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CAS No. : | 79463-77-7 | MDL No. : | MFCD00010380 |
Formula : | C14H10N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SLIKWVTWIGHFJE-UHFFFAOYSA-N |
M.W : | 238.24 | Pubchem ID : | 688090 |
Synonyms : |
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 67.19 |
TPSA : | 54.61 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.19 cm/s |
Log Po/w (iLOGP) : | 2.76 |
Log Po/w (XLOGP3) : | 3.61 |
Log Po/w (WLOGP) : | 2.98 |
Log Po/w (MLOGP) : | 2.68 |
Log Po/w (SILICOS-IT) : | 2.62 |
Consensus Log Po/w : | 2.93 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.82 |
Solubility : | 0.036 mg/ml ; 0.000151 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.44 |
Solubility : | 0.00857 mg/ml ; 0.000036 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -4.58 |
Solubility : | 0.00625 mg/ml ; 0.0000262 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 3.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 2.66 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302+H312+H332-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 |
---|---|---|
80% | With triethylamine; In DMF (N,N-dimethyl-formamide); isopropyl alcohol; at 20℃; for 18h; | To a solution of 150 mg of (2S, 3S, 4R)-6-cyano-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydro-2H-1-benzopyran prepared in the preparation example 6 dissolved in 3 ml of isopropanol-DMF (2:1), were added 141 mg of <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> and 97 ul of triethylamine. The reaction mixture was stirred for 18 hours at room temperature, and extracted with 10 ml of water and 30 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane : ethyl acetate = 1:2) to afford 182 mg (yield : 80percent) of the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In isopropyl alcohol; at 75℃; for 4h; | 4-Amino-benzenesulfonamide (2mmol) was added in one portion to a solution of diphenoxycyanoimidate (2mmol) in isopropanol. The reaction mixture was stirred at 75C for 4 hours. The reaction mixture was then allowed to cool to room temperature. A solid precipitated out and was filtered off. It was washed with isopropanol to afford the title compound (0,33g; 70percent yield). 1H-NMR (400 MHz, DMSO-d6) delta 7.30-7.40 (5H, m), 7.45-7.50 (2H, t), 7.65-7.70 (2H, d), 7.80-7.85 (2H, d), 11.20 (1H, s); MS (ES+) m/e=317 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In isopropyl alcohol; at 20℃; for 24 - 48h; | To a suspension of diphenyl-cyanocarbon-imidate (3.0g, 12.59mmol) in isopropanol (15mL) was added 2,4-dimethoxyaniline (2.02g, 13.22mmol). The reaction was stirred at RT for 24-48h. The solid was filtered, washed with iso-propanol and dried under high vacuum to give the title compound as a brown solid (3.55g, 95percent yield). 1H-NMR (500 MHz, DMSO-d6) 10.60 (br s, 1H), 7.52-7.40 (m, 3H), 7.35-7.07 (m, 3H), 7.00 (d,d, 1H), 6.85 (dd, 1H)3.81 (s, 3H) ppm; LC-MS 289.12 (M+H); HPLC (method A) 3.32 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In isopropyl alcohol; at 100 - 110℃; for 1h;Heating / reflux; | A mixture of 3,4,5-trimethoxyaniline (1.83 g, 10 mmol) and diphenyl-cyanocarbon-imidate (2.62 g, 11 mmol) in iso-propanol (30 mL) was stirred at 100-1l0oC for 1h. The reaction was cooled and filtered, washing with ether to provide the title compound (2.79 g, 85percent yield) as a white solid. 1H-NMR (500 MHz, DMSO-d6) 10.8 (s, 1H), 7.45 (t, 2H), 7.31 (m, 3H), 6.83 (s, 2H), 3.76 (s, 6H), 3.65 (s, 3H) ppm; MS (FIA) 328.1 (M+H); HPLC (method A) 3.211 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | In Isobutyronitrile; at 150℃; for 0.5h; | A mixture of <strong>[350684-49-0]4-(4-amino-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester</strong> (520 mg, 1.70 mmol) and diphenyl cyanocarbonimide (406 mg, 1.70 mmol) in dimethylacetonitrile (3.0 mL) was heated at 150 C for 30 min. The mixture was concentrated and purified by silica gel column chromatograghy eluted with EtOAc:hexanes (5 to 35% EtOAc) to give the title compound (177 mg, 23%) as a white solid. MS (ES+): m/z = 450.1; 1H NMR (CDCl3, 500 MHz): 5 1.48 (s, 9H), 3.26-3.83 (m, 8H), 7.16 (d, 2H), 7.34 (t, 1H), 7.42-7.49 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine; In dichloromethane; isopropyl alcohol; at 20℃; for 2.5h; | A solution of 0.20 g (0.32 mmol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-[4-(2-aminoethoxy)benzyl]-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxypropylcarbamate, 83 mg (0.35 mmol) of <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong>, and 66 muL of (0.47 mmol) triethylamine in 12 mL of 1:1 i-PrOH/CH2Cl2 was stirred at RT. After 2.5 hours the solution was concentrated to dryness at reduced pressure and the residue subjected to flash chromatography (SiO2, 95:5 CH2Cl2/MeOH) to afford 0.24 g (96percent) of the desired compound as a white foam. 1H NMR (CDCl3): 7.47-7.21 (m, 4H), 7.20-7.02 (m, 5H), 6.88-6.63 (m, 3H), 6.42 (br s, 1H), 6.05 (s, 2H), 5.61 (d, 1H), 4.99 (m, 2H), 4.20-3.50 (m, 11H), 3.09 (m, 1H), 3.01-2.82 (m, 4H), 2.76 (m, 2H), 1.78 (m, 1H), 1.72-1.43 (m, 2H), 0.90 (d, 3H), 0.81 (d, 3H). MS(ESI): 780(M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In toluene; at 100℃; | A mixture of 4-(4-amino-2,6-dimethoxy-phenoxy)-piperidine-1-carboxylic acid benzyl ester (57.8 mg, 0.180 mmol) and diphenyl cyanocarbonimide (42.8 mg, 0.180 mmol) in toluene (1.0 mL) was heated at 100 C overnight. The mixture was concentrated and purified by silica gel column chromatograghy eluted with EtOAc:hexanes (40 to 60percent EtOAc) to give the title compound (65.3 mg, 82percent) as a colorless oil. MS (ES+): m/z = 531.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With potassium carbonate; In water; ethyl acetate; at 20℃; for 18h; | To a solution of N-(2-dimethylaminoethyl)-2,5-dimethoxybenzene 1,4-diamine hydrochloride (0.05g, 0.143mmol) in distilled water (1mL) was added K2CO3 (0.065g, 0.47mmol). This was diluted with EtOAc (1mL) and diphenylcyano-carbonimidate (0.032g, 0.136mmol) was added. The reaction was stirred at RT for 18h. The precipitate was filtered and washed with minimal EtOAc to give the title compound as a light purple solid (0.015g, 29percent yield). 1H-NMR (500 MHz, DMSO-d6) 10.11 (s, 1H), 7.51-7.33 (m, 2H), 7.31-6.98 (m, 3H), 6.81-6.64 (m, 1H), 6.28 (br s, 1H), 4.87 (br s, 1H), 3.85-3.62 (m, 5H), 3.12 (s, 3H), 2.17 (s, 6H) ppm; LC-MS 384.3 (M+H); HPLC 1.9 min(method A). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In isopropyl alcohol; at 80℃; for 24h; | 1-(3-Bromo-8-chloro-6,11-dibydro-5H-benzo[5,61-cyclohepta[1,2-b] pyridin-11-yl)-4-[(4-piperidinyl)acetyl]-piperazine (Preparative Example 11) (2.5g) (1 equivalent) and diphenylcyanocarbonimidate (1.38g) (1.2 equivalents) were dissolved in 2-propanol (65ml) and the solution was heated at 80°C under reflux and under nitrogen for 24h. The mixture was evaporated to dryness and the product was chromatographed on a silica gel column (60X2.5cm) using neat ethyl acetate as the eluant to give the title compound (2.7921g; 87percent), FABMS: m/z 661 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.6% | In tetrahydrofuran; 10ml; tert-butyl alcohol; at 20 - 90℃; for 8h; | Step A: N-4-[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-N6-(2-phenyl-N-cyano-isourea)-quinazoline-4,6-diamine is prepared by stirring N-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4,6-diamine (0.63 g, 1.60 mmol) and diphenyl N-cyanocarbonimidate (1.0 g, 4.20 mmol), in THF (20 mL), DCE (10 mL) and t-BuOH (10 mL) at room temperature for 2 hours, then at 80-90° C. for 3 hours. An additional 0.40 g of diphenyl N-cyanocabonimidate is added. After stirring at 80-90° C. for 3 hours, the reaction mixture is cooled to room temperature and concentrated. DCM (100 mL) is added, and the solid is isolated by filtration through a sintered glass funnel and dried, yielding 0.67 g (77.6percent) of tan-yellow material. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In isopropyl alcohol; at 20℃; for 18h; | To a solution of N-[4-(aminomethyl)cyclohexyl]methyl}-N-(4-chlorobenzyl)-(4- chlorophenyl) methanamine (100mg, 0.256 mmol, 1 eq) IN I-PROPANOL (1 ML) was added <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (64mg, 0. 