Structure of 211915-84-3
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CAS No. : | 211915-84-3 |
Formula : | C27H26N6O3 |
M.W : | 482.53 |
SMILES Code : | O=C(OCC)CCN(C1=NC=CC=C1)C(C2=CC=C3N(C)C(CNC4=CC=C(C#N)C=C4)=NC3=C2)=O |
MDL No. : | MFCD09833627 |
InChI Key : | OZBOESGNDSVMDK-UHFFFAOYSA-N |
Pubchem ID : | 11627749 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
* 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 |
---|---|---|
95% | Step 1 : Crude product 10.0 g of N-(4-cyanophenyl)glycine and 10.35 g of N,N'-carbonyldiimidazole (CDI) are mixed at room temperature in 150 mL of isopropyl acetate. Then, 19.43 g of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate are added and the mixture reacts for 4 hours at room temperature. After this time, 20 mL of acetic acid are added and the mixture is refluxed for 2 hours. It is allowed to cool at room temperature and 33 mL of water are added. The organic phase is separated and further 33 mL of water are added. The pH of the mixture is adjusted to 10-11 with a dissolution of 25% of sodium hydroxide, forming a suspension. The suspension is filtered and the solid obtained is dried at 45 C in a vacuum oven. Yield: 24.6 g of crude base of the compound (III); (90% yield). Product purity: 94% measured by HPLC. Melting point: 1 16 C measured by differential scanning calorimetry technique (DSC); X-rays (angle 2-theta values ()): 7.6, 10.2, 10.9, 14.6, 15.2, 20.5, and 25.5 measured on a x-ray diffractometer with Cu K alpha radiation (1.5418 A). - Step 2: Purification of the compound (III) in free base form The crude product is recrystallized from 100 mL of ethanol, and a white solid with a high purity of 99% (HPLC) is obtained. Yield: 23,4 g of the purified base of the compound (III); (95% recrystallization yield). Product purity: 99% measured by HPLC; Melting point: 148C measured by differential scanning calorimetry technique (DSC); X-rays (angle 2-theta values ()): 5.9; 12.0; 13.7; 16.8; 18.9; 19.5; 21 .3; 24.4, and 27.6 measured on a x-ray diffractometer with Cu K alpha radiation (1.5418 A). | |
93.97% | Take SM02 (20.00g, 58.41mmol) in a 100ml single-mouth bottle, toluene (60ml) was added, magnetically stirred at ambient temperature, and set aside.At room temperature, SM01 (12.35g, 70.09mmol), CDI (11 · 84g, 73 · 01mmol) and toluene (120.0ml) were added to the reaction flask. Stirred and heated to 50 C. After 2-4 h, the reaction was monitored by TLC and the reaction was completed. The heating was stopped, the temperature of the reaction solution was lowered to 25 C, the toluene solution of SM02 was quickly added, and the mixture was stirred at 20-25 C for 5-16 h. The reaction was monitored by TLC. After completion of the reaction, acetic acid (8.0 ml) was added, and the reaction mixture was heated to 100 C, and kept for 1-2 h. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature and then concentrated, the residue was dissolved in a solvent, and the solvent used were dichloromethane, chloroform, 1, 2-dichloroethane or the like. The resulting solution was adjusted to pH 7, using a saturated aqueous solution of sodium bicarbonate, after layering, the aqueous phase was extracted once with dichloromethane, and the organic phase was combined; Washed once with water, after stratification, the aqueous phase was extracted once more with dichloromethane, organic phases were combined, the solvent was concentrated under reduced pressure to give DB02 crude material. | |
91.1% | In a 500 ml reaction flask,23.2 g (0.132 mol) of N- (4-cyanophenyl) -aminoacetic acid were added,100 ml of dimethylformamide,19.6 g (0.145 mol) of 1-hydroxybenzotriazole was added at 3 C,A solution of 29.9 g (0.145 mmol) of dicyclohexylcarbodiimide in 50 ml of dimethylformamide was added dropwise.Stirring reaction 1h,Slowly rose to room temperature,A solution of 50.0 g (0.145 mol) of compound 3 in dimethylformamide (100 ml) was added dropwise,The reaction was stirred for 6 h.The reaction solution was filtered,The filtrate was added dropwise to 750 ml of water at 1 C,Insulation 1 hour,filter.300 ml of toluene and 20.0 g of glacial acetic acid were heated to 90 C,Incubation reaction 6 hours,After cooling to room temperature, 120 g of water was added,40 ml of ammonia was added dropwise to adjust pH to 9,Stirring to precipitate a solid,Cooling 2 ,Holding 2 hours,filter,Drying was a gray solid .0g,The yield was 91.1%Directly used in the next step reaction. |
86% | This embodiment's darbey adds the group ester method for the preparation of intermediates with the following steps:(1) under the protection of nitrogen, the 28.3g the N-(4-cyano-phenyl)-glycine (0.16mol) and 25.9g condensing agent CDI (0.16mol) dissolved in the 100 ml of methylene chloride and 100 ml of a mixed solvent of the ether in a, stirring and heating to 40 ±2 C reflux, thermal insulation reaction 1-2h.(2) added to the above-mentioned reaction system 50.0g of 3-amino-4-methyl amino-benzoic acid-N-(2-pyridyl)-N - (2-ethoxy carbonyl-ethyl)-amide (0.14mol), in 40 ±2 C continue to return to the temperature of the condensation reaction, to 3-amino-4-methyl amino-benzoic acid-N-(2-pyridyl)-N - (2-ethoxy carbonyl-ethyl)-amide reaction is complete, to stop the reaction.Generating compound IV does not need separation directly used for the next step.(3) in the above-mentioned reaction system is added to 160 ml of acetic acid, first decompression concentrating evaporating methylene chloride and ethyl ether, then heating to 50-60 C to cyclization reaction, until the compound IV the reaction is complete, to stop the reaction.(4) after the reaction, water is poured in the reaction system, cooling to 20-30C, crystallization, filtration, the filter cake after re-crystallization with ethanol, again filtered, the filter cake is drying to obtain 60.6g compound I, to yield 86.0%, | |
