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CAS No. : | 129618-40-2 | MDL No. : | MFCD00866928 |
Formula : | C15H14N4O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NQDJXKOVJZTUJA-UHFFFAOYSA-N |
M.W : | 266.30 | Pubchem ID : | 4463 |
Synonyms : |
BI-RG 587;NVP;Brand name: Viramune Viramune XR.;HSDB 7164;BIRG 0587;NSC 641530
|
Num. heavy atoms : | 20 |
Num. arom. heavy atoms : | 15 |
Fraction Csp3 : | 0.27 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 78.2 |
TPSA : | 63.57 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.53 cm/s |
Log Po/w (iLOGP) : | 2.42 |
Log Po/w (XLOGP3) : | 1.96 |
Log Po/w (WLOGP) : | 2.42 |
Log Po/w (MLOGP) : | 2.14 |
Log Po/w (SILICOS-IT) : | 2.72 |
Consensus Log Po/w : | 2.33 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.21 |
Solubility : | 0.162 mg/ml ; 0.00061 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.92 |
Solubility : | 0.32 mg/ml ; 0.0012 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.75 |
Solubility : | 0.0047 mg/ml ; 0.0000177 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.3 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-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 |
---|---|---|
31% | With oxygen; lithium diisopropyl amide In tetrahydrofuran Ambient temperature; | |
With MoO5*pyridine*HMPA; lithium diisopropyl amide multistep reaction; influence of base; | ||
With MoO5*pyridine*HMPA; lithium diisopropyl amide 1.) THF, hexane, below -40 deg C, 5 min, 2.) -30 to -40 deg C, 75 min; Yield given. Multistep reaction; |
With MoO5*pyridine*HMPA; lithium diisopropyl amide 1.) THF, hexane, -30 deg C, 5 min, 2.) THF, hexane, -30 deg C, 1.5 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With MoO5*pyridine*HMPA; sodium hydride 1.) THF, r.t., 1 h, 2.) 0 deg C to r.t., 2 d; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With diethylene glycol dimethyl ether; sodium hydride; at 100 - 125℃; for 2.5h;Inert atmosphere; | A 250 rnL, 3-neck flask, with an overhead stirrer, a thermocouple and an addition funnel purged with N2 was prepared, charged with NaH (7.14 g, 178.5 mmol, and 1.7 equiv) and diglyme (22.5 ml), and the suspension was heated to 105 C. The reaction mixture containing <strong>[133627-47-1]CYCLOR</strong> (from Step 1A) was slowly transferred into the NaH suspension over a period of 30 minutes, while keeping the temperature of the mixture at 100 - 110 C. The charge line was rinsed of <strong>[133627-47-1]CYCLOR</strong> with 5 ml diglyme. After the addition of <strong>[133627-47-1]CYCLOR</strong> was complete, the reaction mixture was held at 100 - 125 C for about 2 hours, then assayed for reaction completion, e.g. by HPLC or UPLC. The mixture was cooled to 0-5C. The excess sodium hydride was slowly quenched by the addition of 30 mL of water, while keeping the temperature below 50 C. After quenching was complete, 60 - 70 ml of diglyme/water was distilled off from the reaction mixture under reduced pressure at 70 - 80 C. 125 ml of water was added with stirring to ensure that all salt was dissolved. 51 ml of cyclohexane and 15 ml of ethanol were added while stirring and the pH of the mixture was adjusted to 6 - 8 by the addition of glacial acetic acid (19.5 g, 3.09 n2mol), upon which nevirapine precipitates as a solid. The suspension was cooled to 0 -10C, and stirred for about one hour, during which time additional nevirapine precipitated. The product was isolated by vacuum filtration, and washed successively with water (3x30m1) and a 20% ethanol: water (2x20m1) mixture. The product was dried at 90-110C under vacuum to a constant weight. In one preparation, the dried weight of crude nevirapine was 25.4 g (91%).Nevirapine crude (20g, 75.1 rnmol) and purified water (86 mL) were added to a 500 ml 3-neck round-bottom flask fitted with magnetic stirrer, thermocouple and addition funnel. The mixture was stirred at room temperature to dissolve the nevirapine and then the solution temperature was lowered to 0-5C using an ice/water bath. Conc. aq. HC1 (23.2 mL, 277.6 mmol) was added dropwise to the above slurry while keeping temperature below 5C. After HC1 addition was completed, the reaction mixture was stirred for about 30 minutes at 0-5C to make sure all nevirapine had dissolved. Activated carbon (0.6 g) was added and the mixture was stirred for at least another 30 minutes while keeping the temperature at 0-5C. The solution was filtered using a celite pad to capture the carbon. The celite pad was rinsed with 2x 10 mL water and the filtrate was re-filtered using a 4 jim filter to remove any insoluble material/fibers, etc., before moving to next step to precipitate the final product.The clarified filtrate was transferred to a 500 mL 3-neck flask fitted with a magnetic stirrer, thermocouple and an addition funnel. The solution was cooled to 0-5 C and about 10 ml NaOH (50% solution) was added drop-wise to achieve a pH between 4 and 7, while keeping temperature below 5 C. A white precipitate appeared when the desired pH was reached. The mixture was stirred for about 30 minutes and the precipitated product was isolated by vacuum filtration, washing the solid with 3x20m1 water. The wet cake was dried at 90 -110C under vacuum to a constant weight. In an exemplary synthesis, the isolated yield was 19.2g (96%) and the purity was 100% by HPLC. |
83.39% | Example 8: a) Preparation of Nevirapine of formula (I) (diglyme as solvent)N-(2-Chloro-4-methyl-3 -pyridinyl)-2-cyclopropylamino)-3 -pyridine carboxamide of formula (VII; 1.0 kg; 3.305moles) was stirred in diglyme (10 litres) and potassium tertiary butoxide (1.48 kg; 13.188 moles) was then added to the mixture, which was then heated between 1000C and 1100C for 90 minutes. After completion of the reaction, the mixture was cooled between 5C and 100C, the pH of the mixture adjusted between 6.0 and 7.0 by the addition of acetic acid, diluted with chilled water (50 litres) and the nevirapine (I) separating out was filtered. The compound of formula (I) was dried.; b) Recrystallization of Nevirapine of formula (I). Nevirapine (obtained from example 8a) was added to ethylene chloride (24 litres) and refiuxed for 30 minutes at 600C - 700C. The mixture after optional charcoal treatment was EPO <DP n="22"/>concentrated partially and filtered at 50C-IO0C. The wet solid was dried at 100-1100C for 24 hours.Yield: 0.73 kg % Yield: 83.39% HPLC Purity: 99.92%. | |