269MOL, 1.05eq). The mixture was stirred at room temperature for 18hrs, the SOLVENT REMOVED IN VACUO and the residue purified by column chromatography on SI02 using 10-25percent EtOAc/hexane as eluent to give the desired product as a COLOURLESS OIL (1 02MG, 75percent yield). HPLC-MS: m/z 535 [M+H] +.'H NMR (CDCI3) : 6.97-7. 40 (m, 13H), 6.38-6. 50 (m, 1H), 3.39 (s, 4H), 3.13-3. 22 (m, 2H), 2.09-2. 19 (m, 2H), 0.61-1. 88 (m, 10H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | In tetrahydrofuran; i-PrOH; at 20℃; | Step H: 1-(4-{4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]quinazolin-6-yl}-thiazol-2-ylmethyl)-2-phenyl-N-cyano isourea [6-(2-Aminomethyl-thiazol-4-yl)-quinazolin-4-yl]-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine (45 mg, 0.095 mmol) is dissolved in a 1:2 i-PrOH:THF mixture (6 ml). <strong>[79463-77-7]Diphenyl cyanocarbonimidate</strong> (28 mg, 0.12 mmol) is added and the reaction mixture is stirred overnight at room temperature under a nitrogen atmosphere. To drive the reaction to completion <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (20 mg, 0.09 mmol) is added to reaction mixture, which is stirred at room temperature for another 4 hours. The reaction mixture is then concentrated and purified by flash column chromatography on silica eith MeOH-EtOAc as an eluant. The yield of pure desired product is 42 mg (0.07 mmol, 74percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 24h; | A solution of diphenylcyanocarboimidate (10 g, 42 mmol) in 168 mL CH2CI2 was treated with <strong>[15205-15-9]2-chloro-6-fluorobenzylamine</strong> (6.7 g, 42 mmol) and diisopropylethylamine (7.3 mL, 42 mmol). The reaction mixture was stirred at room temperature for 24 hr. The solvent was removed by reduced pressure and the remaining white solid was diluted with CH2Cl2and H20 and extracted 3x with CH2CI2. The organic layers were combined and the solvent removed by reduced pressure yielding a crude white solid. This intermediate (12.8 g, 42 mmol) was dissolved in 80 mL acetonitrile and treated with piperidine (6.2 mL, 63 mmol). The reaction was heated to reflux for 24 hr. The reaction mixture was cooled and the solvent removed by reduced pressure. The crude product was triturated with ether and collected by filtration to yield a white solid (10 g, 82ouzo yield) :'H NMR (CDCI3, 400 MHz) 7.28-7. 23 (m, 1 H), 7.22-7. 18 (m, 1 H), 7.04-6. 98 (m, 1 H), 4.94-4. 85 (m, 1 H), 4.68-4. 63 (m, 2H), 3.45-3. 39 (m, 4H), 1. 65-1. 57 (m, 6H); MS (ESP+) m/e 295 (MH+) ; Analytical CHN. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In ethanol; at 80℃; for 16h; | EXAMPLE 343; 1-(1-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-piperazine-4-yl)-3-cyano-2- phenyl-isourea; The 1- {2- [4- (BENZOTHIAZOL-2-YLOXY)-PHENYL]-ETHYL}-PIPERIDIN-4-YLAMINE hydrochloride was prepared from (1- {2- [4- (BENZOTHIAZOL-2-YLOXY)-PHENYL]-ETHYL}- piperidin-4-yl)-carbamic acid tert-butyl ester EXAMPLE 337 by removal of the Boc group according to EXAMPLE 266, step B. The free base was prepared by suspending 1- {2- [4- (BENZOTHIAZOL-2-YLOXY)-PHENYL]-ETHYL}-PIPERIDIN-4-YLAMINE hydrochloride (1.3 g, 3.3 MMOL) in CH2CI2 (20 mL) and washing with a solution of saturated NaHCO3 (20 mL). The organic layer was dried over NA2SO4, filtered and concentrated under reduced pressure to give 1.0 g (83percent yield) of 1- {2- [4- (BENZOTHIAZOL-2-YLOXY)-PHENYL]-ETHYL}-PIPERIDIN-4-YLAMINE free base. A solution of 1- {2- [4- (BENZOTHIAZOL-2-YLOXY)-PHENYL]-ETHYL}-PIPERIDIN-4-YL AMINE (145 mg, 0.4 MMOL) in ethanol (5 mL) was treated with diphenyl cyanocarbodiimidate (319 mg. 1.34 MMOL) and heated to 80 °C for 16h. The reaction was concentrated under reduced pressure and purified on Si02 (12 g, 0-10percent [2 M NH3 CH30H]/CH2CI2) to give of the title compound (173 mg, 85percent yield). MS (ESI) : exact mass calculated FOR C28H27N502S1, 496.2 ; m/z found, 498.4 [M+H].. H NMR (400 MHz, CDC13) : 7.73 (d, J = 8.7, 1 H), 7.66 (dd, J = 7.9, 0.7, 1 H), 7.45-7. 36 (m, 4H), 7.31-7. 24 (m, 5H), 7.08 (d, J = 7.8, 2H), 6.36 (br d, J = 6.5, 1 H), 3. 87-3. 76 (m, 1 H), 3.02 (br d, J = 11. 2, 2H), 2.83 (dd, J = 8.4, 7.3, 2H), 2.64 (DD, J = 8. 6,5. 4, 2H), 2.21 (t, J = 11. 1, 2H), 2.07 (d, J = 11.0, 2H), 1.76 (dd, J = 20.7, 10.4, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In ethanol; at 20℃; for 24h; | a) A solution of (+-)-6-(cyclopentyloxy)-5-methoxy-beta-methyl-2-pyridineethanamine (0.037 mol) and diphenyl N-cyanocarbonimidate (0.037 mol) in ethanol (100 ml) was stirred for one day at RT. The precipitate was filtered off, washed with ethanol, DIPE, then dried, yielding 9 g (61.7percent) of (+-)-phenyl N'-cyano-N-[2-[6-(cyclopentyloxy)-5-methoxy-2-pyridinyl]propyl]carbamimidate(interm. 9). The filtrate was evaporated under reduced pressure. The residue was dissolved in CH2Cl2. The organic solution was washed three times with 2 N NaOH. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 4.1 g of intermediate (9). Total yield is 89percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | 29.3 g glycine ethylester hydrochloride are added to a solution of 50.0 g diphenyl-N-cyano-carbonimidate in 29 ml triethylamine and 500 ml isopropanol. The solution is stirred for 16 h (hours) at ambient temperature and then evaporated down. The residue is dissolved in ethyl acetate and the organic phase is washed with water and aqueous potassium carbonate solution. The organic phase is dried over sodium sulphate and the solvent is eliminated completely. The residue is washed with diethyl ether and dried. Yield: 35.5 g (68percent of theory) Mass spectrum (ESI+): m/z=248 [M+H]+ | |
68% | With triethylamine; In isopropyl alcohol; at 20℃; for 16h; | EXAMPLE I 1-ethoxycarbonylmethyl-3-cyano-2-phenyl-isourea 29.3 g glycinethylester hydrochloride are added to a solution of 50.0 g diphenyl-N-cyano-carbonimidate in 29 ml triethylamine and 500 ml isopropanol. The solution is stirred for 16 h (hours) at ambient temperature and then evaporated down. The residue is dissolved in ethyl acetate and the organic phase is washed with water and aqueous potassium carbonate solution. The organic phase is dried over sodium sulphate and the solvent is eliminated completely. The residue is washed with diethyl ether and dried. Yield: 35.5 g (68percent of theory) Mass spectrum (ESI+): m/z=248 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; for 16h; | Example 61 1-[(Cyanoimino)(pyrrolidin-1-yl)methyl]-N-hydroxy-4-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl]methyl}piperidine-4-carboxamide Step A Methyl 1-[(cyanoimino)(phenoxy)methyl]-4-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl]methyl}piperidine-4-carboxylate Into a 2-neck-round-bottom flask were added methyl 4-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl]methyl}piperidine-4-carboxylate (183 mg, 0.000484 mol) in anhydrous acetonitrile (10 mL, 0.0484 M), N,N-diisopropylethylamine (450 uL, 0.0026 mol), and <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (230 mg, 0.00096 mol). The solution was heated to 90° C. and the reaction was monitored by HPLC and LC/MS. After stirring for 16 h, the reaction mixture was allowed to cool to ambient temperature and was concentrated in-vacuo. The crude product was purified by CombiFlash chromatography utilizing a 12 g column and eluting with EtOAc/CH2Cl2 (30percent gradient over 15 min.) to afford 240 mg (94percent) of pure product. LC/MS: 523.6 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.7% | In isopropyl alcohol; at 20℃; | Example 4 Preparation of tert-butyl 4-((Z)-1-cyano-2-phenylisoureido)phenylcarbamate (4) To a suspension of <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (11.04 g, 46.4 mmol) in 130 ml isopropanol was added tert-butyl 4-aminophenylcarbamate (9.20 g, 44.2 mmol). The reaction was stirred at room temperature overnight and the solid was collected by filtration. Solid was dried under vacuum and it was weighted at 10.85 g (69.7percent yield). LC/MS (M+1=353.2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine; In 1,2-dichloro-ethane; at 60℃; | Following the procedure described in EXAMPLE 81, 41 mg of (4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-l,3-oxazolidin-2-oneand 17mg of (5-isopropyl-2-methoxyphenyl)boronic