85% | (1) at room temperature,75 g of compound of formula 6,1000 mL THF,100mL triethylamine mixed,Cooled to 0 ,70mL pivaloyl chloride was added below 10 and the reaction was incubated for 0.5h; After the reaction was completed, 155g of compound of formula 4 was added,45 reaction 2h;The organic layer was evaporated to dryness and added to 1500mL n-butyl acetate, at 90 for 4h,700 mL of butyl acetate was distilled off under reduced pressure,The crystals were stirred at 5 C,Filtered and dried to give a dry product of formula 3 175g,The yield is 85%; | |
83% | 4-Nitriloanilino-acetic acid (2.32 g, 13.2 mmol) was dissolved in 80 ml of DMF,1-Hydroxybenzotriazole (H0BT) (1.96 g, 14.5 mmol) was added,Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (2.77 g, 14.5 mmol) was added at 0 C under stirring for 45 min,Slowly rise to room temperature,Ethyl 3- (1-methylamino-2-amino-phenyl-4-yl) -carboxylic acid- (N-2-pyridyl) amidopropionic acid ethyl ester (5.50111111.01) was added at room temperature the reaction overnight, concentrated, diluted with ethyl acetate and large, washed three times with brine, dried over Na2S04 after dried, concentrated and the crude product in 60ml of acetic acid was refluxed for 1.5h, was concentrated, basified added 1.5N aqueous ammonia, extracted three times with ethyl acetate. (60 mL X 3). The organic phase was washed once with brine, dried over Na 2 SO 4 and concentrated. The crude product was purified by silica gel column chromatography.The amorphous solid, 3- (1-methyl-2- (4-nitrile-phenylaminomethyl) -5-yl-carboxylic acid- (N-2-pyridyl) amido) propionic acid ethyl ester (6.4 g, yield 83%). Mass spectrum (ESI-MS): 482 ? 1 (M + H) +, 505.4 (M + Na) +; C27H26N6O3 (482) | |
61% | a) 1-Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide Prepared analogously to Example 25c from N-(4-cyanophenyl)-glycine and 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide. Yield: 61% of theory, Rf value: 0.62 (silica gel; dichloromethane/methanol=19:1) | |
Example 1 - Large-scale industrial synthesis of the compound of formula 4-Br88 kg carbonyl-di-(l,2,4-triazole) are taken and combined with 920 1 tetrahydrofuran. The contents of the apparatus are heated to 35C with stirring. Then 90 kg of compound 3 are added batchwise at 35C within 1 to 2 hours.160 kg of compound 2 are placed in a second reaction vessel, then 350 1 tetrahydrofuran are added and the mixture is heated to 500C with stirring.The solution of 3 is metered into the solution of 2 within 2 to 3 hours at 47C - 53C and the solution obtained is diluted with 115 1 tetrahydrofuran. Then the mixture is stirred for another 4 hours at 47C - 53C ( preferably 500C ). Then 670 1- 695 1 tetrahydrofuran are distilled off in vacuo at 50C-60C. 235 1 of n-butyl acetate are then allowed to flow into the residue. After this, 600 1 -630 1 of a butyl acetate/THF mixture are distilled off in vacuo at 50C-85C. During the distillation 700 1 butyl acetate are metered in. 65 kg acetic acid are allowed to flow into the residue, the contents are heated to 85C-90C and stirred for at least another 2.5 h at this temperature. Then the mixture is cooled to 65C-75C. A solution of 165 1 water and 20 kg common salt is added to the contents and the mixture is rinsed with 300 1 water. Then the temperature is adjusted to 60C-70C and the mixture is stirred for a minimum of 15 min. at this temperature. For phase separation the stirrer is stopped and the mixture is left to settle for at least 15 min. The aqueous phase is drained off into another reaction vessel which contains 120 1 of n-butyl acetate. The mixture is heated to 60C-70C with stirring and stirred for at least 10 min. After phase separation the aqueous phase is drained off into the chemical waste drain. The butyl acetate phases and 20 1 of butyl acetate for rinsing are combined. 590 1 - 620 1 of n-butyl acetate are distilled off from this content in vacuo at a max. internal temperature of 800C. <n="12"/>880 1 isopropanol are allowed to flow into the distillation residue and the content is adjusted to 32C-38C. Then approx. 90 kg of 48% hydrobromic acid are metered in at 32C-38C until the pH value is 0.6 to 1.3. The mixture is stirred for a minimum of 20 min. at 32C-38C and then cooled to 7C-13C and stirred at this temperature for at least one hour. The resulting suspension is centrifuged, washed with a total of 840 1 isopropanol and dried in vacuo at max. 55C. Yield: 211 kg-250 kg. Mp.: 200-2150C (with decomposition).The compound 4-HBr may be isolated using any standard commercially available centrifuge. | ||