79.96% | Example 9: a) Preparation of Nevirapine of formula (I) (toluene as solvent)N-(2-chloro-4-methyl-3-pyridinyl)-2-cyclopropylamino)-3-pyridine carboxamide of formula (VII; 1.0 kg) was stirred in toluene (10 litres) and potassium tertiary butoxide (1.48 kg; 13.188 moles) was then added to the mixture, which was then heated between 1000C and HO0C for 180-210 minutes. After completion of the reaction, the mixture was cooled between 5C and 1O0C the pH of the mixture adjusted between 6.0 and 7.0 by the addition of sulfuric acid and then diluted with water (5 litres) and again the pH was adjusted between pH 1-2 by addition of sulfuric acid. Nevirapine (I) separating out was filtered. The compound of formula (I) was dried.; b) Recrystallization of Nevirapine of formula (I). Nevirapine (obtained from example 9a) was added to ethylene chloride (24 litres) and refluxed for 30 minutes at 600C - 700C. The mixture after optional charcoal treatment was concentrated partially and filtered at 50C-IO0C. The wet solid was dried at 100-1100C for 24 hours.Yield: 0.70 kg % Yield: 79.96%HPLC Purity: 99.92%. |
71% | With sodium hydrogen sulfate; copper(l) iodide; sulfuric acid; potassium tert-butylate; In diethylene glycol dimethyl ether; at 115℃; | Step l[00285] Activated cuprous iodine: Cuprous iodide (1Og) and sodium bisulfate (lmol/L,50ml) were placed in a round-bottom flask. Sulfuric acid (lmol/L, 10) was added and the solution was stirred for 15 minutes at ambient temperature. The solution was filtered; the filter cake was washed with water (5OmL) and tetrahydrofuran (50mLx3), and then dried under reduced pressure.; Step 5[00289] 11 -Cvclopropyl-5.11 -dihvdro-4-methyl-6H-dipyridor3 ,2.-b :2 ' .3 ' -el 1.41- diazepin-2-one (Nevirapine): A solution of 7V-(2-chloro-4-methylpyridin-3-yl)-2-(cyclopropylamino)nicotinamide (1Og, 33.11 mmol, 1.00 equiv) in l-methoxy-2- (2- methoxyethoxy)ethane (300 ml) was placed in a 500 ml 3 -necked round-bottom flask. The reaction was purged with nitrogen and maintained under an inert atmosphere of nitrogen. Potassium 2-methylpropan-2-olate (1 Ig, 98 mmol, 3.00 equiv) and activated cuprous iodide (5 g, 26 mmol) were added to the solution. The solution was allowed to react overnight while maintaining the temperature at 115 C in an oil bath. The solution was filtered, the filter cake was washed with ethyl acetate (5OmL), and the filtrate was collected and concentrated in vacuo using a rotary evaporator. The residue was purified by flash chromatography on silica gel (10% ethyl acetate in petroleum ether). The final product (6.3g, purity: 98%, yield:71%) was obtained as a yellow solid. |
With sodium hydride; In diethylene glycol dimethyl ether; o-xylene; at 135 - 140℃; for 1.16667 - 1.33333h; | Sodium hydride (9.15 g, 65 % w/w) was suspended in o-xylene (187.5 ml) at 25- 300C under nitrogen atmosphere and slowly heated to 130-1350C. N-(2-chloro-4- methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide (25 g) was dissolved in diglyme (50 ml) at 70-800C and added to the above suspension over a period of 10-20 min at 135-138C and stirred for 1 h at 135-1400C. Thereafter the reaction mixture was cooled to 5C and acetic acid (8.75 ml) was added slowly below 15C. Then cold DM water (100 ml) was added to the reaction mixture slowly below 15C and pH of the reaction mixture was adjusted to 6.5 using acetic acid (4.25 ml) at 5-100C. The temperature of the reaction mixture was raised to 20-250C and stirred for 1 h at 20-250C and product crystallizes out. The product obtained was filtered and washed with DM water (75 ml) and then with cyclohexane (50 ml) and suck dried the product under suction for 10 min. The wet product (27.5 g) was suspended in a mixture of methanol (750 ml) and DM water (175 ml) and heated to reflux at 700C, a clear solution formed. Carbon (2.5 g) was added and stirred for 30 min at reflux. Filtered the carbon in hot condition and washed with hot methanol (50 ml, 60-650C). Filtrate was concentrated under reduced pressure at 50-550C up to residual weight attained is approximately 225 g. Thereafter cooled the concentrated mass to 5-100C and stirred for 30 min at 5-100C. The product obtained was filtered and washed with cold DM water (25 ml, 5-100C), suck dried and dried at 65-7O0C under reduced pressure. <n="11"/>Yield - 17.5 gHPLC purity - 99.92 %Moisture content - 0.08 % w/w | |
With sodium hexamethyldisilazane; In tetrahydrofuran; at 30 - 66℃; | EXAMPLE 5 Preparation of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (Nevirapine) Using sodium Hexamethyldisilazane A reaction flask equipped with a magnetic stirrer, temperature controller thermodouple, addition funnel and condenser with an oil bubbler for exclusion of ambient air was inerted with nitrogen and charged with 3.02 g (0.010 mol) of <strong>[133627-47-1]N-(2-chloro-4-methyl-3-pyridinyl)-2-(cyclopropylamino)-3-pyridinecarboxamide</strong> from Example 4 and 30 ml of anhydrous THF. A 40% solution of sodium hexamethyldisilazane in THF (12.7 ml, 0.025 mol) was added dropwise maintaining the temperature of the reaction mixture at no more than 30 C. When the addition of the NaHMDS solution was completed, the reaction mixture was heated to reflux temperature (about 63-66 C.).When the reaction was completed (HPLC analysis), the mixture was cooled to ambient temperature.The reaction mixture was treated with 1.55 g (0.050 mol) of methanol and 0.45 g of water (0.025 mol).The mixture was concentrated on a rotary evaporator at 25-30 in.Hg with a 50-60 water bath temperature.The residual product weighing 4.44 g was triturated with 50 ml of water and the PH 10-12 solution was acidified to PH 3 by adding 10% HCl solution.The solid product was collected by filtration and the filter cake rinsed three times with 10 ml portions of water.The filter cake was dried in a vacuum oven at 50-60 C. to obtain nevirapine. | |
