Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 17794-48-8 | MDL No. : | MFCD00029782 |
Formula : | C10H8F3NO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZDGGJQMSELMHLK-UHFFFAOYSA-N |
M.W : | 247.17 | Pubchem ID : | 2777432 |
Synonyms : |
|
Num. heavy atoms : | 17 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 51.02 |
TPSA : | 66.4 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.31 cm/s |
Log Po/w (iLOGP) : | 1.23 |
Log Po/w (XLOGP3) : | 2.11 |
Log Po/w (WLOGP) : | 2.67 |
Log Po/w (MLOGP) : | 1.84 |
Log Po/w (SILICOS-IT) : | 1.78 |
Consensus Log Po/w : | 1.93 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.63 |
Solubility : | 0.576 mg/ml ; 0.00233 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.14 |
Solubility : | 0.181 mg/ml ; 0.000733 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.07 |
Solubility : | 0.211 mg/ml ; 0.000853 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.52 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H319 | 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 |
---|---|---|
95% | Stage #1: With sodium hydroxide In acetonitrile at 4 - 6℃; for 2.5 h; Stage #2: With hydrogenchloride In water; acetonitrile at 0 - 6℃; for 1.5 h; |
A 12-L 4-neck round bottom flask equipped with a thermocouple controller, mechanical stirrer, heating mantle, condenser and a nitrogen in/outlet adapter was charged with gycine (1, Alfa Aesar) (318 g; 4.19 mol), acetonitrile (1.2 L), and a solution of sodium hydroxide (5.31 L; 10.62 mo) and the mixture was cooled to 4° C. with stirring. A solution of 3-(trifluoromethyl)benzoyl chloride (2, Alfa Aesar) (885.0 g; 4.12 mol) (640 mL) in acetonitrile (0.75 L) (total 1.39 L) was added dropwise over 2 h while the internal temperature was maintained between 4-6° C., and the slightly orange-pinkish solution was stirred at 4° C. for an additional 30 min. The reaction was acidified to pH=3 with conc. 37percent HCl solution (400 mL added over 30 min) at 0-6° C., and stirred for 1 h at 0° C. (until a slightly yellowish suspension resulted). The solid was collected by filtration, washed with cold (0° C.) deionized ("D.I") H2O (300 mL*2), dried under air-suction for 2 h, and then placed in a drying oven at 60° C. under house vacuum (120 mmHg) for 20 h to afford pure 3 as an off-white solid. The filtrate was extracted with EtOAc (1 L*2), and the combined organic phases washed with brine (300 mL), and concentrated at 66° C. under house vacuum and then high vacuum (20 mmHg) to give crude product as an off-white waxy solid, which was triturated and sonicated with toluene (1 L) and stirred at 10° C. for 1 h. The resulting solid was collected by filtration, washed with hexanes (50 mL*2), dried in an vacuum oven at 50° C. under house vacuum to afford additional pure title compound, 3, as an off-white solid. The structure of 3 was confirmed with its 1H-NMR. |
91% | With hydrogenchloride; sodium hydroxide In acetonitrile at 0 - 3℃; for 1 h; | Manufacturing example 1: (3-trifluoromethylbenzoylamino)-acetic acid [Show Image] Glycine 0.763 g (10.16 mmol) were suspended in acetonitrile 20 ml and 2 M NaOH aqueous solution 12.7 ml (25.40 mmol, 2.5 eq.) were also added. After chilling at 0-3°C, 2.12 g (10.16 mmol, 1.0 eq.) of 3- (trifluoromethyl) -benzoyl chloride were diluted with 4 ml acetonitrile and added dropwise slowly to reaction mixture. After one hour agitation at the same temperature, pH was controlled to 2 to 3 with 3N hydrochloric acid aqueous solution. After keeping upright at room temperature, upper organic solution was separated, and lower aqueous solution was extracted with ethylacetate three times. Those organic solutions obtained as described above were brought all together, dried with anhydrous magnesium sulfate and concentrated, removing the solvent under decompression. Residues were solidified with toluene, filtered, washed with normal hexane and 2.28 g (91percent) target compound as white solid were yielded. 1H NMR(400MHz,DMSO-d6) 3.94(2H,d), 7.74(1H,t), 7.93(1H,d), 8.16(1H,d), 8.20(1H,s), 9.12(1H,t) |
91% | With hydrogenchloride; sodium hydroxide In water; acetonitrile at 0 - 3℃; for 1 h; | Manufacturing Example 1 (3-trifluoromethylbenzoylamino)-acetic acid Glycine 0.763 g (10.16 mmol) was suspended into acetonitrile 20 ml and 2M NaOH aqueous solution 12.7 ml (25.40 mmol, 2.5 eq.) was also added. After chilling at 0-3° C., 2.12 g (10.16 mmol, 1.0 eq.) of 3-(trifluoromethyl)-benzoyl chloride was diluted with 4 ml acetonitrile and was added dropwise slowly to reaction mixture. After one hour agitation at same temperature, pH was controlled to 2 to 3 with 3N hydrochloric acid aqueous solution. After keeping upright at room temperature, upper organic solution was separated, and lower aqueous solution was extracted with ethylacetate three times. Those organic solution obtained as above was brought all together, dried with anhydrous magnesium sulfate and concentrated removing its solvent under decompression. Residues was solidified with tolene, filtered, washed with normal hexane and 2.28 g (91percent) target compound as white solid was yielded. 1H NMR (400 MHz, DMSO-d6) 3.94 (2H, d), 7.74 (1H, t), 7.93 (1H, d), 8.16 (1H, d), 8.20 (1H, s), 9.12 (1H, t) |
90% | Stage #1: With sodium hydroxide In water; acetonitrile at 0℃; for 1 h; Stage #2: With hydrogenchloride In water; acetonitrile |