Example 1 : Ethyl N-[(2-[(p-cyanophenyl)amino1methyl)-1 -methyl-1 H- benzimidazole-5-carbonyl1-N-(2-pyridyl)-3-aminopropionate hydrochloride (IV-HCI)Under Ar atmosphere, A/-(p-cyanophenyl)-glycine (V) (7.22 g, 41 .0 mmol) and 1 ,1 '-carbonyldiimidazole (6.64 g, 41 .0 mmol) were suspended in anhydrous THF (315 mL). It was refluxed for 45 minutes and a solution of compound (VI) (12.74 g, 37.2 mmol) in anhydrous THF (56 mL) was added slowly. After 6 h under reflux, the reaction mixture was cooled down, and the solvent was distilled under low pressure. The oil obtained was dissolved in glacial acetic acid (155 mL) and refluxed for 1 h. The solvent was removed under low pressure, the residue was dissolved in CH2CI2 (130 mL) and washed with H2O (2 x 130 mL). The organic phase was dried over anhydrous MgSO4 and the solvent was distilled under low pressure. The residue obtained was dried under vacuum, obtaining 20.19 g of crude (IV) (75% a/a purity according to HPLC/MS).The brown oil was dissolved in isopropanol (101 mL) at 35 C and HCI(c) (37%, 3.40 mL, 41 .1 mmol) was added slowly. After a short time an abundant white solid appeared. It was stirred at 35 C for 30 min and next at 0 C for 30 min. The solid was filtered out, washed with IPA (15 mL) and dried under vacuum, obtaining the product (IV-HCI) (14.25 g, 74% yield, 97% a/a purity according to HPLC/MS). This solid was recrystallized from EtOH (160 mL), washed with EtOH (2 x 10 mL) and dried under vacuum, obtaining 12.13 g (23.4 mmol, 63% global yield, 99% a/a purity according to HPLC/MS) of the product (IV-HCI).1H RMN (400 MHz, CD3OD) : delta (ppm) = 8.33 (ddd, J = 4.8, 2.0, 0.8, 1 H), 7.77 (d, J = 8.8, 1 H), 7.66 (dd, J = 1 .6, 0.8, 1 H), 7.60 (ddd, J = 8.0, 8.0, 2.0, 1 H), 7.55-7.50 (m, 3H), 7.17 (ddd, J = 7.6, 4.8, 0.8, 1 H), 7.09 (d, J = 8.0, 1 H), 6.83 (d, J = 8.8, 2H), 5.02 (s, 2H), 4.34 (t, J = 7.2, 2H), 4.05 (q, J = 7.2, 2H), 4.02 (s, 3H), 2.76 (t, J = 7.2, 2H), 1 .19 (t, J = 7.2, 3H).Melting point (Tme,t): 213-215 CPXRD: FIG. 2, 2theta angle values () = 3.7, 10.0, 10.9, 17.7, 18.3, 20.9, 22.0, 22.5, 23.7, 25.9, 26.4. | ||
Example-20: Preparation of l-methyI-2-[N-(4-cyanophenyl) aminomethyl] benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide compound of formula-14 A mixture of 2-(4-cyanophenylamino)acetic acid (139 g) and tetrahydrofuran (750 ml) was heated to 50-55C. A solution of N,N'-carbonyldiimidazole (177.6 g) in tetrahydrofuran (1000 ml) was added to the above reaction mixture at the same temperature over a period of 1 hour and stirred for 2 hours at 50-55C. A solution of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido) propanoate compound of formula- 12 (250 g) in tetrahydrofuran (1500 ml) was added over a period of 2 hours at 50-55C and heated to 60-65C. The reaction mixture was stirred for 50 hours at 60- 65C. After completion of the reaction, distilled off the solvent from the reaction mixture. Acetic acid was added to the reaction mixture and heated to 95-100C. The reaction mixture was stirred for 5 hours at 95-100C. Distilled off the solvent completely under the reduced pressure and the reaction mixture was cooled to 25-30C. Water was added to the reaction mixture and the product was extracted with dichloromethane. Dichloromethane layer was washed with water followed by sodium chloride. Distilled off the solvent completely from the dichloromethane layer to obtain title compound.Yield: 300 g | ||
Example-4: Process for preparation of the crystalline ethyl 3-(2-((4-cvanophenylamino)methylVl- methvl-N-(pvridin-2-vO-lH-benzotdUmidazole-5-carboxamido) propanoate of Formula (2B) 77 g 2-(4-cyanophenylamino) acetic acid of Formula (E), 71.04 g CDI in 1000 mL Toluene were stirred at 25C to 35C. The reaction mixture was heated to 55C to 60C and maintained for 2 hours. 100 g ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2- yl)benzamido)propanoate of Formula (2A) was added to the reaction mixture and stirred for 3 hours at 60C to 65C. The reaction mixture was further heated at 100C for 3 hours. Toluene was distilled under vacuum. The residue was treated with 500 mL methylene dichloride and organic layer was washed with water. The organic layer was filtered and washed with methylene dichloride. The methylene dichloride was distilled under vacuum and 100 mL ethyl acetate was added at 40C to 45C and stirred for 15 minutes. The reaction mixture was heated to 75C and cooled to 10C to 15C. The reaction mixture was stirred for 2 hours and the precipitated product was filtered and washed with 150 mL ethyl acetate to obtain crystalline ethyl 3-(2-((4-cyanophenylamino)methyl)-l-methyl-N- (pyridin-2-yl)-lH-benzo[d]imidazole-5-carboxamido) propanoate of Formula (2B). The compound of Formula (2B) is characterized by x-ray powder diffraction as depicted in Fig.2. | ||
300 g | A mixture of 2-(4-cyanophenylamino)acetic acid (139 g) and tetrahydrofuran (750 ml) was heated to 50-55 C. A solution of N,N?-carbonyldiimidazole (177.6 g) in tetrahydrofuran (1000 ml) was added to the above reaction mixture at the same temperature over a period of 1 hour and stirred for 2 hours at 50-55 C. A solution of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido) propanoate compound of formula-12 (250 g) in tetrahydrofuran (1500 ml) was added over a period of 2 hours at 50-55 C. and heated to 60-65 C. The reaction mixture was stirred for 50 hours at 60-65 C. After completion of the reaction, distilled off the solvent from the reaction mixture. Acetic acid was added to the reaction mixture and heated to 95-100 C. The reaction mixture was stirred for 5 hours at 95-100 C. Distilled off the solvent completely under the reduced pressure and the reaction mixture was cooled to 25-30 C. Water was added to the reaction mixture and the product was extracted with dichloromethane. Dichloromethane layer was washed with water followed by sodium chloride. Distilled off the solvent completely from the dichloromethane layer to obtain title compound. | |