acid gave 39 mg of the title compound (95percent). Massspectrum (ESI) 620.4 (M+l). IH NMR signals are doubled because of atropoisomerism. *H NMR (500MHz, CDCls): 5 7.53-7.80 (m, 5H), 7.33 (d, J=8 Hz, IH), 7.21-7.29 (m, IH), 7.00, 6.76 (d, J=2.5 Hz,IH), 6.91, 6.86 (d, J= 8.5 Hz, 0.4H), 5.15, 5.10 (d, J=4.5 Hz, IH), 4.80, 4.74 (d, J=16 Hz, IH), 4.25, 4.21(d, 16 Hz, IH), 3.76 (s, 2H), 3.49 (s, IH), 3.43 (m, 0.4H), 3.18 (m, 0.5H), 2.77-2.98 (m, IH), 1.24 (m,3H), 1.16 (m, 3H), 0.78, 0.61 (d, J=6.5 Hz, 3 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium hydrogencarbonate; In ethyl acetate; acetonitrile; | 6.1 To a solution of 4-(2-keto-1-benzimidazolinyl)piperidine (1.3 g; 5.98 mmol) in acetonitrile was added diphenyl N-cyanocarbonimidate (1.56 g; 6.55 mmol; 1.1 equiv). The reaction mixture was stirred at 60° C. for 48 h under nitrogen atmosphere and then concentrated under reduced pressure. The crude product was suspended in ethyl acetate (50 mL) and a saturated aqueous solution of sodium bicarbonate (50 mL) and stirred overnight at room temperature. The solid was collected by filtration and dried to give N-cyano-4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboximidic acid phenyl ester (1.85 g; 85percent) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With ethylenediamine; In ethanol; | EXAMPLE 94 (2R)-N-(2-Amino-ethyl)-N'-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-benzyl)-cyanoguanidine A solution of 2-(2-aminomethyl-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-ethanone (0.025 g, 0.062 mmol) and <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (0.016 g, 0.068 mmol) in ethanol (1 mL) was heated on a shaker plate at 60° C. After 22 h, ethylenediamine (0.008 mL, 0.123 mmol) was added and the resulting solution was heated on a shaker plate at 60° C. for an additional 21 h. The solution was cooled to ambient temperature, concentrated and purified using radial chromatography to yield the title compound (0.021 g, 67percent). The title compounds for Examples 95-96 were prepared by a method analogous to that described in Example 94. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In isopropyl alcohol; at 20℃; | A solution of (8S)-A/-methyl-A/-({1-[(3S)-3-piperidinylmethyl]-1H-benzimidazol-2-yl}methyl)-5,6,7,8-tetrahydro-8-quinolinamine (170 mg, 0.44 mmol) in isopropanol (10 ml_) was treated with <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (104 mg, 0.44 mmol). After stirring at RT overnight, the reaction mixture was concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution of acetonitrile to 95:5 acetonitrile/NH4OH) to afford 227 mg (97percent) of phenyl (3R)-A/-cyano-3-[2-({methyl[(8S)-5,6,7,8-tetrahydro-8-quinolinyl]amino}methyl)-1H-benzimidazol-1-yl]methyl}-1-piperidinecarboximidoate as a colorless oil. 1H NMR (CD3OD): 8 8.42 (m, 1H), 7.58-7.15 (m, 10H), 6.72 (brm, 1H), 4.32-3.91 (m, 7H), 3.08-2.70 (m, 4H), 2.10 (m, 7H), 1.81 -1.24 (m, 5H). MS m/z 534 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In 1,4-dioxane; at 20℃; for 24h; | A solution of afford trans-l-(4-amino-phenyl)-4-morpholin-4-yl-cyclohexane carbonitrile (18. Ig, 63.5mmol) and <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (18. Ig, 76.2mmol) was stirred in 1,4-dioxane (14OmL) at RT for 24h. Distilled water (20OmL) was added to afford a white precipitate which was filtered and washed with water (10OmL), saturated sodium bicarbonate solution (15OmL), and water (20OmL). The solid was dried in a dessicator under vacuum overnight, to give the title compound 6 (21. Ig, 78percent yield). 1H-NMR (DMSO, 500 MHz) 7.55 (m, 4H), 7.45 (m, 2H), 7.3 (m, 3H), 3.6 (m, 4H), 2.45 (m,4H), 2.37 (t, IH), 2.15 (d, 2H), 2.0 (d, 2H), 1.9 (t, 2H), 1.6 (m, 2H)]MS+ 430.18, MS- 428.13, HPLC Rt=4.652min (conditions 10-90percentAcetonitrile over7.5min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In isopropyl alcohol; at 20℃; for 5h; | Specifically, a solution of 3-benzyloxyaniline 2e (0.84 g, 4.2 mmol) and diphenylcyanocarbonimidate 1 (1.0 g, 4.2 mmol) in 2-PrOH (15 ml_) was stirred at ambient temperature under N2. After 5 h, the solids were collected by filtration washing with cold 2-PrOH to afford 3e (1.25g, 86percent) as a white solid: 1H NMR (300 MHz, DMSO- d6) delta 7.47-7.26 (m, 12H), 7.17 (s, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 5.10 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | In isopropyl alcohol; at 20℃; for 20h; | Alternatively, a mixture of 21 (1.68 g, 7.56 mmol) and diphenylcyanocarbimidate 1 (1.80 g, 7.56 mmol) in 2-PrOH (20 mL) was stirred at ambient temperature under N2 for 20 h. The solids that formed were collected by filtration and washed with 2-PrOH, to afford 3i (2.04 g, 74percent) as a yellow-white solid: 1H NMR (300 MHz, DMSO-d6) delta 10.82 (br s, 1H), 7.50-7.26 (m, 6H), 7.09-7.01 (m, 2H), 6.85-6.73 (m, 1H), 4.08 (t, J = 5.7 Hz1 2H), 3.58-3.55 (m, 4H), 2.70 (t, J = 5.7 Hz, 2H), 2.50-2.46 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In isopropyl alcohol; at 20℃; for 20h; | Alternatively, a mixture of 2m (2.56 g, 11.6 mmol) and diphenylcyanocarbimidate1 (2.77 g, 11.6 mmol) in 2-PrOH (70 mL) was stirred at ambient temperature under N2 for 20 h. The 2-PrOH was removed under reduced pressure and the residue was partitioned between EtOAc (75 mL) and water (75 mL). The aqueous layer was extracted with EtOAc (75 mL) and the combined organics were dried (Na2SO4), and concentrated to give the crude product. Purification by flash chromatography (CH2CI2, then 95:5 CH2CI2/Me0H) afforded 3j (3.68 g, 87percent) as a beige foam: 1H NMR (300 MHz1 DMSO-d6) delta 10.36 (br s, 1H), 7.50-7.41 (m, 2H), 7.29-7.23 (m, 4H), 7.12-6.96 (m, 2H), 6.80-6.73 (m, 1H), 4.09-4.05 (m, 2H), 2.73-2.69 (m, 2H), 2.49-2.42 (m, 4H), 1.54-1.37 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; at 20℃; | Preparation of 5-Amino-1-(4-(iso-propoxy)phenyl)carbonyl-3-[4-[2-(pyrrolidin-1- yl)ethoxy]phenylamino]-1H-1,2,4-triazole (la-2)(la-2). Specifically, diphenylcyanocarbonimidate 1 (1.1 equiv) and aniline 2a (1 equiv) were stirred in /so-propyl alcohol at ambient temperature overnight. The white precipitate was filtered and washed with /so-propyl alcohol and dried to yield 3a. Then hydrazine hydrate (2 equiv) was added to a slurry of 3a in methanol. After stirring at ambient temperature overnight the solution was concentrated and the oily residue was triturated with diethyl ether to remove impurities and give 4a as a white solid. The 3,5- diamino-1 ,2,4-triazole compound 4a was then acylated with benzoic acid 5a mediated by HOAt /EDCI. HCI and 'Pr2NEt in anhydrous DMF. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was separated and concentrated. Purification of the residue by silica gel column chromatography in 5% triethylamine/ethyl acetate gave 5-amino-1-(4-(/so- propoxy)phenyl)carbonyl-3-[4-[2-(pyrrolidin-1-yl)ethoxy]phenylamino]-1 H-1 ,2,4-triazole (la-2), as a yellow solid (38% yield); 1H-NMR (DMSO-d6, 300 MHz) 9.01 (s, 1H), 8.22 (d, J = 8.7 Hz, 2H), 7.69 (br. s, 2H), 7.41 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 4.78 (m, 1 H), 3.98 (br. s, 2H), 2.77 (br. s, 2H)1 2.48 (m, 4H), 1.67 (m, 4H), 1.30 (d, J = 6.0 Hz1 6H) ppm; MS (ES) 451.4 (M+H), 449.0 (M-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In isopropyl alcohol; at 20℃; for 8h; | Specifically, a mixture of (3-aminophenoxy)acetonitrile 2k (1.0 g, 6.70 mmol) and diphenylcyanocarbimidate 1 (1.64 g, 6.90 mmol) in 2-PrOH (20 ml.) was stirred at ambient temperature under N2 for 8 h. The solids that formed were collected by filtration and washed with 2-PrOH, to afford 3h (1.76 g, 88percent) as a white solid: 1H NMR (300 MHz, DMSO-d6) delta 10.94 (s, 1H), 7.50-7.37 (m, 3H), 7.34-7.27 (m, 3H), 7.23-7.17 (m, 2H), 6.99-6.95 (m, 1H), 5.18 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In isopropyl alcohol; at 20℃; for 20h; | Alternatively, a mixture of 2n (4.46 g, 21.3 mmol) and diphenylcyanocarbimidate (5.07 g, 21.3 mmol) in 2-PrOH (100 mL) was stirred at ambient temperature under N2 for 20 h. The solids that formed were collected by filtration and washed with 2-PrOH to afford 3k (5.90 g, 78percent) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) delta 10.82 (s, 1 H), 7.50-7.37 (m, 2H), 