With sodium hydride; In diethylene glycol dimethyl ether; mineral oil; at 80 - 130℃; | EXAMPLE 6 Preparation of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (Nevirapine) Using sodium Hydride A 500 ml 4NRB flask with stirrer, temperature controller thermocouple, addition funnel and condenser with an oil bubbler to exclude air was inerted with nitrogen and charged with 15.00 g of 60% sodium hydride in a mineral oil slurry and 120 ml of diglyme.The mixture was heated to 130 C. and treated dropwise with a solution of 41.7 g (0.138 mol) of <strong>[133627-47-1]N-(2-chloro-4-methyl-3-pyridinyl)-2-(cyclopropylamino)-3-pyridinecarboxamide</strong>, from Example 4, in 70 ml of diglyme at 80 C. The reaction mixture was heated at 130 C. until hydrogen evolution ceased.The mixture was cooled to ambient temperature and water (6.75 g) was added dropwise cautiously.When hydrogen evolution ceased, an additional 100 ml of water was added.Acetic acid (20 ml) was added to reduce the PH of the mixture from 11-13 to about 7.An additional 100 ml of water was added and the reaction mixture stirred under ambient conditions for 30 minutes while the product crystallized.The solid product was collected by filtration and the filter cake rinsed with 100 ml of water followed by 50 ml of cyclohexane to remove any residual mineral oil from the mineral oil-sodium hydride slurry.The wet cake was dried in a vacuum oven at 50 C. for 18 hours to obtain 35.58 g of nevirapine. | |
EXAMPLE 7Preparation of NevirapineSodium hydride (9.15 g, 65% w/w) was suspended in o-xylene (187.5 ml) at 25-30 C. under nitrogen atmosphere and slowly heated to 130-135 C. <strong>[133627-47-1]N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide</strong> (25 g) was dissolved in diglyme (50 ml) at 70-80 C. and added to the above suspension over a period of 10-20 min at 135-138 C. and stirred for 1 h at 135-140 C. Thereafter the reaction mixture was cooled to 5 C. and acetic acid (8.75 ml) was added slowly below 15 C. Then cold DM water (100 ml) was added to the reaction mixture slowly below 15 C. and pH of the reaction mixture was adjusted to 6.5 using acetic acid (4.25 ml) at 5-10 C. The temperature of the reaction mixture was raised to 20-25 C. and stirred for 1 h at 20-25 C. and product crystallizes out. The product obtained was filtered and washed with DM water (75 ml) and then with cyclohexane (50 ml) and suck dried the product under suction for 10 min. The wet product (27.5 g) was suspended in a mixture of methanol (750 ml) and DM water (175 ml) and heated to reflux at 70 C., a clear solution formed. Carbon (2.5 g) was added and stirred for 30 min at reflux. Filtered the carbon in hot condition and washed with hot methanol (50 ml, 60-65 C.). Filtrate was concentrated under reduced pressure at 50-55 C. up to residual weight attained is approximately 225 g. Thereafter cooled the concentrated mass to 5-10 C. and stirred for 30 min at 5-10 C. The product obtained was filtered and washed with cold DM water (25 ml, 5-10 C.), suck dried and dried at 65-70 C. under reduced pressure. Yield-17.5 g HPLC purity-99.92% Moisture content-0.08% w/w |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
multistep reaction; reaction of nevirapine with phenyldimethylchlorosilane; | ||
Yield given. Multistep reaction. Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride 1.) DMSO, 2.) DMSO; Multistep reaction; | ||
Stage #1: Nevirapine With sodium hydride In N,N-dimethyl-formamide at 60℃; for 2h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 9% 2: 17% 3: 0.9% | With dihydrogen peroxide; acetic acid at 95℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen In diethylene glycol dimethyl ether at 100℃; for 12h; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With pyridine; sodium hexamethyldisilazane at 90℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | Stage #1: Nevirapine With dihydrogen peroxide; acetic acid at 95 - 100℃; for 48h; Stage #2: With hydrogen In ethyl acetate for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With nitronium tetrafluoborate; 4 A molecular sieve In acetonitrile at 0℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | In ethanol Irradiation; microwave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In ethanol Irradiation; microwave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In ethanol Irradiation; microwave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In ethanol Irradiation; microwave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In ethanol Irradiation; microwave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In ethanol Irradiation; microwave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In ethanol Irradiation; microwave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In ethanol Irradiation; microwave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | In ethanol Irradiation; microwave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 20 percent / 4A molecular sieves; nitronium tetrafluoroborate / acetonitrile / 20 h / 0 °C 2: 86 percent / tin(II) chloride; conc. aq. HCl; acetic acid / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: 20 percent / 4A molecular sieves; nitronium tetrafluoroborate / acetonitrile / 20 h / 0 °C 2.1: 86 percent / tin(II) chloride; conc. aq. HCl; acetic acid / 20 °C 3.1: aq. H2SO4; sodium nitrite / 0.5 h / 0 °C 3.2: 30 percent / aq. NaOH / pH 7 - 8 | ||
Multi-step reaction with 2 steps 1: iodine / dichloromethane / 0.08 h / 104 °C 2: methanol; potassium hydroxide / 0.25 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 87 percent / CH2Cl2 / 1.) -78 deg C, 1 h, 2.) RT, 23 h 2: 94 percent / 4 h / 140 °C 3: 67 percent / 80percent NaH / bis-(2-methoxy-ethyl) ether / 1.5 h / 185 °C | ||
Multi-step reaction with 3 steps 1: 65.5 percent / pyridine / cyclohexane; dioxane / 48 h / Ambient temperature 2: 83 percent / xylene / 18 h / 110 °C 3: 67 percent / NaH / various solvent(s) / 1.5 h / Heating | ||
Multi-step reaction with 3 steps 1: pyridine / acetonitrile / 20 - 45 °C 2: calcium oxide / xylene / 140 °C 3: sodium hydrogen sulfate; copper(l) iodide; sulfuric acid; potassium <i>tert</i>-butylate / diethylene glycol dimethyl ether / 115 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 99 percent / thionyl chloride / 1 h / Heating 2: 87 percent / CH2Cl2 / 1.) -78 deg C, 1 h, 2.) RT, 23 h 3: 94 percent / 4 h / 140 °C 4: 67 percent / 80percent NaH / bis-(2-methoxy-ethyl) ether / 1.5 h / 185 °C | ||
