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CAS No. : | 1744-22-5 | MDL No. : | MFCD00210213 |
Formula : | C8H5F3N2OS | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FTALBRSUTCGOEG-UHFFFAOYSA-N |
M.W : | 234.20 | Pubchem ID : | 5070 |
Synonyms : |
PK 26124;RP-54274;Riluzole, Rilutek, PK 26124, PK26124, PK-26124, RP 54274, RP54274
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 50.71 |
TPSA : | 76.38 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) : | -5.17 cm/s |
Log Po/w (iLOGP) : | 2.04 |
Log Po/w (XLOGP3) : | 3.61 |
Log Po/w (WLOGP) : | 4.05 |
Log Po/w (MLOGP) : | 1.44 |
Log Po/w (SILICOS-IT) : | 2.93 |
Consensus Log Po/w : | 2.81 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.88 |
Solubility : | 0.031 mg/ml ; 0.000132 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.9 |
Solubility : | 0.00294 mg/ml ; 0.0000126 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -3.25 |
Solubility : | 0.133 mg/ml ; 0.000569 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 2.24 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P264-P270-P301+P310+P330-P405-P501 | UN#: | 2811 |
Hazard Statements: | H300 | Packing Group: | Ⅱ |
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 benzyltrimethylazanium tribroman-2-uide; In acetonitrile; at 20℃; for 24h; | 2-Amino-6-(trifluoromethoxyVbenzothiazoleTo a mixture of 4-trifluoromethoxyaniline (2.07 mmol) and ammonium thiocyanate (2 mmol) in acetonitrile, is added benzyltrimethylammonium tribromide, at room temperature. The reaction is left to proceed while stirring at room temperature for 24 <n="29"/>hours; it is then neutralised with NaHCO3 and extracted with CH2Cl2 . The combined organic extracts are washed with H2O, dried over Na2SO4, filtered and then evaporated under vacuum. The crude product is purified by chromatography through silica, eluting with petroleum ether/AcOEt (1:1), and a solid obtained that is recrystallised from hexane/ethyl ether to give 2-amino-6-(trifluoromethoxy)-benzothiazole as pale yellow flakes, with a yield of 80%. |
61% | With bromine; acetic acid; at 0 - 20℃; | [190] Preparation 1. 6-trifluoromethoxybenzo[d]thiazol-2-amine[191] Ammonium thiocyanate (1.70 g, 22.30 mmol) was added to a solution of 4-(trifluoromethoxy)aniline (3.54 g, 20.00 mmol) in acetic acid (30 mL). The reaction mixture was cooled to 0?10 ?. A solution of bromine (1.10 mL, 22.00 mmol) in acetic acid (5 mL) was added dropwise to the reaction mixture, which was then stirred at room temperature overnight. The resulting solid was filtered, and then dissolved in water. The aqueous layer was basified to pH 11-12 with solid sodium carbonate. The resulting solid was filtered, washed with water, and then dried in vacuo to give the titled compound (2.84 g) as a white solid. The product was used in the subsequent step without further purification (Yield: 61%). |
61% | With bromine; acetic acid; In water; at 0 - 20℃; | Preparation 1. 6-trifluoromethoxybenzo[d]thiazol-2-amine Ammonium thiocyanate (1.70 g, 22.30 mmol) was added to a solution of 4-(trifluoromethoxy)aniline (3.54 g, 20.00 mmol) in acetic acid (30 mL). The reaction mixture was cooled to 0-10 C. A solution of bromine (1.10 mL, 22.00 mmol) in acetic acid (5 mL) was added dropwise to the reaction mixture, which was then stirred at room temperature overnight. The resulting solid was filtered, and then dissolved in water. The aqueous layer was basified to pH 11-12 with solid sodium carbonate. The resulting solid was filtered, washed with water, and then dried in vacuo to give the titled compound (2.84 g) as a white solid. The product was used in the subsequent step without further purification (Yield: 61%). |
With benzyltrimethylammonium tribromide; In acetonitrile; at 20℃; for 24h; | [00102] To a mixture of 4-trifluormethoxy aniline 1 (2. 1 mmol) and ammonium thiocvanate (2.0 mmol) in 15 ml of CH3CN was added benzyltrimethylammonium tribromide 2 (2.0 mmol) at room temperature. The reaction mixture was stirred at room temperatiife for 24 h, neutralized with aqueous NaHCOs and extracted with DCM. (2 10 ml). The combined organic layers were washed with water, dried over a2S04, filtered and evaporated in vacuo. The crude material was purified by flash column chromatography on silica gel eluiing with petether/ethyl acetate (l :l,v/v) mixture to give a solid 3 that after recrysialSi ation from hexane gave light yellow crystals | |
With benzyltrimethylammonium tribromide; In acetonitrile; at 20℃; for 24h; | Step-1: Synthesis of Compound 3: [0140] To a mixture of 4-trifluormethoxy aniline 1 (2.1 mmol) and ammonium thiocyanate (2.0 mmol) in 15 ml of CH3CN was added benzyltrimethylammonium tribromide 2 (2.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 h, neutralized with aqueous NaHCO3 and extracted with DCM. (2×10 ml). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated in vacuo. The crude material was purified by flash column chromatography on silica gel eluting with petether/ethyl acetate (1:1,v/v) mixture to give a solid 3 that after recrystallization from hexane gave light yellow crystals |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With hydrazine hydrate; hydrazinium sulfate; In water; at 130℃; for 4h;Inert atmosphere; | 6-Trifluoromethoxy-2-amino-benzothiazole (23.42 g, 0.10 mol),hydrazinium sulfate (NH2NH2? H2SO4, 19.52 g, 0.15 mol)and hydrazine hydrate (80% aqueous solution, 80 mL) wereadded to ethylene glycol (350 mL). The mixture was heatedand stirred under nitrogen at 130 C for 4 h. TLC (CH2Cl2/MeOH = 20:1) was used to confirm the completion of thereaction. After cooling to room temperature, the mixturewas poured into the ice-water. A lot of gray solid wasprecipitated. The precipitate was filtered and washed threetimes with water. The solid was dried in vacuum to constantweight. Compound 2 (18.7 g, Yield 75%) was obtained.Gray schistose; mp 205-206 C; IR (KBr) upsilonmax 3362, 3205,3124, 2963, 2880, 2361, 1660, 1564, 1464, 1261, 1123 cm-1; 1H NMR (DMSO-d6, 500MHz): delta = 9.22 (1H, s,-NH-), 7.79 (1H, s, Ar-H), 7.35 (1H, d, J = 8.7 Hz, Ar-H),7.17 (1H, d, J = 8.7 Hz, Ar-H), 5.12 (2H, s, -NH2); ESIMSm/z 248.39[M-H]-; C8H6F3N3OS (calcd. 249.21) Anal.Calcd. for C8H6F3N3OS: C, 38.56; H, 2.43; N, 16.86.Found: C, 38.44; H, 2.34; N, 16.75. |
65% | With hydrazinium sulfate; hydrazine; In ethylene glycol; at 140℃; for 2.5h; | EXAMPLE 1 (6-Trifluoromethoxy-benzothiazol-2-yl)-hydrazine 1 A suspension of 6-trifluoromethoxy-2-amino-benzothiazole (crude, 1 g, 4.27 mmol), hydrazinium sulfate (NH2NH2.H2SO4, 0.85 g, 6.53 mmol) and hydrazine hydrate (~82% aqueous solution, 2.7 ml, ~45 mmol) in ethylene glycol (10 ml) was heated with stirring under N2 atm. at 140 C. for 2.5 h.When the solution was cooled to rt a white solid precipitated, water (10 ml) was added to complete precipitation, the product filtered, washed with water and vacuum dried to give 1 (0.7 g, 65%) as a white powder. 1H-NMR (CD3CN) delta 7.70 (br s, 1H, NH), 7.63 (dq, 1H, J=2, 1 Hz, H-7), 7.41 (d, 1H, J=9 Hz, H-4), 7.18 (ddq, 1H, J=9, 2, 1 Hz, H-5), 4.50 (br s, 2 H, NH2); 13C (CD3CN) delta 115.81, 120.35, 120.58 (3*CH, C-4, C-5, C-7), 120.93 (CF3O), 133.01, 143.89, 153.47 (3*C, C-3a, C-7a, C-6), 176.27 (C-2); MS (CI)(NH3) m/z (234, MH+-NH3+H+), 250 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Potassium thiocyanate (40 mmol)was added to a solution of 4-(trifluoromethoxy)aniline (10 mmol)in glacial acetic acid (20 mL). After the mixture stirring for 20 minat r. t., the reaction was cooled down just to keep the solution liquid. The solutionof bromine (15 mmol) in glacial acetic acid (5 mL) was added dropwiseover the 30 min. The reaction was allowed to reach r. t. and stirred overnight.The mixture was diluted with H2O, alkalized with Na2CO3and extracted with ethyl acetate (3 x 50 mL). The combined organiclayers were dried over Na2SO4, filtered and the solventwas under reduced pressure to dryness. The residue was recrystallized from diethylether-petrol ether to yield 6-(trifluoromethoxy)benzo[d]thiazol-2-amine as light-yellow solid(94%). 1H and 13C NMR, melting point and analytical data werein agreement with those reported in literature. | |