127 g | A mixture of N-(4-cyanophenyl) glycine (56.6 g), CDI (61.6 g) and imidazole*HC1 (7.6g) in anhydrous EtOAc (1000 mL), was stirred for lh at 45-50C, under inert atmosphere. phenylene-l,2-diamine of formula 2 (lOOg) was, lot-wise, charged to the reaction mass. After stirring for another lh at the same temp, Glacial acetic acid (100mL) was added and the temperature of the reaction mass maintained at reflux for another6h. The reaction mixture cooled to 45-50C, and washed, successively with water and brine solution. The separated organic layer was concentrated under vacuum, till approx. 3 volumes were left behind. The reaction mass was cooled to room temp and 5% Brine solution (500 mL) was charged and the precipitate obtained was slurred for 3h. Theprecipitate was filtered, washed with EtOAc and dried under vacuum at 50C, to afford compound of formula 3 as off-white solid material (127.Og, 98.8% HPL pure). | |
77 g 2-(4-cyanophenylamino) acetic acid of Formula (E), 71.04 g CDI in 1000 mL Toluene were stirred at 25 C. to 35 C. The reaction mixture was heated to 55 C. to 60 C. and maintained for 2 hours. 100 g ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate of Formula (2A) was added to the reaction mixture and stirred for 3 hours at 60 C. to 65 C. The reaction mixture was further heated at 100 C. for 3 hours. Toluene was distilled under vacuum. The residue was treated with 500 mL methylene dichloride and organic layer was washed with water. The organic layer was filtered and washed with methylene dichloride. The methylene dichloride was distilled under vacuum and 100 mL ethyl acetate was added at 40 C. to 45 C. and stirred for 15 minutes. The reaction mixture was heated to 75 C. and cooled to 10 C. to 15 C. The reaction mixture was stirred for 2 hours and the precipitated product was filtered and washed with 150 mL ethyl acetate to obtain crystalline ethyl 3-(2-((4-cyanophenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido) propanoate of Formula (2B). The compound of Formula (2B) is characterized by x-ray powder diffraction as depicted in FIG.2. | ||
1 kg of organic solvent a, 1.5 kg of SM2, and 1.2 kg of CDI were sequentially added to the reaction vessel, and the reaction was stirred at 10 to 50 C for 3 hours.Then, 1 kg of SM1 and 1 kg of organic solvent b were sequentially added, and the reaction was further stirred for 12 hours, and the solvent was distilled off under reduced pressure at 40 C to the reaction kettle.The acetic acid was put into the mixture, heated to 110 C for 5 hours, and the solvent was distilled off under reduced pressure at 100 C or less.Washing with water, recovering the solvent under reduced pressure in the organic phase, adding ethyl acetate to the residue, stirring to dissolve, and adding oxalic acidThe hydrate solution was stirred and crystallized at 22 C for 2 hours, centrifuged, and the filter cake was washed with ethyl acetate. The filter cake was dried under reduced pressure at 45 C for 6 hours.When, a pale yellow solid PR-I;Wherein, the solution of oxalic acid dihydrate is an ethanol solution containing oxalic acid dihydrate, and the oxalic acid dihydrate is in solution.The part by mass is 10%.Wherein, the organic solvent a and the organic solvent b are both N,N-dimethylformamide;Among them, the mass ratio of other materials is SM1: acetic acid = 1:8, SM1: dichloromethane = 1:3, dichloromethane: water =1:3, SM1: solution containing oxalic acid dihydrate = 1:5; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen bromide; In water; isopropyl alcohol; at 7 - 38℃; for 1.33333h;pH 0.6 - 1.3;Industry scale; | Example 1 - Large-scale industrial synthesis of the compound of formula 4-Br88 kg carbonyl-di-(l,2,4-triazole) are taken and combined with 920 1 tetrahydrofuran. The contents of the apparatus are heated to 35C with stirring. Then 90 kg of compound 3 are added batchwise at 35C within 1 to 2 hours.160 kg of compound 2 are placed in a second reaction vessel, then 350 1 tetrahydrofuran are added and the mixture is heated to 500C with stirring.The solution of 3 is metered into the solution of 2 within 2 to 3 hours at 47C - 53C and the solution obtained is diluted with 115 1 tetrahydrofuran. Then the mixture is stirred for another 4 hours at 47C - 53C ( preferably 500C ). Then 670 1- 695 1 tetrahydrofuran are distilled off in vacuo at 50C-60C. 235 1 of n-butyl acetate are then allowed to flow into the residue. After this, 600 1 -630 1 of a butyl acetate/THF mixture are distilled off in vacuo at 50C-85C. During the distillation 700 1 butyl acetate are metered in. 65 kg acetic acid are allowed to flow into the residue, the contents are heated to 85C-90C and stirred for at least another 2.5 h at this temperature. Then the mixture is cooled to 65C-75C. A solution of 165 1 water and 20 kg common salt is added to the contents and the mixture is rinsed with 300 1 water. Then the temperature is adjusted to 60C-70C and the mixture is stirred for a minimum of 15 min. at this temperature. For phase separation the stirrer is stopped and the mixture is left to settle for at least 15 min. The aqueous phase is drained off into another reaction vessel which contains 120 1 of n-butyl acetate. The mixture is heated to 60C-70C with stirring and stirred for at least 10 min. After phase separation the aqueous phase is drained off into the chemical waste drain. The butyl acetate phases and 20 1 of butyl acetate for rinsing are combined. 