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 5 h / 60 - 65 °C 2: 5 h / 60 - 65 °C 3: 5%-palladium/activated carbon; hydrogen / ethanol; toluene / 6 h / 30 - 35 °C / 1500.15 - 2250.23 Torr / Autoclave 4: benzenesulfonic acid / 6 h / 90 - 95 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 98 percent / SnCl2 * 2 H2O, conc. HCl / diethyl ether / 0.33 h / Ambient temperature 2: 87 percent / CH2Cl2 / 1.) -78 deg C, 1 h, 2.) RT, 23 h 3: 94 percent / 4 h / 140 °C 4: 67 percent / 80percent NaH / bis-(2-methoxy-ethyl) ether / 1.5 h / 185 °C | ||
Multi-step reaction with 4 steps 1: 75 percent / H2 / 5percent Rh/C / ethanol / 3 h / 2585.7 Torr 2: 65.5 percent / pyridine / cyclohexane; dioxane / 48 h / Ambient temperature 3: 83 percent / xylene / 18 h / 110 °C 4: 67 percent / NaH / various solvent(s) / 1.5 h / Heating | ||
Multi-step reaction with 3 steps 1: 5 h / 60 - 65 °C 2: 5%-palladium/activated carbon; hydrogen / ethanol; toluene / 6 h / 30 - 35 °C / 1500.15 - 2250.23 Torr / Autoclave 3: benzenesulfonic acid / 6 h / 90 - 95 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 94 percent / 4 h / 140 °C 2: 67 percent / 80percent NaH / bis-(2-methoxy-ethyl) ether / 1.5 h / 185 °C | ||
Multi-step reaction with 2 steps 1: 83 percent / xylene / 18 h / 110 °C 2: 67 percent / NaH / various solvent(s) / 1.5 h / Heating | ||
Multi-step reaction with 2 steps 1: calcium oxide / xylene / 140 °C 2: sodium hydrogen sulfate; copper(l) iodide; sulfuric acid; potassium <i>tert</i>-butylate / diethylene glycol dimethyl ether / 115 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide; Cyclopropylamine With triethylamine In toluene at 130℃; for 10h; Autoclave; Stage #2: With sodium amide In diethylene glycol dimethyl ether at 15 - 110℃; for 2h; Autoclave; | 1 200ml of toluene was added in the autoclave, 2-chloro -N- (2-chloro-4-methyl-3-pyridinyl) -3-pyridinecarboxamide (100.0g, 0.35mol), triethylamine (100ml, 0.72 mol), cyclopropylamine (51.0ml, 0.74mol), stirred open. It was slowly heated to 130 , incubated for 10 hours. Sample testing surplus stock.Opening the autoclave, the above mixture into the reaction vessel, was added diglyme 100ml, stirring, cooling to 15 , was added sodium amide (44.0g, 1.13mol), stirred for 10 minutes incubation. Heating slowly warmed to 110 , incubated for 2 hours. After the reaction monitored by TLC starting material, toluene was distilled off under reduced pressure. The residue was cooled to 20 , water was added dropwise 500ml, pale yellow solid gradually precipitated. An aqueous solution of 50% glacial acetic acid was added dropwise under ice-water bath, neutralized to pH 7-7.5, stirred for half an hour. Filtration, the filter cake washed with 50ml water, and air dry to give crude nevirapine.Added to the above crude product in dichloromethane 200ml, warmed to reflux, beating one hour, cooled to 5 , suction filtered after stirring for half an hour. The filter cake was added percentage of 55% by weight aqueous solution of 1000ml of ethanol, warmed to reflux, stirred for half an hour, the solid dissolved, active carbon, hot filtration, the filtrate was distilled at atmospheric pressure to a volume of about 500 ml, 1 hour iced water, suction to obtain purified nevirapine 80.2g, yield 86%, HPLC purity 99.8% detection. |
Stage #1: 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide; Cyclopropylamine With calcium oxide In diethylene glycol dimethyl ether at 135 - 145℃; Stage #2: With sodium hydride at 140℃; for 0.5 - 1h; Stage #3: With water; acetic acid; ethyl acetate at 0 - 10℃; for 1 - 2h; | 2-Chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide (150 grams, 0.5319 moles), calcium oxide (30 grams, 0.5357 moles), cyclopropylamine (95.1 grams, 1.6684 moles) in diglyme (300 ml) was heated to a temperature of 135-145° C. until the reaction was completed to form a reaction mass. The reaction mass was subsequently cooled to temperature of 20-30° C., filtered and washed with diglyme (150 ml). Half of the initial volume of the solvent was distilled off from the filtrate under vacuum before diglyme (37.5 ml) was added at a temperature of 50-60° C. This reaction mass was slowly added to a hot suspension of sodium hydride (57.6 grams, 1.44 moles) in diglyme (105 ml) at about 140° C. The reaction mass was maintained at a temperature of 140° C. for about 30-60 minutes. The reaction mass was then cooled to a temperature of 40-50° C. before ethyl acetate (360 ml) was added and further cooled to a temperature of 0-10° C. Acetic acid (103 ml) followed by water (105 ml) was added to the reaction mass and stirred for 1-2 hours, filtered the separated compound and washed with ethyl acetate (60 ml) The compound was dried at a temperature of 60-80° C. to afford the crude Nevirapine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.33% | In isopropyl alcohol for 0.5h; Heating / reflux; | 14 Example 14: Recrystallization of Nevirapine of formula (I) Nevirapine (15gms; obtained from example 9a) was added to isopropanol (660 ml) and refluxed for 30 minutes. The mixture after optional charcoal treatment was cooled between 0°C-5°C and filtered. The wet solid was dried at 100-11O0C for 24 hours.Yield: 11.3 gms % Yield: 75.33% HPLC Purity: 99.63%. Melting point: 245-247°C. |
74.67% | In methanol at 60 - 70℃; for 0.5h; | 13 Example 13: Recrystallization of Nevirapine of formula (I) Nevirapine (15gms; obtained from example 9a) was added to methanol (510 ml) and refluxed for 30 minutes at 6O0C - 7O0C. The mixture after optional charcoal treatment was cooled between 50C-IO0C and filtered. The wet solid was dried at 100-1100C for 24 hours.Yield: 11.2 gms % Yield: 74.67% HPLC Purity: 99,89%. Melting point: 245-247°C |
69% | In chloroform for 0.5h; Heating / reflux; | 16 Example 16: Recrystallization of Nevirapine of formula (I) EPO Nevirapine (lOgms; obtained from example 9a) was added to chloroform (200 ml) and refluxed for 30 minutes. The mixture after optional charcoal treatment was concentrated and a mixture of chloroform (10ml) and methylene dichloride (50ml) was added at ambient temperature and filtered. The wet solid was dried at 100-1100C for 24 hours. Yield: 6.9gms % Yield: 69% |
40% | In nitromethane at 75 - 80℃; for 0.5h; | 15 Example 15: Recrystallization of Nevirapine of formula (I)Nevirapine (5 gms; obtained from example 9a) was added to nitromethane (165 ml) and heated between 75°C-80°C for 30 minutes. The mixture after optional charcoal treatment was cooled between 00C-IO0C and filtered. The wet solid was dried at 100-1100C for 24 hours.Yield: 2.0 gms % Yield: 40%HPLC Purity: 99.20%. Melting point: 245-247°C |
