2 ml of thionyl chloride,Heated to 80 C reflux2 hours,After completion of the reaction, the solvent was dried to give an oily compound,The oily compound was placed on an oil pump for half an hour,Immediately put the next step.The compound of the previous step was quickly dissolved in dry toluene,And ethyl 3- (dimethylamino) acrylate (1 g, 7 mmol) was added,Triethylamine (1.01 g, 10 mmol)Heated to 90 C,Fully stirred for 12h,Cooled to room temperature, spin dry solvent, dissolved in ethyl acetate and washed several times with water,After concentration, the compound 1a (1.42 g, 85%) was obtained as a yellow oil by column chromatography elution (petroleum ether: ethyl acetate = 10: 1 to 2: 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 20 - 90℃; for 3.33333h; | 3-Dimethylaminoethyl acrylate(2.9g, 20.3mmol)Mixture with triethylamine (4.1 g, 40.6 mmol),Stir at room temperature through the addition funnelJoin2.4-Dichloro-5-fluorobenzoyl chloride(4.7 g, 24.5 mmol) solution,After stirring for 20 minutes,80-90C reaction for 3 hours,The mixture is filtered and the solid is washed with toluene and the solid is washed.Dissolve in water and gradually add a small amount of ethyl acetate.Dissolve the solution completely, cool down, stand still until a white solid precipitates, and centrifuge.Dry for 2 hours to give a white solid. | |
With triethylamine; at 20 - 90℃; for 3.33h; | 1. 3-Dimethylaminoethyl acrylate (2.9 g, 20.3 mmol) and triethylamine (4.1 g, 40.6 mmol)The mixture is stirred at room temperature, through the addition funnel, 2.4-dichloro-5-fluorobenzoyl chloride is added.(4.7 g, 24.5 mmol) solution, after stirring for 20 minutes, 80-90 C. for 3 hours,The mixture is formed by filtration, the solid is washed with toluene, the solid is washed, dissolved in water,A small amount of ethyl acetate was gradually added dropwise to completely dissolve the solution and reduce the temperature.White solids precipitated upon standing, centrifuged and dried for 2 hours to give a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With acetic acid; In toluene; for 6h;Reflux; | In a reaction flask equipped with a reflux condenser and hydrochloric acid absorption dimethylamine device,100 g (0.698 mol) of ethyl N,N-dimethylacrylate, 300 ml of toluene, 89 g (1.047 mol) of piperidine and 2 g of acetic acid were added,After stirring, the mixture was heated to reflux and refluxed for 6 hours. GC analysis showed that the raw material was almost completely converted and the reaction released dimethylamine.After being absorbed with aqueous hydrochloric acid, the reaction was completed and concentrated under reduced pressure to recover toluene and piperidine.The product yield was 130.8 g with a yield of 99.0%.The internal standard content is 97.3%.The content of the internal standard refers to the amount of 3-piperidyl-ethyl acrylate contained in the product of the present example detected by gas chromatography GC and the amount of 3-piperidyl-ethyl acrylate contained in the standard sample by gas chromatography GC.ratio. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With indium(III) triflate; In acetonitrile; at 20℃; for 4h; | A solution of MeCN (1 mmol) containing chromene diene 13 (0.5 mmol) and the corresponding enamino ester 9 or? -enaminokone 11 (0.6 mmol) shown in Table 1 3.0 mL) was stirred at room temperature while adding indium (III) trifluoromethanesulfonate [Indium (III) trifluoromethanesulfonate].The reaction mixture was stirred for 2-8 hours, and after completion of the reaction was confirmed by TLC (hexane-EtOAc, 4: 1, v / v), 10 mL of water was added and the solution was extracted with ethyl acetate (10 mL x 3) .The solvent was evaporated and the residue was subjected to silica gel column chromatography using hexane-ethyl acetate (4: 1, v / v) to obtain the following compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With triethylamine; In tetrahydrofuran; at 16℃; for 12h; | [1424] to a solution of <strong>[924-99-2]ethyl 3-(dimethylamino)acrylate</strong> (825 mg, 5.8 mmol) and tea (583 mg, 5.8 mmol) in THF (15 ml) was added a solution of compound 323b (1 g, 5.8 mmol) in THF (35 ml) dropwise over a period of 30 mins. The mixture was stirred at 16 C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1 : 0 to 30: 1) to give compound 323c (800 mg, yield: 59%) as a pale yellow oil. 1H NMR (400mhz, CDCl3) delta 9.03 (s, 1h), 7.62 - 7.51 (m, 2h), 7.45 (dt, = 5.8, 8.0 hz, 1h), 7.25 - 7.17 (m, 1h), 4.32 (q, = 7.1 hz, 2h), 1.33 (t, = 7.2 hz, 3h). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.2% | With triethylamine; In tetrahydrofuran; at 10℃; for 12h; | [1429] a suspension of compound 324b (500 mg, 3.17 mmol) in THF (4 ml) was added in portions to a mixture of 3-amino-2-hydroxy-4-phenylbutanamide (454 mg, 3.17 mmol) and tea (321 mg, 3.17 mmol) in THF (6 ml), the mixture was stirred at 10 C for 12h. The mixture was filtered and the filtrate was concentrated, the residue was purified by preparatory- tlc (petroleum ether: ethyl acetate = 1 : 1) to give compound 324c (300 mg, yield: 43.2%) as yellow oil. 1H NMR (400mhz, CDCl3) delta 7.46 - 7.39 (m, 1h), 7.39 - 7.32 (m, 2h), 7.30 - 7.27 (m, 1h), 7.25 - 7.19 (m, 4h), 7.05 - 7.00 (m, 2h), 6.87 (br s, 1h), 5.92 - 5.85 (m, 2h), 5.40 (br s, 1h), 4.22 (dd, j = 1.3, 4.9 hz, 1h), 4.17 - 4.09 (m, 1h), 2.92 - 2.81 (m, 2h). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.4% | With triethylamine; In tetrahydrofuran; at 20℃; for 12h; | [1311] to a solution of <strong>[924-99-2]ethyl 3-(dimethylamino)acrylate</strong> (165 mg, 1.2 mmol) and tea (233 mg, 2.3 mmol) in THF (15 ml) was added a solution of compound 277b (400 mg, 2.3 mmol) in THF (5 ml) drop-wise over 30 mins. The mixture was stirred at 20 C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparatory-tlc (SiO2, petroleum ether: ethyl acetate = 1: 1) to give compound 277c (240 mg, yield: 44.4%) as a pale yellow oil. 1H NMR (400mhz, CDCl3) delta 8.94 (s, 1h), 7.51 - 7.36 (m, 2h), 7.21 - 7.14 (m, 1h), 7.13- 7.04 (m, 1h), 4.17 (q, 7 = 7.1 hz, 2h), 1.15 (t, 7 = 7.2 hz, 3h). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.8% | With triethylamine; In tetrahydrofuran; at 20℃; for 12h; | [1353] to a mixture of ethyl 3-(dimethylamino)acrylate (92 mg, 639 umol), tea (129 mg, 1.28 mmol) in THF (10 ml) was added a solution of compound 288b (200 mg, 1.28 mmol) in THF (10 ml) over a period of 20 min. The mixture was stirred at 20 C and stirred for 12 hours. The reaction mixture was concentrated. The residue was purified by preparatory- tlc (SiO2, petroleum ether: ethyl acetate = 1 : 1) to give compound 288c (150 mg, yield: 53.8%) as yellow oil. 1H NMR (400mhz, CDCl3) delta 9.02 - 8.97 (m, 1h), 8.75 (d, = 4.6 hz, 1h), 7.87 - 7.76 (m, 2h), 7.45 - 7.36 (m, 1h), 4.27 (q, j = 7.3 hz, 2h), 1.26 (t, j = 7.2 hz, 3h). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.6% | In N,N-dimethyl-formamide; at 115 - 125℃;Reflux; | N-[2-methoxyl-4[4-(dimethyl amino)piperid-1-yl]aniline]guanidine (II) (2.9 g, 10 mmol), N,N-dimethylaminoethyl acrylate (2.0 g, 14.0 mmol) and N,N-dimethylformamide 30 mL were added in a reaction bottle, were heated to a temperature of 115-125 C., and were subjected to stirring reaction for 22-24 hours to finish TLC detection reaction. Concentration under reduced pressure was carried out, obtained residues were added with 50 mL of ethanol, and were cooled to room temperature while stirring, and then solid was separated out. The solid was filtered, a filter cake was washed with cold ethanol, and was dried under vacuum to obtain off-white solid N2-[4-[4-(dimethyl amino)-1-piperidyl]-2-methoxyphenyl]amino-4(1H)-pyrimidone (III) 2.73 g, the yield was 79.6%, and FAB-MS m/z: 344 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.8% | With water; sodium hydroxide; In ethanol; at 50 - 60℃; for 3h; | Ethanol (100 ml) and ethyl ester of compound III-1 (28.6 g, 0.2 mol) were added to a reaction flask equipped with a thermometer and a stirring device, and stirring was carried out, and 120 ml of a 10% aqueous sodium hydroxide solution was added dropwise, 50 C - 60 C the reaction was carried out for 3 h, and was monitored by TLC to show that the reaction was completed. The reaction solution was evaporated to dryness under reduced pressure. EtOAc (EtOAc)EtOAc. Filtration and evaporation of ethyl acetate under reduced pressure afforded compound III-1, yield: 58.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.5% | With solid base catalyst; In 5,5-dimethyl-1,3-cyclohexadiene; at 50℃; under 7500.75 Torr; for 4h;Autoclave; | Ethyl acetate (88 g, 1 mol),Dimethylamine (54g, 1.2mol),250 mL of xylene and 4.4 g of a solid base catalyst were placed in the autoclave.Access to CO,The control pressure is 1 MPa and the temperature is raised to 50 C to keep the reaction for 4 h.CO pressure no longer drops,Cool to room temperature,filter,Recovering a solid base catalyst,The filtrate is added to the solvent xylene and separated into the water layer.The organic layer recovers the solvent (xylene),The residue is distilled under reduced pressure;Collecting fractions at 118-121 C (7.5 mmHg),The target product, 136.5 g of N,N-dimethylaminoethyl acrylate, was obtained.The yield was 95.5%, and the HPLC content was 99.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 100℃; under 12751.3 Torr; for 0.333333h;Microwave irradiation; Sealed tube; | General procedure: All microwave reactions were carried out in a capped (10 mL) microwave-vessel (Borosilicate glass vial sealed) that was placed in a microwave cavity. The pressure was set at 17 bar (average of an effective pressure = 4 bar) with power 75 W. DIEA (3.4 g, 3.4 mmol) was added to a solution of either 2,5-difluoro-4-(pyrrolidin-1-yl) benzoylchloride 12 (0.83 g, 3.4 mmol) or 2,5-difluoro-4-(pyrrolidin-1-yl)benzothioyl chloride 13 (0.88 g, 3.4 mmol) and ethyl-3-(diethylamino)acrylate 14 (0.45 g, 3.1 mmol) in acetonitrile (5 mL). The mixture reaction was held at 100 C for 20 min. After the reaction vessel was cooled to room temperature, the crude product was diluted with water (10 mL) and extracted with ethyl acetate(3 × 10 mL). The organic layers were combined, dried over Na2SO4, filtered, evaporated and purified by a flash column chromatography (eluent n-hexane: acetone, 3:1)to give the titled compounds. Ethyl-2-(2,5-difluoro-4-(pyrrolidin-1-yl)benzoyl)-3-(dimethylamino) acrylate (15)Yellow oil (Rf = 0.3), Yield 85%. IR (KBr) numax in cm-1:2993 (C-H, Ar), 2953 (C-H), 1760 (C=O), 1692 (C=O),1654 (C=C, Ar), 1592 (C-N). 