7.32-7.26 (m, 4H), 7.08-7.03 (m, 2H), 6.82 (dd, J = 7.9, 1.9 Hz, 1H), 4.98 (t, J = 4.9 Hz, 1 H), 4.07 (t, J = 6.5 Hz, 2H), 3.93-3.76 (m, 4H), 2.06-2.00 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In isopropyl alcohol; at 20℃; for 20h; | A mixture of 2d (2.62 g, 13.6 mmol) and diphenylcyanocarbimidate (3.23 g, 13.6 mmol) in 2-PrOH (40 mL) was stirred at ambient temperature under N2 for 20 h. The solids that formed were collected by filtration and washed with 2-PrOH to afford 3d (3.08 g, 67percent) as a white solid: 1H NMR (300 MHz, CDCI3) delta 7.90 (br s, 1 H), 7.47-7.40 (m, 2H), 7.36-7.28 (m, 2H), 7.21-7.14 (m, 2H), 7.10 (t, J = 2.1 Hz, 1H), 6.97 (dt, J - 7.6, 1.6 Hz, 2H), 5.40 (t, J = 3.2 Hz, 1 H), 3.87 (dt, J = 11.7, 3.0 Hz, 1 H), 3.63-3.58 (m, 1H), 2.05-1.91 (m, 1 H), 1.88-1.83 (m, 2H), 1.74-1.62 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With hydrazine; In tetrahydrofuran; nitrogen; | Example 15 1-[(5-ethyl-2-thienyl)carbonyl]-N3-[4-(1H-imidazol-1-yl)phenyl]-1H-1,2,4-triazole-3,5-diamine (Cpd 90) Using the published procedure (Webb et al., J. Heterocyclic Chem., 1987, 24, 275-278), 4-imidazol-1-yl-aniline (0.50 g, 3.14 mmol), diphenyl cyanocarbonimidate (0.75 g, 3.14 mmol) and THF (30 mL) were combined in a nitrogen purged flask. The mixture was refluxed for 2 hrs, then cooled down to ice temperature and hydrazine (31.4 mL, 1.0 M solution in THF, 31.4 mmol) was added dropwise. The mixture was then refluxed for 2 hrs. The precipitate was filtered and collected, washed with ethyl acetate and air dried to produce the intermediate Compound 15A (0.60 g, 79%). 1H NMR (300 MHz, (CD3)2SO) delta 11.15 (s, 1H), 8.85 (s, 1H), 8.05 (s, 1H), 7.57 (s, 1H), 7.48 (d, 2H), 7.35 (d, 2H), 7.04 (s, 1H), 5.85 (s, 2H); MS (ESI) m/z: 242 (M+H+). Using the procedure of Example 1, Compound 15A was acylated with 5-ethylthiophene-2-carboxylic acid Compound 15B mediated by DIC/HOBt in DMF to provide Compound 90 (59% yield). 1H NMR (300 MHz, (CD3)2SO) delta 9.63 (s, 1H), 8.14 (d, 1H), 7.85-7.70 (m, 7H), 7.56-7.53 (m, 2H), 7.07 (d, 2H), 2.95 (q, 2H), 1.33 (t, 3H); MS (ESI) m/z: 380 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.8% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 20℃; | SYNTHETIC PREPARATION 3; Compound of formula (C-1 )A mixture of the compound of formula (Cd), 5',5'-dimethyl-6,8,9,10-tetrahydro- 5H-spiro[cycloocta[ib]pyridine-7,2'-[1 ,3]dioxan]-3-amine ( 1.08 g, 3.9 mmol), diphenylcyanocarboimidate (0.93g, 3.9 mmol), diisopropylethylamine (680 mul, 3.9 mmol) and isopropyl alcohol (15 ml.) was stirred at ambient temperature overnight. The solvent was evaporated, and the residue was purified by flash chromatography on silica gel (ethyl acetate) to the compound of formula (C-1 ), phenyl lambda/'-cyano-lambda/-(5',5'- dimethyl-6,8,9, 1 O-tetrahydro-deltaH-spirofcycloocta^pyridine^^'-fi ,3]dioxane]-3- yl)carbamimidate, (1.09 g, 66.8percent); 1H NMR (DMSOd6, 300 MHz) 10.81 (s, 1 H), 8.36 (s, 1 H), 7.64 (s, 1 H), 7.42 (t, 2H), 7.28 (m, 3H), 3.37 (m, 4H), 2.87 (t, 2H), 2.73 (m, 2H), 1.97 (m, 2H), 1.70 (m, 2H), 1.54 (m, 2H), 0.85 (d, 6H) ppm; MS (ES) 421.01 (M+H). |
66.8% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 20℃; | Synthetic Preparation 3; Compound of Formula (C-1)A mixture of the compound of formula (Cd), 5',5'-dimethyl-6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxan]-3-amine (1.08 g, 3.9 mmol), diphenylcyanocarboimidate (0.93 g, 3.9 mmol), diisopropylethylamine (680 mul, 3.9 mmol) and isopropyl alcohol (15 mL) was stirred at ambient temperature overnight. The solvent was evaporated, and the residue was purified by flash chromatography on silica gel (ethyl acetate) to the compound of formula (C-1), phenyl N'-cyano-N-(5',5'-dimethyl-6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2'-[1,3]dioxane]-3-yl)carbamimidate, (1.09 g, 66.8percent); 1H NMR (DMSO-d6, 300 MHz) 10.81 (s, 1H), 8.36 (s, 1H), 7.64 (s, 1H), 7.42 (t, 2H), 7.28 (m, 3H), 3.37 (m, 4H), 2.87 (t, 2H), 2.73 (m, 2H), 1.97 (m, 2H), 1,70 (m, 2H), 1.54 (m, 2H), 0.85 (d, 6H) ppm; MS (ES) 421.01 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In isopropyl alcohol; at 20℃; | A solution of 5-amino-2-[(pyrrolidin-1-yl)methyl]benzoxazole (200 mg, 0.92 mmol) and diphenylcyanocarbonimidate (263 mg, 1.10 mmol) in isopropyl alcohol (3.5 mL) was stirred overnight at ambient temperature, the resulting white solid product, (Z)-phenyl /V- cyano-/V-(2-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-5-yl)carbamimidate, was filtered and used directly for the next step (290 mg, 87percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In isopropyl alcohol; at 20℃; | D. Synthesis of N-Cyano-N'-(4-(4-(bicvclor2.2.1lhept-2-yl)-1-piperazinyl)phenyl}-0-phenylisourea. A mixture of 1-bicyclo[2.2.1]hept-2-yl-4-(4-aminophenyl)piperazine (2.0 g; 7.4 mmol; 1.0 equiv) and diphenyl cyanocarboimidate (1.76 g; 7.4 mmol; 1.0 equiv) in 20 mL of /sopropanol was stirred at ambient temperature overnight. The solid was filtered, washed with /sopropanol and dried to give N-cyano-N'-{4-[4-(1-bicyclo[2.2.1]hept-2-yl)-1- piperazinyl]phenyl}-O-phenylisourea as a pale-pink solid (2.84 g, 92percent yield). 1H-NMR (DMSO-d6, 300 MHz) 10.56 (br. s, 1 H), 7.41 (t, J = 6.0 Hz, 2H), 7.26-7.21 (m, 5H), 6.90 (d, J = 6.9 Hz, 2H), 3.15-3.05 (m, 4H), 2.45-2.34 (m, 4H), 2.29-2.14 (m, 3H), 1.78-1.62 (m, 2H), 1.50-1.40 (m, 1 H), 1.36-1.17 (m, 4H), 0.89-0.86 (m, 1 H) ppm; MS (ES) 416.55 (M+H), 414.24 (M-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; at 20℃; | SYNTHETIC EXAMPLE 1. Synthesis of 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-N3-(4-(2- (pyrrolidin-1-yl)ethoxy)phenyl)-1H-1 ,2,4-triazole-3,5-diamine- Diphenylcyanocarbonimidate (1.1 equiv) and <strong>[50609-01-3]4-(2-(pyrrolidin-1-yl)ethoxy)aniline</strong>(1 equiv) were stirred in /so-propyl alcohol at ambient temperature overnight. The resulting white precipitate was filtered and washed with /so-propyl alcohol and dried to yield (Z)-phenyl /V-cyano-N-(4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)carbamimidate. 3-Hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (82 mg, 0.36 mMol) and (Z)-phenyl lambda/'-cyano-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)carbamimidate (128 mg, 0.36 mMol) were suspended in isopropanol (3 ml_) and subjected to microwave irradiation (150 0C, 20 min). The precipitate which formed in the microwave vial was re- dissolved in hot isopropanol. The mixture was cooled to ambient temperature and then filtered to give 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1 ,2-c]pyridazin-3-yl)-/V3-(4-(2- (pyrrolidin-1-yl)ethoxy)phenyl)-1H-1 ,2,4-triazole-3,5-diamine, compound No.1, as a yellow solid, 23 mg. 1H NMR (CDCI3, 300 MHz) 7.90 (s, 1 H), 7.83 (t, 1 H), 7.43 (m, 3H), 7.29 (t, 1 H), 6.93 (d, 1 H), 6.83 (br s, 2H)1 6.39 (s, 1 H), 4.17 (m, 2H), 2.98 (m, 2H), 2.60-2.80 (m, 8H), 2.32 (m, 2H), 1.87 (m, 4H) ppm; MS (ES) 483.16 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In isopropyl alcohol; at 20℃; | SYNTHETIC PREPARATION 5. Synthesis of Phenyl N'-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H- benzo[7]annulene-2-yl)carbamimidate Compound of formula (C-1 ). A mixture of 7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-amine (1.7 g; 7.39 mmo) and diphenyl cyanocarboimidate (1.76 g, 7.39 mmol) in 20 mL of /sopropanol was stirred at ambient temperature overnight. The solid was filtered, washed with /sopropanol and ether and dried to give phenyl N'-cyano-N-(7-(pyrrolidin-1- yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate, as a white solid (2.2 g, 80%). MS (m/e): 375 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | Example 26(Z)-2-(3-(2-Cvano-3-methylmuuanidino)propyl)-5-f2.5-difluorophenylVN-methoxLambda'-N-methyl-2- plienv I- 1.3.4-thiadiazole-3(2 H)-carboxam ide[00247] Step A: Preparation of (ZV2-(3-(2-cvano-3-mcthylguanidino)propyD-5-(2.5- difluororhohcnvD-N-mcthoxy-N-mcthyl-2-rhohcnyl-1.3.4-lhiadia/olc-3(2H)-carboxamidc: 2-(3- aminopropyl)-5-(2,5-difluorophenyl)-N-niethoxj'-N-mcthyl-2-phenyl-J,3,4-thJadiazoIc-3(2H)- carboxamide (61 mg, 0.145 mmol, prepared as described in WO 2006/044825 Example 121) was weighed into a flask, then dissolved in 2.0 mL IPA. Tricthylamine (0.051 ml, 0.362 mmol) was