590 1 - 620 1 of n-butyl acetate are distilled off from this content in vacuo at a max. internal temperature of 800C. <n="12"/>880 1 isopropanol are allowed to flow into the distillation residue and the content is adjusted to 32C-38C. Then approx. 90 kg of 48% hydrobromic acid are metered in at 32C-38C until the pH value is 0.6 to 1.3. The mixture is stirred for a minimum of 20 min. at 32C-38C and then cooled to 7C-13C and stirred at this temperature for at least one hour. The resulting suspension is centrifuged, washed with a total of 840 1 isopropanol and dried in vacuo at max. 55C. Yield: 211 kg-250 kg. Mp.: 200-2150C (with decomposition). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45 g | Calcium chloride dihydrate (12.5 g) was added to a mixture of 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)amide compound of formula-14 (50 g) and ethanol (750 ml) and stirred for 20 minutes. The reaction mixture was cooled to 0-5 C. and HCl gas was passed into the reaction mixture over a period of 5 hours at a temperature below 10 C. The temperature of the reaction mixture was raised to 25-30 C. and stirred for 8 hours at the same temperature. After completion of the reaction, the solvent was expelled out under N2 pressure. The reaction mixture was cooled to 0-5 C. and slowly added ammonium formate (150 g). The reaction mixture was stirred for 30 minutes and ammonium carbonate (300 g) was added. The temperature of the reaction mixture was raised to 25-35 C. and stirred for 10 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was distilled under reduced pressure. A solution of 10% ethanol in ethyl acetate was added to the reaction mixture and stirred for 3 hours to obtain a solid. Filtered the obtained solid, washed with ethyl acetate and then dried to get the title compound. Yield: 45 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In isopropyl alcohol; at 0 - 35℃; for 1h; | The brown oil was dissolved in isopropanol (101 mL) at 35 C and HCI(c) (37%, 3.40 mL, 41 .1 mmol) was added slowly. After a short time an abundant white solid appeared. It was stirred at 35 C for 30 min and next at 0 C for 30 min. The solid was filtered out, washed with IPA (15 mL) and dried under vacuum, obtaining the product (IV-HCI) (14.25 g, 74% yield, 97% a/a purity according to HPLC/MS). This solid was recrystallized from EtOH (160 mL), washed with EtOH (2 x 10 mL) and dried under vacuum, obtaining 12.13 g (23.4 mmol, 63% global yield, 99% a/a purity according to HPLC/MS) of the product (IV-HCI).1H RMN (400 MHz, CD3OD) : delta (ppm) = 8.33 (ddd, J = 4.8, 2.0, 0.8, 1 H), 7.77 (d, J = 8.8, 1 H), 7.66 (dd, J = 1 .6, 0.8, 1 H), 7.60 (ddd, J = 8.0, 8.0, 2.0, 1 H), 7.55-7.50 (m, 3H), 7.17 (ddd, J = 7.6, 4.8, 0.8, 1 H), 7.09 (d, J = 8.0, 1 H), 6.83 (d, J = 8.8, 2H), 5.02 (s, 2H), 4.34 (t, J = 7.2, 2H), 4.05 (q, J = 7.2, 2H), 4.02 (s, 3H), 2.76 (t, J = 7.2, 2H), 1 .19 (t, J = 7.2, 3H).Melting point (Tme,t): 213-215 CPXRD: FIG. 2, 2theta angle values () = 3.7, 10.0, 10.9, 17.7, 18.3, 20.9, 22.0, 22.5, 23.7, 25.9, 26.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.61% | 100 gm (0.207 mol) Ethyl3 - { [(2- { [(4-cyanophenyl)amino]methyl } - i-methyl-i Hbenzimidazol-5 -yl)carbonylj(pyridin-2-yl)amino} propanoate was added to 500 ml ethanolic hydrochloride solution having HC1 content between 34 to 36 at temperature not more than 35C. Upon domplete addition reaction mixture was stirred for 10-15 mm. and temperature of reaction was raised to 38-42C. Completion of reaction was monitored by HPLC. Reaction mixture was then cooled to 25-309C and diluted with 1500 ml ethanol. reaction mixture was then cooled to 0-5C and was purged with ammonia gas till to achieve neutral pH. To the reaction mixture was added 75 gm ammonium carbonate and reaction mixture was warmed to 28-32C and stirred for 10-12 hr. completion of reaction was monitored by HPLC. Reaction mixture was filtered and the residue was washed with ethanol 500 ml. combined filtrate was concentrated under vacuum to obtain residue. To the obtained residue was added 500 ml ethanol and 1000 ml ethyl acetate. Mixture was refluxed for 30 mm. and then cooled to 25-30C. precipitated product was stirred for 60 mm. at 25-30C and then filtered and dried at 40-45C to obtain crude Ethyl3-[(2-[(4- {carbamimidoyl } phenyl)amino]methyl} -1-methyl-i H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino } propanoate.Yield: lOOg (96.61%); Purity by HPLC: 95.3 %. | |
95% | With lithium hexamethyldisilazane; In tetrahydrofuran; at -5 - 20℃; for 2h; | A process for preparing dabigatran etexilate intermediate, comprising the following steps: (1) the 480g compound 2 dissolved in 2500 ml in tetrahydrofuran (room temperature stirring to complete dissolution), cooling the reaction liquid to the -5 C, slowly dropping 1mol/L lithium hexamethyldisilazane solution of 1200 ml, about 50 minutes drops; (2) completion of the dropping, to maintain the temperature of reaction solution 15-20C, HPLC detection, compound 2 remaining amount in the 1.0% the following, stop reaction (timing reaction time is about 2 hours); (3) continue to lower the temperature to 5 C the following, dropping concentrated hydrochloric acid (density is 1.179g/cm 3) to the reaction solution in pH 2-3 between, by adding 1200 ml water and 800 ml methyl tert-butyl ether stirring and mixing, separating the aqueous phase (concentrated hydrochloric acid: can remove the generated basic impurities, compound 1 under acidic conditions is dissolved in water, methyl tert-butyl ether separating the weakly polar organic impurity, the whole operation is the compound 1 was a purification process); (4) the resulting aqueous phase into the 1500 ml dichloromethane, stirring next adds by drops 40 wt % sodium hydroxide aqueous solution to the pH to 8.5, organic phase is separated, the aqueous phase using 1200 ml dichloromethane extraction a, combined with the phase, after drying of the organic additive anhydrous sodium sulfate, concentrated under reduced pressure to dry, shall be 475g compound 1, the yield is 95%. |