1H NMR (400 MHz, DMSOd6):delta = 7.77 (1H, s, CH), 7.32 (1H, d, J = 5.0 Hz, CH-Ar),6.88 (1H, d, J = 5.2 Hz, CH-Ar), 4.2 (2H, q, J = 7.1 Hz,CH2), 3.47-3.42 (4H, m, 2CH2), 3.1 (6H, s, 2CH3), 2.01-1.97 (4H, m, 2CH2), 1.32 (3H, t, J = 4.2 Hz, CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 100℃; under 12751.3 Torr; for 0.333333h;Microwave irradiation; Sealed tube; | General procedure: All microwave reactions were carried out in a capped (10 mL) microwave-vessel (Borosilicate glass vial sealed) that was placed in a microwave cavity. The pressure was set at 17 bar (average of an effective pressure = 4 bar) with power 75 W. DIEA (3.4 g, 3.4 mmol) was added to a solution of either 2,5-difluoro-4-(pyrrolidin-1-yl) benzoylchloride 12 (0.83 g, 3.4 mmol) or 2,5-difluoro-4-(pyrrolidin-1-yl)benzothioyl chloride 13 (0.88 g, 3.4 mmol) and ethyl-3-(diethylamino)acrylate 14 (0.45 g, 3.1 mmol) in acetonitrile (5 mL). The mixture reaction was held at 100 C for 20 min. After the reaction vessel was cooled to room temperature, the crude product was diluted with water (10 mL) and extracted with ethyl acetate(3 × 10 mL). The organic layers were combined, dried over Na2SO4, filtered, evaporated and purified by a flash column chromatography (eluent n-hexane: acetone, 3:1)to give the titled compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | A mixture of 3,6-dichloropyridazine-4-carboxylic acid (5.3 g, 27.5 mmol), thionyl chloride (10 ml, 137 mmol), DMF (0.5 ml, 6.5 mmol) and toluene (50 ml) was stirred in a sealed tube at H0C for 3h. After cooling and evaporation of the solvents, the residue was dissolved in dry THF (20 ml) and added to a mixture of ethyl-3 -dimethylaminoacrylate (4.3 g, 30.0 mmol) and triethylamine (4.6 ml, 33.0 mmol) in dry THF (20 ml). The mixture formed was stirred in a sealed tube at 75C for 8h. After evaporation of the solvents, the crude obtained was purified by FC (120 g, Si02, CHiCb/AcOEt 100:0 70:30) leading to the expected product (5.8 g, 66%) as a brown oil. NMR (300 MHz, DMSC J) 6 8.11 (s, 1H), 8.00 (s, 1H), 3.90 (qd, j = 7.1 Hz, 2H), 3.46 (s, 3H), 3.01 (s, 3H), 0.93 (t, j = 7.1 Hz, 3H). ESIMS m/z [M+H]+ 318.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With aluminum (III) chloride; In N,N-dimethyl-formamide; at 110℃; for 3h; | General procedure: Ethyl 4-(4-chlorophenyl)-2-thioxo-1,2,3,4-tertahydropyrimidine-5-carboxylate 6a (Table 2, entry 1). To a mixture of thiourea 12a (23.0 mg, 0.302 mmol), 4-chlorobenzaldehyde 13a (63.0 mg, 0.448 mmol), and ethyl 3-dimethylaminoacrylate 9 (64.0 mg, 0.447 mmol) in anhydrous DMF (0.3 mL) was added anhydrous aluminum chloride (8.0 mg, 0.0600 mmol) at room temperature, and the reaction mixture was stirred at 110 C for 3 h. To the mixture was added EtOAc (10 mL) and 1 M HCl aqueous solution (5 mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (10 mL), and the combined organic layers were washed with water (5 mL) and brine (5 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane-EtOAc (4:1 to 2:1)] to give 6a (78.9 mg, 0.266 mmol, 88%) as pale yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With aluminum (III) chloride; In N,N-dimethyl-formamide; at 110℃; for 3h; | General procedure: Ethyl 4-(4-chlorophenyl)-2-thioxo-1,2,3,4-tertahydropyrimidine-5-carboxylate 6a (Table 2, entry 1). To a mixture of thiourea 12a (23.0 mg, 0.302 mmol), 4-chlorobenzaldehyde 13a (63.0 mg, 0.448 mmol), and ethyl 3-dimethylaminoacrylate 9 (64.0 mg, 0.447 mmol) in anhydrous DMF (0.3 mL) was added anhydrous aluminum chloride (8.0 mg, 0.0600 