then added, followed by diphenyl cyanocarboniniidate (69 mg, 0.290 mmol). The reaction was stirrcd at <n="58"/>230C for 1.5 hours, then transferred to a pressure tube,, followed by addition of 3 niL of methyl amine (2.4 ml, 4.9 mmol) in McOH. The reaction was then placed in a 600C bath for 12 hours and then concentrated. The residue was purified by flash column chromatography (3 -7 percent McOH/DCM) affording the desired product (27 nig, 37percent) as an orange foam film. MS ESl (+) tpi/z 502 (M+E) detected; 1H NMR (400 MHz, CDCl3) delta 7.52 (m, I H)5 7.46 (d, J = 8.0 Hz, 2H), 7.37 (m, 2H): 7.30 (m, IH), 7.10 (in, 2H), 5.70 (m Ih), 3.79 (s, 3H)5 3.40 (in, 3H), 3.16 (in, IH), 3.14 (s, 3H), 2.85 (s, 3H).2.45 (m. IH), 2.10 (in, I H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | Step C: Preparation of (Z)-2-cvaiio-l-(3-(5-(2.5-difltiorophcnyl)-2-phcnyl-3- pivaloyl-2.3-dihvdro-l.3.4-thiadia2psil-2-yl')propyl)-3-incthylguaiotaiidinc: l-(2-(3-aininopropyl)-5-<2,5- difluorophenyl)-2-phcnyl-l ,3,4-thiadiazol-3(2H)-yl)-2,2-dimcthylpropan-l -one (66 mg. 0.158 mmol) was weighed into a flask, then dissolved in 2.0 mL IPA. Triethylamine (0.055 ml, 0.38 mmol) was then added followed by diphenyl cyanocarboniniidate (75 mg, 0.316 mmol). The reaction was then stirred at room temperature for 1.5 hours. The reaction was then transferred to a scaled tube, followed by addition of 3 mL of methyl amine (2.4 ml, 4.9 mmol) in McOH. The reaction was then placed in a 6O0C bath for 12 hours. The reaction was then removed and concentrated, and the residue was purified by flash column chromatography (3 -7 percent McOH/ CH2CN) to provide the desired product (32 mg, 41percent) as a light orange foam film. MS ESl (+) m/z 499 (M+E) detected; 1H NMR (400 MHz, McOH) delta 7.48 (m, IH). 7.44 (d, J - 8.0 H/, 2H), 7.38 (m, 2H), 7.28 (m, 3H), 3.45 (m, IH)5 3.39 (m, IH), 3.27 (m, IH), 2.78 (s, 3H), 2.45 (m, IH), 1.99 (m, I H), 1.59 (m, I H)5 1.39 (ss 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Step C: Preparation of (ZV2-cvano-l -(3-(5-(2.5-difluorophenylV3-isobutyryl-2- phcnyl-2.3-dihvdro-1.3.4-thiadiaxol-2-\\i)propyl)-3-mcthyleuanidinc: I-(2-(3-aininopropyl)-5-(2,5- difluorophenyl)-2-phen\\i-l,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-l-onc (66 nig, 0.163 mmol) was weighed into a 25 mL I neck round bottom flask, then dissolved in 2.0 mL IPLambda. Tricthylamine (0.057 ml, 0.41 mmol) was then added followed by diphcnyl cyanocarbonimidate (78 mg, 0.327 mmol). The reaction was stirred at 230C for 1.5 hours. The reaction was then transferred to a pressure tube (20 mL), followed by addition of 3 mL of methyl amine (2.4 nil, 4.9 mmol) in McOH. The reaction was then placed in a 6O0C bath for 12 hours. The reaction was then removed and concentrated, and purified by flash column chromatography (3 -7 percent McOH/DCM) to provide die desired product (41 mg, 52percent) as a tan film. MS ESl (+) m/z 485 (M+E) detected; 1H NMR (400 MHz5 MeOH) 6 7.61 (m, IH), 7.45 (d, J = 7.8 Hz, 2H), 7.38 (m. 2H), 7.28 (m, 3H), 3.57 (m, IH), 3.35 (m, 2H), 3.13 (in, IH), 2.77 (s, 3H), 2.45 (m, IH), 2.08 (m, IH), 1.61 (m, IH), 1 19 (d, 3H. J = 6.2 Hz), 1.16 (d, 3H, ./= 7.2 H/). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Diisopropylethylamine (43.9 uL, 0.252 mmol) was added to a solution of (3R) 3-AMINO- 2-OXO-5-PHENYL-1-(2, 2, 2-HIFLUOROETHYL)-2, 3-DIHYDRO-LH-1, 4-benzodiazepine (84 mg, 0.252 mmol) and diphenyl N-cyanocarbonimidate (102 mg, 0.428 mmol) in methylene chloride (5 mL). The reaction was stirred at room temperature for 5 h, then quenched with 0.5 N sodium hydroxide. The methylene chloride was washed with water and saturated brine, and dried over sodium sulfate. The resulting solid was dissolved in 1-pentanol along with 3- (4-piperidinyl)-3, 4-dihydroquinazolin-2 (1H)-ONE hydrochloride (80.2 mg, 0.299 mmol) and diisopropylethylamine (52.2 uL, 0.299 mmol), and refluxed under argon overnight. The reaction was concentrated and purified by chromatography (silica gel, 0-5% methanol in methylene chloride gradient elution), providing the title compound (54.6 mg). MS 615 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In acetonitrile; at 50℃; | 6.6. Example 6(S)-N-(3-chlorophenyl)-N'-cyano-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboximidamide A. Preparation of phenyl N-3-chlorophenyl-N'-cyanocarbamimidate. Diphenyl-N-cyanocarbonimidate (2 g, 8.4 mmol) and 3-chloroaniline (0.88 ml, 8.4 mmol) were added to acetonitrile (20 ml). The solution was heated at 50° C. overnight and cooled to room temperature, resulting in precipitation of the product. The white crystalline solid was filtered to give phenyl N-3-chlorophenyl-N'-cyanocarbamimidate (2 g, 7.3 mmol, 88percent).1H NMR (400 MHz, chloroform-d) delta ppm 7.42-7.48 (m, 3H), 7.28-7.36 (m, 2H), 7.24-7.27 (m, 2H), 7.13-7.18 (m, 2H); MS (ES+) [M+H]+=272. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In acetonitrile; at 50℃; | 6.5. Example 5(S)-N-(3-bromophenyl)-N'-cyano-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboximidamide A. Preparation of phenyl N-3-bromophenyl-N'-cyanocarbamimidate. 3-bromoaniline (1.44 g, 8.4 mmol), diphenyl-N-cyanocarbonimidate (2 g, 8.4 mmol) were added to acetonitrile (20 ml). The solution was heated at 50° C. overnight and cooled to room temperature, resulting in precipitation of the product. The white crystalline solid was filtered to give phenyl N-3-bromophenyl-N'-cyanocarbamimidate (2 g, 6.3 mmol, 75percent).1H NMR (400 MHz, CHLOROFORM-d) delta ppm 7.59 (t, J=2.02 Hz, 1H), 7.42-7.47 (m, 2H), 7.40 (ddd, J=8.15, 1.45, 1.26 Hz, 1H), 7.31-7.36 (m, 2H), 7.24-7.29 (m, 2H), 7.13-7.18 (m, 1H); MS (ES+) [M+H]+=316, 318. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In acetonitrile; at 20 - 50℃; | 6.13. Example 13(S)-phenyl N-cyano-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carbimidate (S)-5-Methyl-4-(3-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine, from Example 1, step B, (347 mg, 1.5 mmol) and diphenyl-N-cyanocarbonimidate (357 mg, 1.5 mmol) were combined in acetonitrile (3 ml) and heated at 50° C. for 2 hours, then stirred overnight at room temperature. The reaction was concentrated under vacuum, and the residue was purified by flash chromatography (40 g SiO2, 0-5percent MeOH:CH2Cl2) to give (S)-phenyl N-cyano-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carbimidate (481 mg, 1.3 mmol, 86percent) as an off-white solid.1H NMR (400 MHz, MeOD) delta ppm 8.24 (s, 1H), 7.41-7.47 (m, 2H), 7.28 (t, J=7.5 Hz, 1H), 7.18 (d, J=7.6 Hz, 2H), 7.04 (d, J=1.0 Hz, 1H), 4.72 (br. s., 1H), 4.17-4.29 (m, 2H), 3.96 (dt, J=13.4, 1.9 Hz, 1H), 3.78 (ddd, J=13.5, 11.9, 3.4 Hz, 1H), 3.55 (dd, J=13.4, 4.0 Hz, 1H), 3.21-3.29 (m, 1H), 2.45 (d, J=1.0 Hz, 3H), 1.38 (d, J=6.8 Hz, 3H); MS (ES+) [M+H]+=376. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In acetonitrile; at 85℃; for 16h; | (R,E)-2-(4-(4-chlorobenzyl)-5-methyl-4H-1,2,4-triazol-3-yl)-N'-cyano-N-(4-(trifluoromethyl)phenyl)pyrrolidine-1-carboxamidine; Step A; <strong>[79463-77-7]Diphenyl cyanocarbonimidate</strong> (238 mg, 1.0 mmol) was dissolved in acetonitrile (2 ml). 4-(trifluoromethyl)aniline (0.116 ml, 1.0 mmol) was added and the mixture stirred at 85° C. for 16 h. The reaction mixture was evaporated and the residue purified by silica gel column chromatography (ethyl acetate/hexane gradient, 10-100percent EtOAc with 10percent of MeOH) to afford the desired product as a white amorphous solid (200 mg, 66percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In tetrahydrofuran; for 20h;Reflux; | A mixture of 3-aminobenzotrifiuoride (15 g, 93 mmol) and diphenyl cyanocarbon- imidate (22.2 g, 93 mmol) was heated at reflux in THF (100 ml) for 20 h. The r.m. was then concentrated under reduced pressure. H20 was then added and the resulting solid was filtered and dried in vacuo, yielding 20.7 g of intermediate 35 (72 percent). |