(3-Trifluoromethyl-benzoylamino)acetic acid. To a rapid stirring solution of glycine (15.014 g, 0.20 mol) in MeCN (400 mL) and 2 M NaOH (250 mL) at 0° C. was slowly added a solution of 3-(trifluoromethyl)-benzoyl chloride (41.714 g, 0.20 mol) in 75 mL of MeCN over 30 min. The cloudy yellow solution was stirred at 0° C. for 30 min. The reaction mixture was acidified with 3 M HCl to pH=3, followed by removal of MeCN on rotary evaporator. The resulting mixture was then extracted with EtOAc (400 mL.x.3). The combined organic layers were dried, filtered and concentrated to give a light yellow solid (48.53 g), which was triturated with toluene (500 mL). After filtration, the solid product was washed with cold toluene until the filtrate was colorless. After dried under high vacuum over the weekend, a white powder product: 44.60 g (90percent) was afforded. MS (M+H+)=248.1. 1H NMR (DMSO-d6) δ 12.70 (br s, 1 H), 9.17 (m, 1H), 8.20 (dd, 2H), 7.94 (dd, 1H), 7.78 (m, 1H), 3.97 (d, 2H). |
90% | Stage #1: With sodium hydroxide In water; acetonitrile at 0℃; for 1 h; Stage #2: With hydrogenchloride In water; acetonitrile |
Step A(3-Trifluoromethyl-benzoylamino)acetic acid. To a rapid stirring solution of glycine (15.014 g, 0.20 mol) in MeCN (400 mL) and 2 M NaOH (250 mL) at 0 °C was slowly added a solution of 3-(trifluoromethyl)-benzoyl chloride (41.714 g, 0.20 mol) in 75 mL of MeCN over 30 min. The cloudy yellow solution was stirred at 0 °C for 30 min. The reaction mixture was acidified with 3 M HCI to pH = 3, followed by removal of MeCN on rotary evaporator. The resulting mixture was then extracted with EtOAc (400 mL x 3). The combined organic layers were dried, filtered and concentrated to give a light yellow solid (48.53 g), which was triturated with toluene (500 mL). After filtration, the solid product was washed with cold toluene until the filtrate was colorless. After dried under high vacuum over the weekend, a white powder product: 44.60 g (90percent) was afforded. MS (M+H+) = 248.1. 1H NMR (DMSO-d6) δ 12.70 (br s, 1 H), 9.17 (m, 1 H), 8.20 (dd, 2H), 7.94 (dd, 1 H), 7.78 (m, 1 H), 3.97 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Trans-4-aminocyclohexanol hydrochloride (500 mg) was dissolved DMF (11 mL) prior to the addition of <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (815.0 mg) and 4-methylmorpholine (1.0 mL). After 5 min, BOP reagent (1.4 g) was added and the reaction was stirred overnight. Ethyl acetate was added, and the solution was washed with brine, 1N HCl, and saturated NaHCO3. The desired (trans)-N-[(4-hydroxy-cyclohexylcarbamoyl)-methyl]-3-trifluoromethyl-benzamide (480.5 mg) was then collected as a solid. MS found: (M+H)+=345.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N,N-diethyl-N-isopropylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In DMF (N,N-dimethyl-formamide); dichloromethane; at 20℃; for 12h; | Step 3 A sample of [(1R,3R,4S)-4-amino-3-(3-methyl-butyl)-cyclohexyl]-carbamic acid tert-butyl ester (50 mg, 0.18 mmol) was dissolved in 1:1 CH2Cl2/DMF (2 mL). The resultant solution was charged successively with N,N-diethylisopropylamine (0.16 mL, 0.9 mmol), <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (47 mg, 0.19 mmol, prepared as described in WO PCT 0250019), and BOP (116 mg, 0.26 mmol). The reaction was stirred for 12 h at RT and then partitioned between EtOAc and sat. NaHCO3; the aqueous phase was back extracted with EtOAc (1*). The organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography afforded {(1R, 3R,4S)-3-(3-methyl-butyl)-4-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-cyclohexyl}-carbamic acid tert-butyl ester (33 mg). MS found: (M+H)+=514.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 2.75h; | Step 3 A solution of tert-butyl (1R,3R,4S)-4-amino-3-(methoxymethyl)cyclohexylcarbamate (45 mg, assumed 0.163 mmol) in acetonitrile (1.5 mL) was treated sequentially with <strong>[17794-48-8]2-(3-(trifluoromethyl)benzamido)acetic acid</strong> (43 mg, 0.174 mmol, see PCT WO 0250019), diisopropylethylamine (61 muL, 0.348 mmol) and TBTU (62 mg, 0.192 mmol). The mixture was stirred at rt for 2.75 h, then was diluted with ethyl acetate, washed sequentially with 1.0 M aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluding with 1:3 v/v hexane-ethyl acetate, to provide tert-butyl (1R,3R,4S)-3-(methoxymethyl)-4-(2-(3-(trifluoromethyl)benzamido)acetamido)cyclohexylcarbamate as a white solid (48 mg). MS found: (M+H)+=488.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 0 - 20℃; | (8a) (2S, 3S)-(2-Amino-3-hydroxy-hex-4-ynyl)-carbamic acid benzyl ester (2.53 g, prepared as in WO PCT 0250019) was dissolved in CH2Cl2 (50 ml) and 4-methylmorpholine (2.53 ml) and cooled to 0 C. prior to the addition of <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (1.49 g) and HATU (2.23 g). After the reaction was stirred overnight at room temperature, the CH2Cl2 was removed and EtOAc was added. The organic layer was washed with saturated NH4Cl solution (aq) brine, dried, filtered, and concentrated. Flashed chromatography of the resulting residue gave (2S, 3S)-{3-hydroxy-2-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-hex-4-ynyl}-carbamic acid benzyl ester (1.3 g). MS found: (M+H)+=492.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In DMF (N,N-dimethyl-formamide); dichloromethane; | A sample of (1s,4s)-4-(aminomethyl)-N,N-dibenzylcyclohexanamine (0.475 g) was taken through the procedure of Example 1h, Step 1 to give (1s,4s)-N,N-dibenzyl-4-((isopropyl(methyl)amino)methyl)cyclohexanamine (280 mg). This material was hydrogenated according to the procedure of Example 1h, Step 4 to give (1s,4s)-4-((isopropyl(methyl)amino)methyl)cyclohexanamine. The entirety of this sample (95 mg) was dissolved in methylene chloride (5 mL) and DMF (2 mL). The resultant solution was charged successively with <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (127 mg), PyBOP (268 mg), and triethylamine (0.14 mL). The mixture was stirred overnight and diluted with methylene chloride before being washed with water thrice. The organic phase was then washed with sat. sodium bicarbonate, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by RP-HPLC to afford the title compound as an oil (5 mg). MS found: (M+H)+=414. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; HATU; In dichloromethane; at 0 - 20℃; | (8a) (2S, 3S)- (2-AMINO-3-HYDROXY-HEX-4-YNYL)-CARBAMIC acid benzyl ester (2.53 g, prepared as in WO PCT 0250019) was dissolved in CH2CL2 (50 ml) and 4-methylmorpholine (2.53 ml) and cooled to 0 C prior to the addition of (3- TRIFLUOROMETHYL-BENZOYLAMINO)-ACETIC acid (1.49 g) and HATU (2.23 g). After the reaction was stirred overnight at room temperature, the CH2CL2 WAS removed and EtOAc was added. The organic layer was washed with saturated NH4Cl solution (aq) brine, dried, filtered, and concentrated. Flashed chromatography of the resulting residue gave (2S, 3S)- {3-HYDROXY-2- [2- (3-TRIFLUOROMETHYL-BENZOYLAMINO)- ACETYLAMINO]-HEX-4-YNYL}-CARBAMIC acid benzyl ester (1.3 g). MS found : (M+H) + = 492. 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; | tert-Butyl [(3S)-1-([3-(Trifluoromethyl)benzoyl]amino}acetyl)pyrrolidin-3-yl]carbamate. To a solution of the carboxylic acid (2.7 g, 11 mmol) from step A and tert-butyl (3S)-pyrrolidin-3-ylcarbamate (2.0 g, 11 mmol) in DMF (30 mL) cooled in an ice bath was added BOP (5 g, 11 mmol) followed by triethylamine (3 mL, 22 mmol). The mixture was allowed to warm to temperature and stirred overnight. Ethyl acetate (150 mL) was added. The resulting solution was washed with NaHCO3 and brine each three times, dried over MgSO4 and concentrated. Chromatography on silica gel eluting with EtOAc provided 4.4 g (96%) of the desired product. MS (M-Boc+H)+ 316. |
96% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃;cooling with ice; | Step BBocHN'tert-Butyl [(3S)-1 -([3-(Trifluoromethyl)benzoyl]amino}acetyl)pyrrolidin-3-yl]carbamate. To a solution of the carboxylic acid (2.7 g, 1 1 mmol) from step A and tert-butyl (3S)-pyrrolidin-3-ylcarbamate (2.0 g, 1 1 mmol) in DMF (30 mL) cooled in an ice bath was added BOP (5 g, 1 1 mmol) followed by triethylamine (3 mL, 22 mmol). The mixture was allowed to warm to temperature and stirred overnight. Ethyl acetate (150 mL) was added. The resulting solution was washed with NaHC03 and brine each three times, dried over MgS04 and concentrated. Chromatography on silica gel eluting with EtOAc provided 4.4 g (96%) of the desired product. MS (M-Boc+H)+ 316. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 4h; | (3R,5R)-5-Methylpyrrolidin-3-ol hydrochloride (1.80 g, 13 mmol) was dissolved in dichloromethane (50 mL) and diisopropylethylamine (2.1 mL, 12.0 mmol) under nitrogen. (3-Trifluoromethyl-benzoylamino)-acetic acid (2.93 g, 11.85 mmol) was added followed by EDC (3.41 g, 17.8 mmol) and the mixture was stirred at room temperature for four hours. The mixture was diluted with NH4Cl/H2O and extracted twice with ethyl acetate. The combined extracts were washed with NaHCO3/H2O and brine, dried over MgSO4, filtered and concentrated to give a dark orange oil. Chromatography on silica gel eluting with ethyl acetate to 5% methanol/ethyl acetate gave the coupled product as a pale orange solid, 3.19 g (81%, 2 steps). LC/MS (M+H)+ m/z=331.1. 1H NMR (CDCl3, major rotamer) delta 8.12 (s, 1H), 8.01 (d, 1H), 7.76 (d, 1H), 7.57 (t, 1H), 7.50 (m, 1H), 4.56 (m, 1H), 4.34 (m, 1H), 4.23 (m, 1H), 4.11 (m, 1H), 3.61 (dd, 1H), 3.51 (d, 1H), 2.71 (d, 1H), 2.17 (m, 1H), 1.81 (m, 1H), 1.32 (d, 3H). |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 4h;Inert atmosphere; | Step GN-{2-[(2f?,4f?)-4-Hydroxy-2-methylpyrrolidin-1 -yl]-2-oxoethyl}-3-(trifluoro- methyl)benzamide. (3f?,5f?)-5-Methylpyrrolidin-3-ol hydrochloride (1.80 g) was dissolved in dichloromethane (50 mL) and diisopropylethylamine (2.1 mL, 12.0 mmol) under nitrogen. (3- Trifluoromethyl-benzoylamino)-acetic acid (2.93 g, 1 1.85 mmol) was added followed by EDC (3.41 g, 17.8 mmol) and the mixture was stirred at room temperature for four hours. The mixture was diluted with NH4CI/H20 and extracted twice with ethyl acetate. The combined extracts were washed with NaHC03/H20 and brine, dried over MgS04, filtered and concentrated to give a dark orange oil. Chromatography on silica gel eluting with ethyl acetate to 5% methanol/ethyl acetate gave the coupled product as a pale orange solid, 3.19 g (81 %, 2 steps). LC/MS (M+H)+ m/z = 331 .1. 1H NMR (CDCI3, major rotamer) delta 8.12 (s, 1 H), 8.01 (d, 1 H), 7.76 (d, 1 H), 7.57 (t, 1 H), 7.50 (m, 1 H), 4.56 (m, 1 H), 4.34 (m, 1 H), 4.23 (m, 1 H), 4.1 1 (m, 1 H), 3.61 (dd, 1 H), 3.51 (d, 1 H), 2.71 (d, 1 H), 2.17 (m, 1 H), 1.81 (m, 1 H), 1.32 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 4.5h;Heating / reflux; | (2S,4R)-4-(Benzyloxy)-2-isopropylpyrrolidine (0.410 g, 1.90 mmol) was dissolved in dichloromethane (30 mL) under nitrogen. (3-Trifluoromethylbenzoylamino)-acetic acid (0.462 g; 1.90 mmol) was added followed by EDC (0.394 g, 2.06 mmol) and the mixture was stirred at room temperature-overnight. LC/MS revealed the reaction was not yet complete. More (3-Trifluoromethyl-benzoylamino)-acetic acid (0.12 g, 0.48 mmoles) and more EDC (0.30 g, 1.6 mmoles) were added and stirring continued for 3 hours at room temperature, then at reflux for 1.5 hours. The mixture was chromatographed on silica gel eluting with 30% ethyl acetate/hexane to provide 0.66 g (79%) of the coupled product as a colorless oil. LC/MS (M+H)+ m/z=449.2; 1H NMR (CDCl3) delta 8.03 (m, 1H), 7.76 (m, 1H), 7.58 (m, 2H), 7.34 (m, 5H), 4.52 (m, 2H), 4.03-4.34 (m, 4H), 3.65 (m, 1H), 3.48 (m, 1H), 2.54 (m, 1H), 2.12 (m, 1H), 1.92 (m, 1H), 0.92 (d, 3H), 0.77 (d, 3H). |
79% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;Inert atmosphere; Reflux; | Step FN-{2-[(2S,4f?)-4-Benzyloxy-2-isopropylpyrrolidin-1-yl]-2-oxoethyl}-3- (trifluoromethyl)benzamide. (2S,4f?)-4-(Benzyloxy)-2-isopropylpyrrolidine (0.410 g, 1 .90 mmol) was dissolved in dichloromethane (30 mL) under nitrogen. (3-Trifluoromethyl- benzoylamino)-acetic acid (0.462 g, 1 .90 mmol) was added followed by EDC (0.394 g, 2.06 mmol) and the mixture was stirred at room temperature overnight. LC/MS revealed the reaction was not yet complete. More (3-Trifluoromethyl-benzoylamino)-acetic acid (0.12 g, 0.48 mmoles) and more EDC (0.30 g, 1 .6 mmoles) were added and stirring continued for 3 hours at room temperature, then at reflux for 1 .5 hours. The mixture was chromatographed on silica gel eluting with 30% ethyl acetate/hexane to provide 0.66 g (79%) of the coupled product as a colorless oil. LC/MS (M+H)+ m/z = 449.2; 1H NMR (CDCI3) delta 8.03 (m, 1 H), 7.76 (m, 1 H), 7.58 (m, 2H), 7.34 (m, 5H), 4.52 (m, 2H), 4.03-4.34 (m, 4H), 3.65 (m, 1 H), 3.48 (m, 1 H), 2.54 (m, 1 H), 2.12 (m, 1 H), 1 .92 (m, 1 H), 0.92 (d, 3H), 0.77 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 18.5h; | Part F: Preparation of 4-endo-4-propyl-5-[2-(3-trifluoromethylbenzoylamino)acetylamino]octahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester A solution of 4-endo-5-amino-4-propyloctahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (48 mg, 186 mumol) in acetonitrile (1 mL) was treated sequentially with (3-trifluoromethylbenzoylamino)acetic acid (46 mg, 186 mumol), diisopropylethylamine (65 muL, 372 mumol) and TBTU (66 mg, 204 mumol). The mixture was stirred at room temperature for 18.5 h, then was diluted with ethyl acetate. The solution was washed sequentially with 1N aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and saturated aqueous sodium chloride, then was dried over sodium sulfate and concentrated under vacuum. The residue was purified by preparative radial thin layer chromatography to provide a pale tan glassy foam (61 mg, 66%) which was a mixture of diastereomers (ca. 3:1) by NMR. 1H NMR (400 MHz, CDCl3) delta 8.19 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.68 (m, 1H), 7.43 (bm, ca. 0.25H), 7.31 (bm, ca. 0.75H), 6.52 (bm, ca. 0.25H), 6.31 (bm, ca. 0.75H), 4.3-4.0 (m, 3H), 3.52 (m, 2H), 3.38 (m, 2H), 2.9-2.6 (m, 1H), 2.5-2.3 (m, 2H), 1.59 (m, 2H), 1.54 (s, 9H), 1.36 (m, 4H), 0.96 (m, 3H). MS (ES+) m/z 498.20 (M+H+), 398.20 ([M+H-COOC4H9]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; trifluoroacetic acid; In hexane; dichloromethane; ethyl acetate; N,N-dimethyl-formamide; | (27c) 4-Chlorobenzoic acid (258 mg) was dissolved in DMF (8 mL) prior to the addition of Hunig's base (1.0 mL). After cooling to 0 C., BOP Reagent (729 mg) was added. This was stirred for 15 min before (1S,2R)-1-(N-(t-butoxycarbonyl))-1,2-cyclopentanediamine, (27b), (300 mg) was added as a DMF solution (2 mL). The resulting mixture warmed to rt and was stirred overnight. EtOAc was added along with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO3 solution, and brine. The EtOAc was dried (MgSO4), filtered, and concentrated. The resulting material was dissolved in CH2Cl2 (10 mL) and cooled to 0 C. TFA (1.2 mL) was added and the reaction was stirred for 2 h. This solution was concentrated prior to the addition of DMF (8 mL). After cooling to 0 C., Hunig's base (1 mL) and <strong>[17794-48-8][[3-(trifluoromethyl)benzoyl]amino]acetic acid</strong> (386 mg) were added. BOP Reagent (655 mg) was added next, and the mixture was stirred overnight. EtOAc was added along with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO3 solution, and brine. The EtOAc was dried (MgSO4), filtered, and concentrated. This was stirred in 1:1 EtOAc/hexane and then filtered to give the title benzamide N-[2-[[(1S,2R)-2-[(4-chlorobenzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide (310 mg) as a solid. MS found: (M+H)+=468.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine; In dichloromethane; water; | Reference Example 29 Preparation of 1-(tert-Butoxycarbonyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine N-{3-(Trifluoromethyl)benzoyl}glycine (4.22 g, 17.0 mmol), EDCI (4.25 g, 22.1 mmol), 1-hydroxybenzotriazole hydrate (2.99 g, 22.1 mmol) and Et3N (1.72 g) were added to a solution of 1-(tert-butoxycarbonyl)-4-(aminomethyl)piperidine (4.03 g) in dry CH2Cl2 (200 mL). The reaction mixture was stirred at 25 C. for 20 h. H2O (100 mL) was added to the reaction mixture and the mixture was extracted with CH2Cl2 (2*50 mL). The combined extracts were washed with H2O (2*50 mL), brine (50 mL) and dried (MgSO4). The solvent was removed under reduced pressure to afford an yellow oil which was purified by column chromatography (SiO2, 70% EtOAc-hexane) to give 1-(tert-butoxycarbonyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine as a white solid (6.39 g, 85%): 1H-NMR (CDCl3, 300 MHz) delta1.4 (s, 9H), 1.0-1.8 (m, 5H), 2.6-2.8 (m, 2H), 3.15-3.3 (m, 2H), 4.0-4.3 (m, 4H), 6.6-6.7 (m, 1H), 7.64 (s, 1H), 7.60 (dd, 1H, J=7.2, 7,2 Hz), 7.79 (d, 1H, J=7,2 Hz), 8.0 (d, 1H, J=7.2 Hz), 8.11 (s, 1H); The purity was determined by RPLc/MS (97); ESI/MS m/e 444.3 (M++H, C21H28F3N3O4). |