mmol) at room temperature, and the reaction mixture was stirred at 110 C for 3 h. To the mixture was added EtOAc (10 mL) and 1 M HCl aqueous solution (5 mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (10 mL), and the combined organic layers were washed with water (5 mL) and brine (5 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane-EtOAc (4:1 to 2:1)] to give 6a (78.9 mg, 0.266 mmol, 88%) as pale yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With aluminum (III) chloride; In N,N-dimethyl-formamide; at 110℃; for 3h; | General procedure: Ethyl 4-(4-chlorophenyl)-2-thioxo-1,2,3,4-tertahydropyrimidine-5-carboxylate 6a (Table 2, entry 1). To a mixture of thiourea 12a (23.0 mg, 0.302 mmol), 4-chlorobenzaldehyde 13a (63.0 mg, 0.448 mmol), and ethyl 3-dimethylaminoacrylate 9 (64.0 mg, 0.447 mmol) in anhydrous DMF (0.3 mL) was added anhydrous aluminum chloride (8.0 mg, 0.0600 mmol) at room temperature, and the reaction mixture was stirred at 110 C for 3 h. To the mixture was added EtOAc (10 mL) and 1 M HCl aqueous solution (5 mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (10 mL), and the combined organic layers were washed with water (5 mL) and brine (5 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane-EtOAc (4:1 to 2:1)] to give 6a (78.9 mg, 0.266 mmol, 88%) as pale yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With aluminum (III) chloride; In N,N-dimethyl-formamide; at 110℃; for 3h; | General procedure: Ethyl 4-(4-chlorophenyl)-2-thioxo-1,2,3,4-tertahydropyrimidine-5-carboxylate 6a (Table 2, entry 1). To a mixture of thiourea 12a (23.0 mg, 0.302 mmol), 4-chlorobenzaldehyde 13a (63.0 mg, 0.448 mmol), and ethyl 3-dimethylaminoacrylate 9 (64.0 mg, 0.447 mmol) in anhydrous DMF (0.3 mL) was added anhydrous aluminum chloride (8.0 mg, 0.0600 mmol) at room temperature, and the reaction mixture was stirred at 110 C for 3 h. To the mixture was added EtOAc (10 mL) and 1 M HCl aqueous solution (5 mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (10 mL), and the combined organic layers were washed with water (5 mL) and brine (5 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane-EtOAc (4:1 to 2:1)] to give 6a (78.9 mg, 0.266 mmol, 88%) as pale yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With aluminum (III) chloride; In N,N-dimethyl-formamide; at 110℃; for 3h; | General procedure: Ethyl 4-(4-chlorophenyl)-2-thioxo-1,2,3,4-tertahydropyrimidine-5-carboxylate 6a (Table 2, entry 1). To a mixture of thiourea 12a (23.0 mg, 0.302 mmol), 4-chlorobenzaldehyde 13a (63.0 mg, 0.448 mmol), and ethyl 3-dimethylaminoacrylate 9 (64.0 mg, 0.447 mmol) in anhydrous DMF (0.3 mL) was added anhydrous aluminum chloride (8.0 mg, 0.0600 mmol) at room temperature, and the reaction mixture was stirred at 110 C for 3 h. To the mixture was added EtOAc (10 mL) and 1 M HCl aqueous solution (5 mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (10 mL), and the combined organic layers were washed with water (5 mL) and brine (5 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane-EtOAc (4:1 to 2:1)] to give 6a (78.9 mg, 0.266 mmol, 88%) as pale yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With aluminum (III) chloride; In N,N-dimethyl-formamide; at 110℃; for 3h; | General procedure: Ethyl 4-(4-chlorophenyl)-2-thioxo-1,2,3,4-tertahydropyrimidine-5-carboxylate 6a (Table 2, entry 1). To a mixture of thiourea 12a (23.0 mg, 0.302 mmol), 4-chlorobenzaldehyde 13a (63.0 mg, 0.448 mmol), and ethyl 3-dimethylaminoacrylate 9 (64.0 mg, 0.447 