72% | In tetrahydrofuran; for 20h;Reflux; | A mixture of 3-aminobenzotrifluoride (15 g, 93 mmol) and diphenyl cyanocarbon-imidate (22.2 g, 93 mmol) was heated at reflux in THF (100 ml) for 20 h. The r.m. was then concentrated under reduced pressure. H2O was then added and the resulting solid was filtered and dried in vacuo, yielding 20.7 g of intermediate 35 (72percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In isopropyl alcohol; at 20℃; | A mixture of 1-(2-amino-6,7,8,9-tetrahydro-5/-/-benzo[7]annulene-7-yl)pyrrolidine (1.7 g; 7.39 mmo) and diphenyl cyanocarboimidate (1.76 g, 7.39 mmol) in 20 mL of /sopropanol was stirred at ambient temperature overnight. The solid was filtered, washed with /sopropanol and ether and dried to give phenyl N'-cyano-N-(7-(pyrrolidin-1- yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate, as a white solid (2.2 g, 80%). MS (m/e): 375 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | 5.30 N"-(3-Chloro-4-methyl-phenvn-N'-[2- (2.6-dioxo-piperidin-3-vn-l-oxo-2. 3-dihvdro-lH-isoindol-5-ylmethyll-N-cvano-guanidine; Step 1: Preparation of (3-chloro-4-methyl-phenyl)-carbamic acid phenyl ester.; 2-chloro-4-amino toluene (282 mg, 2 mmol) was dissolved in THF (10 mL). The mixture was added sodium hydride (128 mg, 3.2 mmol) and stirred at room temperature for 15 minutes. Dipehnyl N- cyano-carbonimidate (715 mg, 3.0 mmol) was added and the mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, quenched by saturated NH4Cl (10 mL), filtered and the solid was dried in oven to give (3-chloro-4-methyl-phenyl)-carbamic acid phenyl ester as solid (0.5 g, 87percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Specifically, a mixture of 4-benzyloxyaniline hydrochloride 2b (10.26 g, 43.5 mmol) and triethylamine (4.40 g, 43.5 mmol) in 2-propanol (100 ml.) was stirred at ambient temperature. After 10 min, diphenylcyanocarbimidate 1 (10.37 g, 43.5 mmol) was added and stirring continued at ambient temperature. After 3.5 h the solids that formed were collected by filtration, washing with 2-propanol, to afford 3b (14.64 g, 98percent) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) delta 10.68 (br s, 1H), 7.47-7.02 (m, 14H), 5.11 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Example 157 N-(3-Chloro-4-fluorophenyl)-4-[((E/Z)-(cyanoimino)[(4-methoxybenzyl)amino]-methylamino)methyl]-N'-hydroxy-1,2,5-oxadiazole-3-carboximidamide trifluoroacetate Into the reaction was dissolved 3-[4-(aminomethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one trifluoroacetate (30 mg, 0.07 mmol) in THF (0.74 mL). <strong>[79463-77-7]Diphenyl cyanocarbonimidate</strong> (20 mg, 0.08 mmol) and TEA (29 muL, 0.21 mmol) were added and the reaction was stirred at room temperature for 2 hr. A solution of sodium hydroxide in water (0.5 mL, 1 N) was added and the mixture was stirred at room temperature for 30 minutes. Acidification with acetic acid and purification by preparative LCMS gave the desired product (40 mg, 97percent). MF=C22H19ClF4N8O5; LCMS calculated for C22H20ClF4N8O5 (M+H)+: m/z=473.1. 1H NMR (400 MHz, CD3OD): delta 7.2 (m, 2H), 7.03 (m, 1H), 6.95 (m, 1H), 6.8 (m, 2H), 6.74 (m, 1H), 4.68 (s, 2H), 4.38 (s, 2H), 3.75 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In isopropyl alcohol; at 20℃; | a) (Z)-phenyl N'-cyano-N-(3,4-difluorophenyl)carbamimidate; To a solution of 3,4-difluoroaniline (646 mg, 5 mmol) in isopropanol (10 mL) was added <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (1.19 g, 5.00 mmol) and the suspension was stirred at room temperature over night. The precipitate was filtered off, washed with isopropanol and dried under reduced pressure to yield the title compound as a white solid (1.18 g, 86percent).MS ISP (m/e): 274.1 (100) [(M+H)+].1H NMR (DMSO-D6, 300 MHz): 6(ppm)=10.92 (s, 1H), 7.65 (m, 1H), 7.43 (m, 3H), 7.29 (m, 4H). |
86% | In isopropyl alcohol; at 20℃; | To a solution of 3,4-difluoroaniline (646 mg, 5 mmol) in isopropanol (10 mL) was added <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (1.19 g, 5.00 mmol) and the suspension was stirred at room temperature over nigth. The precipitate was filtered off, washed with isopropanol and dried under reduced pressure to yield the title compound as a white solid (1.18 g, 86percent).MS ISP (m e): 274.1 (100) [(M+H)+].1H NMR (DMSO-D6, 300 MHz): 5(ppm) = 10.92 (s, 1H), 7.65 (m, 1H), 7.43 (m, 3H), 7.29 (m, 4H). |
86% | In isopropyl alcohol; at 20℃; | To a solution of 3,4-difluoroaniline (646 mg, 5 mmol) in isopropanol (10 mL) was added <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (1.19 g, 5 mmol) and the suspension was stirred at room temperature over night. The precipitate was filtered off, washed with isopropanol and dried under reduced pressure to yield the title compound as a white solid (1.18 g, 86percent).MS ISP (m/e): 274.1 (100) [(M+H)+].1H NMR (DMSO-D6, 300 MHz): 5(ppm) = 10.92 (s, 1H), 7.65 (m, 1H), 7.43 (m, 3H), 7.29 (m, 4H). |
79% | In isopropyl alcohol; at 20 - 25℃; | 3,4-Difluoroaniline (3.00 g, 23.20 mmol) and <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (5.53 g, 23.20 mmol) were dissolved in 2-propanol (64.00 mL). The reaction mixture was stirred at RT overnight. The crude was evaporated in vacuo and purified by column chromatography (Hept:EtOAc 100:0 to 50:50) to afford (Z)-phenyl N-cyano-N-(3,4-difluorophenyl) carbamimidate as a white solid (5.00 g, 79percent). MS (ES+) m/z: 274.1 [M+Hj. |
79% | In isopropyl alcohol; at 20 - 25℃; | 3,4-Difluoroaniline (3.00 g, 23.20 mmol) and <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (5.53 g, 23.20 mmol) were dissolved in 2-propanol (64.00 mL). The reaction mixture was stirred at RT overnight. The crude was evaporated in vacuo and purified by column chromatography (Hept:EtOAc 100:0 to 50:50) to afford (Z)-phenyl N'-cyano-N-(3,4-difluorophenyl) carbamimidate as a white solid (5.00 g, 79percent). MS (ES+) m/z: 214.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | To solution of (R)-3-tert-butoxycarbonylaminopipiridine (154.0 g, 0.769 mol) in iPrOH (3.0 L) was added <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (183.2 g, 0.769 mol). The mixture was stirred at room temperature for 2.5 h. To the reaction mixture was added glycine ethyl ester*hydrochloride (536.7 g, 3.85 mol) at 0 °C, and the mixture was stirred at 80 °C for 6 h. After cooling to room temperature, the reaction mixture was diluted with AcOEt (1.4 L) and the precipitate was removed by filtration through a Celite pad. The filtrate was concentrated in vacuo, and the residue was diluted with 5percent sodium carbonate solution and extracted with CHCl3 three times. The combined organic layers were dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica-gel column chromatography to give 7 (249.2 g, yield 92percent) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) delta 5.68 (br s, 1H), 4.66 (br s, 1H), 4.28-4.19 (m, 4H), 3.81-3.34 (m, 5H), 2.05-1.51 (m, 4H), 1.45 (s, 9H), 1.30 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) delta 169.6, 160.0, 155.5, 117.1, 80.1, 61.8, 51.2, 47.3, 45.4, 44.6, 29.8, 28.3, 22.8, 14.1; HRMS (ESI) [M+H]+ calcd for C16H28N5O4 354.2136, found 354.2128; IR (ATR): 1743, 1685, 1575, 1531, 1440, 1390, 1365, 1309, 1243, 1197, 1162, 1051, 1031, 1018 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.7% | In dichloromethane; at 20 - 25℃; for 1h; | Step 1 : Preparation of C281. A solution of C26 (1 .68 g, 5 mmol) and diphenylcyano carbonimidate (1.19 g, 5 mmol) in dry dichloromethane (25 mL) was stirred at ambient temperature for 1 hour. The resulting product (C281 ) was collected by filteration, washed with a minimal amount of dichloromethane and air-dried. Concentration of the filtrate and trituration with methyl tert-butyl ether produced additional C281 which was combined with the previously isolated product. Yield 2.03 g, 4.23 mmol, 84.7percent. LCMS m/z 481.8 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) delta 9.30 (br s, 0.5 H), 8.77 (br s, 0.5 H), 8.00 - 8.07 (m, 1 H), 6.95 - 7.52 (m, 15 H), 6.01 (br s, 0.5 H), 5.93 (br s, 0.5 H), 5.24 (s, 2 H), 4.99 (d, J=6.63 Hz, 2 H), 4.34 (d, J=18.73 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In dichloromethane; at 20℃; for 24h; | <strong>[79463-77-7]Diphenyl cyanocarbonimidate</strong> (2.62 g, 10.68 mmol) in DCM (26 mL) was added to a sol. of l-(4-methoxyphenyl)-piperazine (5 g, 10.68 mmol) in DCM (94 mL). The r.m. was stirred at r.t. for 24 h. Water was added and the mixture was extracted with DCM. The separated organic layer was dried (MgS04), filtered and the solvent wasevaporated. Yield: 