12 11-Cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one Example 12 11-Cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one Using a procedure analogous to that employed in Example 11, but using cyclopropylamine instead of ethylamine, yielded the title compound, m.p. 247°-249° C. | ||
I D.PREPARATION OF 11-CYCLOPROPYL-5,11-DIHYDRO-4-METHYL-6H-DIPYRIDO[3,2-b:2',3'-e][1,4]DIAZEPIN-6-ONE STR14 D.PREPARATION OF 11-CYCLOPROPYL-5,11-DIHYDRO-4-METHYL-6H-DIPYRIDO[3,2-b:2',3'-e][1,4]DIAZEPIN-6-ONE STR14 To a solution of 33g of 60% sodium hydride on mineral oil dispersion (0.825 mole of sodium hydride) in 100ml of 2-methoxyethyl ether, heated to 120° C. under nitrogen, was added dropwise over 0.5 hour 80g (0.237 mole) of 2,6-dichloro-3-(2'-cyclopropylamino-3'-nicotinyl)carboxamide-4-methylpyridine in 400 ml of 2-methoxyethyl ether. The reaction mixture was stirred at 130° C.-135° C. for 1 hour longer, cooled to room temperature, and quenched by the careful addition of ethanol. The solution was then hydrogenated as is at 50 PSI with 8g of 10% palladium on carbon catalyst for 2 days. The catalyst was filtered and the ethanol was removed under reduced pressure. The methoxyethyl ether solution was poured into 3l of water and brought to pH7 with glacial acetic acid. The crystalline product was stirred overnight, collected and washed with pentane. The filter cake was dissolved in 500ml of hot pyridine and slow addition of 3l of water gave crystalline product. After aging overnight, the product was collected and suspended in 500 ml of isopropanol, heated to reflux, cooled and filtered. Final recrystallization from pyridiine and water gave, after drying at 100° C., 45.8g (72.5%) (mp:253° C.-254° C.) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.5% | In tetrahydrofuran; mineral oil | 13 11-Cyclopropyl-5,11-dihydro-5-hydroxy-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one Example 13 11-Cyclopropyl-5,11-dihydro-5-hydroxy-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one To a mixture of 0.5 g of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (Example 12) in 25 ml of tetrahydrofuran was added 0.12 g of 50% sodium hydride in mineral oil. The reaction mixture was stirred at room temperature for one hour and then cooled to 0° C., at which time 0.9 g of oxodiperoxymolybdenum(pyridine)hexamethylphosphoramide (MoOPH) was added in one portion. The reaction mixture was then allowed to warm to room temperature and was allowed to stir overnight. The mixture was quenched with water and the solvents removed in vacuo. The residue was extracted with warm ethyl acetate, concentrated in vacuo and purified on a silica gel column (eluent: ethyl acetate) to give 0.05 g of pure 11-cyclopropyl-5,11-dihydro-5-hydroxy-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, m.p. 239°-241° C. The yield was 9.5% of theory. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With NaH; benzaldehyde; lithium diisopropyl amide In tetrahydrofuran; cyclohexane; ethyl acetate | 143 11-Cyclopropyl-5,11-dihydro-4-phenacyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one Example 143 11-Cyclopropyl-5,11-dihydro-4-phenacyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one To a solution of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (1.0 g) in tetrahydrofuran (25 mL) was added NaH (80% in oil, 0.12 g). The mixture was stirred at room temperature for 30 min. and then cooled to -78° C. Lithium diisopropylamide (1.5M in cyclohexane, 6.6 mL) was added and the mixture was stirred for an additional 45 min. Benzaldehyde (0.53 g) was added, the mixture was stirred at -65° C. for 1 hour and then allowed to warm to room temperature. The reaction was quenched with water and the volatile materials were removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried, filtered, and evaporated. The residue was chromatographed over silica gel with 40% ethyl acetate/hexane, and then purified by preparative layer chromatography to give 0.1 g of the title compound, m.p. 195°-197° C., |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; diethylene glycol dimethyl ether; cyclohexane; water; acetic acid | 1 EXAMPLE 1 EXAMPLE 1 117.5 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide (4), 23.3 kg of calcium oxide and 59.4 kg of cyclopropylamine (molar ratio: 1:1:2.5) are heated to between 135° and 145° C. in 235 l ofdiglyme (diethylene glycoldimethylether) in a 500 l VA autoclave over a period of 6 to 8 hours. The reaction mixture is then cooled to a temperature of 20° to 30° C. and filtered. The filter cake is washed with 58.8 l of diglyme. The filtrates are combined and initially 200 l of solvent is distilled off. The residue is then diluted with a further 117.5 l of diglyme. The resultant diluted solution is added over a period of 20 to 40 minutes to a suspension of 45.0 kg of 60% sodium hydride in 352.5 l of diglyme, heated to 130° C. The storage vessel and conduits are rinsed with a further 55.8 l of diglyme, and the mixture is stirred at a temperature of between 130° and 140° C. for a further 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 470 l of water. After cooling to a temperature of about 25° C., 235.0 l of cyclohexane and 57.11 of glacial acetic acid are added to the reaction mixture. The mixture is then stirred for about 1 hour at temperature of 10° to 25° C. The resultant suspension is centrifuged and the centrifuged material is then washed with 235.0 l of methyl-tert.-butylether and subsequently with 353.5 l of water and finally with 235 l of ethanol. In this way, after drying, 92.5 kg (83.5% of theory) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (nevirapine) is isolated. | |