92% | With hydrogenchloride; In ethanol; at 20℃; | 3- [[[2- [[(4-cyanophenyl) amino] methyl] -1- Methyl-1H-benzimidazol-5-yl] carbonyl] (pyridin-2-yl) amino] propionate (III) (10.0 g, 0.021 mol) was added 6M hydrogen chloride in ethanol (50 ml) Stir at room temperature for one night. The excess solvent was evaporated and the residue was dissolved in 40 ml of ethanol. Ammonium carbonate (19.2 g, 0.2mo 1) was added and stirred at room temperature overnight. The insoluble material was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 60 ml of a mixed solution of ethyl acetate and ethanol (5: 1) and stirred at room temperature for 2 h. Filtered and dried to give the hydrochloride of compound IV (10.2 g, 92%). |
90% | With sodium amide; In ethanol; dichloromethane; at 0 - 25℃; | (2) 100 g of a compound of formula 3,150 mL dichloromethane,500mL anhydrous ethanol followed by adding 1000mL three-necked flask,Stirring until solid dissolved,The temperature is controlled at 0 ~ 10 state by adding sodium amide 5 ~ 10g,Then slowly warmed to 20 ~ 25 C reaction to TLC monitoring reaction disappeared compounds of formula 3;Dichloromethane was removed under reduced pressure,Control the water bath temperature is 20 ~ 25 ,To be three bottles of the same temperature and the temperature of the water bath and then decompression removal 10min;Add 100mL absolute ethanol to the three-necked flask and stir well,Control temperature below 10 ,With 40% ammonium carbonate solution to adjust the pH of the reaction solution to 9 ~ 10;Heated to 25 reaction 4h,After the reaction was completed by adding 1200mL water to dissolve all solids,Continue stirring to precipitate a solid,Then cooled to 2 C and stirred for 2h,Filtration and drying of the resulting solid with 0 C ethanol:Water = 1: 3 mixed solvent 100mL × 2 wash,Obtained as an off-white solid 200g,Blast at 40 for 12h,107g of compound of formula 2 was obtained,Yield 90%; |
90% | Add the intermediate DG1 (23.2g, 48mmol, 1.0eq) and 200mL ethanol to the 1000mL reaction flask,Stir to dissolve, then add 120mL of 2N hydrochloric acid ethanol (240mmol, 5.0eq), and stir the reaction at room temperature for 24h. After the reaction was completed, the hydrochloric acid ethanol was distilled off, and 500 mL of anhydrous ethanol solution was added; after cooling to 10 C, 100 mL of ammonia water was added. After the addition, the reaction was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, 500 mL of water was added to beat, filtered with suction, and dried to obtain 21.7 g of solid product DG2, yield: 90% | |
82.5% | Add a hydrogen chloride ethanol solution (30-40% w/w, 300 mL) to a 500 mL reaction flask equipped with a thermometer, and add Compound B (30.0 g, 62.2 mmol) in portions at room temperature with stirring.Stir until the solid is completely dissolved, and the reaction solution is heated to 30 C and stirred for 40 hours.Thin layer chromatography showed that Compound 2 disappeared,The reaction solution was concentrated to 1/3 of the original by rotary evaporation under reduced pressure.The concentrate was dissolved in 200 mL of ethanol, and slowly added with ammonia (25%) with stirring.The pH was adjusted to 9-10 and stirred at room temperature for 12 h.Thin layer chromatography showed that stirring was stopped after the reaction was completed.The insoluble material was removed by filtration, and the filtrate was evaporated to dryness to afford 34.6 g (yield of pale yellow oil).The crude product of Compound A obtained above was dissolved in ethanol (50 mL), 45 g of silica gel was added, and the mixture was evaporated to dryness under reduced pressure. The obtained silica gel adsorbate solid on a silica gel column(300 g silica gel, methanol: dichloromethane: ammonia = 1:10:0.05),Compound A (white crystals 25.6 g, yield 82.5%) was obtained. | |
53% | With N-acetylcystein; ammonia; In ethanol; at 60 - 65℃; for 4h; | Example 6. Preparation of ethyl 3-(2-((4-carbamimidoylphenylamino)methyl)-l-methyl-N- (pyridin-2-yl)-IH-benzo[d]imidazole-5-carboxamido) propanoate of Formula (ll)using N-acetyl cysteine 10 g (0.020 mol) of ethyl 3-(2-((4-cyanophenylamino)methyl)- l-methyl-N- (pyridin-2-yl)-IH- benzo[d]- imidazole-5-carboxamido) propanoate of Formula (IV) was dissolved in 600 ml EtOH.NH3 (15-18%w/w) and stirred at 25C. Added 3.38 g (0.020 mol) of N-acetyl cysteine to the reaction mass and stirred for 24 hours at 70-75C under 2.0-2.3 kg of pressure. The ethanol was distilled under vacuum and residue was purified by column. Yield: 5.5 g Efficiency: 53% |