3.45 g of intermediate 8 (96 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In dichloromethane; at 20℃; for 1h; | <strong>[79463-77-7]Diphenyl cyanocarbonimidate</strong> (3.01 g, 12.25 mmol) in DCM (15 mL) was added to a sol. of l-(pyridin-4-yl)piperazine (2 g, 12.25 mmol) in DCM (32 mL). The r.m. was stirred at r.t. for 1 h. The solvent was evaporated. The residue was purified by flash column chromatography (eluent: DCM/MeOH from 100/0 to 90/10). The product fractions were collected and concentrated in vacuo. The residue was suspended in DIPE, filtered off and dried in the oven. Yield: 3.7 g of intermediate 9 (98 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 4h; | DIPEA (2.51 mL, 14.59 mmol) then <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (3.58 g, 14.59 mmol) in DCM (36 mL) were added to a sol. of intermediate 3 (2.6 g, 14.59 mmol) in DCM (126 mL). The r.m. was stirred at r.t. for 4 h. Water was added and the mixture was extracted with DCM. The separated organic layer was dried (MgS04), filtered and the solvent was evaporated. The residue was purified by flash column chromatography (eluent: DCM/MeOH from 100/0 to 95/5). The product fractions were collected and concentrated in vacuo. Yield: 2.84 g of intermediate 4 (60 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In dichloromethane; at 20℃; for 1h; | Diphenyl cyanocarbonimidate (2.77 g, 11.28 mmol) in DCM (15 mL) was added to a sol. of l-(4-pyridylmethyl)-piperazine (2 g, 11.28 mmol) in DCM (16 mL). The r.m. was stirred at r.t. for 1 h. The solvent was evaporated. The residue was purified by flash column chromatography (eluent: DCM/MeOH from 100/0 to 95/5). The product fractions were collected and concentrated in vacuo. The residue was suspended in DIPE, filtered off and dried in the oven. Yield: 3.5 g of intermediate 14 (96 %) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | In dichloromethane; at 20℃; for 24h; | <strong>[79463-77-7]Diphenyl cyanocarbonimidate</strong> (5.3 g, 21.56 mmol) in DCM (50 mL) was added to a sol. of l-(4methoxyphenyl)-2,2-dimethylpiperazine (5 g, 21.56 mmol) in DCM (190 mL). The r.m. was stirred at r.t. for 24 h. Water was added and the mixture was extracted with DCM. The separated organic layer was dried (MgS04), filtered and the solvent was evaporated. The residue was suspended in DIPE, filtered off and dried in the oven. Yield: 6.12 g of intermediate 1 (77 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; | DIPEA (3 mL, 17.41 mmol) then <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (2.14 g, 8.71 mmol) in DCM (21 mL) were added to a sol. of intermediate 6 (2 g, 8.71 mmol) in DCM (77 mL). The r.m. was stirred at r.t. for 1 h. Water was added and the mixture was extracted with DCM. The separated organic layer was dried (MgS04), filtered and the solvent was evaporated. The residue was purified by flash column chromatography (eluent:DCM/MeOH from 100/0 to 97.5/2.5). The product fractions were collected and concentrated in vacuo. Yield: 2.09 g of intermediate 7 (71 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; | DIPEA (1.52 mL, 8.82 mmol) then <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (1.08 g, 4.41 mmol) in DCM (11 mL) were added to a sol. of intermediate 12 (1 g, 4.41 mmol) in DCM (39 mL). The r.m. was stirred at r.t. for 1 h. The solvent was evaporated. Yield: 0.5 g of intermediate 13 (34 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.9% | In tetrahydrofuran; at 50℃;Inert atmosphere; | General procedure: 10.0 g (0.042 mol) of diphenyl-N-cyanocarbonate and 2.44 g (0.026 mol) of 4-aminopyridine were successively added to 10 mL of tetrahydrofuran (redistilled) under argon atmosphere with stirring, and the mixture was slowly heated to 50° C. and allowed to react at this temperature for 2.5 h. The solid was dissolved completely. The reaction was cooled to room temperature and stirred overnight. The reaction was stopped, placed in a refrigeratory for 20 min, filtered under reduced pressure to obtain 4.7 g of a solid. Yield 75.9percent. Compound 5b (1-cyano-2-phenyl-3-(pyrid-3-yl)-isourea) was synthesized by the method for preparing compound 5a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | General procedure: Example 1-177 [(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amino]-morpholin-4-yl-methylene-cyanamide To a stirred solution of 3-(aminomethyl)-7-chloro- l-phenylquinolin-4(lH)-one(intermediate D) (30 mg, 0.105 mmol) and N,N-diisopropylethylamine (40.9 mg, 55.2 muL·, 0.316 mmol) in NuMuRho (0.5 mL) was added diphenyl-cyanocarbonimidate (25.1 mg, 0.105 mmol). After 1 hr., morpholine (11.9 mg, 12.0 mu?^, 0.137 mmol) was added and the mixture was warmed to 120 I in a sealed microwave tube. After lhr., LCMS showed complete conversion to product. The mixture was allowed to cool to room temp, and the crude product was purified using preparative reverse-phase HPLC. The product [(7- chloro-4-oxo- 1 -phenyl- 1 ,4-dihydro-quinolin-3ylmethyl)-amino]-morpholin-4-yl- methylene-cyan- amide (25 mg, 56percent) was obtained as a white solid. 1H NMR (400 MHz, DMSO-cfo) 6 ppm 8.26 (d, 7=8.8 Hz, 1 H) 8.07 (s, 1 H) 7.61 - 7.76 (m, 3 H) 7.57 - 7.62 (m, 2 H) 7.48 - 7.53 (m, 1 H) 7.46 (dd, .7=8.8, 1.9 Hz, 1 H) 6.93 (d, 7=1.9 Hz, 1 H) 4.36 (d, 7=4.8 Hz, 2 H) 3.51 - 3.62 (m, 4 H) 3.35 - 3.46 (m, 4 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridine; In isopropyl alcohol; at 20℃; for 2h; | [00606] 147A. l-(3-Chloro-2-fiuorophenyl)-N-[(10R,14S)-5-[(lZ)- (cyanoimino)(phenoxy)methyl] amino } - 10-methyl-9-oxo-8 , 16- diazatricyclo[13.3.1.02'7]nonadeca-l(19),2(7),3,5,15,17-hexaen-14-yl]-5-methyl-lH- l,2,3-triazole-4-carboxamide: A mixture of Example 89 (Alternative, HC1 salt) (10 mg, 0.016 mmol), pyridine (10.42 mu?, 0.129 mmol) and <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (7.67 mg, 0.032 mmol) in 2-propanol (0.15 mL) was stirred in a pressure-tested vial at room temperature for 2 h. The reaction mixture was concentrated to give the product (11 mg, 99percent) as an oily solid. MS(ESI) m/z: 692 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine; In diethyl ether; at 20℃; for 1h; | To a mixture of 3-(2-aminoethyl)-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-1,3,5-triazinane -2,4-dion hydrochloride (200 mg, 0.413 mmol) and ethyl ether (8 mL) were added triethylamine (0.126 mL, 0.908 mmol) and diphenyl-N-cyanocarbonimidate (216 mg, 0.908 mmol), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(4-cyanoimino-4-phenoxy-3-aza butyl)-1,3,5-triazinane-2,4-dion (170 mg, Yield: 70percent) as colorless solid. 1H-NMR (delta ppm TMS/CDCl3): 1.40 (6H, d, J=6.0 Hz), 3.70 (2H, m), 4.07 (2H, m), 4.49 (1H, sept, J=6.0 Hz), 5.17 (2H, s), 6.47-6.61 (1H, m), 6.94 (1H, t, J=8.7 Hz), 7.16-7.20 (4H, m), 7.30-7.46 (4H, m), 7.79 (1H, m), 8.25 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine; In dichloromethane; at 20℃; for 2h; | 8-Azabicyclo[3.2.1]octan-3-one hydrochloride (0.50 mg, 3.09 mmol) was dissolved in DCM (30 mL). <strong>[79463-77-7]Diphenyl cyanocarbonimidate</strong> (0.81 g, 3.40 mmol) and Et3N (0.86 mL, 6.19 mmol) were added. The reaction mixture was stirred at rt for 2 h and then washed with water. The water layer was extracted with DCM (3×10 mL). The organic layers were combined, dried over Na2SO4, and evaporated to dryness. The crude product was purified by column chromatography (silica gel, heptane/EtOAc 0?50percent) to give 25 (754 mg, 91percent) as a white solid; LC-MS (m/z) 270 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | In acetonitrile; at 50℃; under 760.051 Torr;Inert atmosphere; | A solution of 3-bromoaniline (198 mg, 125 mu, 1.15 mmol, Eq: 1.00) and <strong>[79463-77-7]diphenyl cyanocarbonimidate</strong> (277 mg, 1.16 mmol, Eq: 1.01) in acetonitrile (5 mL) was heated at 50 overnight. The reaction mixture was concentrated and chromatographed (40 g Analogix, 100percent hex to 30percent EtO Ac/hex) to give 119 mg (33percent) of desired product as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60 mg | With triethylamine; In isopropyl alcohol; for 3h;Reflux; Sealed tube; | A mixture of EZ-Link Amine Peg2 Biotin (82 mgs, 0.218 mmoles, Fisher Scientific,Pittsburgh, PA) 1, diphenyl N-cyanocarbonimidate (58 