In diglyme (diethylene glycol-dimethylether); ethanol; diethylene glycol dimethyl ether; cyclohexane; water; acetic acid | 2 EXAMPLE 2 EXAMPLE 2 117.5 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide (4), 46.7 kg of calcium oxide and 47.5 kg of cyclopropylamine (molar ratio: 1:2:2) are heated to 135° to 145° C. in 235 l of diglyme (diethylene glycol dimethylether) in a 500 l VA autoclave over a period of 6 to 8 hours. The reaction mixture is then cooled to a temperature of 20° to 30° C. and filtered. The filter cake is washed with 58.8 l of diglyme. The filtrates are combined and about 188 l of solvent is distilled off. The residue is then diluted with a further 117.5 l of diglyme. Over a period of 20 to 40 minutes, the resultant diluted solution is added to a suspension of 45.0 kg of 60% sodium hydride in 352.5 l of diglyme, heated to 130° C. The storage vessel and conduits are rinsed with a further 55.8 l of diglyme and the mixture is stirred at a temperature of 130° to 140° C. for a further 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 470.0 l of water. The reaction mixture is cooled to a temperature of about 25° C. and 235.0 l of cyclohexane and 57.1 l of glacial acetic acid are added. The mixture is then stirred for about 1 hour at a temperature of 10° to 25° C. The resultant suspension is centrifuged and the centrifuged material is washed with 235.0 l of methyl tert.-butylether, followed by 353.5 l of water and finally with 235 l of ethanol. In this way, after drying, 90.6 kg (81.7% of theory) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido-[3,2-b:2',3'-e][1,4]diazepin-6-one (nevirapine) is isolated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate at 110℃; for 8h; | 6-Chloro-11-cyclopropyl-4-methyl-11H-dipyrido[3,2-b:2',3'-e][1,4]diazepine (8) A mixture of nevirapine (2.50 g, 9.4 mmol), N,N-dimethylaniline (0.41 mL, 3.3 mmol) and phosphorus(V) oxychloride (25 mL) was heated at reflux for 8 hours. The volatiles were removed in vacuo, the residue diluted with ice-cold water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title product (2.13 g, 80%) as pale yellow solid. M.p. 196-198°C; 1H NMR (400 MHz, CDCl3): δ 8.49 (dd, J = 4.9, 1.8 Hz, 1H, HPy), 8.17 (d, J = 4.9 Hz, 1H, HPy), 7.88 (dd, J = 7.8, 1.8 Hz, 1H, HPy), 7.05 (dd, J = 7.7, 4.8 Hz, 1H, HPy), 6.92 (d, J = 4.9 Hz, 1H, HPy), 3.71- 3.61 (m, 1H, CH), 2.36 (s, 3H, PyCH3), 1.02 - 0.89 (m, 2H, CH2), 0.60 - 0.41 (m, 2H, CH2) ppm; 13C NMR (100 MHz, CDCl3): δ 162.5, 152.9, 152.7, 152.2, 146.7, 144.8, 138.7, 133.1, 123.0, 122.2, 118.9, 28.9, 17.8, 8.6, 8.5 ppm; HRMS (ESI), m/z calcd for C15H14ClN4 [M+H]+ 285.0902, found 285.0899. |
In toluene | 1 6-Chloro-11-cyclopropyl-4-methyl-11H-dipyrido[3,2-b:2',3'-e][1,4]diazepine Example 1 6-Chloro-11-cyclopropyl-4-methyl-11H-dipyrido[3,2-b:2',3'-e][1,4]diazepine A mixture of 1.00 g (3.76 mmole) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, 0.79 g (3.79 mmole) of phosphorus pentachlofide and 25 mL of toluene was refluxed for 30 min., then cooled and poured onto crushed ice. The mixture was extracted with three 100 mL portions of methylene chloride, and the extract was dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was chromatographed over silica gel (eluted with 25% ethyl acetate/hexane) to give 0.52 g of a solid, which was recrystallized from heptane to give 0.40 g (1.39 mmol) of the title compound, m.p. 196°-198° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In dichloromethane; ethyl acetate | 2.a a. a. 11-Cyclopropyl-4-methyl-6-trifluoromethanesulfonyloxy-11H-dipyrido[3,2-b:2',3'-e][1,4]-diazepine Trifluoromethanesulfonie anhydride (5.02 g, 17.8 mmole) was added dropwise to a cooled mixture of 3.00 g (11.3 mmole) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, 2.32 g (18.0 mmole) of diisopropylethylamine, and 45 mL of methylene chloride. After the addition was complete, the ice bath was removed and the mixture was stirred for one hour. Ethyl acetate (500 mL) was added and the resulting solution was washed with three 100 mL portions of water. The organic solution was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed over silica gel (eluted with 50% ethyl acetate/hexane) to provide 3.18 g (8.0 mmole) of the title compound as a yellow oil, suitable for the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With water-d2; sodium formate In 1,4-dioxane at 200℃; for 48h; | 3.6 d%- 11 -Cvclopropyl-5.11 -dihvdro-4-methyl-6H-dipyrido [3.2.-b :2 ' .3 ' -el 1.41- diazepin-2-one (Js-Nevirapine): A mixture of l l-cyclopropyl-SJ l-dihydro^-methyl-βH- dipyrido[3,2,-b:2',3'-e][l,4]-diazepin-2-one (nevirapine) (500mg, 1.88mmol), 10% Pd/C (20% weight, O.lg), sodium formate (64mg, 0.98mmol), deuterium oxide and dioxane (11ml, U2θ/dioxane, 10/1, v/v) was degassed by bubbling a stream of nitrogen into the mixture for 2 minutes. The reaction was then heated to 200 0C for 48 hours. The reaction was cooled, filtered, washed with methanol, concentrated, and purified by flash column to give a white solid (299mg, 58% yield). This solid was then further purified by preparative HPLC (methanol/water, 40/60, v/v, isogradient) to afford lOOmg (pure) of the title compound. 1U NMR (300 MHz, CDCl3) δ 8.55(s, 0.02H), 8.16(s, 0.09H), 8.13(s, 0.96H), 7.64(br, IH), 7.07(d, 0.19H), 6.93(s, 0.68H), 3.77(m, IH), 2.33(s, 0.13H), 1.01(m, 2H), 0.46(m, 2H); ESI-MS m/z=273.1, (MH +); HPLC, 99.481% (214nm), 97.292(254nm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: Nevirapine With hydrogenchloride; water at 18 - 30℃; for 0.25h; Stage #2: With sodium hydroxide In water at 15 - 30℃; for 0.5h; | 8 Anhydrous nevirapine (75 g) was suspended in DM water (300 ml) at 20-250C. The reaction mass was cooled to 18-22°C and cone. HCl (86 ml) was added over a period of 10 min below 30°C. Thereafter the reaction mixture was stirred for 5 min at 25- 300C, a clear solution was formed. Carbon (3.75 g) was added to the reaction mixture and stirred for 15 min at 23-25°C and filtered the carbon and washed with DM watei (75 ml, 20-250C). The pH of filtrate was adjusted to 6.72 using 20 % w/w aqueous sodium hydroxide solution at 25-300C and cooled to 15-200C and stirred for 30 min and product crystallizes out.. The product so obtained was filtered and washed with DM water (2x1 12.5 ml, 20-250C), suck dried and dried under reduced pressure at 40- 45°C till moisture is 3.1-3.9 % w/w. Yield: 74.45 g HPLC purity - 99.96 % Moisture content - 3.54 % w/w |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With strong base |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: Nevirapine With hydrogenchloride In water at 18 - 30℃; for 0.25h; Stage #2: With sodium hydroxide In water | 8 EXAMPLE 8Preparation of Nevirapine HemihydrateAnhydrous nevirapine (75 g) was suspended in DM water (300 ml) at 20-25° C. The reaction mass was cooled to 18-22° C. and conc. HCl (86 ml) was added over a