85% | With triethylamine; In dichloromethane; water; | [Reference Example 29] Synthesis of 1-(tert-butoxycarbonyl)-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine N-[3-(Trifluoromethyl)benzoyl]glycine (4.22 g, 17.0 mmol), EDCI (4.25 g, 22.1 mmol), 1-hydroxybenzotriazole hydrate (2.99 g, 22.1 mmol) and triethylamine (1.72 g) were added to an anhydrous dichloromethane (200 mL) solution of 1-(tert-butoxycarbonyl)-4-(aminomethyl)piperidine (4.03 g). The resulting reaction mixture was stirred at 25 C for 20 hours, and H2O (100 mL) was then added to the mixture. The obtained mixture was extracted with dichloromethane (50 mL * 2). The extracts were combined, washed with H2O (50 mL * 2) and brine (50 mL), dried (over MgSO4) and concentrated to thereby afford a yellow oil. The obtained crude product was purified by column chromatography (SiO2,70% ethyl acetate-hexane) to provide 1-(tert-butoxycarbonyl)-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine as a white solid (6.39 g, 85%). 1H NMR(CDCl3, 300MHz) delta 1.4 (s, 9H), 1.0-1.8 (m, 5H), 2.6-2.8 (m, 2H), 3.15-3.3 (m, 2H), 4.0-4.3 (m, 4H), 6.6-6.7 (m, 1H), 7.64 (s, 1H), 7.60 (dd, 1H, J = 7.2, 7.2 Hz), 7.79 (d, 1H, J = 7.2 Hz), 8.0 (d, 1H, J = 7.2 Hz), 8.11 (s, 1H). The purity was determined by RPLC/MS (97%). ESI/MS m/e 444.3 (M++H, C21H28N3O4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane;Product distribution / selectivity; | [00202] To a solution of afford benzyl 4-[(3/?)-3-aminopyrrolidin-l-yl]azerhoane-l-carboxylate (bis- hydrochloride salt) (1.09 g, 2.79 mmol) in methylene chloride (15 mL) was added [3- (trifluoromethyl)benzoyl]amino} acetic acid (1.04 g, 4.188 mmol), HOBt (0.755 g, 5.59 mmol), EDCI (1.07 g, 5.59 mmol) and triethylamine (1.17 mL, 8.38 mmol). The reaction mixture was stirred overnight, and to the mixture was added NaHCO3 (sat. aq., 50 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford benzyl 4- {(37?)-3-[([3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-l-yl}azepane-l-carboxylate (0.875 g, 57%) as a white solid.[00203] Diastereomer A 1H-NMR (CD3OD) delta: 1.52-2.00 (m, 7H), 2.14-2.30 (m, IH), 2.24-2.42 (m, 2H), 2.46-2.59 (m, IH), 2.60-2.72 (m, IH), 2.76-2.90 (m, 2H), 3.28-3.46 (m, 2H), 3.46-3.60 (m, 2H), 3.63-3.74 (m, IH), 4.02 (d, J = 2.4 Hz, 2H), 4.30-4.40 (m, IH), 5.11 (dd, / = 12.6, 2.1 Hz, IH) 5.14 (dd, J = 17.1, 4.5 Hz, IH), 7.26-7.40 (m, 5H), 7.68 (t, J = 7.5 Hz, IH), 7.86 (d, J = 7.8 Hz, IH), 8.14 (d, 7 = 7.8 Hz, IH), 8.21 (s, IH), MS m/z: 547 (M + 1).[00204] Diastereomer B 1H-NMR (CD3OD) delta: 1.40-1.78 (m, 4H), 1.80-2.04 (m, 3H), 2.12-2.30 (m, IH), 2.24-2.39 (m, 2H), 2.46-2.62 (m, 2H), 2.72-2.88 (m, 2H), 3.28-3.46 (m, 2H), 3.46-3.60 (m, 2H), 3.63-3.74 (m, IH), 4.02 (s, 2H), 4.28-4.42 (m, IH), 5.07-5.18 (m, 2H), 7.26-7.40 (m, 5H), 7.69 (t, J = 7.5 Hz, IH), 7.86 (d, J = 7.8 Hz, IH), 8.14 (d, J = 7.8 Hz, IH), 8.22 (s, IH), MS m/z: 547 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane;Product distribution / selectivity; | [00202] To a solution of afford benzyl 4-[(3/?)-3-aminopyrrolidin-l-yl]azerhoane-l-carboxylate (bis- hydrochloride salt) (1.09 g, 2.79 mmol) in methylene chloride (15 mL) was added [3- (trifluoromethyl)benzoyl]amino} acetic acid (1.04 g, 4.188 mmol), HOBt (0.755 g, 5.59 mmol), EDCI (1.07 g, 5.59 mmol) and triethylamine (1.17 mL, 8.38 mmol). The reaction mixture was stirred overnight, and to the mixture was added NaHCO3 (sat. aq., 50 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford benzyl 4- {(37?)-3-[([3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidin-l-yl}azepane-l-carboxylate (0.875 g, 57%) as a white solid.[00203] Diastereomer A 1H-NMR (CD3OD) delta: 1.52-2.00 (m, 7H), 2.14-2.30 (m, IH), 2.24-2.42 (m, 2H), 2.46-2.59 (m, IH), 2.60-2.72 (m, IH), 2.76-2.90 (m, 2H), 3.28-3.46 (m, 2H), 3.46-3.60 (m, 2H), 3.63-3.74 (m, IH), 4.02 (d, J = 2.4 Hz, 2H), 4.30-4.40 (m, IH), 5.11 (dd, / = 12.6, 2.1 Hz, IH) 5.14 (dd, J = 17.1, 4.5 Hz, IH), 7.26-7.40 (m, 5H), 7.68 (t, J = 7.5 Hz, IH), 7.86 (d, J = 7.8 Hz, IH), 8.14 (d, 7 = 7.8 Hz, IH), 8.21 (s, IH), MS m/z: 547 (M + 1).[00204] Diastereomer B 1H-NMR (CD3OD) delta: 1.40-1.78 (m, 4H), 1.80-2.04 (m, 3H), 2.12-2.30 (m, IH), 2.24-2.39 (m, 2H), 2.46-2.62 (m, 2H), 2.72-2.88 (m, 2H), 3.28-3.46 (m, 2H), 3.46-3.60 (m, 2H), 3.63-3.74 (m, IH), 4.02 (s, 2H), 4.28-4.42 (m, IH), 5.07-5.18 (m, 2H), 7.26-7.40 (m, 5H), 7.69 (t, J = 7.5 Hz, IH), 7.86 (d, J = 7.8 Hz, IH), 8.14 (d, J = 7.8 Hz, IH), 8.22 (s, IH), MS m/z: 547 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | [00299] To a solution of (3S,45)-4-amino-l-(tetrahydro-2eta-pyran-4-yl)pyrrolidin-3-ol (0.20Og, 1.07 mmol) in DCM (2 mL), was added 2-<strong>[17794-48-8][[3-(trifluoromethyl)benzoyl]amino]acetic acid</strong> (0.279g, 1.13mmol), EDCI (0.31Og, 1.60 mmol), 1-hydroxybenzotriazole (0.22Og, 1.60 mmol) and N,N-diisopropylethylamine (0.6 mL, 3.00 mmol). The mixture was stirred at RT overnight, and the organic phase was washed with sat. NaHCO3 solution, dried over MgSO4, concentrated, and subjected to flash chromatography (EtOAc :MeOH:Et3N 9:1:0.1) to generate the title compound as a light yellow powder (0.180 g, 42%). 1H- NMR (DMSO) delta: 1.32-1.57 ( m, 2H), 1.73-1.92 (m, 2H), 2.32-2.40 (m, IH), 2.49-2.62 (m, 2H), 2.99-3.12 (m, 2H), 3.25-3.47 (m, 2H), 3.87-4.01 (m, 2H), 4.07 (s, 2H), 4.12-4.19 (m, 2H), 7.66 (t, J = 6.0 Hz, IH), 7.88 (d, J = 8.1 Hz, IH), 8.15 (d, J = 6.7 Hz, IH), 8.22 (s, IH). MS m/z: 416 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; | [00327] To a solution of rel-(3R,4R)-4-ethoxy-l-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine (36 mg, 0.168 mmol) in DCM was added { [3-(trifluoromethyl)benzoyl] amino} acetic acid (41.5 mg, 0.168 mmol), etaATU (76.7 mg, 0.202 mmol), etaOBt (27.2 mg, 0.202 mmol) and DIPEA (0.044 mL, 0.252 mmol) and was stirred at RT overnight. The resulting crude mixture was subjected to flash chromatography (15%MeOeta, 1% NH4OH in EtOAc) to afford the title compound (38 mg, 51%) as a white solid. 