mgs, 1.1equiv) 2, triethylamine (65 ml, 2 equiv) in 3ml of anhydrous isopropanol was heated at reflux in a sealed tube for 3 hours.The reaction mixture was cooled, concentrated, and redissolved in CH2Cl2/Methanol(9:1,1 ml) and purified by tlc eluting with CH2Cl2/Methanol(9:1). Purification gave 60 mgs of a colorless film 3. NMR (CD3OD, 400 MHz): delta 7.1-7.5(m, 5H), 4.46 (m, 1H), 4.28 (m, 1H), 3.4-3.7 (m, 11H), 3.36 (m, 2H), 3.2 (m,1H), 2.9 (m, 1H) 2.68 (d, 1H),2.2 (m, 2H), 1.2-1.76 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | In isopropyl alcohol; for 2.5h;Reflux; | 4-Aminopyridine (259 mg, 2.10 mmol) was dissolved in 2-propanol (5 mL) and diphenyl N-cyanocarbonimidate (500 mg, 2.1 mmol) was added. The mixture was heated at reflux for 2.5 h, cooled and the white precipitate was collected by filtration and washed with 2-propanol (2 x 10 mL). The white powder was dried overnight under vacuum to yield S11 (285 mg, 51percent). mp 208?210 °C; IR (ZnSe cell): 3082 (C?H), 2857 (C?H), 2180 (C?N), 1619 (C=N) cm-1; 1H NMR (300 MHz, CDCl3): delta 8.79 (1H, br s), 8.60?8.57 (2H, m), 7.47 (2H, t, J = 7.7 Hz), 7.39?7.36 (3H, m), 7.18 (2H, t, J = 7.9 Hz) ppm; 13C NMR (75 MHz, DMSO-d6): delta 161.0, 155.3, 155.2, 147.8, 138.5, 118.6, 109.5, 108.8, 108.2 ppm; HRMS (+ESI) m/z: [M+Na]+ Calcd for C13H10N4NaO 261.0747; Found 261.0745; LRMS (?ESI) m/z: 237 ([M?H]?, 100percent). |
47% | With triethylamine; In acetonitrile; at 20 - 80℃; for 14h; | A solution of 4-aminopidine (0.612 g, 6.5 mmol), diphenyl N-cyanocarbonimidate (1.540 g, 6.5 mmol) and triethylamine (1.0 mL, 6.5 mmol) in acetonitrile (15 mL) was stirred at 80 °C for 2h and illowed to stir at room temperature for 12 h. The reactionmixture was concentrated under reduced pressure to give a residue. The residue was diluted with ethyl acetate, washed with water. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanoll dichloromethane = 10/90) to give titled compound (0.700 g, 47 percent) as green thickmass.LCMS: mlz 239.10 [M+H] . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In isopropyl alcohol;Reflux; | To a stirred suspension of rac-allyl [3-(3,4-dichlorophenyl)-4,5-dihydro-lH-pyrazol-4-yl]carbamate (intermediate 7), 50.0 g (0.159 mol) in 2-propanol (860 mL) was added diphenyl N- cyanocarbonimidate, 38.0 g (0.159 mol). The reaction mixture was heated to reflux at which point the suspension dissolved into solution after a further 10 minutes at reflux a white precipitate formed. The reaction mixture was stirred at reflux for a further 1 hour before allowing to slowly cool to room temperature overnight. The precipitate was filtered, washing with diethyl ether (2 x 250 mL) and the resulting white solid was allowed to dry to yield rac-phenyl 4-{ [(allyloxy)carbonyl]amino}-N-cyano- 3-(3,4-dichlorophenyl)-4,5-dihydro-lH-pyrazole-l-carboximidate as a white solid, 48.6 g (67 percent). NMR (400 MHz, DMSO-d6): delta [ppm] = 4.13 (apparent d, IH), 4.47 (m, 3H), 5.14 (dd, 2H), 5.51- 5.63 (m, IH), 5.79-5.90 (m, IH), 7.23 (d, 2H), 7.30 (t, IH), 7.45 (t, 2H), 7.79 (br m, 2H), 7.97 (br s, IH), 8.19 (d, IH). LCMS (method 3): Rt 1.75 min MS (ESI): [M + H]+ = 458.0 |
67% | In isopropyl alcohol; for 1.17h;Reflux; | Intermediate 9 n/e-Plienyl 4- { [(allyloxy)carbonyl]amino } -N-cyano-3 -(3 ,4-dichlorophenyl)-4,5-dihydro- li7-pyrazole- 1-carboximidate To a stirred suspension of rac-allyl [3-(3,4-dichlorophenyl)-4,5-dihydro-l /-pyrazol-4-yl]carbamate (intermediate 7), 50.0 g (0.159 mol) in 2-propanol (860 mL) was added diphenyl Ar- cyanocarbonimidate, 38.0 g (0.159 mol). The reaction mixture was heated to reflux at which point the suspension dissolved into solution after a further 10 minutes at reflux a white precipitate formed. The reaction mixture was stirred at reflux for a further 1 hour before allowing to slowly cool to room temperature overnight. The precipitate was filtered, washed with diethyl ether (2 x 250 mL) and the resulting white solid was allowed to dry to yield rac-phenyl 4- { [(allyloxy)carbonyl]amino} -N-cyano- 3-(3,4-dichlorophenyi)-4,5-dihydro-lH-pyrazole-l -carboximidate as a white solid, 48.6 g (67 percent). 'H NMR (400 MHz, DMSO-d6): delta [ppm] = 4.13 (apparent d, 1H), 4.47 (m, 3H ). 5. 14 (dd, 2H), 5.5 1 - 5.63 (in, 1H), 5.79-5.90 (m, 1H), 7.23 (d, 2H), 7.30 (t, 1H), 7.45 (t, 2 H ). 7.79 (br m, 2H), 7.97 (br s, 1H), 8.19 (d, 1H). LCMS (method 3): Rt = 1.75 min MS (ESI): [M + Hf = 458.0 |
67% | In isopropyl alcohol;Reflux; | To a stirred suspension of roc-allyl [3-(3,4-dicUorophenyl)-4,5-dihydro-lH-pyi^ol-4-yl]carbamate (intermediate 4), 50.0 g (0.159 mol) in 2-propanol (860 mL) was added diphenyl N- cyanocarbonimidate, 38.0 g (0.159 mol). The reaction mixture was heated to reflux at which point the suspension dissolved into solution after a further 10 minutes at reflux a white precipitate formed. The reaction mixture was stirred at reflux for a further 1 hour before allowing to slowly cool to room temperature overnight. The precipitate was filtered, washing with diethyl ether (2 x 250 mL) and the resulting white solid was allowed to dry to yield rac-phenyl 4-[(allyloxy)carbonyl]amino}-N-cyano- 3-(3,4-dicUorophenyl)-4,5-dmydro-lH-pyrazole-1-carboximidate as a white solid, 48.6 g (67 percent). 1H NMR (400 MHz, DMSO-d6): delta [ppm] = 4.13 (apparent d, 1H), 4.47 (m, 3H), 5.14 (dd, 2H), 5.51- 5.63 (m, 1H), 5.79-5.90 (m, 1H), 7.23 (d, 2H), 7.30 (t, 1H), 7.45 (t, 2H), 7.79 (brm, 2H), 7.97 (br s, lH), 8.19 (d, 1H). LCMS (method 2): = 1.75 min. MS (ESI): [M + H]+ = 458.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; | 3-Hydrazinyl-2-naphthoic acid (1.213 g, 5.1 mmol) was addedportionwise to a stirred solution of diphenyl-N-cyanoimidocarbonate(1.190 g, 5 mmol) in DMF (20 mL) atroom temperature. This was followed by dropwiseaddion of triethylamine (16 mmol) over a period of15 min and the reaction mixture was stired overnight.Acidification of the mixture by ice cool conc. HCl was followed by its refluxing for 1?4 h. Upon cooling, themixture was poured into ice/water, the the precipitatefiltered off, washed with water and dried to give theproduct 1. Yield 1.230 g (75percent), brown amorphouspowder, mp 269?270°C (DMF). 1H NMR spectrum, delta,ppm: 7.28 br.t (1H, J = 7.5 Hz, H4'), 7.36 d.d (2H, J =8.2 Hz, H2',6'), 7.48 t.d (2H, J = 8.2 Hz, H3',5'), 7.61 br.t(1H, J = 7.5 Hz, H9), 7.72 br.t (1H, J = 7.5 Hz, H8),8.17 br.d (1H, J = 8 Hz, H10), 8.23 br.d (1H, J = 8 Hz,H7), 8.26 s (1H, H11), 8.89 s (1H, H6), 13.00 s (1H,NH). 13C NMR spectrum, deltaC, ppm: 110.7 (C11), 116.4(C6a), 119.5 (C2',6'), 124.9 (C4'), 126.3 (C6), 127.6 (C9),129.6 (C7,8), 129.7 (C5a), 129.8 (C3',5'), 130.6 (C10),131.7 (C10a), 135.7 (C11a), 147.5 (C3a), 154.2 (C1'),159.7 (C5), 165.8 (C2). HRMS (EI): Found, m/z:328.0978. C19H12N4O2. Calculated, m/z: 328.0960. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.9 mg | In tetrahydrofuran; for 3.5h;Reflux; | 86.63 mg diphenyl cyanocarbonimidate, 52.1 mg <strong>[23687-26-5]isoquinolin-6-amine</strong>, and 6 ml THF were added to a reaction bottle with thermal reflux for 3.5 hrs. After removing THF by vacuum, the residue was added to 10 ml EA. The precipitated solid was filtered to obtain 32.9 mg 1-cyano-3-(isoquinolin-6-yl)-2-phenylisourea. The intermediate was reacted with equivalent tert-butyl-2-(benzylamino)ethylcarbamate and 20 mg of DIPEA in 5 ml DMF at 110 C. for 18 hrs. After cooling, 1N NaOH was added and extracted twice with EA. After the combined EA layer was dried and concentrated by Na2SO4, 26.4 mg intermediate product was eluted out by a SiO2 column (EA/Hexane 4:1). The intermediate was added to 1.5 ml 6N HCl at room temperature with stirring overnight. After the reaction solution was evaporated under reduced pressure, 2 ml acetone/methanol (10:1) was added. The precipitate was filtered and washed with acetone, and then the solid was taken and evaporated in vacuum to give 18.7 mg of product. |
Tags: 79463-77-7 synthesis path| 79463-77-7 SDS| 79463-77-7 COA| 79463-77-7 purity| 79463-77-7 application| 79463-77-7 NMR| 79463-77-7 COA| 79463-77-7 structure
[ 25458-44-0 ]
4-(Methoxymethoxy)benzoic acid
Similarity: 0.52
[ 4421-09-4 ]
3,4-(Methylenedioxy)benzonitrile
Similarity: 0.53
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