period of 10 min below 30° C. Thereafter the reaction mixture was stirred for 5 min at 25-30° C., a clear solution was formed. Carbon (3.75 g) was added to the reaction mixture and stirred for 15 min at 23-25° C. and filtered the carbon and washed with DM water (75 ml, 20-25° C.). The pH of filtrate was adjusted to 6.72 using 20% w/w aqueous sodium hydroxide solution at 25-30° C. and cooled to 15-20° C. and stirred for 30 min and product crystallizes out. The product so obtained was filtered and washed with DM water (2×112.5 ml, 20-25° C.), suck dried and dried under reduced pressure at 40-45° C. till moisture is 3.1-3.9% w/w. Yield: 74.45 g HPLC purity-99.96% Moisture content-3.54% w/w |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | Stage #1: Nevirapine With dilithium magnesium bis(2,2,6,6-tetramethylpiperidin-1-ide) dichloride In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Stage #2: With iodine In tetrahydrofuran at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol at 70℃; for 2h; Evaporation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With iodine In dichloromethane at 104℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: iodine / dichloromethane / 0.08 h / 104 °C 2: methanol; potassium hydroxide / 0.25 h / 20 °C 3: potassium nitrososulfonate / ethyl acetate / 20 °C / pH 10 / aq. phosphate buffer |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: iodine / dichloromethane / 0.08 h / 104 °C 2: methanol; potassium hydroxide / 0.25 h / 20 °C 3: potassium nitrososulfonate / ethyl acetate / 20 °C / pH 7.4 / aq. phosphate buffer |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: iodine / dichloromethane / 0.08 h / 104 °C 2: methanol; potassium hydroxide / 0.25 h / 20 °C 3: sodium periodate / N,N-dimethyl-formamide / 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 9% 2: 8% 3: 9% | With tert.-butylhydroperoxide; trifluoroacetic acid; zinc(II) chloride In water; dimethyl sulfoxide at 50℃; for 11h; Cooling with ice; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tert.-butylhydroperoxide; zinc sulfinate; bis(((trifluoromethyl)sulfinyl)oxy)zinc In water; dimethyl sulfoxide at 20 - 50℃; for 12h; Overall yield = 28 %; Overall yield = 10.9 mg; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With CYP3A4 supersomes In aq. buffer at 37℃; for 1h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium hydroxide; bromine / toluene; water / 0 - 60 °C 2.1: sodium hydride / 3.5 h / 30 - 60 °C / Inert atmosphere 2.2: 2 h / 55 - 65 °C / Inert atmosphere 3.1: sodium hydride; diethylene glycol dimethyl ether / 2.5 h / 100 - 125 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1.1: sodium hydroxide; bromine / water / 2 h / 0 - 20 °C 2.1: sodium hydride / diethylene glycol dimethyl ether / 0.5 h / 20 °C 2.2: 2 h / 60 °C 3.1: sodium hydride / diethylene glycol dimethyl ether / 4 h / 105 - 117 °C / Green chemistry |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: triethylamine / water; isopropyl alcohol / 140 °C / 517.16 - 3102.97 Torr / Inert atmosphere 2.1: water; potassium hydroxide / isopropyl alcohol / 12 h / 80 °C 3.1: thionyl chloride / toluene / 0.58 h / 20 - 50 °C / Inert atmosphere 3.2: 40 - 50 °C 4.1: sodium hydride / 3.5 h / 30 - 60 °C / Inert atmosphere 4.2: 2 h / 55 - 65 °C / Inert atmosphere 5.1: sodium hydride; diethylene glycol dimethyl ether / 2.5 h / 100 - 125 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1.1: triethylamine / water; isopropyl alcohol / 6 h / 140 °C / 517.16 - 3102.97 Torr / Inert atmosphere 2.1: potassium hydroxide / 12 h / 20 - 40 °C 3.1: thionyl chloride / toluene / 0.5 h / 20 - 50 °C / Inert atmosphere 3.2: 2 h / 50 °C / Inert atmosphere 4.1: sodium hydride / diethylene glycol dimethyl ether / 65 - 165 °C / Flow reactor; Green chemistry | ||
Multi-step reaction with 5 steps 1.1: triethylamine / water; isopropyl alcohol / 6 h / 140 °C / 517.16 - 3102.97 Torr / Inert atmosphere 2.1: potassium hydroxide / 12 h / 20 - 40 °C 3.1: thionyl chloride / toluene / 0.5 h / 20 - 50 °C / Inert atmosphere 3.2: 2 h / 50 °C / Inert atmosphere 4.1: sodium hydride / diethylene glycol dimethyl ether / 0.5 h / 20 °C 4.2: 2 h / 60 °C 5.1: sodium hydride / diethylene glycol dimethyl ether / 4 h / 105 - 117 °C / Green chemistry |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: water; potassium hydroxide / isopropyl alcohol / 12 h / 80 °C 2.1: thionyl chloride / toluene / 0.58 h / 20 - 50 °C / Inert atmosphere 2.2: 40 - 50 °C 3.1: sodium hydride / 3.5 h / 30 - 60 °C / Inert atmosphere 3.2: 2 h / 55 - 65 °C / Inert atmosphere 4.1: sodium hydride; diethylene glycol dimethyl ether / 2.5 h / 100 - 125 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1.1: potassium hydroxide / 12 h / 20 - 40 °C 2.1: thionyl chloride / toluene / 0.5 h / 20 - 50 °C / Inert atmosphere 2.2: 2 h / 50 °C / Inert atmosphere 3.1: sodium hydride / diethylene glycol dimethyl ether / 65 - 165 °C / Flow reactor; Green chemistry | ||
Multi-step reaction with 4 steps 1.1: potassium hydroxide / 12 h / 20 - 40 °C 2.1: thionyl chloride / toluene / 0.5 h / 20 - 50 °C / Inert atmosphere 2.2: 2 h / 50 °C / Inert atmosphere 3.1: sodium hydride / diethylene glycol dimethyl ether / 0.5 h / 20 °C 3.2: 2 h / 60 °C 4.1: sodium hydride / diethylene glycol dimethyl ether / 4 h / 105 - 117 °C / Green chemistry |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: hydrogenchloride / 2 h / 50 - 55 °C 2.1: sulfuric acid / 1.25 h / 40 - 105 °C 2.2: 70 - 75 °C 3.1: sodium hydroxide; bromine / toluene; water / 0 - 60 °C 4.1: sodium hydride / 3.5 h / 30 - 60 °C / Inert atmosphere 4.2: 2 h / 55 - 65 °C / Inert atmosphere 5.1: sodium hydride; diethylene glycol dimethyl ether / 2.5 h / 100 - 125 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1: hydrogenchloride / toluene / 20 - 55 °C 2: sulfuric acid / water / 8.25 h / 40 - 105 °C 3: sodium hydroxide; bromine / water / 2 h / 0 - 20 °C 4: sodium hydride / diethylene glycol dimethyl ether / 65 - 165 °C / Flow reactor; Green chemistry | ||