1H-NMR (CDCl3) delta: 1.17 (t, J = 6.9 Hz, 3H), 1.40-1.60 (m, 2H), 1.65-1.82 (m, 2H), 2.22- 2.40 (m, 2H), 2.63-2.80 (m, 2H), 3.22-3.51 (m, 4H), 3.63-3.80 (m, 2H), 3.89-4.00 (m, 2H), 4.10-4.20 (m, 2H), 4.24-4.37 (m, IH), 6.45-6.58 (m, IH), 7.20-7.30 (m, IH), 7.56 (t, / = 8.1 Hz, IH), 7.76 (d, J = 7.5 Hz, IH), 7.99 (d, J = 7.8 Hz, IH), 8.08 (s, IH). MS m/z: 444 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; | [00307] To the solution of benzyl rel-(3R,4R)-3-(aHyloxy)-4-[(tert- butoxycarbonyl)amino]pyrrolidine-l-carboxylate (200 mg, 0.53 mmol) in MeOH (5 mL) was added HCl (4.0 M in 1, 2 dioxane, 15 mL) dropwise. The reaction mixture was stirred at room temperature for 6 h, and the reaction mixture was concentrated under reduced pressure and the crude product was used in the following stop without further purification. The crude product was dissolved in DCM (5 mL). To this solution was added TEA (33.7 mg, 1.61 mmol), <strong>[17794-48-8][3-(trifluoromethyl)benzoyl]amino}acetic acid</strong> (200 mg, 0.81 mmol), EDC (205 mg, 1.07 mmol) and HOBt (145 mg, 1.07 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched by adding water (5 mL). The mixture was extracted with EtOAc (5 mL x 3). The organic layers were combined, dried over MgSO4, filtered, concentrated under reduced pressure and subjected to column chromatography (EtOAc:hexanes, 1:3 to 1:1) to afford benzyl rel-(3 R,4R)-3-(allyloxy)-4-[([3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidine-l-carboxylate (222.5 mg (82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; | To the <n="93"/>product was added 4N HCl (in dioxane, 5 mL) and the mixture was stirred 2 hours. AU volatiles were removed, and the salt was dissolved in DMF (5 mL), to which was added [3- (trifluoromethyl)benzoyl]amino}acetic acid (174 mg, 0.705 mmol), HATU (268 mg, 0.705 mmol), diisopropylethylamine (246 muL, 1.41 mmol) and HOBt (95 mg, 0.705 mmol) and the mixture was allowed to stir overnight. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography to afford benzyl rac- (3 R,4R)-3-(benzyloxy)-4-[( { [3-(trifluoromethyl)benzoyl]amino } acetyl)amino]pyrrolidine-l -carboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 4 A dry sample of <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (37 mg, 0.15 mmol) was dissolved in 1.1 mL of the amine/DIEA/DMAP solution from Step 3 above. The resultant solution was charged with BOP (0.3 mL of a 0.5 M solution in DMF) and stirred for 12 h at RT. The reaction was partitioned between EtOAc and sat. NaHCO3, and the aqueous phase was back extracted with EtOAc (1*). The organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by reverse phase-HPLC to afford the TFA salt of N-(2-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide as a white powder (16 mg) after lyopholization. MS found: (M+H)+=442. A sample of the diastereomer of this compound, N-(2-((1S,2R,4S)-4-(isopropyl(methyl)amino)-2-propylcyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide, was also isolated from this same purification. MS found: (M+H)+=442. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1 2-(3-(trifluoromethyl)-benzamido)acetic acid (277 mg, 1.12 mmol, 1.2 eq) and triethylamine (0.15 mL, 1.12 mmol, 1.2 eq) were dissolved in THF (15 mL) at room temperature under nitrogen. Cooled to 0 C. Added isobutyl chloroformate (0.16 muL, 1.12 mmol, 1.2 eq) dropwise. Stirred for 10 mintues followed by the dropwise addition of tert-butyl cis-4-amino-cyclo-hexylcarbamate (200 mg, 0.93 mmol, 1 eq) in THF ((5 mL). Warmed to room temperature. Worked up after 3 hours by adding methylene chloride (25 mL) and rinsing 3 times with saturated sodium bicarbonate (25 mL). The organic layer was dried (sodium sulfate) and stripped to give an oil. Purified over silica gel in 1:1 hexanes/ethyl acetate to give tert-butyl cis-4-(2-(3-(trifluoromethyl)-benzamido)acetamido)cyclohexylcarbamate (350 mg) as an oil. MS found: (M+Na)+=466.20. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Part C: Preparation of endo-5-[2-(3-trifluoromethylbenzoylamino)acetylamino]octahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester A solution of (3-trifluoromethylbenzoylamino)acetic acid (71 mg, 503 mumol) in tetrahydrofuran (1.5 mL) was treated with N-methylmorpholine (83 muL, 756 mumol). The solution was stirred in an ice/acetone bath, and treated dropwise with isobutyl chloroformate. The resulting mixture was stirred for about 2 min, and then a solution of endo-5-aminooctahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (114 mg, 503 mumol) in tetrahydrofuran (1 mL) and N,N-dimethylformamide (1 mL) containing N-methylmorpholine (50 muL) was added. The mixture was warned to room temperature where it stirred for 40 min. After this time, the mixture was concentrated under vacuum to yield a residue. The residue was partitioned between water and ethyl acetate. The organic phase was washed sequentially with pH 4 buffer, a saturated aqueous sodium hydrogen carbonate solution, water, and a saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated to yield a residue. The residue was purified by flash column chromatography to provide an amorphous solid (115 mg, 50%). 1H NMR (400 MHz, CDCl3) delta 8.04 (s, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.33 (bt, J=4.6 Hz, 1H), 6.58 (d, J=7.1 Hz, 1H), 4.19 (m, 1H), 4.04 (d, J=4.6 Hz, 2H), 3.38 (m, 2H), 3.23 (dd, J=11.4, 2.8 Hz, 2H), 2.56 (m, 2H), 2.28 (m, 2H), 1.39 (s, 9H), 1.26 (m, 2H). MS (ES+) m/z 456.27 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Manufacturing Example 2 N-[(1-benzylpyrrolidine-(3R)-yl-carbamoyl)-methyl]-3-trifluoromethylbenzamide 10.74 g (43.4 mmol) (3-trifluoromethylbenzoylamino)-acetic acid and 6.58 g (65.10 mmol, 1.5 eq.) N-methylmorpholine described at manufacturing example 1 dissolved into 80 ml tetrahydrofuran under argon gas. After cooling at -10 C., 7.11 g (52.08 mmol, 1.2 eq.) of isobutylchloroformate was diluted with 10 ml tetrahydrofuran and was added dropwise slowly into reaction solution. It was stirred at the same temperature and 8.03 g (45.57 mmol, 1.1 eq.) (3R)-(-)-1-benzyl-3-aminopyrrolidine was diluted with 10 ml tetrahydrofuran and was added dropwise slowly. After mixing at -10 C. for one hour, 100 ml purified water was added. It was three times continuously extracted with 100 ml ethyl acetate and organic layer was recovered. It was dried with anhydrous magnesium sulfate, decompressed and concentrated. After residues are solidified with t-butylmethylether and filtered, 12.18 g (69%) target compound as white solid was yielded. 