mmol) in anhydrous DMF (0.3 mL) was added anhydrous aluminum chloride (8.0 mg, 0.0600 mmol) at room temperature, and the reaction mixture was stirred at 110 C for 3 h. To the mixture was added EtOAc (10 mL) and 1 M HCl aqueous solution (5 mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (10 mL), and the combined organic layers were washed with water (5 mL) and brine (5 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane-EtOAc (4:1 to 2:1)] to give 6a (78.9 mg, 0.266 mmol, 88%) as pale yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With aluminum (III) chloride; In N,N-dimethyl-formamide; at 110℃; for 3h; | General procedure: Ethyl 4-(4-chlorophenyl)-2-thioxo-1,2,3,4-tertahydropyrimidine-5-carboxylate 6a (Table 2, entry 1). To a mixture of thiourea 12a (23.0 mg, 0.302 mmol), 4-chlorobenzaldehyde 13a (63.0 mg, 0.448 mmol), and ethyl 3-dimethylaminoacrylate 9 (64.0 mg, 0.447 mmol) in anhydrous DMF (0.3 mL) was added anhydrous aluminum chloride (8.0 mg, 0.0600 mmol) at room temperature, and the reaction mixture was stirred at 110 C for 3 h. To the mixture was added EtOAc (10 mL) and 1 M HCl aqueous solution (5 mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (10 mL), and the combined organic layers were washed with water (5 mL) and brine (5 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane-EtOAc (4:1 to 2:1)] to give 6a (78.9 mg, 0.266 mmol, 88%) as pale yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With aluminum (III) chloride; In N,N-dimethyl-formamide; at 110℃; for 3h; | General procedure: Ethyl 4-(4-chlorophenyl)-2-thioxo-1,2,3,4-tertahydropyrimidine-5-carboxylate 6a (Table 2, entry 1). To a mixture of thiourea 12a (23.0 mg, 0.302 mmol), 4-chlorobenzaldehyde 13a (63.0 mg, 0.448 mmol), and ethyl 3-dimethylaminoacrylate 9 (64.0 mg, 0.447 mmol) in anhydrous DMF (0.3 mL) was added anhydrous aluminum chloride (8.0 mg, 0.0600 mmol) at room temperature, and the reaction mixture was stirred at 110 C for 3 h. To the mixture was added EtOAc (10 mL) and 1 M HCl aqueous solution (5 mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (10 mL), and the combined organic layers were washed with water (5 mL) and brine (5 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane-EtOAc (4:1 to 2:1)] to give 6a (78.9 mg, 0.266 mmol, 88%) as pale yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With aluminum (III) chloride; In N,N-dimethyl-formamide; at 110℃; for 3h; | General procedure: Ethyl 4-(4-chlorophenyl)-2-thioxo-1,2,3,4-tertahydropyrimidine-5-carboxylate 6a (Table 2, entry 1). To a mixture of thiourea 12a (23.0 mg, 0.302 mmol), 4-chlorobenzaldehyde 13a (63.0 mg, 0.448 mmol), and ethyl 3-dimethylaminoacrylate 9 (64.0 mg, 0.447 mmol) in anhydrous DMF (0.3 mL) was added anhydrous aluminum chloride (8.0 mg, 0.0600 mmol) at room temperature, and the reaction mixture was stirred at 110 C for 3 h. To the mixture was added EtOAc (10 mL) and 1 M HCl aqueous solution (5 mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (10 mL), and the combined organic layers were washed with water (5 mL) and brine (5 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane-EtOAc (4:1 to 2:1)] to give 6a (78.9 mg, 0.266 mmol, 88%) as pale yellow crystals. |
Tags: 924-99-2 synthesis path| 924-99-2 SDS| 924-99-2 COA| 924-99-2 purity| 924-99-2 application| 924-99-2 NMR| 924-99-2 COA| 924-99-2 structure
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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.
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