Multi-step reaction with 5 steps 1.1: hydrogenchloride / toluene / 20 - 55 °C 2.1: sulfuric acid / water / 8.25 h / 40 - 105 °C 3.1: sodium hydroxide; bromine / water / 2 h / 0 - 20 °C 4.1: sodium hydride / diethylene glycol dimethyl ether / 0.5 h / 20 °C 4.2: 2 h / 60 °C 5.1: sodium hydride / diethylene glycol dimethyl ether / 4 h / 105 - 117 °C / Green chemistry |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: triethylamine; acetic anhydride / toluene / 2 h / 5 - 20 °C / Inert atmosphere 2.1: hydrogenchloride / 2 h / 50 - 55 °C 3.1: sulfuric acid / 1.25 h / 40 - 105 °C 3.2: 70 - 75 °C 4.1: sodium hydroxide; bromine / toluene; water / 0 - 60 °C 5.1: sodium hydride / 3.5 h / 30 - 60 °C / Inert atmosphere 5.2: 2 h / 55 - 65 °C / Inert atmosphere 6.1: sodium hydride; diethylene glycol dimethyl ether / 2.5 h / 100 - 125 °C / Inert atmosphere | ||
Multi-step reaction with 5 steps 1.1: acetic anhydride / toluene / 5 - 10 °C / Inert atmosphere 1.2: 2 h / 5 - 20 °C / Inert atmosphere 2.1: hydrogenchloride / toluene / 20 - 55 °C 3.1: sulfuric acid / water / 8.25 h / 40 - 105 °C 4.1: sodium hydroxide; bromine / water / 2 h / 0 - 20 °C 5.1: sodium hydride / diethylene glycol dimethyl ether / 65 - 165 °C / Flow reactor; Green chemistry | ||
Multi-step reaction with 6 steps 1.1: acetic anhydride / toluene / 5 - 10 °C / Inert atmosphere 1.2: 2 h / 5 - 20 °C / Inert atmosphere 2.1: hydrogenchloride / toluene / 20 - 55 °C 3.1: sulfuric acid / water / 8.25 h / 40 - 105 °C 4.1: sodium hydroxide; bromine / water / 2 h / 0 - 20 °C 5.1: sodium hydride / diethylene glycol dimethyl ether / 0.5 h / 20 °C 5.2: 2 h / 60 °C 6.1: sodium hydride / diethylene glycol dimethyl ether / 4 h / 105 - 117 °C / Green chemistry |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: hydrogenchloride; dihydrogen peroxide / water / 20 °C 1.2: pH 8 2.1: pyridine / acetonitrile / 20 - 45 °C 3.1: calcium oxide / xylene / 140 °C 4.1: sodium hydrogen sulfate; copper(l) iodide; sulfuric acid; potassium <i>tert</i>-butylate / diethylene glycol dimethyl ether / 115 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate / 8 h / 110 °C 2.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 5 h / 110 °C / Microwave irradiation 2.2: 12 h / 20 °C 3.1: acetonitrile / 5 h / 120 °C / Sealed tube; Microwave irradiation 3.2: 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate / 8 h / 110 °C 2.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 5 h / 110 °C / Microwave irradiation 2.2: 12 h / 20 °C 3.1: acetonitrile / 5 h / 120 °C / Sealed tube; Microwave irradiation 3.2: 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate / 8 h / 110 °C 2.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 5 h / 110 °C / Microwave irradiation 2.2: 12 h / 20 °C 3.1: acetonitrile / 5 h / 120 °C / Sealed tube; Microwave irradiation 3.2: 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate / 8 h / 110 °C 2.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 5 h / 110 °C / Microwave irradiation 2.2: 12 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate / 8 h / 110 °C 2.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 5 h / 110 °C / Microwave irradiation 2.2: 12 h / 20 °C 3.1: acetonitrile / 5 h / 120 °C / Sealed tube; Microwave irradiation 3.2: 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With 1,2-dimethoxyethane; potassium hexamethylsilazane for 3h; Inert atmosphere; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: ammonium hydroxide / 5 h / 40 - 45 °C 2: trichlorophosphate / 1,2-dichloro-ethane / 8 h / 70 - 75 °C 3: 5 h / 60 - 65 °C 4: 5%-palladium/activated carbon; hydrogen / ethanol; toluene / 6 h / 30 - 35 °C / 1500.15 - 2250.23 Torr / Autoclave 5: benzenesulfonic acid / 6 h / 90 - 95 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.6 g | With benzenesulfonic acid at 90 - 95℃; for 6h; | 7; 8 Example 7: Preparation of nevirapine (I) Into a 500 ml stainless steel autoclave, 120 g of ethanol, 50 g of toluene, and 15.5 g (0.05 mol) of 2-[N-cyclopropyl-N-(3-nitro-4-methylpyridin-2-yl)]aminonicotinic acid (VI), were added. 5% palladium carbon catalyst 0.5 g, after replacing three times with nitrogen, hydrogen gas was introduced, the hydrogen pressure was maintained at 0.2-0.3 MPa, and the reaction was carried out at 30-35 ° C for 6 hours.After the reaction was completed, the nitrogen was replaced three times, the palladium carbon was removed by filtration, and the filter cake was washed with 20 g of ethanol, and the filtrate was transferred to a 500 ml four-necked flask equipped with a stirring, a thermometer, a water separator and a reflux condenser, and 0.6 g of a pair was added. The benzenesulfonic acid was heated to an internal temperature of 90-95 ° C, stirred for 6 hours, cooled to 20-25 ° C, filtered, and the filter cake was washed successively with 30 g of water and 20 g of isopropyl alcohol, and dried to obtain 12.6 g of nevirapine. The yield was 94.7%, and the liquid phase purity was 99.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: ammonium hydroxide / 5 h / 50 - 55 °C 2: trichlorophosphate / 1,2-dichloro-ethane / 8 h / 70 - 75 °C 3: 5 h / 60 - 65 °C 4: 5%-palladium/activated carbon; hydrogen / ethanol; toluene / 6 h / 30 - 35 °C / 1500.15 - 2250.23 Torr / Autoclave 5: benzenesulfonic acid / 6 h / 90 - 95 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: trichlorophosphate / 1,2-dichloro-ethane / 8 h / 70 - 75 °C 2: 5 h / 60 - 65 °C 3: 5%-palladium/activated carbon; hydrogen / ethanol; toluene / 6 h / 30 - 35 °C / 1500.15 - 2250.23 Torr / Autoclave 4: benzenesulfonic acid / 6 h / 90 - 95 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 20℃; for 0.166667h; Milling; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 20℃; for 0.166667h; Milling; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 20℃; for 0.166667h; Milling; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 20℃; for 0.166667h; Milling; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 20℃; for 0.166667h; Milling; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 20℃; for 0.166667h; Milling; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 20℃; for 0.166667h; Milling; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With potassium carbonate In N,N-dimethyl-formamide for 12h; Reflux; |
Tags: 129618-40-2 synthesis path| 129618-40-2 SDS| 129618-40-2 COA| 129618-40-2 purity| 129618-40-2 application| 129618-40-2 NMR| 129618-40-2 COA| 129618-40-2 structure
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
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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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