86% | Ref.: J. Med. Chem., 42:2828 (1999). A mixture of 4-trifluoromethoxy aniline (10 g, 56.5 mmol) and potassium thiocyanate (22 g, 226 mmol) in acetic acid (90 mL) was stirred for 10 min. To this mixture was added a solution of bromine (9.03 g, 56.5 mmol) in acetic acid (20 mL) over a period of 15 min. The resulting mixture was stirred overnight, then was poured into cold water and basified with cone, ammonium hydroxide. The resulting yellow solid was collected by filtration and triturated in heptane. The product was filtered and dried under vacuum to give the title material (11.4 g, 86%) as a yellow solid. LCMS: Anal. Calcd. for C8H5F3N2OS: 234.01; found: 235.02 (M+1)+. 1H NMR (600 MHz, DMSO-d6) delta 7.74 (br d, 1H), 7.62 (s, 2H), 7.32 (d, J= 8.7 Hz, 1H), 7.14 (br dd, J= 8.7 Hz, 1H), 1.83 (br d, J= 3.7 Hz, 2H). | |
With bromine; acetic acid; at -10 - 0℃; for 4h; | General procedure: A mixture of substituted aniline (0.01mol) and potassium thiocyanate (0.01mol) in glacial acetic acid was cooled and stirred. To this solution, bromine (0.01mol) was added drop-wise at such a rate to keep the reaction temperature between 0 and -10 C throughout the addition. Stirring was continued for additional 4 h and the separated hydrochloride salt was filtered, washed with acetic acid and dried. The reaction was monitored using TLC (toluene: methanol, 8:2). It was dissolved in hot water and neutralized with aqueous ammonia solution (25 %). The precipitate obtained was filtered, washed with water, dried and re-crystallized with benzene to afford the substituted-1, 3-benzothiazol-2-amine (1a-j). Yield: 70 %, m. p.: 245-248 C, IR (KBr) upsilonmax (cm-1): 3240 (NH2), 3020 (Ar-CH), 1565 (C=N); 1H-NMR (delta) DMSO-d6: 7.89-8.16 (m, 3H, Ar- H), 9.70 (s, 2H, NH2, D2O exchangeable). |
1.8 g | With bromine; acetic acid; at 20℃; for 16h; | 4-Trifluoromethoxyaniline (2 g, 1 1 .3 mmol) and potassium thio- cyanate (4.38 g, 45.1 mmol) was solved in acetic acid (20 ml). Bromine (0.57 ml, 1 1 .3 mmol) in acetic acid (5 ml) was added dropwise. The resulting mixture was stirred at RT for 16 hours. After completion of the reaction, the reaction mixture was poured into ice water and neutralized with aqueous ammonia. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulphate and concentrated under reduced pressure. Yield of 6-(trifluoromethoxy)-1 ,3-benzothiazol-2- amine (IV-2) after flash chromatography (100-200 mesh size silica gel, 20% ethyl acetate in hexane) was 1 .8 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With benzyltrimethylazanium tribroman-2-uide In dichloromethane at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1,1'-carbonyldiimidazole; Riluzole In acetonitrile at 20℃; Stage #2: Bronner acid In N,N-dimethyl-formamide at 100℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution containing copper chloride (II) (0.87 g, 6.45 mmol) and tri(ethylene glycol) dimethyl ether (3 mL) in acetonitrile (50 mL) was added isoamyl nitrite (0.94 g, 8.06 mmol), and the reaction mixture was stirred at rt for 30 minutes. To this suspension was added dropwise a solution of 4,6-difluoro-1,3-benzothiazol-2-amine (1.0 g, 5.37 mmol) in tri(ethylene glycol) dimethyl ether (5 mL). The reaction mixture was stirred at rt for 10 minutes, and then heated at 50 C. for 2.5 h. The reaction mixture was cooled to rt, and then poured cautiously into cold aqueous 6 M HCl (200 mL). The solution was extracted with EtOAc. The organic layer was washed with HCl (1.0 M), water and brine, filtered and concentrated down to afford 2-chloro-4,6-difluoro-1,3-benzothiazole (1.1 g, 99%). 1H NMR (400 MHz, DMSO-d6) 7.05 (m, 1H), 7.36 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | 2-[2-arm'no-5-(trifluoromethoxy)phenylthio]-acetonitrile.A suspension of 2-amino-6-trifluoromethoxybenzothiazole (1.8 g, 7.7 mmol) in IO N NaOH (30 ml) is refluxed, under a current of nitrogen, for 2 hours, after which time the suspension becomes a clear solution, and to which chloroacetonitrile (0.48 ml, 7.7 mmol) in CH2Cl2 (50 ml) and tetrabutylammonium hydrogensulphate (0.26 g, 0.77 mmol) are added. The resulting reaction mixture is stirred for 18 hours at room temperature, then the organic phase is separated, washed with water and dried over Na2SO4. The solvent is evaporated and the residue chromatographed through silica, eluting with petroleum ether/AcOEt (1:1 ) to give the product as a dark oil (1.1 g, 58% yield). 1H-NMR (CDCl3): 3.45 (s, 2H), 4.44 (br s, 2H), 6.74 (d, J = 8.8, IH), 7.10 (m, IH), 7.39 (m, IH). MS(ESI): m/z 249 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Examples of Preparation of the Compounds of the InventionN'-r6-(trifluoromethoxy)benzothiazol-2-yl"|acetamidine, Example 1.Acetamide (0.47 mmol) is added to a solution of POCl3 (0.85 mmol) in toluene (20 ml), chilled to 5-0C, and the reaction mixture allowed to return to room temperature and then stirred for a further 30 minutes. 6-(trifluoromethoxy)-2-aminobenzothiazole (0.42 mmol), dissolved in toluene, is then added dropwise. On completion of addition, the reaction <n="25"/>mixture is heated and refluxed for 6 hours, then cooled and poured into ice-water and basified using 1 N NaOH. The reaction mixture is extracted with CHCl3, and washed with H2O until neutrality, then dried over Na2SO4, and concentrated. The crude product thus obtained is chromato graphed through silica, eluting with petroleum ether/AcOEt (4:6). The product is obtained as a yellow oil, with yield: 67%. 1H-NMR (CDCl3) delta ppm: 2.35 (s, 3H), 5.62 (br s, 2H), 7.20 (m, 2H), 7.48 (d, IH, J= 8.9). MS-ESI: m/z 276 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With triethylamine; In toluene; for 30h;Heating / reflux; | l-Ethyl-3-[6-ftrifluoromethoxy)benzothiazol-2-yllthiourea, Example 9.To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (2.7 mmol) in toluene (20 ml) is added triethylamine (0.43 mmol) and ethylisothiocyanate (3.78 mmol). The resulting reaction mixture is heated and refluxed for 30 hours. The reaction mixture is cooled then evaporated and the residue diluted with CH2Cl2. The residue is washed with H2O, dried over Na2SO4 then concentrated. The residue is chromatographed through silica gel, eluting with petroleum ether/AcOEt (65:35). Concentration of the appropriate fractions gives a solid that is then recrystallised from AcOEt/Et2O, to give the desired product as pale yellow needles, m.p. 199-200C (36% yield). 1H-NMR (DMSO) delta ppm: 1.17 (t, 3H, J = 7.20), 3.55 (m, 2H), 7.37 (d, IH, J = 8.4), 7.70 (d, IH, J = 8.7), 8.02 (s, IH), 9.54 (br s 2H). MS-ESI: m/z 320 (M-H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester may be prepared from <strong>[66315-16-0]3-amino-4-methylamino-benzoic acid methyl ester</strong>, 2-amino-6-(trifluoromethoxy)benzothiazole, 1,1?-thiocarbonyl-diimidazole, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). 1,1?-Thiocarbonylimidazole may be added to a solution of 2-amino-6-(trifluoromethoxy)benzothiazole in DMF, and the reaction mixture stirred at 90-100 C. for a day. To this reaction mixture at room temperature is added EDC and stirred at 60 C. for 5 min. To this reaction mixture at room temperature is added <strong>[66315-16-0]3-amino-4-methylamino-benzoic acid methyl ester</strong> and stirred at 90 C. The reaction mixture may then be cooled to room temperature, poured into ice-cold water and the solid collected by filtration. The crude product thus obtained may be purified by trituration with dichloromethan-methanol (9:1). LC/MS: m/z 423.8 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | General procedure: To a solution of 2-aminobenzothiazole (150 mg, 1 mmol) in dichloromethane (20 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (210 mg, 1.1 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then compound 8 (402 mg, 1 mmol) was added and the reaction mixture was stirred at room temperature for 14 h and the reaction was monitored by TLC. After completion of reaction, water was added to reaction mixture and extracted with dichloromethane (2 × 30 ml). The organic layer was dried with Na2SO4 and evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane (1:1) as solvent system to obtain the pure product 9a as yellow solid. (449 mg, 84% yield); |
80% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃; for 24h; | To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (234 mg, 1.0 mmol) in dichloromethane (20 mL) was added l -Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1 -hydroxy- 1 ,2,3 -benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxy phenyl)- l-propenyl]phenoxy} acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25 C for 24h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9j) (498 mg, 80% yield) NMR (CDC13): D D 10.62 (br s, 1H), 7.77 (d, 1H, J = 9.0 Hz), 7.66-7.73 (m, 2H), 7.27- 7.39 (m, 3H), 7.24 (d, 1H, J = 15.1 Hz), 7.22 (s, 2H), 6.98 (d, 1H, J = 8.3 Hz), 4.83 (s, 2H), 4.07 (s, 3H), 3.95 (s, 6H), 3.91 (s, 3H); ESIMS:619 (M+l)+ |