Example-21: Preparation of l-methyl-2r[N-[4-amidino phenyl] aminomethyl] benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyI) amide compound of formula-5Calcium chloride dihydrate (12.5 g) was added to a mixture of l-methyl-2-[N- (4-cyanophenyl) aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2- ethoxycarbonylethyl)amide compound of formula- 14 (50 g) and ethanol (750 ml) and stirred for 20 minutes. The reaction mixture was cooled to 0-5 C and HC1 gas was passed into the reaction mixture over a period of 5 hours at a temperature below 10C. The temperature of the reaction mixture was raised to 25-30C and stirred for 8 hours at the same temperature. After completion of the reaction, the solvent was expelled out under N2 pressure. The reaction mixture was cooled to 0-5C and slowly added ammonium formate (150 g). The reaction mixture was stirred for 30 minutes and ammonium carbonate (300 g) was added. The temperature of the reaction mixture was raised to 25-35C and stirred for 10 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was distilled under reduced pressure. A solution of 10% ethanol in ethyl acetate was added to the reaction mixture and stirred for 3 hours to obtain a solid. Filtered the obtained solid, washed with ethyl acetate and then dried to get the title compound. Yield: 45 g | ||
Example 12: Preparation of Preparation of 1 -Methyl-2-[N-(4-amidinophenyl)- aminomethyl]-benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonyl ethyl)-amide. Triethyl orthoformate (400 mL) and water (26.1 mL) were charged into a round bottom flask and cooled the reaction mixture to 0-5 C. Dry HCI gas was purged into the reaction mixture until HCI strength in the reaction mixture was more than 25% (w/w). 1 -Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl- carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (100 g) was added to the reaction mixture and raised the reaction mixture temperature to 25-35 ^. Dry HCI gas was purged again into the reaction mixture until HCI strength in the reaction mixture was greater than 25% (w/w) and maintained for about 10 hours at 25-35 C. The reaction mixture obtained was divided into two portions and further process was proceeded with one portion (275 mL, i.e., equivalent of 50 g batch) The above reaction mixture (275 mL, i.e., equivalent of 50 g batch) was cooled to 0±5C followed by addition of dimethylformamide (250 mL) over a period of about 30 minutes at OmicronIotadelta'. Ammonia gas was purged into the reaction mixture at 0±5C until the pH of reaction mass was greater than 9.0, and then temperature of the reaction mixture was raised to 25-35 C and maintained for the completion of reaction, confirmed by using TLC. The reaction mass was filtered, the unwanted salts were washed twice with dimethylformamide (100 and 50 mL), collected the obtained filtrate in a flask and degassed for about 1 hour. The temperature of the filtrate was raised to 50-55 C followed by addition of ethyl acetate (300 mL) to the reaction mixture over a period of about 1 hour at 50-55C, then seed (1 g) was added to the reaction mixture and maintained for 30 minutes. Again, ethyl acetate (700 mL) was added slowly to the reaction mixture over a period of 1 hour at 50- 55 C, and then the reaction mixture was cooled to 25-35 C and maintained for about 8 hours at the same temperature. The obtained solid was filtered and washed with ethyl acetate (100 mL). The wet compound thus obtained was divided into two parts and one part was dried at 60-65 C and second part was purified as below: Purification of crude compound: The second part of crude compound obtained in the above step, ethyl acetate (250 mL) and water (200mL) were charged and the reaction mixture was heated to 50-55 C to obtain a clear solution. The reaction mixture was maintained for 15-30 minutes at 50-55 C then cooled to 20-25 C and maintained for 5-6 hours at the same temperature. The solid thus obtained was collected by filtration, washed with ethyl acetate (50 mL) and dried at 60-65 C to afford the title compound. Yield: 20.5 g; Purity by HPLC: 98.79%; Assay by HPLC: 84.9; ammonia content: 0.03%; chloride content: 6.3%. Purity of crude compound: Yield: 24.0 g; Purity by HPLC: 97.64%; Assay by HPLC: 74.0%; ammonia content: 1 .7%; chloride content: 10.9% | ||
45 g | Calcium chloride dihydrate (12.5 g) was added to a mixture of 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide compound of formula-14 (50 g) and ethanol (750 ml) and stirred for 20 minutes. The reaction mixture was cooled to 0-5 C. and HCl gas was passed into the reaction mixture over a period of 5 hours at a temperature below 10 C. The temperature of the reaction mixture was raised to 25-30 C. and stirred for 8 hours at the same temperature. After completion of the reaction, the solvent was expelled out under N2 pressure. The reaction mixture was cooled to 0-5 C. and slowly added ammonium formate (150 g). The reaction mixture was stirred for 30 minutes and ammonium carbonate (300 g) was added. The temperature of the reaction mixture was raised to 25-35 C. and stirred for 10 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was distilled under reduced pressure. A solution of 10% ethanol in ethyl acetate was added to the reaction mixture and stirred for 3 hours to obtain a solid. Filtered the obtained solid, washed with ethyl acetate and then dried to get the title compound. Yield: 45 g | |