1H NMR (400 MHz, DMSO-d6) 1.62-1.66 (1H, m), 2.26-2.36 (2H, m), 2.54-2.59 (1H, m), 2.63-2.66 (1H, m), 2.89-2.93 (1H, m), 3.62 (2H, d), 4.10 (2H, d), 4.46-4.90 (1H, m), 6.45 (1H, br s), 7.15 (1H, br s), 7.29-7.34 (5H, m), 7.59 (1H, t), 7.78 (1H, d), 8.00 (1H, d), 8.11 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 30h;Product distribution / selectivity; | compound/ Purity d wt. or reagent name (%) MW (g/mL) eq. mol vol. 3 99.0 247.17 1.00 1.00 2.40 600.0 g N-Boc-3- 98.00 172.23 1.38 1.06 2.55 448.0 g (amino) azetidine (4) HOBT 98.00 135.13 1.00 0.117 0.28 37.7 g EDCl 99.00 191.70 1.02 1.42 3.41 660.0 g Tri- 99.0 101.19 0.73 1.30 3.13 0.44 L ethylamine Di- 99.0 84.93 1.32 135.91 8.8 L chloro- methane To a 22-L 4-neck round bottom flask equipped with a thermocouple controller, mechanical stirrer, heating mantle, condenser and a nitrogen inlet adapter was charged with acid 3 as prepared in the previous step (600 g; 2.40 mol), dichloromethane (8.8 L), TEA (440 mL; 3.13 mol), N-Boc-3-(amino)azetidine (4, CNH Technologies, Inc.) (448 g; 2.55 mol) and HOBT (37.7 g; 0.28 mol, AK Scientific), and the mixture was stirred at 20 C. for 5 min, EDCI (506 g; 2.64 mol; 1.1 eq., AK Scientific) was added as one portion. The mixture was stirred at 20 C. for an additional 6 h. More EDCI (120.0 g, 0.626 mol; 0.26 eq) was added and the reaction was stirred at 20 C. for 20 h. EDCI (33.3 g; 0.174 mol; 0.05 eq.) was added again at the 21st h and the reaction was stirred at 20 C. for an additional 4 h. The reaction was washed with saturated NaHCO3 (4 L×2) (aqueous pH=9) and brine (3 L×2), and the separated organic phase was concentrated at 60 C. under house vacuum (120 mmHg) and then high vacuum (20 mmHg) to give crude 5 as a yellowish think syrup.To a 22-L 4-neck round bottom flask equipped with a thermocouple controller, mechanical stirrer, heating mantle, condenser and a nitrogen inlet adapter was charged a warm solution (60 C.) of crude 5 in EtOAc (3.1 L) and the mixture was heated to 73 C. with stirring, while warm (60 C.) heptane (10.0 L) was added as five portions (2 L×5) over 30 min. The resulting slightly white turbid solution was stirred at 73 C. for 10 min. The heating mantle was removed and the mixture was gradually cooled to 20 C. over 3 h, and further to 10 C. in a water bath and stirred for 1 h. The solid was collected by filtration, washed with hexanes (300 mL×2), dried under air-suction and then placed in a drying oven at 50 C. under house vacuum for 20 h to afford pure title compound, 5, as an off-white crystalline solid. The structure of 5 was confirmed by 1H-NMR. |
80% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 4h; | General procedure: N-(Azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide TFA salt: 3-Amino-azetidine-1-carboxylic acid tert-butyl ester (1.2 g, 6.97 mmol) and <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (1.57 g, 6.36 mmol) were treated with EDCI (1.57 g, 6.36 mmol), HOBT (1.22 g, 6.36 mmol) in DCM (10 mL) at room temperature for 4 hours. The reaction solution was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give yellow oil, which was then purified by silica gel column on a CombiFlash system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford 3-[2-(3-trifluoro-methyl-benzoylamino)-acetylamino]-azetidine-1-carboxylic acid tert-butyl ester as white solid, 2.23 g, 80% yield. 1H NMR (400 MHz, CDCl3) d 8.10 (s, 1H), 8.02 (d, J = 6.6 Hz, 1H), 7.80 (d, J = 6.8 Hz, 1H), 7.56 (t, J = 6.5 Hz, 1H), 4.61 (m, 1H), 4.25 (t, J = 7.2 Hz, 2H), 4.18 (d, J = 5.5 Hz, 2H), 3.82 (t, J = 7.5 Hz, 2H), 1.41 (s, 9H). 3-[2-(3-Trifluoromethyl-benzoylamino)-acetylamino]-azetidine-1-carboxylic acid tert-butyl ester (2.10 g, 5.24 mmol) was dissolved in 1:1 TFA and DCM mixed solution (10 mL) at room temperature. The reaction was stirred for another 2 hours. The solvent was removed and the residue was dried to give N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide as a TFA salt containing extra TFA (colorless oil), ~ 2.5 g, 100% yield. 1H NMR (400 MHz, CDCl3) d 8.10 (s, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.78 (d, J = 6.2 Hz, 1H), 7.55 (m, 2H), 4.78 (m, 1H), 4.15 (d, J = 3.2 Hz, 2H), 3.95 (t, J = 7.0 Hz, 2H), 3.52 (t, J = 7.0 Hz, 2H).8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene (PCT Int. Appl. WO2006064189, 0.292 g, 1.10 mmol), 5-bromobenzo[d][1,3]dioxole (Aldrich, 161 mg, 0.801 mmol), and tetrakis (triphenylphosphino)palladium(0) (Aldrich, 0.048 g, 0.042 mmol) were dissolved in 1,4-dioxane (9 mL), treated with 2M aqueous Na2CO3 (2.0 mL, 4.0 mmol), bubbled with argon for a few minutes, and heated to 100oC under reflux condenser for 24 h. After cooling to ambient temperature, the reaction was diluted with water (30 mL), extracted thrice with dichloromethane, aqueous layer acidified to ca. pH 7, extracted twice more with dichloromethane, and the combined organic layers washed with brine, dried over Na2SO4, filtered, and the filtrate concentrated in vacuo to give an orange oil. This was purified by thin layer chromatography on silica gel (EtOAc) to give 5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzo[d][1,3]dioxole as a yellow solid (110 mg, 53%). 5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzo[d][1,3]dioxole (110 mg, 0.42 mmol) in MeOH (5 mL) was placed in a hydrogenation Par Shaker under 40 psi at room temperature using 5% Pd/C (~ 50 mg) as catalyst for 2 hour. The resulting solution was filtered through a pad of Celite , concentrated and purified by silica gel column on a CombiFlash system to afford 5-(1,4-dioxaspiro[4.5]decan-8-yl)benzo[d][1,3]dioxole as white solid, 91 mg, 82% yield. 