80% | To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (234 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(E)-3-oxo-3-(3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25 C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9j) (498 mg, 80% yield) 1H NMR (CDCl3): ??10.62 (br s, 1H), 7.77 (d, 1H, J=9.0 Hz), 7.66-7.73 (m, 2H), 7.27-7.39 (m, 3H), 7.24 (d, 1H, J=15.1 Hz), 7.22 (s, 2H), 6.98 (d, 1H, J=8.3 Hz), 4.83 (s, 2H), 4.07 (s, 3H), 3.95 (s, 6H), 3.91 (s, 3H); ESIMS: 619 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃; for 24h; | To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (234 mg, 1.0 mmol) in dichloromethane (20 mL) was added l-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1 -hydroxy- 1 , 2, 3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{5-[l-acetyl-3-(3,4,5-trimethoxyphenyl)-4.5-dihydro-lH-5-pyrazolyl]-2- methoxyphenoxy} acetic acid (3) (458 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25 C for 24h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (lOj) (531 mg, 80% yield). NMR (CDC13): delta 10.71 (br s, 1H), 7.79 (d, 1H, J = 8.3 Hz), 7.69 (d, 1H, J = 1.5 Hz), 7.29- 7.34-(dd, 1H, J= 9.0, 1.5 Hz), 6.98-7.02 (dd, 1H, J= 8.3, 1.5 Hz), 6.96 (s, 2H), 6.89-6.94 (m, 2H), 5.50-5.58 (dd, 1H, J = 1 1.3, 4.5 Hz), 4.77 (s, 2H), 3.98 (s, 3H), 3.91 (s, 6H), 3.90 (s, 3H), 3.69-3.81 (dd, 1H, J= 18.1 , 12.0 Hz), 3.08-3.17 (dd, 1 H, J = 17.3, 4.5 Hz), 2.43 (s, 3H); ESIMS:675 (M+l)+. |
80% | To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (234 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetic acid (3) (458 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25 C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (10j) (531 mg, 80% yield). 1H NMR (CDCl3): delta 10.71 (br s, 1H), 7.79 (d, 1H, J=8.3 Hz), 7.69 (d, 1H, J=1.5 Hz), 7.29-7.34 (dd, 1H, J=9.0, 1.5 Hz), 6.98-7.02 (dd, 1H, J=8.3, 1.5 Hz), 6.96 (s, 2H), 6.89-6.94 (m, 2H), 5.50-5.58 (dd, 1H, J=11.3, 4.5 Hz), 4.77 (s, 2H), 3.98 (s, 3H), 3.91 (s, 6H), 3.90 (s, 3H), 3.69-3.81 (dd, 1H, J=18.1, 12.0 Hz), 3.08-3.17 (dd, 1H, J=17.3, 4.5 Hz), 2.43 (s, 3H); ESIMS: 675 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃; for 24h; | To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (234 mg, 1.0 mmol) in dichloromethane (20 mL) was added l-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and l -hydroxy-l ,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-l-ethenyl]phenoxy}aceticacid (1) (374 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25 C for .24h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (8j) (470 mg, 80% yield)1H NMR (CDCI3): delta 7.80 (d, 1H, J = 8.8 Hz), 7.69 (s, 1H), 7.29-7.36 (dd, 1H, J = 8.4, 2.2 Hz), 7.01-7.06 (dd, 1H, J = 8.4, 1.7 Hz), 6.95 (d, 1H, J = 1.7 Hz), 6.85 (d, 1H, J = 8.3 Hz), 6.42-6.53 (m, 4H), 4.65 (s, 2H), 3.99 (s, 3H), 3.85 (s, 3H), 3.70 (s, 6H); ESIMS:591 (M+l)+ |
80% | To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (234 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetic acid (1) (374 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25 C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (8j) (470 mg, 80% yield) 1H NMR (CDCl3): delta 7.80 (d, 1H, J=8.8 Hz), 7.69 (s, 1H), 7.29-7.36 (dd, 1H, J=8.4, 2.2 Hz), 7.01-7.06 (dd, 1H, J=8.4, 1.7 Hz), 6.95 (d, 1H, J=1.7 Hz), 6.85 (d, 1H, J=8.3 Hz), 6.42-6.53 (m, 4H), 4.65 (s, 2H), 3.99 (s, 3H), 3.85 (s, 3H), 3.70 (s, 6H); ESIMS: 591 (M+1)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 24h; | To a solution of 6-(trifluoromethoxy)- l ,3- benzothiazol-2-amine (<strong>[1744-22-5]Riluzole</strong>, 5.0 g, 21 mmol), (^-N-t-butyloxycarbonyl-serine-O- benzyl ether (7.6 g, 26 mmol), hydroxybenzotriazole (4.0 g, 26 mmol), 4- dimethylaminopyridine (0.32 g, 2.6 mmol) and diisopropylethylamine (3.4 g, 26 mmol, 4.7 mL) in Nu, N-dimethylformamide (100 mL) was added l-ethyl-3-(3- dimethylaminopropyl)carbodiimide) (5.0 g, 26 mmol) and the mixture stirred for 24 hours. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with water (2 X 300 mL), IN HC1 (6 X 200 mL), water (300 mL), 1M sodium carbonate (200 mL), brine (100 mL), dried (Na2SC>4) and evaporated to a colorless viscous oil (5.0 g, 47%). 'H-NMR (300 MHz, CDC13) delta 7.77 (d, J = 9.1 Hz, 1H), 7.69 (d, J = 1.1 Hz, 1H), 7.30 (m, 6H), 5.45 (d, J = 7.3 Hz, 1H), 4.61 (d ABq, J = 12.0 Hz, 1H), 4.56 (d ABq, J = 12.0 Hz, 1H), 4.03 (m, 1H), 3.69 (dd, J = 9.6 Hz, J = 5.5 Hz, 1H), 1.47 (s, 9H); ESI MS (M + H)+ = 512. |
47% | With dmap; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 24h; | Synthesis of tert-butyl-N-[(5)-2-(benzyloxy)-l-[6-(trifiuoromethoxy)-l,3- benzothiazol-2-yl]carbamoyl}ethyl]carbamate. To a solution of 6-(trifluoromethoxy)-l,3- benzothiazol-2-amine (<strong>[1744-22-5]Riluzole</strong>, 5.0 g, 21 mmol), (5)-N-t-butyloxycarbonyl-serine-O- benzyl ether (7.6 g, 26 mmol), hydroxybenzotriazole (4.0 g, 26 mmol), 4- dimethylaminopyridine (0.32 g, 2.6 mmol) and diisopropylethylamine (3.4 g, 26 mmol, 4.7 mL) in N, N-dimethylformamide (100 mL) was added l-ethyl-3-(3- dimethylaminopropyl)carbodiimide) (5.0 g, 26 mmol) and the mixture stirred for 24 hours. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with water (2 X 300 mL), IN HC1 (6 X 200 mL), water (300 mL), 1M sodium carbonate (200 mL), brine (100 mL), dried (Na2S04) and evaporated to a colorless viscous oil (5.0 g, 47%). 1H-NMR (300 MHz, CDC13) delta 7.77 (d, J = 9.1 Hz, 1H), 7.69 (d, J = 1.1 Hz, 1H), 7.30 (m, 6H), 5.45 (d, J = 7.3 Hz, 1H), 4.61 (d ABq, J = 12.0 Hz, 1H), 4.56 (d ABq, J = 12.0 Hz, 1H), 4.03 (m, 1H), 3.69 (dd, J = 9.6 Hz, J = 5.5 Hz, 1H), 1.47 (s, 9H); ESI MS (M + H)+ = 512. |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; for 96h; | General procedure: 6-Trifluoromethoxy-benzothiazol-2-ylamine (1, 100 mg, 0.42 mmol), a carboxylic acid (0.43 mmol), and EDCI (123 mg, 0.65 mmol) were combined in methylene chloride(5 mL) and stirred 4 days. The reaction was washed with 0.1 N HCl (2 × 10 mL), dried over magnesium sulfate, filtered, and then concentrated. Chromatography on silica gel afforded the t-Boc protected compounds as well as compound 26 directly. Compounds 4-10, 24, and 25 were dissolved in 4 N HCl and 1,4-dioxane and stirred 3 h at ambient temperature. The reactions were then concentrated to afford the products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; for 96h; | General procedure: 6-Trifluoromethoxy-benzothiazol-2-ylamine (1, 100 mg, 0.42 mmol), a carboxylic acid (0.43 mmol), and EDCI (123 mg, 0.65 mmol) were combined in methylene chloride(5 mL) and stirred 4 days. The reaction was washed with 0.1 N HCl (2 × 10 mL), dried over magnesium sulfate, filtered, and then concentrated. Chromatography on silica gel afforded the t-Boc protected compounds as well as compound 26 directly. Compounds 4-10, 24, and 25 were dissolved in 4 N HCl and 1,4-dioxane and stirred 3 h at ambient temperature. The reactions were then concentrated to afford the products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; for 96h; | General procedure: 6-Trifluoromethoxy-benzothiazol-2-ylamine (1, 100 mg, 0.42 mmol), a carboxylic acid (0.43 mmol), and EDCI (123 mg, 0.65 mmol) were combined in methylene chloride(5 mL) and stirred 4 days. The reaction was washed with 0.1 N HCl (2 × 10 mL), dried over magnesium sulfate, filtered, and then concentrated. Chromatography on silica gel afforded the t-Boc protected compounds as well as compound 26 directly. Compounds 4-10, 24, and 25 were dissolved in 4 N HCl and 1,4-dioxane and stirred 3 h at ambient temperature. The reactions were then concentrated to afford the products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 24h; | General procedure: 6-Trifluoromethoxybenzothiazol-2-ylamine (1, 100 mg, 0.42 mmol), chloroformate (0.74 mmol), and triethylamine (64 mg, 0.64 mmol) were combined in methylene chloride (3 mL) and stirred 24 h at ambient temperature. The reaction was concentrated. The residue was treated with methanol/water (1:1, 5 mL) and the solid collected by filtration and dried under vacuum to afford product. | |
With triethylamine; In dichloromethane; at 20℃; for 24h; | 6-Trifluoromethoxy-benzothiazol-2-ylamine (100 mg, 0.42 mmol), methylchloroformate (70 mg, 0.74 mmol), and triethylamine (64 mg, 0.64 mmol) were combined in methylene chloride (3 mL) and strirred 24h at ambient temperature. The reaction was concentrated. The residue was treated with methanol/water (1 : 1 , 5 mL) and the solid collected by filtration and dried under vacuum to afford (6-Trifluoromethoxy- benzothiazol-2-yl)-carbamic acid methyl ester, Cpd 12. 1H NMR (300 MHz, DMSO) delta 8.22 (s, 1H), 7.89 (d, / = 8.8 Hz, 1H), 7.52 (d, / = 9.0 Hz, 1H), 3.97 (s, 1H), 3.44 (s, 3H).MS m/z (M+) 292.9 | |
With triethylamine; In dichloromethane; at 20℃; for 24h; | General procedure: [0280] Example 2: (6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid methyl ester, Cpd 12. [0281] 6-Trifluoromethoxy-benzothiazol-2-ylamine (100 mg, 0.42 mmol), methylchloro formate (70 mg, 0.74 mmol), and triethylamine (64 mg, 0.64 mmol) were combined in methylene chloride (3 mL) and strirred 24h at ambient temperature. The reaction was concentrated. The residue was treated with methanol/water (1 : 1, 5 mL) and the solid collected by filtration and dried under vacuum to afford (6-Trifluoromethoxy- benzothiazol-2-yl)-carbamic acid methyl ester, Cpd 12. 1H NMR (300 MHz, DMSO) delta 8.22 (s, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 9.0 Hz, 1H), 3.97 (s, 1H), 3.44 (s, 3H).MS m/z (M+) 292.9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With triethylamine; In dichloromethane; at 20℃; for 24h; | General procedure: 6-Trifluoromethoxybenzothiazol-2-ylamine (1, 100 mg, 0.42 mmol), chloroformate (0.74 mmol), and triethylamine (64 mg, 0.64 mmol) were combined in methylene chloride (3 mL) and stirred 24 h at ambient temperature. The reaction was concentrated. The residue was treated with methanol/water (1:1, 5 mL) and the solid collected by filtration and dried under vacuum to afford product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine; In dichloromethane; at 20℃; for 24h; | General procedure: 6-Trifluoromethoxybenzothiazol-2-ylamine (1, 100 mg, 0.42 mmol), chloroformate (0.74 mmol), and triethylamine (64 mg, 0.64 mmol) were combined in methylene chloride (3 mL) and stirred 24 h at ambient temperature. The reaction was concentrated. The residue was treated with methanol/water (1:1, 5 mL) and the solid collected by filtration and dried under vacuum to afford product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | In dichloromethane; at 20℃; for 24h; | General procedure: 6-Trifluoromethoxybenzothiazol-2-ylamine (1, 100 mg, 0.42 mmol), chloroformate (0.74 mmol), and triethylamine (64 mg, 0.64 mmol) were combined in methylene chloride (3 mL) and stirred 24 h at ambient temperature. The reaction was concentrated. The residue was treated with methanol/water (1:1, 5 mL) and the solid collected by filtration and dried under vacuum to afford product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With triethylamine; In dichloromethane; at 20℃; for 24h; | General procedure: 6-Trifluoromethoxybenzothiazol-2-ylamine (1, 100 mg, 0.42 mmol), chloroformate (0.74 mmol), and triethylamine (64 mg, 0.64 mmol) were combined in methylene chloride (3 mL) and stirred 24 h at ambient temperature. The reaction was concentrated. The residue was treated with methanol/water (1:1, 5 mL) and the solid collected by filtration and dried under vacuum to afford product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With triethylamine; In dichloromethane; at 20℃; for 24h; | General procedure: 6-Trifluoromethoxybenzothiazol-2-ylamine (1, 100 mg, 0.42 mmol), chloroformate (0.74 mmol), and triethylamine (64 mg, 0.64 mmol) were combined in methylene chloride (3 mL) and stirred 24 h at ambient temperature. The reaction was concentrated. The residue was treated with methanol/water (1:1, 5 mL) and the solid collected by filtration and dried under vacuum to afford product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With triethylamine; In dichloromethane; at 20℃; for 24h; | General procedure: 6-Trifluoromethoxybenzothiazol-2-ylamine (1, 100 mg, 0.42 mmol), chloroformate (0.74 mmol), and triethylamine (64 mg, 0.64 mmol) were combined in methylene chloride (3 mL) and stirred 24 h at ambient temperature. The reaction was concentrated. The residue was treated with methanol/water (1:1, 5 mL) and the solid collected by filtration and dried under vacuum to afford product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With triethylamine; In dichloromethane; at 20℃; for 24h; | General procedure: 6-Trifluoromethoxybenzothiazol-2-ylamine (1, 100 mg, 0.42 mmol), chloroformate (0.74 mmol), and triethylamine (64 mg, 0.64 mmol) were combined in methylene chloride (3 mL) and stirred 24 h at ambient temperature. The reaction was concentrated. The residue was treated with methanol/water (1:1, 5 mL) and the solid collected by filtration and dried under vacuum to afford product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; for 96h; | General procedure: 6-Trifluoromethoxy-benzothiazol-2-ylamine (1, 100 mg, 0.42 mmol), a carboxylic acid (0.43 mmol), and EDCI (123 mg, 0.65 mmol) were combined in methylene chloride (5 mL) and stirred 4 days. The reaction was washed with 0.1 N HCl (2 × 10 mL), dried over magnesium sulfate, filtered, and then concentrated. Chromatography on silica gel afforded compounds 20, and 21. Compound 21 was dissolved in dichloromethane and trifluoroacetic acid (1:1). After stirring 2 h the solvents were removed in vacuo to yield compound 19. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -10 - 0℃; for 1.5h; | 00104J To a solution of compound 3 (1.0 rnmol) in dry DCM (1.8 ml) was added N, N- diisopropylethylamine (2.0 ramo) at 0C, followed by drop wise addition of 1- chloroethylchloroforniate 4(1 .2 mmol) for 30 rain at the same temperature and the reaction mixture was allowed to stir for 1 h at i C. On completion, of the reaction (monitored by TLC), the reaction mixture the solvent was evaporated and the crude was purified through column to get chio.ro compound 5. | |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -10 - 0℃; for 1.5h; | Step-2: Synthesis of Compound 5: [0142] To a solution of compound 3 (1.0 mmol) in dry DCM (1.8 ml) was added N, N-diisopropylethylamine (2.0 mmol) at -10 C., followed by drop wise addition of 1-chloroethylchloroformate 4 (1.2 mmol) for 30 min at the same temperature and the reaction mixture was allowed to stir for 1 h at 0 C. On completion of the reaction (monitored by TLC), the reaction mixture the solvent was evaporated and the crude was purified through column to get chloro compound 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 24h; | 6-Trifluoromethoxy-benzothiazol-2-ylamine (50 mg, 0.21 mmol), succinic anhydride (21 mg, 0.21 mmol), and triethylamine (42 mg, 0.42 mmol) were combined in tetrahydrofuran and dimethylformamide (1 mL of each) and starred 24h at ambient temperature. The reaction was purified using reverse phase chromatography (10-90% acetonitrile: water both containing 0.1% trifluoroacetic acid). The fractions containing product were combined and lyophilized to afford N-(6-Trifluoromethoxy-benzothiazol-2- yl)-succinamic acid, Cpd 20. lU NMR (300 MHz, DMSO) delta 8.11 (s, 1H), 7.81 (d, / = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 2.72 (d, J = 6.8 Hz, 2H), 2.68 - 2.44 (m, 2H). MS m/z (M+) 334.8 | |
With triethylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 24h; | General procedure: [0283] Example 3: N-(6-Trifluoromethoxy-benzothiazol-2-yl)-succinamic acid, Cpd 20. [0284] 6-Trifluoromethoxy-benzothiazol-2-ylamine (50 mg, 0.21 mmol), succinic anhydride (21 mg, 0.21 mmol), and triethylamine (42 mg, 0.42 mmol) were combined in tetrahydroiuran and dimethylformamide (1 mL of each) and strirred 24h at ambient temperature. The reaction was purified using reverse phase chromatography (10-90% acetonitrile: water both containing 0.1% trifluoro acetic acid). The fractions containing product were combined and lyophilized to afford N-(6-Trifluoromethoxy-benzothiazol-2- yl)-succinamic acid, Cpd 20. 1H NMR (300 MHz, DMSO) delta 8.11 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 2.72 (d, J = 6.8 Hz, 2H), 2.68 - 2.44 (m, 2H). MS m/z (M+) 334.8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 20h; | To a mixture of <strong>[1744-22-5]Riluzole</strong> (0.6 gm, 2.4 mmol), (S^-Boc proline (0.77 gm, 3.6 mmol) was added l-ethyl-3-(3-dimethylaminopropyl)carbodiimide) ( 0.7 gm, 3.6 mmol), diisopropylethylamine (0.47 gm, 3.6 mmol) and 4- Dimethylaminopyridine (0.06 gm, 0.5 mmol) in anhydrous N, N-dimethylformamide (8 mL) and stirred for 20 hours. The reaction mixture was quenched with water (5 mL) diluted with ethyl acetate (50 mL) and the aqueous layer was extracted with ethyl acetate (2X 5 mL). The combined organic layers were washed with IN HC1 (10 mL), saturated NaHC03 (10 mL), water (2 X 20 mL) and brine (10 mL). The organic layer was then filtered through Na2S04 concentrated under reduced pressure and purified via flash column chromatography using 20-30% ethyl acetate that afforded a white solid. This was dissolved in 1 : 1 4N HC1 in 1,4-dioxane: 1,4-dioxane and stirred for 3 hours. After 3 hours the solvent was removed under reduced pressure and the resulting solid was washedwith ethyl acetate (5 mL) and ether (5 mL). The solid was then filtered and dried to afford (5')-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide (60%). | |
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 20h; | Example 4: Synthesis of (5)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2- yl)pyrrolidine-2-carboxamide. To a mixture of <strong>[1744-22-5]Riluzole</strong> (0.6 gm, 2.4 mmol), (5)-Boc proline (0.77 gm, 3.6 mmol) was added l -ethyl-3-(3-dimethylaminopropyl)carbodiimide) ( 0.7 gm, 3.6 mmol), diisopropylethylamine (0.47 gm, 3.6 mmol) and 4- Dimethylaminopyridine (0.06 gm, 0.5 mmol) in anhydrous N, N-dimethylformamide (8 mL) and stirred for 20 hours. The reaction mixture was quenched with water (5 mL) diluted with ethyl acetate (50 mL) and the aqueous layer was extracted with ethyl acetate (2X 5 mL). The combined organic layers were washed with IN HCl (10 mL), saturated NaHC03 (10 mL), water (2 X 20 mL) and brine (10 mL). The organic layer was then filtered through Na2S04 concentrated under reduced pressure and purified via flash column chromatography using 20-30% ethyl acetate that afforded a white solid. This was dissolved in 1 : 1 4N HCl in 1,4-dioxane: 1,4-dioxane and stirred for 3 hours. After 3 hours the solvent was removed under reduced pressure and the resulting solid was washed with ethyl acetate (5 mL) and ether (5 mL). The solid was then filtered and dried to afford (S)- N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)pyrrolidine-2-carboxamide (60%). 1H NMR (300 MHz, DMSO) delta 8.19 - 8.17 (m, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.53 - 7.22 (m, 1H), 4.56 (dd, J = 8.5, 6.7 Hz, 1H), 3.41 - 3.13 (m, 2H), 2.48 - 2.34 (m, 1H), 2.10 - 1.75 (m, 3H). MS m/z (M+) 331.9. | |
With 1-hydroxy-7-aza-benzotriazole; 2-chloro-1-methyl-pyridinium iodide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | Asolution of 2 (100 mg, 0.43 mmol), 1-(tert-butoxycarbonyl)-L-proline(138 mg, 0.64 mmol), N1-hydroxy-7-azabenzotriazole(85 mg, 0.64 mmol) and N,N-diisopropylethylamine (83 mg, 0.64mmol) in anhydrous DMF (2 mL) was treated with 2-chloro-1-methylpyridiniumiodide (163 mg, 0.64 mmol) and the mixture stirred at 20 oC for 18h. The mixture was diluted with ethyl acetate (50 ml) and washed with 1N HCl(50 ml), water (2 X 50 mL), saturated sodium bicarbonate solution (50 mL) andbrine (25 mL). The organic layer was dried with Na2SO4and evaporated. The residue was purified by reversed phase HPLC (methoddescribed in the general experimental section) and the product fractions wereevaporated under reduced pressure at <45 oC. The residue wasdissolved in 4N HCl in 1,4-dioxane (2 mL) and stirred for 2 h. The solventswere evaporated under reduce pressure to provide 5 as a white solid HCl salt (117 mg, 50%). 1H-NMR (CD3OD)d 7.89 (bs, 1H), 7.83 (d, 1H, J = 8.7 Hz), 7.39 (d, 1H, J = 8.7 Hz), 4.57 (dd, 2H, J = 7.0 Hz, J = 7.0 hz), 3.55-3.38 (m, 2H), 2.65-2.55 (m, 1H), 2.25-2.10 (m, 3H);LC/MS M+H+ = 332, Rt= 3.72 mins, purity >95%. Exact mass calc?d for C13H12F3N3O2S= 331.0602, found = 331.0594 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 24h; | 6-Trifluoromethoxy-benzothiazol-2-ylamine (100 mg, 0.42 mmol), tert- butoxycarbonylamino-acetic acid (75 mg, 0.43 mmol), and EDCI (123 mg, 0.65 mmol) were combined in methylene chloride (5 mL) and strirred 24h at ambient temperature. The reaction was washed with 0.1N HCl (2xl0mL), dired over magnesium sulfate, filtered, and then concentrated. Chromatography on silica gel using 20% ethyl acetate: hexanes as eluent and then concentration afforded an oil. The oil was dissolved in 4N HCl and 1,4-dioxane and stirred 3h. The reaction was concentrated to afford 2-Amino-N-(6- trifluoromethoxy-benzothiazol-2-yl)-acetamide, Cpd 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Example 1 : 2-Amino-N-(6-trifluoromethoxy-benzothiazol-2-yl)-acetamide, Cpd 1. Cpd 1 [0278] 6-Trifluoromethoxy-benzothiazol-2-ylamine (100 mg, 0.42 mmol), tert- butoxycarbonylamino-acetic acid (75 mg, 0.43 mmol), and EDCI (123 mg, 0.65 mmol) were combined in methylene chloride (5 mL) and strirred 24h at ambient temperature. The reaction was washed with 0.1N HCl (2x1 OmL), dried over magnesium sulfate, filtered, and then concentrated. Chromatography on silica gel using 20% ethyl acetate: hexanes as eluent and then concentration afforded an oil. The oil was dissolved in 4N HCl and 1,4- dioxane and stirred 3h. The reaction was concentrated to afford 2-Amino-N-(6- trifiuoromethoxy-benzothiazol-2-yl)-acetamide, Cpd 1. 1H NMR (300 MHz, DMSO) delta 8.43 (s, 1H), 8.17 (s, 1H), 7.89 (t, J = 10.4 Hz, 1H), 7.56 - 6.99 (m, 2H), 3.98 (m, 2H). MS m/z (M+) 291.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-7-aza-benzotriazole; 2-chloro-1-methyl-pyridinium iodide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | A solution of benzo[d]thiazol-2-amine(65 mg, 0.43 mmol), 1-(tert-butoxycarbonyl)-L-proline (138 mg, 0.64mmol), N1-hydroxy-7-azabenzotriazole(85 mg, 0.64 mmol) and N,N-diisopropylethylamine(83 mg, 0.64 mmol) in anhydrous DMF (2 mL) was treated with2-chloro-1-methylpyridinium iodide (163 mg, 0.64 mmol) and the mixture stirredat 20 oC for 18 h. The mixture was diluted with ethyl acetate (50ml) and washed with 1N HCl (50 ml), water (2 X 50 mL), saturated sodiumbicarbonate solution (50 mL) and brine (25 mL). The organic layer was driedwith Na2SO4 and evaporated. The residue was purified byreversed phase HPLC (method described in the general experimental section) andthe product fractions were evaporated under reduced pressure at <45 oC.The residue was dissolved in 4N HCl in 1,4-dioxane (2 mL) and stirred for 2 h.The solvents were evaporated under reduced pressure to provide 7 as a white solid HCl salt (65 mg,53%). 1H-NMR (CD3OD) d7.89 (d, J = 8.1 Hz, 1H), 7.75 (d, J =8.2 Hz, 1H), 7.48 (dd, J = 8.2 Hz, J = 8.1 Hz, 1H), 7.35 (dd, J = 8.2 Hz, J = 8.1 Hz, 1H), 4.58 (dd, J= 7.1 Hz, J = 6.8 Hz, 1H), 3.49(m, 2H), 2.58 (m, 1H), 2.17 (m, 3H). LC/MS M+H+ = 248, Rt = 2.77 mins, purity>95%. Exact mass calc?d for C12H13N3OS =247.0779, found = 247.0791. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-7-aza-benzotriazole; 2-chloro-1-methyl-pyridinium iodide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | A solution of benzo[d]thiazol-2-amine(65 mg, 0.43 mmol), 1-(tert-butoxycarbonyl)-L-proline (138 mg, 0.64mmol), N1-hydroxy-7-azabenzotriazole(85 mg, 0.64 mmol) and N,N-diisopropylethylamine(83 mg, 0.64 mmol) in anhydrous DMF (2 mL) was treated with2-chloro-1-methylpyridinium iodide (163 mg, 0.64 mmol) and the mixture stirredat 20 oC for 18 h. The mixture was diluted with ethyl acetate (50ml) and washed with 1N HCl (50 ml), water (2 X 50 mL), saturated sodiumbicarbonate solution (50 mL) and brine (25 mL). The organic layer was driedwith Na2SO4 and evaporated. The residue was purified byreversed phase HPLC (method described in the general experimental section) andthe product fractions were evaporated under reduced pressure at <45 oC.The residue was dissolved in 4N HCl in 1,4-dioxane (2 mL) and stirred for 2 h.The solvents were evaporated under reduced pressure to provide 7 as a white solid HCl salt (65 mg,53%). 1H-NMR (CD3OD) d7.89 (d, J = 8.1 Hz, 1H), 7.75 (d, J =8.2 Hz, 1H), 7.48 (dd, J = 8.2 Hz, J = 8.1 Hz, 1H), 7.35 (dd, J = 8.2 Hz, J = 8.1 Hz, 1H), 4.58 (dd, J= 7.1 Hz, J = 6.8 Hz, 1H), 3.49(m, 2H), 2.58 (m, 1H), 2.17 (m, 3H). LC/MS M+H+ = 248, Rt = 2.77 mins, purity>95%. Exact mass calc?d for C12H13N3OS =247.0779, found = 247.0791. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-7-aza-benzotriazole; 2-chloro-1-methyl-pyridinium iodide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | A solution of benzo[d]thiazol-2-amine(65 mg, 0.43 mmol), 1-(tert-butoxycarbonyl)-L-proline (138 mg, 0.64mmol), N1-hydroxy-7-azabenzotriazole(85 mg, 0.64 mmol) and N,N-diisopropylethylamine(83 mg, 0.64 mmol) in anhydrous DMF (2 mL) was treated with2-chloro-1-methylpyridinium iodide (163 mg, 0.64 mmol) and the mixture stirredat 20 oC for 18 h. The mixture was diluted with ethyl acetate (50ml) and washed with 1N HCl (50 ml), water (2 X 50 mL), saturated sodiumbicarbonate solution (50 mL) and brine (25 mL). The organic layer was driedwith Na2SO4 and evaporated. The residue was purified byreversed phase HPLC (method described in the general experimental section) andthe product fractions were evaporated under reduced pressure at <45 oC.The residue was dissolved in 4N HCl in 1,4-dioxane (2 mL) and stirred for 2 h.The solvents were evaporated under reduced pressure to provide 7 as a white solid HCl salt (65 mg,53%). 1H-NMR (CD3OD) d7.89 (d, J = 8.1 Hz, 1H), 7.75 (d, J =8.2 Hz, 1H), 7.48 (dd, J = 8.2 Hz, J = 8.1 Hz, 1H), 7.35 (dd, J = 8.2 Hz, J = 8.1 Hz, 1H), 4.58 (dd, J= 7.1 Hz, J = 6.8 Hz, 1H), 3.49(m, 2H), 2.58 (m, 1H), 2.17 (m, 3H). LC/MS M+H+ = 248, Rt = 2.77 mins, purity>95%. Exact mass calc?d for C12H13N3OS =247.0779, found = 247.0791. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-7-aza-benzotriazole; 2-chloro-1-methyl-pyridinium iodide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | Asolution of 2 (100 mg, 0.43 mmol), 1-(tert-butoxycarbonyl)-L-proline(138 mg, 0.64 mmol), N1-hydroxy-7-azabenzotriazole(85 mg, 0.64 mmol) and N,N-diisopropylethylamine (83 mg, 0.64mmol) in anhydrous DMF (2 mL) was treated with 2-chloro-1-methylpyridiniumiodide (163 mg, 0.64 mmol) and the mixture stirred at 20 oC for 18h. The mixture was diluted with ethyl acetate (50 ml) and washed with 1N HCl(50 ml), water (2 X 50 mL), saturated sodium bicarbonate solution (50 mL) andbrine (25 mL). The organic layer was dried with Na2SO4and evaporated. The residue was purified by reversed phase HPLC (methoddescribed in the general experimental section) and the product fractions wereevaporated under reduced pressure at <45 oC. The residue wasdissolved in 4N HCl in 1,4-dioxane (2 mL) and stirred for 2 h. The solventswere evaporated under reduce pressure to provide 5 as a white solid HCl salt (117 mg, 50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-7-aza-benzotriazole; 2-chloro-1-methyl-pyridinium iodide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | Asolution of 2 (100 mg, 0.43 mmol), 1-(tert-butoxycarbonyl)-L-proline(138 mg, 0.64 mmol), N1-hydroxy-7-azabenzotriazole(85 mg, 0.64 mmol) and N,N-diisopropylethylamine (83 mg, 0.64mmol) in anhydrous DMF (2 mL) was treated with 2-chloro-1-methylpyridiniumiodide (163 mg, 0.64 mmol) and the mixture stirred at 20 oC for 18h. The mixture was diluted with ethyl acetate (50 ml) and washed with 1N HCl(50 ml), water (2 X 50 mL), saturated sodium bicarbonate solution (50 mL) andbrine (25 mL). The organic layer was dried with Na2SO4and evaporated. The residue was purified by reversed phase HPLC (methoddescribed in the general experimental section) and the product fractions wereevaporated under reduced pressure at <45 oC. The residue wasdissolved in 4N HCl in 1,4-dioxane (2 mL) and stirred for 2 h. The solventswere evaporated under reduce pressure to provide 5 as a white solid HCl salt (117 mg, 50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-7-aza-benzotriazole; 2-chloro-1-methyl-pyridinium iodide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | Asolution of 2 (100 mg, 0.43 mmol), 1-(tert-butoxycarbonyl)-L-proline(138 mg, 0.64 mmol), N1-hydroxy-7-azabenzotriazole(85 mg, 0.64 mmol) and N,N-diisopropylethylamine (83 mg, 0.64mmol) in anhydrous DMF (2 mL) was treated with 2-chloro-1-methylpyridiniumiodide (163 mg, 0.64 mmol) and the mixture stirred at 20 oC for 18h. The mixture was diluted with ethyl acetate (50 ml) and washed with 1N HCl(50 ml), water (2 X 50 mL), saturated sodium bicarbonate solution (50 mL) andbrine (25 mL). The organic layer was dried with Na2SO4and evaporated. The residue was purified by reversed phase HPLC (methoddescribed in the general experimental section) and the product fractions wereevaporated under reduced pressure at <45 oC. The residue wasdissolved in 4N HCl in 1,4-dioxane (2 mL) and stirred for 2 h. The solventswere evaporated under reduce pressure to provide 5 as a white solid HCl salt (117 mg, 50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.35 g | With potassium hydroxide; In water; at 120℃; for 16h; | 6-(trifluoromethoxy)-1 ,3-benzothiazol-2-amine (IV-2) (0.5 g, 2.14 mmol) was suspended with 25% aqueous KOH (20 ml) solution. The mixture was heated at 120C for 16 hours. After completion of the reaction the mixture was cooled to RT and poured into ice water. The mixture was neutralized with 50% HCI solution and extracted with ethyl acetate. Organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure. The yield of 2-[2-amino-5-(trifluoromethoxy)phenyl]disulfanyl}-4-(tri- fluoromethoxy)aniline (llb-2) after flash chromatography (100-200 mesh size silica gel, 10% ethyl acetate in hexane) was 0.35 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; water; at 70℃; for 4h; | RLZ inclusion complexes with CDs (beta-CD and DM-beta-CD) were prepared in molar ratio of 1:1 via co-precipitation andvacuum-drying techniques, respectively. Co-precipitation was per-formed as described by Marcolino, Zanin, Durrant, Benassi, and Matioli (2011) with few modifications.beta-CD (3.40 g) was completely dissolved in 30 mL of triple-distilled water and stirred at 70C. RLZ (0.70 g) was dissolved in ethanol at 70C and added drop-wise to the solution. The mixture was then magnetically stirredfor 4 h. The final solution was filtered, and the filtrate was cooledovernight at 1C. Subsequently, the solid residue was washed thricewith ethanol and triple-distilled water to remove unreacted RLZ and beta-CD. The final solid inclusion complex was collected after drying at 70C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; at 40℃; for 4h; | DM-beta-CD (1.33 g) and RLZ (0.23 g) were completely dissolved in 10 mL of methanol. After magnetic stirring at 40C for 4 h, the resulting solution was filtered and vacuum dried at 40C to collectthe final inclusion complex. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bromine; acetic acid; lithium bromide at 40℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Pyridine (0.1 mol) and compound 2a(0.05 mol) were successively added with stirring to a solution ofcompound 1 (0.05 mol) in benzene (50 mL) at 20 C. The reaction mixture was stirred for 30 min. Then SOCl2 (0.05 mol) wasadded, the mixture was stirred for 1 h and filtered, and the residues was recrystallized from hexane. Yield 14.6 g (78%), m.p.79-81 C. 1H NMR (CDCl3), delta: 3.85 (s, 3 H, CH3O); 7.52 (d, 1 H,CHAr, 3JH,H = 7.6 Hz); 7.90 (d, 1 H, CHAr, 3JH,H = 7.5 Hz);8.16 (s, 1 H, CHAr). 19F NMR (CDCl3), delta: 6.01 (s, 3 F, CF3);17.79 (s, 3 F, CF3O). Found (%): C, 38.51; H, 1.85; N, 7.72.C12H6F6N2O3S. Calculated (%): C, 38.72; H, 1.62; N, 7.53. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | General procedure: Pyridine (0.1 mol) and compound 2a(0.05 mol) were successively added with stirring to a solution ofcompound 1 (0.05 mol) in benzene (50 mL) at 20 C. The reaction mixture was stirred for 30 min. Then SOCl2 (0.05 mol) wasadded, the mixture was stirred for 1 h and filtered, and the residues was recrystallized from hexane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60 mg | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 48h; | j0244J 5 -chloro-2-methoxy-3 -methylbenzoic acid (96mg, 0. 48mmol) was dissolved in DCM (3.0 mL), followed by the addition of catalytic amount of DMF (1 drop)and oxalyl chloride (68 uL, 0.58mmol) respectively. The reaction was allowed to stir at rt for 30 mm and concentrated in vacuo. The residue was re-dissolved in THF (5.0 mL), and Hunig?s base (125uL, 0.72mmol) and 6-(trifluoromethoxy)benzo[d]thiazol-2-amine (135mg, 0.576mmo1) were added. The mixture was stirred at rt for 48 hours before silica gel was added to quench the reaction. Solvent was evaporated and the resulting residue was purified via silica gel column chromatography to yield 5-chloro-2-methoxy-3-methyl-N-(6- (trifluoromethoxy)benzo[d]thiazol-2-yl)benzamide (60mg, 31% yield) as a white solid. ?H NIVIR (300 MHz, Chloroform-cl) 11.46 (s, 1H), 8.05 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.74 (dd, J= 2.4, 1.1 Hz, 1H), 7.44 (d, J= 2.8 Hz, 1H), 7.39-7.31 (m, 1H), 3.96 (s, 3H), 2.40 (s, 3H). MS (ESI) [M+H]+requires m/z 417.03, found m/z 417.20. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: N-(tert-butoxycarbonyl)sarcosine; Riluzole With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 20h; Inert atmosphere; Stage #2: Inert atmosphere; Acidic conditions; Stage #3: 2-(tert-butoxycarbonyl(isopropyl)amino)acetic acid Further stages; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With copper(I) thiophene-2-carboxylate; (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(5-methyl-2-(4-fluorophenyl)pyridine(-1H))-iridium(III) hexafluorophosphate; N,N,N?,N?-tetramethyl-N?-tert-butylguanidine; bathophenanthroline; iodomesitylene diacetate; In 1,4-dioxane; at 20℃; for 1h;Inert atmosphere; Irradiation; | General procedure: To a 20 ml or 40 ml viale quipped with a stir bar was added photocatalyst, nitrogen nucleophile, iodomesitylene dicarboxylate, copper salt, and ligand. Dioxane was added followed by addition of the base. The solution was sonicated for 1-3 min until it became homogeneous. Next, the solution was degassed by sparging with nitrogen for 5-10 min before sealing with Parafilm. The reaction was stirred and irradiated using two 34-W blue LED lamps (3 cm away, with cooling fan to keep the reaction at room temperature) for 1 h. The reaction mixture was removed from the light, cooled to ambient temperature, diluted with water (15 ml) and ethyl acetate (25 ml), and the aqueous layer was extracted with ethyl acetate (3 × 25 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel to afford the desired decarboxylative C-N coupling product. For aniline substrates, a solution of these nitrogen nucleophiles in dioxane was used; additionally, if the iodomesitylene dicarboxylate is a liquid, its solution in dioxane was used. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With copper(I) thiophene-2-carboxylate; (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(5-methyl-2-(4-fluorophenyl)pyridine(-1H))-iridium(III) hexafluorophosphate; N,N,N?,N?-tetramethyl-N?-tert-butylguanidine; bathophenanthroline; iodomesitylene diacetate; In 1,4-dioxane; at 20℃; for 1h;Inert atmosphere; Irradiation; | General procedure: To a 20 ml or 40 ml viale quipped with a stir bar was added photocatalyst, nitrogen nucleophile, iodomesitylene dicarboxylate, copper salt, and ligand. Dioxane was added followed by addition of the base. The solution was sonicated for 1-3 min until it became homogeneous. Next, the solution was degassed by sparging with nitrogen for 5-10 min before sealing with Parafilm. The reaction was stirred and irradiated using two 34-W blue LED lamps (3 cm away, with cooling fan to keep the reaction at room temperature) for 1 h. The reaction mixture was removed from the light, cooled to ambient temperature, diluted with water (15 ml) and ethyl acetate (25 ml), and the aqueous layer was extracted with ethyl acetate (3 × 25 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel to afford the desired decarboxylative C-N coupling product. For aniline substrates, a solution of these nitrogen nucleophiles in dioxane was used; additionally, if the iodomesitylene dicarboxylate is a liquid, its solution in dioxane was used. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Carboxylic acid 3 (0.2 mmol, 1 equiv.) and HATU (0.2 mmol, 1 equiv.) were dissolved in 1 mL DCE in a one dram vial charged with a stir bar. DIPEA (0.1 mL, 0.6 mmol, 3 equiv.) was added and the resulting solution was stirred at RT for 10 minutes. Amine 2 (0.2 mmol, 1 equiv.) was added to the mixture. The reaction solution was heated to 45 C and stirred overnight. Upon completion the reaction mixture was condensed and loaded onto a 60g C-18 cartridge and purified over a gradient of 5-95% ACN/H2O. The fractions containing product were identified by LC-MS and condensed under vacuum to give the final product 4. The final product was characterized by NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Carboxylic acid 3 (0.2 mmol, 1 equiv.) and HATU (0.2 mmol, 1 equiv.) were dissolved in 1 mL DCE in a one dram vial charged with a stir bar. DIPEA (0.1 mL, 0.6 mmol, 3 equiv.) was added and the resulting solution was stirred at RT for 10 minutes. Amine 2 (0.2 mmol, 1 equiv.) was added to the mixture. The reaction solution was heated to 45 C and stirred overnight. Upon completion the reaction mixture was condensed and loaded onto a 60g C-18 cartridge and purified over a gradient of 5-95% ACN/H2O. The fractions containing product were identified by LC-MS and condensed under vacuum to give the final product 4. The final product was characterized by NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Carboxylic acid 3 (0.2 mmol, 1 equiv.) and HATU (0.2 mmol, 1 equiv.) were dissolved in 1 mL DCE in a one dram vial charged with a stir bar. DIPEA (0.1 mL, 0.6 mmol, 3 equiv.) was added and the resulting solution was stirred at RT for 10 minutes. Amine 2 (0.2 mmol, 1 equiv.) was added to the mixture. The reaction solution was heated to 45 C and stirred overnight. Upon completion the reaction mixture was condensed and loaded onto a 60g C-18 cartridge and purified over a gradient of 5-95% ACN/H2O. The fractions containing product were identified by LC-MS and condensed under vacuum to give the final product 4. The final product was characterized by NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Carboxylic acid 3 (0.2 mmol, 1 equiv.) and HATU (0.2 mmol, 1 equiv.) were dissolved in 1 mL DCE in a one dram vial charged with a stir bar. DIPEA (0.1 mL, 0.6 mmol, 3 equiv.) was added and the resulting solution was stirred at RT for 10 minutes. Amine 2 (0.2 mmol, 1 equiv.) was added to the mixture. The reaction solution was heated to 45 C and stirred overnight. Upon completion the reaction mixture was condensed and loaded onto a 60g C-18 cartridge and purified over a gradient of 5-95% ACN/H2O. The fractions containing product were identified by LC-MS and condensed under vacuum to give the final product 4. The final product was characterized by NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Carboxylic acid 3 (0.2 mmol, 1 equiv.) and HATU (0.2 mmol, 1 equiv.) were dissolved in 1 mL DCE in a one dram vial charged with a stir bar. DIPEA (0.1 mL, 0.6 mmol, 3 equiv.) was added and the resulting solution was stirred at RT for 10 minutes. Amine 2 (0.2 mmol, 1 equiv.) was added to the mixture. The reaction solution was heated to 45 C and stirred overnight. Upon completion the reaction mixture was condensed and loaded onto a 60g C-18 cartridge and purified over a gradient of 5-95% ACN/H2O. The fractions containing product were identified by LC-MS and condensed under vacuum to give the final product 4. The final product was characterized by NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Carboxylic acid 3 (0.2 mmol, 1 equiv.) and HATU (0.2 mmol, 1 equiv.) were dissolved in 1 mL DCE in a one dram vial charged with a stir bar. DIPEA (0.1 mL, 0.6 mmol, 3 equiv.) was added and the resulting solution was stirred at RT for 10 minutes. Amine 2 (0.2 mmol, 1 equiv.) was added to the mixture. The reaction solution was heated to 45 C and stirred overnight. Upon completion the reaction mixture was condensed and loaded onto a 60g C-18 cartridge and purified over a gradient of 5-95% ACN/H2O. The fractions containing product were identified by LC-MS and condensed under vacuum to give the final product 4. The final product was characterized by NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Carboxylic acid 3 (0.2 mmol, 1 equiv.) and HATU (0.2 mmol, 1 equiv.) were dissolved in 1 mL DCE in a one dram vial charged with a stir bar. DIPEA (0.1 mL, 0.6 mmol, 3 equiv.) was added and the resulting solution was stirred at RT for 10 minutes. Amine 2 (0.2 mmol, 1 equiv.) was added to the mixture. The reaction solution was heated to 45 C and stirred overnight. Upon completion the reaction mixture was condensed and loaded onto a 60g C-18 cartridge and purified over a gradient of 5-95% ACN/H2O. The fractions containing product were identified by LC-MS and condensed under vacuum to give the final product 4. The final product was characterized by NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.6% | The compound phosphorus oxychloride (1.2 g, 7.6 mmol) was dissolved in dichloromethane (15 mL) at 0 C,Under a nitrogen atmosphere, a solution of riluzole 11A (1.80 g, 7.6 mmol) and triethylamine (1.08 ml) in dichloromethane (10 mL) was added dropwise, and the mixture was stirred at room temperature and then stirred for 1 hour. A solution of L-alanine ethyl ester (2.1 g, 15.2 mmol) in dichloromethane (5 ml),The remaining triethylamine (4.4 ml) was slowly added dropwise and stirring was continued for 3 hours. The reaction liquid was washed with water (20 mL), and the organic layer was dried over anhydrous sodium sulfate.Concentration and purification of the residue by silica gel column chromatography ( petroleum ether: ethyl acetate (v/v) = 1:1-0:1)Compound 14 was obtained as a white solid (0.49 g, yield 12.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2% | (Methoxymethyl)phosphoryl dichloride (1.25 g, 7.69 mmol) was dissolved in 8 mL of dichloromethane at -10 C under nitrogen. A solution of 11A (1.50 g, 6.41 mmol) and triethylamine (5.2 g, 51.24 mmol) in dichloromethane (3 mL) After the completion of the drop, keep the ice bath for 2 hours.L-Alanine ethyl ester (0.90 g, 7.69 mmol) was added at this temperature and reacted at room temperature for 4 h. Wash with water (20 mL) and dry over anhydrous sodium sulfate for 0.5 h. Concentrated and the residue was separated by column chromatography on neutral alumina (PE / EA = 1 / 1 ? DCM / MeOH = 10/1), then isolated by preparative HPLC to give a yellow oil ethyl (2S)-2-[[methoxymethyl-[[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino]phosphoryl]amino]propanoate (compound 11) (70 mg, yield 2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.2% | The compound phosphorus oxychloride (1.2 g, 7.6 mmol) was dissolved in dichloromethane (15 mL) at 0 C,Under a nitrogen atmosphere, a solution of riluzole 11A (1.80 g, 7.6 mmol) and triethylamine (1.08 ml) in dichloromethane (10 mL) was added dropwise, and the mixture was stirred at room temperature and then stirred for 1 hour. A solution of <strong>[39825-33-7]isopropyl L-alanine</strong> (2.7 g, 15.2 mmol) in dichloromethane (5 ml) was added dropwise.The remaining triethylamine (4.4 ml) was slowly added dropwise and stirring was continued for 3 hours. The reaction liquid was washed with water (20 mL), and the organic layer was dried over anhydrous sodium sulfate.Concentrated and the residue was purified by silica gel column chromatography ( petroleum ether: ethyl acetate (v/v) = 1:1-0:1) Compound 3 was obtained as a pale yellow oil (0.5 g, yield 12.2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | (Methoxymethyl)phosphoryl dichloride (1.25 g, 7.69 mmol) was dissolved in 8 mL of dichloromethane at -10 C under nitrogen atmosphere. A solution of 11A (1.50 g, 6.41 mmol) and triethylamine (5.2 g, 51.24 mmol) in dichloromethane (3 mL), After the completion of the drop, keep the ice bath for 2 hours. L-Alanine isopropyl ester (1.01 g, 7.69 mmol) was added at this temperature and reacted at room temperature for 4 h. Wash with water (20 mL) and dry over anhydrous sodium sulfate for 0.5 h. Concentrated and the residue was purified by silica gel column chromatography (PE/EA=1:1-0:1) and then Compound 2 was obtained by preparative HPLC. Yellow oil (80 mg, 3% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.6% | The compound phosphorus oxychloride (1.2 g, 7.6 mmol) was dissolved in dichloromethane (15 mL) at 0 C,Under a nitrogen atmosphere, a solution of riluzole (1.80 g, 7.6 mmol) and triethylamine (1.08 ml) in dichloromethane (10 mL) was added dropwise, and the mixture was stirred at room temperature and then stirred for 1 hour.A solution of isopropyl glycinate (2.1 g, 15.2 mmol) in dichloromethane (5 ml) was added dropwise.The remaining triethylamine (4.4 ml) was slowly added dropwise and stirring was continued for 3 hours. The reaction liquid was washed with water (20 mL), and the organic layer was dried over anhydrous sodium sulfate.concentrate, Concentrated and the residue is separated and purified by silica gel column chromatography.(Petroleum ether: ethyl acetate (v/v) = 1:1 - 0: 1) gave Compound 15 as pale yellow oil (0.49 g, yield 12.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.2% | The compound phosphorus oxychloride (1.2 g, 7.6 mmol) was dissolved in dichloromethane (15 mL) at 0 C,Under a nitrogen atmosphere, a solution of riluzole 11A (1.80 g, 7.6 mmol) and triethylamine (1.08 ml) in dichloromethane (10 mL) was added dropwise, and the mixture was stirred at room temperature and then stirred for 1 hour. A solution of A solution of isopropyl glycinate (1.65 g, 15.2 mmol) in dichloromethane (5 ml) was added dropwise.The remaining triethylamine (4.4 ml) was slowly added dropwise and stirring was continued for 3 hours.The reaction liquid was washed with water (20 mL), and the organic layer was dried over anhydrous sodium sulfate.Concentrated and the residue is separated and purified by silica gel column chromatography.(Petroleum ether: ethyl acetate (v/v) = 1:1 - 0: 1) gave Compound 16 as a white solid (0.45 g, yield 12.2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | In ethanol; at 100℃; for 0.5h;Sealed tube; Microwave irradiation; | General procedure: All microwave irradiation experiments were carried out in CEM-Discover monomode microwavedevice, operating at a frequency of 2.45 GHz. Substituted aminobenzothiazole, equimolar amount ofsubstituted benzaldehyde (1.5 mmol) and mercaptoacetic acid in absolut ethanol (3 mL) were placed ina 10 mL reaction vial containing a stirring bar. The vial was sealed with a Teflon septum and placedinto the microwave cavity. It was irradiated at 100 C using 100 W as maximum power for 30 min.at the end of the reaction the mixture was rapidly cooled with gas jet cooling to room temperature.The clean product was obtained after filter under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | In ethanol; at 100℃; for 0.5h;Sealed tube; Microwave irradiation; | General procedure: All microwave irradiation experiments were carried out in CEM-Discover monomode microwavedevice, operating at a frequency of 2.45 GHz. Substituted aminobenzothiazole, equimolar amount ofsubstituted benzaldehyde (1.5 mmol) and mercaptoacetic acid in absolut ethanol (3 mL) were placed ina 10 mL reaction vial containing a stirring bar. The vial was sealed with a Teflon septum and placedinto the microwave cavity. It was irradiated at 100 C using 100 W as maximum power for 30 min.at the end of the reaction the mixture was rapidly cooled with gas jet cooling to room temperature.The clean product was obtained after filter under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In ethanol; at 100℃; for 0.5h;Sealed tube; Microwave irradiation; | General procedure: All microwave irradiation experiments were carried out in CEM-Discover monomode microwavedevice, operating at a frequency of 2.45 GHz. Substituted aminobenzothiazole, equimolar amount ofsubstituted benzaldehyde (1.5 mmol) and mercaptoacetic acid in absolut ethanol (3 mL) were placed ina 10 mL reaction vial containing a stirring bar. The vial was sealed with a Teflon septum and placedinto the microwave cavity. It was irradiated at 100 C using 100 W as maximum power for 30 min.at the end of the reaction the mixture was rapidly cooled with gas jet cooling to room temperature.The clean product was obtained after filter under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In ethanol; at 100℃; for 0.5h;Sealed tube; Microwave irradiation; | General procedure: All microwave irradiation experiments were carried out in CEM-Discover monomode microwavedevice, operating at a frequency of 2.45 GHz. Substituted aminobenzothiazole, equimolar amount ofsubstituted benzaldehyde (1.5 mmol) and mercaptoacetic acid in absolut ethanol (3 mL) were placed ina 10 mL reaction vial containing a stirring bar. The vial was sealed with a Teflon septum and placedinto the microwave cavity. It was irradiated at 100 C using 100 W as maximum power for 30 min.at the end of the reaction the mixture was rapidly cooled with gas jet cooling to room temperature.The clean product was obtained after filter under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With isopentyl nitrite In tetrahydrofuran for 1h; Reflux; | |
With isopentyl nitrite In tetrahydrofuran for 0.5h; Schlenk technique; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With trifluoromethylsulfonic anhydride; [bis(acetoxy)iodo]benzene; iodine In water at 110℃; for 6h; Sealed tube; Green chemistry; | c 1. Procedure for benzo[d]thiazol-2-amine (2a) synthesis General procedure: To a 35 mL sealed tube was added benzo[d]thiazole 1a (0.2 mmol), KSeCN (43.2 mg, 0.3 mmol), I2 (10.2 mg, 20 mol %), PIDA (96.6 mg, 1.5 equiv) and Tf2O (0.8 equiv)in H2O (3 mL) under air. The reaction was heated at 110 oC for 6 h (oil bath), and then cooled down to room temperature. Ethyl acetate (20 mL) was added and the mixture was washed with water (3 × 10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC on silica gel plates using petroleum ether/EtOAc = 3/1 as the eluent to give the corresponding product 2a. |
Tags: 1744-22-5 synthesis path| 1744-22-5 SDS| 1744-22-5 COA| 1744-22-5 purity| 1744-22-5 application| 1744-22-5 NMR| 1744-22-5 COA| 1744-22-5 structure
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
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P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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