49.8 g | Ethanol (400 ml) was added to the reaction flask,At 1 hydrogen chloride gas to hydrogen chloride concentration of 35.3%,Compound 4 (58.6 g, 0.1 mol) was added,The mixture was stirred at room temperature for 20 h.Cooled to 0 C,Ethanol (400 ml) was added,Through ammonia to adjust pH to 10,Heating 35 stirring reaction 16h,filter,The filtrate was concentrated to dryness under reduced pressure.Ethanol (200 ml) was added,Heating temperature 66 ,Dissolved after clearing the crystallization temperature,The reaction was stirred at room temperature for 2 h.Filtration,Filter cake drying,To give compound 4 (49.8 g),Directly used in the next step reaction. | |
A solution of ethyl 3- (1-methyl-2- (4-nitrile-phenylaminomethyl) -benzoimidazol-5-yl- carboxylic acid- (N-2-pyridyl) (11. lg, 23mmol) was dissolved in 200ml absolute ethanol, dry HCl gas was passed until saturation, stirring at room temperature for 12h. After concentration under reduced pressure, 200 ml of saturated ethanol saturated with NH 3 was added, reacted at room temperature for 5 hours, concentrated and the crude product was purified by silica gel column chromatography.(1-methyl-2-(4-amidinophenylaminomethyl)benzoimidazol-5-yl-carboxylic acid(N-2-pyridyl)amido)propanoic acid ethyl ester(9.3 g, yield 81%). Mass spectrum (ESI-MS): 500.2 (M + H) +, 522.3 (M + Na) +; C27H29N73 (499). | ||
The hydrochloric acid ethanol solution and PR-I were added to the reaction vessel, and the reaction was stirred for 5 hours, and the reaction was completed, and the temperature was reduced below 60 C.The solvent is distilled off, the residue is added by adding ethanol, and the mixture is ammoniated to a hydrazine at a temperature control temperature of 30 C. The reaction is completed, filtered, and the filter cake is made with an organic solvent.Washing, combining the filtrate, distilling off the solvent under reduced pressure at 60 C or less, dissolving the residue with organic solvent d, adding ethyl acetate, stirring at 22 CThe crystals were mixed for 4 hours, filtered by centrifugation, washed with ethyl acetate, and the filter cake was dried under reduced pressure at 45 C for 6 hours to obtain white-like solid PR-II;Among them, the mass ratio of adding PR-I, hydrochloric acid ethanol solution and ethanol is 1:10:10, adding PR-I and organic solvent dThe mass ratio is 1:3, the mass ratio of the organic solvent d to ethyl acetate is 1:3;Among them, ammonia is used for ammoniation;Among them, the organic solvent c and the organic solvent d are both ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In dimethyl sulfoxide; at -10 - 40℃; | Preparing inorganic alkali liquor In 50L dry glass double-layer in the reactor, adding 15L anhydrous ethanol, benzyl trimethyl ammonium hydroxide is added under stirring methanol solution 1.2L (40%), adding purified water 1.5L, four batches adding NaOH 4.0 kg. Stir at room temperature 8h, get white emulsion, for use. Inorganic alkali liquor application In 50L dry glass double-layer in the reactor, the substrate and 3 - (3 - (2 - (4 - cyano-anilino) acetyl) 4 - (methylamino) - N - (pyridine -2 - yl) benzamido-) - ethyl propionate 1 kg, adding 6L anhydrous ethanol, open at low temperature cooling circulating pump, stirring cooling to -10 C. The beginning of the dried hydrogen chloride gas, to control the temperature of the solution is lower than 25 C, to the solution of hydrogen chloride in reach saturation. The cessation of hydrogen chloride gas, heating up to 30 C. 3 . 0h after HPLC monitoring, the remaining substrate is about 8.9%, up to 40 C, depressurized distillation excess hydrogen chloride gas, to a detecting overflow gas pH>2.0, stop is distilled under reduced pressure. To the reaction kettle is added 2L anhydrous ethanol, to cool down to -5 C, under stirring add the above-mentioned preparation of the inorganic alkali white emulsion, control solution at a temperature of 25 - 30 C. Detecting the reaction fluid to the pH=7.0, stop into the lye. The beginning of the inject ammonia, detection reaction fluid to the pH=9.0, stop ammonia gas, heating up to 30 C. By HPLC monitoring, by the substrate conversion of imino ethyl ester intermediate remaining about 5% when, by adding dichloromethane 1L, and depressurized distillation of the excess ammonia, to the detecting overflow gas pHThe reaction of the mixed liquid filter, 1L anhydrous ethanol washing the filter cake, and transferred to the filtrate 200L in the reactor, stirring while adding ethyl acetate 50L, separating out a large quantity of solid, 25 C stirring 12h, filtered, the filter cake is ethyl acetate/ethanol=1/4 (volume ratio) solution 20L to wash. Vacuum drying the filter cake, the obtained product is 0.89 kg. For the product 5L purified water 80 C dissolved, after dissolving slowly stirring to cooling, 20 C stirring crystallization 12h, centrifugal, cake 1L purified water washing, 60 C vacuum drying 12h to obtain 3 - (3 - (2 - (4 - amidino - anilino) acetyl) 4 - (methylamino) - N - (pyridine -2 - yl) benzamido-) - propionic acid ethyl ester hydrochloride, a total of 0.84 kg, HPLC detection purity>99%.; Example 2 - Example 8 The above process steps were used, and only the values of the test parameters were different, so that they were presented in a list manner. |
Tags: 211915-84-3 synthesis path| 211915-84-3 SDS| 211915-84-3 COA| 211915-84-3 purity| 211915-84-3 application| 211915-84-3 NMR| 211915-84-3 COA| 211915-84-3 structure
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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 |
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