5-(1,4-dioxaspiro[4.5]decan-8-yl)benzo[d][1,3]dioxole (91 mg, 0.35 mmol) was treated with 1N HCl ( ~ 2 mL) in acetone (4 mL) at room temperature for 4 hours. The reaction was neutralized with saturate NaHCO3 solution and the solvent was removed. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give yellow solid, which was then purified by silica gel column on a CombiFlash system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford 4-(benzo[d][1,3]dioxol-5-yl)cyclohexanone as white solid, 75 mg, 98% yield.4-(benzo[d][1,3]dioxol-5-yl)cyclohexanone (75 mg, 0.35 mmol) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide TFA salt (151 mg, 0.50 mmol) in DCM (2 mL) was treated with TEA (0.1 mL, 0.75 mmol) for 10 min followed by NaBH(OAc)3 (Aldrich, 225 mg, 1.05 mmol) for another 4 hours at room temperature. The reaction was quenched with saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted 3 times with chloroform and IPA "cocktail" (~ 3:1, v/v). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford two title compounds as white solids: 8a, less polar isomer (cis), 67 mg, 38% yield; 9a, more polar isomer (trans), 45 mg, 26% yield. |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 4h; | A solution of 3-amino-azetidine-1-carboxylic acid tert-butyl ester (BetaPharma, 1.2 g, 6.97 mmol) and <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (Bionet, 1.57 g, 6.36 mmol) in DCM (10 mL) was treated with EDCI (Aldrich, 1.57 g, 6.36 mmol) and HOBT (Aldrich, 1.22 g, 6.36 mmol) at room temperature for 4 hours. The reaction solution was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, which was then purified by silica gel column on a CombiFlash system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid. 1H NMR (400 MHz, CDCl3) delta 8.10 (s, 1H), 8.02 (d, J=6.6 Hz, 1H), 7.80 (d, J=6.8 Hz, 1H), 7.56 (t, J=6.5 Hz, 1H), 4.61 (m, 1H), 4.25 (t, J=7.2 Hz, 2H), 4.18 (d, J=5.5 Hz, 2H), 3.82 (t, J=7.5 Hz, 2H), 1.41 (s, 9H). |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 4h; | Step D: 3-[2-(3-Trifluoromethyl-benzoylamino)-acetylamino]-azetidine-1-carboxylic acid tent-butyl ester 3-Amino-azetidine-1-carboxylic acid tert-butyl ester (AstaTech, 1.2 g, 6.97 mmol) and <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (Bionet Building Blocks, 1.57 g, 6.36 mmol) were treated with EDCI (Aldrich, 1.57 g, 6.36 mmol), HOBT (Aldrich, 1.22 g, 6.36 mmol) in DCM (10 mL) at room temperature for 4 hours. The reaction solution was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, and purified by silica gel column on a CombiFlash system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid. 1H NMR (400 MHz, CDCl3) delta 8.10 (s, 1H), 8.02 (d, J=6.6 Hz, 1H), 7.80 (d, J=6.8 Hz, 1H), 7.56 (t, J=6.5 Hz, 1H), 4.61 (m, 1H), 4.25 (t, J=7.2 Hz, 2H), 4.18 (d, J=5.5 Hz, 2H), 3.82 (t, J=7.5 Hz, 2H), 1.41 (s, 9H). | |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 4h; | Step B: 3-[2-(3-Trifluoromethyl-benzoylamino)-acetylamino]azetidine-1-carboxylic acid tent-butyl ester 3-Amino-azetidine-1-carboxylic acid tert-butyl ester (AstaTech, 1.2 g, 6.97 mmol) and <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (Bionet Building Blocks, 1.57 g, 6.36 mmol) were treated with EDCI (Aldrich, 1.57 g, 6.36 mmol), HOBT (Aldrich, 1.22 g, 6.36 mmol) in DCM (10 mL) at room temperature for 4 hours. The reaction solution was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, and purified by silica gel column on a CombiFlash system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.1H NMR (400 MHz, CDCl3) delta 8.10 (s, 1H), 8.02 (d, J=6.6 Hz, 1H), 7.80 (d, J=6.8 Hz, 1H), 7.56 (t, J=6.5 Hz, 1H), 4.61 (m, 1H), 4.25 (t, J=7.2 Hz, 2H), 4.18 (d, J=5.5 Hz, 2H), 3.82 (t, J=7.5 Hz, 2H), 1.41 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of 1-(4-benzo[1,3]dioxol-5-yl-cyclohex-3-enyl)-azetidin-3-ylamine TFA salt (as prepared in the previous step, 550 mg, 1.10 mmol) and <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (Bionet, 272 mg, 1.10 mmol) in DCM (10 mL) was treated with TEA (770 muL, 5.5 mmol) at room temperature. The mixture was treated with EDCI (Aldrich, 252 mg, 1.32 mmol), HOBT (Aldrich 149 mg, 1.10 mmol), and the reaction was stirred at room temperature for additional 6 hours. The reaction was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by CombiFlash system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid. 1H NMR (400 MHz, CDCl3) delta 7.85 (d, J=6.5 Hz, 2H), 7.55 (t, J=6.5 Hz, 1H), 7.45 (d, J=7.0 Hz, 2H), 6.85 (s, 1H), 6.75 (d, J=6.5 Hz, 1H), 6.72 (d, J=6.6 Hz, 1H), 5.98 (s, 2H), 5.85 (m, 1H), 4.52 (m, 1H), 4.10 (d, J=3.5 Hz, 2H), 3.65 (t, J=7.0 Hz, 2H), 3.08 (t, J=7.0 Hz, 2H), 2.80 (m, 1H), 2.42 (m, 4H), 1.90 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step E: N-({1-[4-(5-Trichloromethyl-[1,2,4]oxadiazol-3-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide The title compound was prepared by the EDCI coupling of 1-[4-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-cyclohexyl]-azetidin-3-ylamine (as prepared in the previous step) and <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (Bionet Building Blocks). Purification by HPLC gave cis and trans isomers.LC/MS: 568.0 [M+H]. |
Tags: 17794-48-8 synthesis path| 17794-48-8 SDS| 17794-48-8 COA| 17794-48-8 purity| 17794-48-8 application| 17794-48-8 NMR| 17794-48-8 COA| 17794-48-8 structure
[ 451-28-5 ]
2-(4-Fluorobenzamido)propanoic acid
Similarity: 0.75
[ 13450-77-6 ]
2-(4-Chlorobenzamido)acetic acid
Similarity: 0.71
[ 4192-28-3 ]
(S)-2-(1,3-Dioxoisoindolin-2-yl)propanoic acid
Similarity: 0.70
[ 2901-80-6 ]
2-Benzamido-3-methylbutanoic acid
Similarity: 0.69
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :