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CAS No. : | 4659-45-4 | MDL No. : | MFCD00000662 |
Formula : | C7H3Cl3O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JBLIDPPHFGWTKU-UHFFFAOYSA-N |
M.W : | 209.46 | Pubchem ID : | 78392 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 46.65 |
TPSA : | 17.07 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.3 cm/s |
Log Po/w (iLOGP) : | 2.03 |
Log Po/w (XLOGP3) : | 3.21 |
Log Po/w (WLOGP) : | 3.37 |
Log Po/w (MLOGP) : | 3.2 |
Log Po/w (SILICOS-IT) : | 3.62 |
Consensus Log Po/w : | 3.09 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.5 |
Solubility : | 0.0665 mg/ml ; 0.000317 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.24 |
Solubility : | 0.12 mg/ml ; 0.000575 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.2 |
Solubility : | 0.0132 mg/ml ; 0.0000631 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.33 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P264-P280-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P363-P405-P501 | UN#: | 3265 |
Hazard Statements: | H314 | 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 |
---|---|---|
70% | With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 2 h; Inert atmosphere | To a solution of 2, 6-dichlorobenzoic acid (0.1 g, 0.52 mmol) in DCM (5 mL) was added DMF (3.83 mg, 52.35 umol) at 0°C under N2, then oxalyl dichloride (0.20 g, 1.57 mmol) was added drop-wise at 0°C and the reaction mixture was stirred at 0 to 20°C for 2 hours. TLC (Petroleum ether: Ethyl acetate = 5:1, Rf= 0.77) showed the starting material was consumed completely. And the solvent was removed to give 2,6- dichlorobenzoyl chloride (0.11 g, 0.37 mmol, 70percent yield) which was used for next step directly. To 28g-int (65 mg, 0.17 mmol, HCl salt) and DIEA (87.3 mg, 0.68 mmol) in DCM (10 mL), was added drop-wise a solution of 2,6-dichlorobenzoyl chloride (88.43 mg, 0.42 mmol) in DCM (5 mL) at 0°C under N2. The reaction mixture was stirred at 0 - 20°C for 16 hrs after which LCMS indicated that 28h-int was present and 28g-int was consumed. The solvent was removed and the residue was purified by prep-HPLC to give pure 28h-int; LCMS (ESI+): m/z 521.3 (M+H)+, RT: 1.1 min.HPLC purification conditions: Gilson 281 semi-preparative HPLC system; Mobile phase: A: TFA/ H2O = 0.075percent v/v; B: ACN (gradient of B: 20percent at T= 0 to 40percent at T = 12 min); Column: YMC-Actus Triart C18150 x 305u; Flow rate: 20 mL/ min; Monitor wavelength: 220 & 254 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia | ||
With ammonia | ||
With ammonium hydroxide at 0 - 10℃; for 1h; | General synthetic procedure for compounds 3a-3t General procedure: A solution of thionyl chloride (25 mmol) was addeddropwisely to 1 (20 mmol) in toluene(15 mL). The mixture was heated to reflux for 3 h. Excess thionyl chloride wasremoved in vacuo. The remained mixture was added dropwise to ammonia waterbelow 10 °C, then stirred at 10 °C for 1 h. The intermediate 3 was obtained as white solid by filtration. |
With ammonium hydroxide In dichloromethane at 0 - 20℃; for 3.5h; | 4. General Procedure for Preparation of substituent benzoyl isocyanates M6 General procedure: The reaction of substituted benzoic acid M4 (10 mmol) with oxalyl chloride (2.52 g, 20 mmol) gavesubstituted benzoyl chloride. A solution of the substituted benzoyl chloridewas added dropwise to the solution of ammonium hydroxide (5 mL) indichloromethane (10 mL) at 0 oC. Then the reaction mixture wasstirred for 3.5 h at room temperature. Dichloromethane (10 mL) was added to themixture and the mixture was washed with water, a solution of sodium hydroxide(1 M), a solution of diluted hydrochloric acid (1 M) and brine, dried oversodiumsulfate and ltered. The solvent was evaporated under reduced pressure toget crude products. The crude products were recrystallized with dichloromethaneto give the pure compounds M5, whichwere used directly for preparation of isocyanates M6. The key intermediates isocyanates M6wereprepared by the usual method. Substituted benzamides M5 (5mmol), and to this 10mmol of oxalyl chloride was addeddropwisefor 10 min at ice-bath. After addition, the resulting clearsolution was heatedat about 75 oC for 6-8 h, and then the excessive oxalyl chloride wasremoved under reduced pressure to givea clear solution of substituted benzoylisocyanate M6, which was usedfor thenext step reaction without further purication. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium hydride In N,N-dimethyl-formamide for 16h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In dichloromethane at 20℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 15h; | |
88.4% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 15h; | f f) Preparation of (S)-2-tert-butoxycarbonylamino-3-[4-(2,6-dichloro-benzoylamino)-phenyl]-propionic acid methyl ester To a solution of (S)-3-(4-amino-phenyl)-tert-butoxycarbonylamino-propionic acid methyl ester (127.6 mmol, 37.57 g) and 2,6-dichlorobenzoyl chloride (140.6 mmol, 29.45 g) in dichloromethane (350 mL) was added DIPEA (192 mmol, 24.8 g) at RT. The brown solution was stirred for 15 h at RT to afford a white suspension. At this time TLC analysis of the mixture indicated the absence of starting material. Then, the solids were collected by filtration and the solids were washed with dichloromethane (150 mL) and air dried to obtain 52.75 g (88.4% yield) of (S)-2-tert-butoxycarbonylamino-3-[4-(2,6-dichloro-benzoylamino)-phenyl]-propionic acid methyl ester as a white solid: mp 192-194° C. ES(+)-HRMS m/e calcd. for C22H24Cl2N2O5 (M+H)+ 466.1062, obsd. 466.1069. |
88.4% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 15h; | 6 Step 6: Preparation of (S)-2-tert-butoxycarbonylamino-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester (RO0270513) Step 6: Preparation of (S)-2-tert-butoxycarbonylamino-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester (RO0270513) To a solution of (S)-3-[4-aminophenyl]-2-tert-butoxycarbonylamino-propionic acid methyl ester (127.6 mmol, 37.57 g) and 2,6-dichlorobenzoyl chloride (140.6 mmol, 29.45 g) in dichloromethane (350 mL) was added DIPEA (192 mmol, 24.8 g) at room temperature. The brown solution was stirred for 15 h at room temperature to afford a white suspension at this time TLC analysis of the mixture indicated the absence of starting material. Then, the solids were collected by filtration and the solids were washed with dichloromethane (150 mL) and air dried to obtain 52.75 g (88.4% yield) of (S)-2-tert-butoxycarbonylamino-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester as a white solid: mp 192-194° C. ES(+)-HRMS m/e calcd. for C22H24Cl2N2O5 (M+H)+ 466.1062, obsd. 466.1069. |
88.4% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 15h; | 1.6 Step 6: Preparation of (S)-2-tert-butoxycarbonylamino-3 - [4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester: To a solution of(S)-3-[4-aminophenyl]-2-tert-butoxycarbonylamino-propionic acid methyl ester (37.57 g, 127.6 mmol) and 2,6-dichlorobenzoyl chloride (29.45 g, 140.6 mmol) indichloromethane (350 mL) was added DIPEA (24.8 g, 192 mmol) at room temperature. The brown solution was stirred for 15 h at room temperature to afford a white suspension at this time TLC analysis of the mixture indicated the absence of starting material. Then, the solids were collected by filtration and the solids were washed with dichloro methane (150 mL) and air dried to obtain 52.75 g (88.4% yield) of(S)-2-tert-butoxycarbonylamino-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester as a white solid: mp 192-194 °C. ES(+)-HRMS m/e calcd. for C22H24C12N205 (M+H)+ 466.1062, obsd. 466.1069. |
With N-ethyl-N,N-diisopropylamine In dichloromethane | 44 Synthesis of 4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine Methyl Ester Example 44 Synthesis of 4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine Methyl Ester To a solution of 4-(amino)-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (2.6 g, 8.6 mmol) in dichloromethane (20 mL) were added diisopropylethylamine (2.3 mL, 13 mmol) followed by 2,6-dichlorobenzoyl chloride (1.99 g, 9.5 mmol) at room temperature. The mixture was stirred for 15 h at which time a white precipitate was formed. The mixture was diluted with 30 mL of dichloromethane and 50 mL of water. The layers were separated and the aqueous layer was extracted with 100 mL (2*50 mL) of dichloromethane. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. | |
52.75 g (88.4%) | With N-ethyl-N,N-diisopropylamine In dichloromethane | Preparation 4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine Methyl Ester Preparation 4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine Methyl Ester To a solution of 4-amino-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (127.6 mmol, 37.57 g) and 2,6-dichlorobenzoyl chloride (140.6 mmol, 29.45 g) in dichloromethane (350 mL) was added diisopropylethylamine (192 mmol, 33.4 mL) at room temperature. The brown solution was stirred for 15 h at room temperature to afford a white suspension. At this time, TLC analysis of the mixture indicated the absence of starting material. The solids were collected by filtration and were washed with dichloromethane (150 mL) and air dried to obtain 52.75 g (88.4%) of a white solid: mp 192-194° C. 1H NMR (DMSO-d6) (400 MHz) δ 10.68 (s, 1H), 7.47-7.6 (m, 5H), 7.2-7.29 (m, 3H), 4.12-4.17 (m, 1H), 3.62 (s, 3H), 2.79-2.99 (m, 2H), 1.33 (s, 9H). 13C NMR, CDCl3 (100 Mhz) d 172.49, 161.82, 155.37, 136.99, 136.36, 131.28, 131.16, 129.48, 128.19, 119.31, 78.27, 55.3, 51.76, 35.9, 27.77. HR MS: Obs. mass, 466.1069. Calcd. mass, 466.1062). |
52.75 g (88.4%) | With N-ethyl-N,N-diisopropylamine In dichloromethane | 146.c Preparation of 4-[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester c. Preparation of 4-[(2,6-dichlorophenylcarbonyl]amino]-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester. To a solution of 4-amino-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (127.6 mmol, 37.57 g) and 2,6-dichlorobenzoyl chloride (140.6 mmol, 29.45 g) in dichloromethane (350 mL) was added diisopropylethylamine (192 mmol, 33.4 mL) at room temperature. The brown solution was stirred for 15 h at room temperature to afford a white suspension. At this time, TLC analysis of the mixture indicated the absence of starting material. The solids were collected by filtration and were washed with dichloromethane (150 mL) and air dried to obtain 52.75 g (88.4%) of a white solid, mp 148-151° C. 1H NMR, DMSO-d6 (400 MHz) δ10.68 (s, 1H), 7.47-7.6 (m, 5H), 7.2-7.29 (m, 3H), 4.12-4.17 (m, 1H), 3.62 (s, 3H), 2.79-2.99 (m, 2H), 1.33 (s, 9H). 13C NMR, CDCl3 (100 Mhz) d 172.49, 161.82, 155.37, 136.99, 136.36, 131.28, 131.16, 129.48, 128.19, 119.31, 78.27, 55.3, 51.76, 35.9, 27.77. HR MS: Obs. mass, 466.1069. Calcd. mass, 466.1062 (M+H). |
With triethylamine In tetrahydrofuran at 0 - 20℃; for 18h; | 75 The aminoester product of preparation 75 is useful as a synthetic intermediate (for example, reagent A-4 of Scheme A). [00611] To a cold (0-5° C.) solution of anhydrous methanolic HCl was added 100 g of L-4-nitrophenylalanine (Advanced ChemTech) portionwise over 15 min. The mechanically stirred mixture was heated to gentle reflux for 48 h. The mixture was allowed to cool and then filtered through a sintered glass filter funnel, washing the collected solids with hot MeOH until only insoluble residues remained. The filtrate was concentrated in vacuo to afford the methyl ester (120 g) as waxy off white solid which was used without further purification. [00612] To a suspension of methyl ester described above (87 g, 0.33 mole) in CH2Cl2 (1500 mL) at ambient temperature was added di-t-butyldicarbonate (109 g, 0.50 mole) followed by the dropwise addition of Et3N (51 mL, 0.37 mole). After 15 min additional Et3N (40 mL, 0.29 mol) was added to maintain a slightly basic mixture (ca. pH 8). The reaction mixture was stirred 18 h and additional CH2Cl2 (1400 mL) and Et3N (15 mL, 0.11 mol) were added. After an additional 2 h the reaction mixture was quenched by the slow addition of MeOH (100 mL), stirred for 1 h and then partitioned between CH2Cl2 and cold 10% aqueous KHSO4. The organic layer was washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography of the residue using hexane and a gradient of a 1:1 mixture of EtOAc/CH2Cl2 (25-33%) afforded the Boc-methyl ester (69 g) as a white solid. Physical properties as follows: 1H NMR (300 MHz; CDCl3) δ 8.16 (2H), 7.31 (2H), 5.04 (1H), 4.63 (1H), 3.73 (3H), 3.18 (2H), 1.41 (9H); MS (ES+) for C15H20N2O6 m/z 325.2 (M+H)+. [00613] Palladium on carbon (10% w/w. 1.25 g) was added to a Parr hydrogenation flask under a N2 atmosphere and carefully wetted with 100 mL of MeOH/THF (1:1). A solution of the Boc-methyl ester described above (25 g, 77 mmol) in 400 mL of MeOH/THF (1:1) was added and the mixture shaken on a hydrogenation apparatus under a hydrogen atmosphere (20 psi) for 1 h at ambient temperature. The reaction mixture was filtered through a pad of Celite and the solids washed several times with MeOH. The combined filtrates were concentrated in vacuo to afford the 4-aminophenylalanyl derivative (22.7 g) which was used without further purification. Physical properties as follows: 1H NMR (300 MHz, CDCl3) δ 6.89 (2H), 6.61 (2H), 4.96 (1H), 4.50 (1H), 3.69 (3H), 2.95 (2H), 1.41 (9H); MS (ES+) for C15H22N2O4 m/z 295.2 (M+H)+. [00614] A cold (0-5° C.) solution of 2,6-dichlorobenzoyl chloride (11.1 mL, 77.5 mmol) in 125 mL of THF was treated dropwise with a solution of the 4-aminophenylalanyl derivative described above (22.7 g, 77.1 mmol) and Et2N (16 mL, 115 mmol) in 125 mL of THF. The reaction mixture was allowed to warm to temperature and stir an additional 18 h. The mixture was diluted with EtOAc (2 L) and then washed with 1N HCl, H2O, 1N NaOH and brine. The organic extract was dried (Na2SO4), filtered, and concentrated in vacuo to give the crude product as a pale yellow solid. This material was recrystallized from acetone/hexanes (ca. 1:1) to afford the amide (30.8 g) as a crystalline solid. Physical properties as follows: mp 192.2-193.1° C.; IR (mull) 3305, 1747, 1736, 1690, 1665, 1609, 1548, 1512, 1433, 1414, 1325, 1277, 1219, 1171, 781 cm-1; 1H NMR (300 MHz; CDCl3) δ 7.57 (2H), 7.34 (4H), 7.14 (2H), 4.98 (1H), 4.60 (1H), 3.74 (3H), 3.11 (2H), 1.42 (9H); MS (ES+) for C22H24Cl2N2O5 m/z 467.0 (M+H)+. [00615] To 650 mL of anhydrous 4M HCl in dioxane at ambient temperature was added the amide described above (30.6 g, 65.5 mmol) portionwise and the resulting mixture was stirred until all the solids had dissolved (ca. 1 h). Volatiles were removed in vacuo to give a light yellow solid which was partitioned between water (500 mL) and ether (1 L). The water layer was separated and concentrated in vacuo to approximately 200 mL. The aqueous solution was then frozen and lyophilized to afford the aminoester product (25.6 g) as a light yellow solid. Physical properties as follows: [α]25D=+5 (c 1, MeOH); IR (mull) 3244, 3186, 3112, 1747, 1660, 1604, 1562, 1539, 1516, 1431, 1416, 1327, 1273, 1243, 799 cm-1; 1H NMR (300 MHz; CD3OD) δ 7.69 (2H), 7.45 (3H), 7.29 (2H), 4.34 (1H), 3.83 (3H), 3.21 (2H); 13C NMR (300 MHz; CD3OD) δ 169.0, 163.9, 137.8, 136.08, 131.8, 131.0, 130.3, 129.7, 127.9, 120.6, 53.8, 52.3,.35.4; MS (ES+) for C17H16Cl2N2O3 m/z 367.1 (M+H)+. | |
With triethylamine In tetrahydrofuran at 0 - 20℃; for 18h; | 6 Compound 6; N-tert-Butoxycarbonyl-4-[(2,6-dichlorobenzoyl)amino]-L-phenylalanine methyl ester (Compound 6) To a cooled (0-5°C) solution of 2,6-dichlorobenzoyl chloride (11.1 mL, 77.5 mmol) in THF (125 mL) was added a solution of the compound 5 (22.7 g, 77.1 mmol) and Et3N (16 mL, 115 mmol) in THF (125 mL). The reaction mixture was allowed to warm to temperature and stir an additional 18 h. The mixture was diluted with EtOAc (2 L) and washed with 1N aqueous HCl, H2O, 1N aqueous NaOH and brine. The organic extract was dried (Na2SO4), filtered, and concentrated in vacuo to give the crude product as a pale yellow solid. This material was recrystallized from acetone/hexanes to afford the amide as a crystalline solid. Physical properties as follows: mp 192.2-193.1°C; IR (mull) 3305, 1747, 1736, 1690, 1665, 1609, 1548, 1512, 1433, 1414, 1325, 1277, 1219, 1171, 781 cm-1; 1H NMR (300 MHz; CDCl3) δ 7.57 (2H), 7.34 (4H), 7.14 (2H), 4.98 (1H), 4.60 (1H), 3.74 (3H), 3.11 (2H), 1.42 (9H); MS (ES+) for C22H24Cl2N2O5 m/z 467.0 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 17; (S)-2-(2,6-Dichloro-benzoylamino)-3-[4-(5-difluoromethoxy-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-propionic acid, Cpd 112; Compound 1e (1.47 mL, 10.2 mmol) was added to a mixture of Compound 1a (<strong>[76410-58-7]4-borono-L-phenylalanine</strong>) (2.04 g, 9.76 mmol) and Na2CO3 (2.07 g, 19.5 mmol) in acetonitrile:water (1:1, 40 mL) at 50 C. The resulting mixture was stirred at 50 C. for 1 h, then was cooled to 0 C. and was acidified to pH 2 by addition of concentrated HCl (aq). The suspension was stirred at 0 C. for 30 min and the precipitated solid was collected by vacuum filtration and was washed with water. The white solid was dried in a vacuum oven at 50 C., affording Compound 17a (2.65 g). 1H NMR (CD3OD) delta 7.55 (d, 2H, J=7.6 Hz), 7.28-7.40 (m, 5H), 4.95 (dd, 1H, J=9.3, 4.7 Hz), 3.30 (dd, 1H, J=13.9, 5.3 Hz), 3.03 (dd, 1H, J=14.1, 9.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In 1,4-dioxane at 45℃; for 2h; | 6.5 To a mixture of 4-amino-1H-pyrazole-3-carboxylic acid (1-methanesulphonyl-piperidin-4- yl)-amide (3.4 g, ~10 mmol) and triethylamine (1.53 ml_, 11 mmol) in dioxane (50 ml_) at 45 0C was slowly added 2,6-dichIorobenzoyl chloride (1.4 mL, 10 mmol). The mixture was heated at 45 0C for 2 h, poured into water (250 mL) and then extracted with EtOAc (2 x 200 mL). The combined organic extracts were reduced in vacuo and purified by column chromatography on silica gel eluting with P. E-EtOAc (1 :0 - 0:1). The product containing fractions were reduced in vacuo and the residue taken up in 2M aqueous NaOH-MeOH (1 :1 , 50 mL) and stirred at ambient temperature for 2 h. The MeOH was removed in vacuo and the mixture extracted with EtOAc. The organic portion was washed with brine, dried over MgSO4 and reduced in vacuo. The residue was purified by hot slurry with EtOH to give the title compound as an off-white solid (2.52 g). | |
Stage #1: 4-amino-1H-pyrazole-3-carboxylic acid (1-methanesulphonyl-piperidin-4-yl) amide; 2,6-Dichlorobenzoyl chloride With triethylamine In 1,4-dioxane at 45℃; for 2h; Stage #2: With sodium hydroxide In methanol; water at 20℃; for 2h; | 6.5 To a mixture of 4-amino-1 H-pyrazole-3-carboxylic acid (1-methanesulphonyl-piperidin-4- yl)-amide (3.4 g, ~10 mmol) and triethylamine (1.53 mL, 11 mmol) in dioxane (50 mL) at 45 0C was slowly added 2,6-dichlorobenzoyl chloride (1.4 mL, 10 mmol). The mixture was heated at 45 0C for 2 h, poured into water (250 mL) and then extracted with EtOAc (2 x 200 mL). The combined organic extracts were reduced in vacuo and purified by column chromatography on silica gel eluting with P. E-EtOAc (1 :0 - 0:1). The product containing fractions were reduced in vacuo and the residue taken up in 2M aqueous NaOH-MeOH (1 :1 , 50 mL) and stirred at ambient temperature for 2 h. The MeOH was removed in vacuo and the mixture extracted with EtOAc. The organic portion was washed with brine, dried over MgSO4 and reduced in vacuo. The residue was purified by hot slurry with EtOH to give the title compound as an off-white solid (2.52 g). | |
With triethylamine In 1,4-dioxane; aqueous NaOH-MeOH | 6.5 Step 5: Step 5: Synthesis of 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid (1-methanesulphonyl-piperidin-4-yl)-amide To a mixture of 4-amino-1H-pyrazole-3-carboxylic acid (1-methanesulphonyl-piperidin-4-yl)-amide (3.4 g, ~10 mmol) and triethylamine (1.53 mL, 11 mmol) in dioxane (50 mL) at 45° C. was slowly added 2,6-dichlorobenzoyl chloride (1.4 mL, 10 mmol). The mixture was heated at 45° C. for 2 h, poured into water (250 mL) and then extracted with EtOAc (2*200 mL). The combined organic extracts were reduced in vacuo and purified by column chromatography on silica gel eluding with P.E-EtOAc (1:0-0:1). The product containing fractions were reduced in vacuo and the residue taken up in 2M aqueous NaOH-MeOH (1:1, 50 mL) and stirred at ambient temperature for 2 h. The MeOH was removed in vacuo and the mixture extracted with EtOAc. The organic portion was washed with brine, dried over MgSO4 and reduced in vacuo. The residue was purified by hot slurry with EtOH to give the title compound as an off-white solid (2.52 g). |
Stage #1: 4-amino-1H-pyrazole-3-carboxylic acid (1-methanesulphonyl-piperidin-4-yl) amide; 2,6-Dichlorobenzoyl chloride With triethylamine In 1,4-dioxane at 45℃; for 2h; Stage #2: With sodium hydroxide In methanol; water at 20℃; for 2h; | 12.5 To a mixture of 4-amino-1 H-pyrazole-3-carboxylic acid (1-methanesulphonyl-piperidin-4- yl)-amide (3.4 g, ~10 mmol) and triethylamine (1.53 mL, 11 mmol) in dioxane (50 ml_) at 45 0C was slowly added 2,6-dichlorobenzoyl chloride (1.4 mL, 10 mmol). The mixture was heated at 45 °C for 2 h, poured into water (250 mL) and then extracted with EtOAc (2 x 200 mL). The combined organic extracts were reduced in vacuo and purified by column chromatography on silica gel eluting with P. E-EtOAc (1:0 - 0:1). The product containing fractions were reduced in vacuo and the residue taken up in 2M aqueous NaOH-MeOH (1 :1 , 50 mL) and stirred at ambient temperature for 2 h. The MeOH was removed in vacuo and the mixture extracted with EtOAc. The organic portion was washed with brine, dried over MgSO4 and reduced in vacuo. The residue was purified by hot slurry with EtOH to give the title compound as an off-white solid (2.52 g). | |
Stage #1: 4-amino-1H-pyrazole-3-carboxylic acid (1-methanesulphonyl-piperidin-4-yl) amide; 2,6-Dichlorobenzoyl chloride With triethylamine In 1,4-dioxane at 45℃; for 2h; Stage #2: With sodium hydroxide In methanol; water at 20℃; for 2h; | 2; 2.5 Step 5: Synthesis of 4-(2,6-dichloro-benzoylammoyiH-pyrazole-3-carboxylic acid fl-methanesulphonyl-piperidin-4-yl)-amideTo a mixture of 4-amino-lH-pyrazole-3-carboxylic acid (1-methanesulphonyl- piperidin-4-yl)-amide (3.4 g, ~10 mmol) and triethylamine (1.53 mL, 11 mnαol) in dioxane (50 mL) at 45 0C was slowly added 2,6-dichlorobenzoyl chloride (1.4 mL, 10 mmol). The mixture was heated at 45 0C for 2 h, poured into water (250 mL) and then extracted with EtOAc (2 x 200 mL). The combined organic extracts were reduced in vacuo and purified by column chromatography on silica gel eluting with P. E-EtO Ac (1:0 - 0:1). The product containing fractions were reduced in vacuo and the residue taken up in 2M aqueous NaOH-MeOH (1 : 1 , 50 mL) and stirred at ambient temperature for 2 h. The MeOH was removed in vacuo and the mixture extracted with EtOAc. The organic portion was washed with brine, dried over MgSO4 and reduced in vacuo. The residue was purified by hot slurry with EtOH to give the title compound as an off-white solid (2.52 g). |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: 2,6-Dichlorobenzoyl chloride; 4-amino-1H-pyrazole-3-carboxylic acid ethyl ester With triethylamine In 1,4-dioxane at 50℃; Stage #2: With sodium hydroxide; water In 1,4-dioxane at 50℃; for 6h; Stage #3: With hydrogenchloride In water | II Preparation II; Synthesis of 4-(2,6-dichloro-benzoylarninoV lH-pγrazole-3-carboxγlic acid2,6-dichlorobenzoyl chloride; (27.6 ml; 193 mmol, 1.1 eq.) in dioxane (50 ml) was added cautiously (dropwise) to a solution of 4-amino-lH-pyrazole-3-carboxylic acid ethyl ester (40 g; 175 mmol, 1 eq.) and triethylamine (80 ml; 578 mmol) in dioxane (350 ml) then heated at 50 0C for 1.5 hours. Further benzoyl chloride (5 ml) was added and the reaction heated at 50 0C overnight. The reaction mixture was filtered and the filtrate washed with dioxane. 2M sodium hydroxide solution (500 ml) was added to the mother liquor, heated at 50 °C for 6 hours, and then evaporated. 400 ml of water was added to the residue then acidified with concentrated hydrochloric acid to pH 3. The solid was collected by filtration, azeotroped with toluene/methanol and the solid dried in vacuo to give 4-(2,6- dichloro-benzoylamino)-lH-pyrazole-3-carboxylic acid (52.2 g) as a cream coloured solid. (LC/MS: Rt 2.31, [M+H]+ 300.08). |
Yield | Reaction Conditions | Operation in experiment |
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Multi-step reaction with 3 steps 1: 79 percent / NEt3 / CH2Cl2 / 3 h / 0 °C 2: 85 percent / BCl3*Me2S / CH2Cl2 / 6 h / 20 °C 3: 87 percent / MsCl; NEt3 / tetrahydrofuran / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
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45% | With 4-methyl-morpholine; In dichloromethane; at 0 - 20℃; for 120h; | 10.0 Grams (60 mmol) of ethyl 6-aminonicotinate ester (b) was dissolved in 150 ml of dichloromethane, and 9.2 ml (84 mmol) of N-methylmorpholine was added. At 0C, 9.5 ml (66 mmol) of 2,6-dichlorobenzoyl chloride (c) was added, and the mixture was stirred at room temperature for 24 hours. Further, 9.2 ml (84 mmol) of N-methylmorpholine and 9.5 ml (66 mmol) of 2,6-dichlorobenzoyl chloride (c) were added, and the mixture was stirred for 4 days. Water was added, and the solvent was removed under vacuum. Water was added, the mixture was subjected to extraction with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was evaporated off under vacuum, and the residue was purified by silica gel column chromatography (chloroform:methanol (volume ratio) = 400:1 - 200:1), to give 14.0 g (yield 45 %) of ethyl N,N-bis(2,6-dichlorobenzoyl)-6-aminonicotinate ester (d). |
Yield | Reaction Conditions | Operation in experiment |
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Fmoc-Phe(4-nitro)-OH (2.5g), 2,6-dichlorobenzoyl chloride (0.745mL) and pyridine (1.5mL) in a solution of NMP (25mL) were added to Wang resin (0.76mmol/g, 2.3g) and stirred at room temperature for 16 hours. After removing the excess solvent, the resin was washed with DMF three times, dichloromethane three times and NMP twice. In order to conduct capping of an unreacted hydroxyl group on the resin, the resin was treated with acetic anhydride (20mL), pyridine (20mL) and NMP (20mL) for 2 hours. After removing the excess solvent, the resin was washed with DMF three times and dichloromethane three times, and dried under reduced pressure.Process 2 Removal of Fmoc group A DMF solution of 20% piperidine (25mL) was added to the resin obtained in Process 1 and reacted for 15 minutes. After removing the solvent, the resin was washed with DMF and dichloromethane three times each, and dried under reduced pressure.Process 3 Acylation reaction 2,6-dichlorobenzoyl chloride (1.1mL), 2,6-lutidine (1.6mL) and NMP (26mL) were added to 2.0g of the resin obtained in Process 2 and reacted for 6 hours. After removing the excess solvent, the resin was washed with DMF and dichloromethane three times each, and dried under reduced pressure.Process 4 Reduction of nitro group NMP (30mL) · EtOH (1.5mL) solution of SnCl2· 2H2O (15.0g) was added to 1.5g of the resin obtained in Process 3 and reacted for 16 hours. After removing the reaction solvent, the resin was washed with DMF and dichloromethane three times each.Process 5 Construction of quinazoline-2,4-dione ring 2g of the resin obtained in Process 4 was reacted in NMP solution (32mL) of methyl 2-isocyanatebenzoate (1.92g) for 16 hours. After removing the reaction solvent, the resin was washed with DMF and dichloromethane three times each. DMF solution of 20% piperidine was added to the resin for 1 hour. After removing the reaction solvent, the resin was washed with DMF and dichloromethane three times each and dried under reduced pressure.Process 6 Alkylation Methyl iodide (0.75mmol), 18-crown-6 (30mg), NMP (1mL) and K2CO3 (35mg) were added to 20mg of the resin obtained in Process 5 and reacted for 3 days. After removing the reaction solvent, the resin was washed with DMF, water, DMF and dichloromethane three times each and dried under reduced pressure.Process 7 Cleavage from resin The resin obtained in Process 6 was treated with trifluoroacetic acid containing 5% of water for 1 hour. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified with high-pressure liquid chromatography (water/acetonitrile) to obtain 8mg of the intended compound. MS(ESI MH+) : 512 CHNO : C25H19Cl2N3O5 |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; In 1,3-dioxane; water; at 20℃; for 24h; | To a mixture of Compound 9 (12.0 g, 42.7 mmol), NaOH (3.4 g, 85.5 mmol) in H2O (80 mL) is added a solution of 2,6-dichlorobenzoylchloride (10.7 g, 51.3 mmol) in dioxane (24 mL). The mixture is stirred for 24 h at rt. It is concentrated partially to remove the dioxane, and is then acidified to precipitate the product. The precipitate is collected by filtration, washed with cold H2O, and dried in a vacuum oven at room temperature overnight. The solid is triturated with THF, and the THF is discarded. The solid is dissolved in MeCN (2 L), and the solution is concentrated to a volume of approximately 300 mL. Water (150 mL) is added. The solution is frozen and lyophilized to giveCompound 10: MS (FAB) m/z453, 399, 398, 397, 353, 307, 280, 278, 175, 173, 57; Anal. C 55.48; H 4.74, Cl 15.37, N 6.25 (calcd corrected for 2.68percent H2O: C 55.64, H 4.89, Cl 15.64, N 6.18) |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine; at 20.0℃; for 24.0h; | 2-Amino-5-iodo-4-trifluoromethylthiazole (0.8 g) was dissolved in pyridine (3 ml) and 2,6-dichlorobenzoylchloride (0.6 g) was added at room temperature with stirring. The mixture was stirred for 1 day at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The solid thus obtained was recrystallized from methanol to give N-(5-iodo-4-trifluoromethylthiazol-2-yl)-2,6-dichlorobenzamide (0.9 g), m. p. 157-159 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 10 - 22℃; for 18h; | 5 Example 5; N-[2-(3-Chloro-5-trifluoromethyl-2-pyridyl)ethyl]-2.6-dichlorobenzamide (Compound 401) To a suspension of 2-(3-chloro-5-trifluoromethyl-2-pyridyl)ethylammonium chloride (0.2 g) in dry dichloromethane at 10°C was added 2.6-dichlorobenzoyl chloride (0.13 ml) followed by dropwise addition of dry triethylamine (0.3 ml). The mixture was warmed with stirring to 22°C over 18 hours. The mixture was evaporated on to flash silica. Chromatography over silica eluting with 20-50% diethyl ether in light petroleum (b.p. 40-60°C) gave the title product. m.p. 103-5°C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; for 12.0h; | EXAMPLE 16 [0322] This example describes the synthesis of which was prepared according to the procedure below. [0323] To a solution of 0.2 mmol of compound 8.4 (Example 8c or 8e) in 1 mmol of Et3N and 5 mL of dry CH2C12 was added 0.22 mmol of 2,6- dichlorobenzoyl chloride at 0C, the resulting mixture was stirred at room temperature for 12 hours. The solvent was removed and the residue was dried in vacuo. Subsequently, the residue was treated with 0. 8 mmol of LiOH-H20 in 2 mL of THF and 0.5 mL of H20. After stirring at room temperature for 30 minutes, the reaction mixture was added 1.0 mL of 1. ON aq. HC1. The organic solvent was removed, and the residue was diluted with 10 mL of brine. The mixture was extracted with EtOAc and the extract was dried with anhydrous Na2SO4. The solvent was removed and the residue was dried in vacuo to give the desired compound in 65% yield. 1H NMR (400 MHz, CD30D) 6 7.92 (s, 1 H), 7. 82 (d, J=6. 85 Hz, 1 H), 7.71 (d, J=6. 85 Hz, 1 H), 7.56 (t, J=7. 83 Hz, 1 H), 7.34 (m, 3 H), 5. 08 (dd, J=9. 78, 4.89 Hz, 1 H), 3.45 (dd, J=14. 67,4. 89 Hz, 1 H), 3.14 (dd, J=14. 67,9. 78 Hz, 1 H), 3.08 (s, 3 H) ppm; ESI-MS (m/z) : (M+H+) 416.00. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In dichloromethane; at 20℃; | 3-Chloro-5-trifluoromethyl)pyrid-2-ylhydrazine (0.32 g) was dissolved in dichloromethane (7 ml) and treated dropwise with 2,6-dichlorobenzoyl chloride (0.31 g) in dichloromethane (2 ml). Triethylamine (0.15 g) was then added and the reaction stirred at room temperature overnight. The organic solution was washed sequentially with sodium bicarbonate solution and brine and evaporated to give a solid. The residue was purified by trituration (dichloromethane) to give the title compound, m.p. 212-5 C. The following compounds of formula Iy (see Table B), i.e. compounds of general formula I where L is -N(R3)NHC(=O)-, may be prepared by methods analogous to those of Example 4. |
Yield | Reaction Conditions | Operation in experiment |
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l lC. 4-(2,6-dichloro-benzoylamino)-lH-pyrazole-3-carboxylic acid2,6-Dichlorobenzoyl chloride (8.2 g; 39.05 mmol) was added cautiously to a solution of 4-amino-lH-pyrazole-3-carboxylic acid methyl ester (5 g; 35.5 mmol) and triethylamine (5.95 ml; 42.6 mmol) in dioxan (50 ml) then stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate treated with methanol (50 ml) and 2M sodium hydroxide solution (100 ml), heated at 50 0C for 4 hours, and then evaporated. 100 ml of water was added to the residue then acidified with concentrated hydrochloric acid. The solid was collected by filtration, washed with water (100 ml) and sucked dry to give 10.05 g of 4-(2,6-dichloro- benzoylamino)-lH-pyrazole-3-carboxylic acid as a pale violet solid. | ||
2,6-dichlorobenzoyl chloride (8.2 g; 39.05 mmol) was added cautiously to a solution of 4-amino-1H-pyrazole-3- carboxylic acid methyl ester (prepared in a manner analogous to 165B) (5 g; 35.5 mmol) and triethylamine (5.95 ml; 42.6 mmol) in dioxan (50 ml) then stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate treated with methanol (50 ml) and 2M sodium hydroxide solution (100 ml), heated at 50 C for 4 hours, and then evaporated. 100 ml of water was added to the residue then acidified with concentrated hydrochloric acid. The solid was collected by filtration, washed with water (100 ml) and sucked dry to give 10.05 g of 4-(2,6-dichloro-benzoylamino)-1H-pyrazo.e-3-carboxylic acid as a pale violet solid. | ||
2,6-dichlorobenzoyl chloride (8.2 g; 39.05 mmol) was added cautiously to a solution of 4-amino-1H-pyrazole-3- carboxylic acid methyl ester (prepared in a manner analogous to 165B) (5 g; 35.5 mmol) and triethylamine (5.95 ml; 42.6 mmol) in dioxan (50 ml) then stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate treated with methanol (50 ml) and 2M sodium hydroxide solution (100 ml), heated at 50 C for 4 hours, and then evaporated. 100 ml of water was added to the residue then acidified with concentrated hydrochloric acid. The solid was collected by filtration, washed with water (100 ml) and sucked dry to give 10.05 g of 4-(2,6-dichloro-benzoylamino)-1H-pyrazo.e-3-carboxylic acid as a pale violet solid. |
2,6-dichlorobenzoyl chloride (8.2 g; 39.05 mmol) was added cautiously to a solution of 4- amino-1H-pyrazole-3-carboxylic acid methyl ester (prepared in a manner analogous to 165B) (5 g; 35.5 mmol) and triethylamine (5.95 ml; 42.6 mmol) in dioxan (50 ml) then stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate treated with methanol (50 ml) and 2M sodium hydroxide solution (100 ml), heated at 50 0C for 4 hours, and then evaporated. 100 ml of water was added to the residue then acidified with concentrated hydrochloric acid. The solid was collected by filtration, washed with water (100 ml) and sucked dry to give 10.05 g of 4-(2,6-dichloro-benzoylamino)-1H- pyrazole-3-carboxylic acid as a pale violet solid. | ||
2,6-dichlorobenzoyl chloride (8.2 g; 39.05 mmol) was added cautiously to a solution of 4- amino-1 H-pyrazole-3-carboxylic acid methyl ester (5 g; 35.5 mmol) and triethylamine (5.95 ml; 42.6 mmol) in dioxane (50 ml) then stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate treated with methanol (50 ml) and 2M sodium hydroxide solution (100 ml), heated at 50 0C for 4 hours, and then evaporated. 100 ml of water was added to the residue then acidified with concentrated hydrochloric acid. The solid was collected by filtration, washed with water (100 ml) and sucked dry to give 10.05 g of 4-(2,6-dichloro-benzoylamino)-1 H-pyrazole-3-carboxylic acid as a pale violet solid. (LC/MS: Rt 2.26, [M+H]+ 300 / 302). | ||
2,6-dichlorobenzoyl chloride (8.2 g; 39.05 mmol) was added cautiously to a solution of 4- amino-1 H-pyrazole-3-carboxylic acid methyl ester (prepared in a manner analogous to 165B) (5 g; 35.5 mmol) and triethylamine (5.95 ml; 42.6 mmol) in dioxan (50 ml) then stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate treated with methanol (50 ml) and 2M sodium hydroxide solution (100 ml), heated at 50 0C for 4 hours, and then evaporated. 100 ml of water was added to the residue then acidified <n="158"/>with concentrated hydrochloric acid. The solid was collected by filtration, washed with water (100 ml) and sucked dry to give 10.05 g of 4-(2,6-dichloro-benzoylamino)-1 H- pyrazole-3-carboxylic acid as a pale violet solid. | ||
2,6-dichlorobenzoyl chloride (8.2 g; 39.05 mmol) was added cautiously to a solution of 4- amino-1H-pyrazole-3-carboxylic acid methyl ester (5 g; 35.5 mmol) and triethylamine (5.95 ml; 42.6 mmol) in dioxane (50 ml) then stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate treated with methanol (50 ml) and 2M sodium hydroxide solution (100 ml), heated at 50 0C for 4 hours, and then evaporated. 100 ml of water was added to the residue then acidified with concentrated hydrochloric acid. The solid was collected by filtration, washed with water (100 ml) and sucked dry to give 10.05 g of 4-(2,6-dichloro-benzoy.amino)-1 H-pyrazole-3-carboxylic acid as a pale violet solid. (LC/MS: Rt 2.26, [M+H]+ 300 / 302). | ||
With triethylamine; In 1,4-dioxane; at 20℃; for 5h; | 2,6-dichlorobenzoyl chloride (8.2 g; 39.05 mmol) was added cautiously to a solution of 4-AMINO-LH-PYRAZOLE-3-CARBOXYLIC acid methyl ester (prepared in a manner analogous to 165B) (5 g; 35.5 mmol) and triethylamine (5.95 ml; 42.6 mmol) in dioxan (50 ml) then stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate treated with methanol (50 ml) and 2M sodium hydroxide solution (100 ml), heated at 50 C for 4 hours, and then evaporated. 100 ml of water was added to the residue then acidified with concentrated hydrochloric acid. The solid was collected by filtration, washed with water (100 ml) and sucked dry to give 10.05 g OF 4-(2, 6-DICHLORO-BENZOYLAMINO)-LH-PYRAZOLE-3-CARBOXYLIC acid as a pale violet solid. | |
With sodium hydroxide; In 1,4-dioxane; methanol; water; triethylamine; | 2A. 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid 2,6-dichlorobenzoyl chloride (8.2 g; 39.05 mmol) was added cautiously to a solution of <strong>[360056-45-7]4-amino-1H-pyrazole-3-carboxylic acid methyl ester</strong> (prepared in a manner analogous to 165B) (5 g; 35.5 mmol) and triethylamine (5.95 ml; 42.6 mmol) in dioxan (50 ml) then stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate treated with methanol (50 ml) and 2M sodium hydroxide solution (100 ml), heated at 50 C. for 4 hours, and then evaporated. 100 ml of water was added to the residue then acidified with concentrated hydrochloric acid. The solid was collected by filtration, washed with water (100 ml) and sucked dry to give 10.05 g of 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid as a pale violet solid. | |
With sodium hydroxide; triethylamine; In 1,4-dioxane; methanol; water; | 1C. 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid 2,6-dichlorobenzoyl chloride (8.2 g; 39.05 mmol) was added cautiously to a solution of <strong>[360056-45-7]4-amino-1H-pyrazole-3-carboxylic acid methyl ester</strong> (5 g; 35.5 mmol) and triethylamine (5.95 ml; 42.6 mmol) in dioxane (50 ml) then stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate treated with methanol (50 ml) and 2M sodium hydroxide solution (100 ml), heated at 50 C. for 4 hours, and then evaporated. 100 ml of water was added to the residue then acidified with concentrated hydrochloric acid. The solid was collected by filtration, washed with water (100 ml) and sucked dry to give 10.05 g of 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid as a pale violet solid. (LC/MS: Rt 2.26, [M+H]+ 300/302). | |
4-(2.6-dichloro-benzovlamino)-1 H-pvrazole-3-carboxylic acid 2,6-dichlorobenzoyl chloride (8.2 g; 39.05 mmol) was added cautiously to a solution of 4- amino-IH-pyrazole-3-carboxylic acid methyl. ester (5 g; 35.5 mmol) and triethylamine (5.95 ml; 42.6 mmol) in dioxane (50 ml) then stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate treated with methanol (50 ml) and 2M sodium hydroxide solution (100 ml), heated at 50 0C for 4 hours, and then evaporated. 100 ml of water was added to the residue then acidified with concentrated hydrochloric acid. The solid was collected by filtration, washed with water (100 ml) and sucked dry to give 10.05 g of 4-(2,6-dichloro-benzoylamino)-1 H-pyrazole-3-carboxylic acid as a pale violet solid. (LC/MS: Rt 2.26, [M+H]+ 300 / 302). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium hydroxide; In water; acetone; at 10 - 15℃; for 2h;pH ~ 14; | 200mL of water and 91mL of acetone were mixed and 72.4g (344mmol) of 4-nitro-L-phenylalanine was added thereto and cooled down to 10C or lower. 68mL of 6M sodium hydroxide aqueous solution was added dropwise to the solution so that the temperature thereof did not exceed 15C. Keeping around pH 14, 73.58g (344mmol) of 2,6-dichlorobenzoyl chloride was slowly added dropwise thereto. In order to keep around pH 14, if needed, a sodium hydroxide aqueous solution was added dropwise. 2 hours later of completion of drop, 86mL of 6M hydrochloric acid was added with keeping the temperature of the reaction solution at 15C or lower to precipitate white crystals. After maturing at 10C or lower, the crystals were separated, dried under reduced pressure at 60C to obtain 128.5g of N?-(2,6-dichlorobenzoyl)-4-nitro-L-phenylalanine. (Yield: 97%)1H NMR (400MHz, DMSO-d6): 9.12 (d, 1H, J=8.42 Hz), 8.16 (d, 2H, J=8.78 Hz), 7.59 (d, J=8.77Hz), 7.42 (m, 3H), 3.29 (m), 3.07 (dd, 1H, J=3.64 and 10.42 Hz).13C NMR (100MHz, DMSO-d6): 172.25, 163.74, 146.68, 146.18, 131.51, 131.37, 131.05, 128.37, 123.55, 53.17, 36.74. MS (FAB) : m/z 383.1 (M+H)+ HRMS (FAB) : m/z 383.0219 (M+H)+ |
95% | Step 1: Synthesis of Nalpha-(2,6-dichlorobenzoyl)-4-nitro-L-phenylalanine: To 13 mL of acetone, there were added 10.04g of p-nitro-L-phenylalanine and 28 mL of water to thus form a suspension and the latter was cooled in an ice-bath. To this suspension, there were alternatively dropwise added 18.4 mL of a 6M sodium hydroxide solution and 10.05 g of 2,6-dichlorobenzoyl chloride in such a manner that the pH value of the suspension was maintained at a level of not less than 13 at a temperature of not more than 15C. After the completion of the dropwise addition, the suspension was further stirred for 2 hours with cooling in an ice-bath, then the progress of the reaction was confirmed by HPLC and 36 mL of a 2M hydrochloric acid solution was dropwise added while taking care to prevent any excess generation of heat. The suspension containing separated solid matter was stirred at 10C overnight, the precipitates were isolated through filtration and then dried under reduced pressure at 60C to thus obtain 17.32 g of the title compound as a white crystalline solid (yield: 95%). 1H-NMR (400MHz, DMSO-d6): delta 9.13 (d, 1H, J=8.3Hz), 8.16 (m, 2H), 7.59 (d, 2H, J=8.4Hz), 7.42 (m, 3H), 4.79 (m, 1H), 3.30 (m, 1H), 3.06 (m, 1H); 13C-NMR (100MHz, DMSO-d6): delta 172.08, 163.56, 146.50, 146.00, 136.18, 131.33, 131.19, 130.88, 128.19, 123.37, 93.39, 52.98, 36.55; Melting Point (DSC): 220.6C; MS (ESI+, m/z): 383.0 (MH+), 385.1 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In 1,4-dioxane; water at 20℃; for 10h; | ||
Stage #1: rac-allylglycine; 2,6-Dichlorobenzoyl chloride With sodium hydroxide In 1,4-dioxane; water at 20℃; for 10h; Stage #2: With hydrogenchloride In water | 35.1 Reference Example 35 2-(2,6-Dichlorobenzamido)pent-4-enoic acid methyl ester [Show Image] (1) Allylglycine (10.11 g) was dissolved in a mixed solvent of 2N aqueous sodium hydroxide solution (176 ml) and dioxane (175 ml), and 2,6-dichlorobenzoyl chloride (15.10 ml) was added dropwise thereto, followed by stirring the resulting mixture at room temperature for 10 hours. After concentrating the reaction solution to remove dioxane, water (150 ml) was added thereto and the resulting solution was washed with ether. Aqueous layer was acidified by adding 3N hydrochloric acid in small portions thereto, and extracted 3 times with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate mixed solvent to obtain 2-(2,6-dichlorobenzamido)pent-4-enoic acid (23.48 g). | |
Stage #1: rac-allylglycine; 2,6-Dichlorobenzoyl chloride With sodium hydroxide In 1,4-dioxane; water at 20℃; for 10h; Stage #2: With hydrogenchloride In water | 35.1 Reference Example 35 2-(2,6-Dichlorobenzamido)pent-4-enoic acid methyl ester [Show Image] (1) Allylglycine (10.11 g) was dissolved in a mixed solvent of 2N aqueous sodium hydroxide solution (176 ml) and dioxane (175 ml), and 2,6-dichlorobenzoyl chloride (15.10 ml) was added dropwise thereto, followed by stirring the resulting mixture at room temperature for 10 hours. After concentrating the reaction solution to remove dioxane, water (150 ml) was added thereto and the resulting solution was washed with ether. Aqueous layer was acidified by adding 3N hydrochloric acid in small portions thereto, and extracted 3 times with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate mixed solvent to obtain 2-(2,6-dichlorobenzamido)pent-4-enoic acid (23.48 g). |
Stage #1: rac-allylglycine; 2,6-Dichlorobenzoyl chloride With sodium hydroxide In 1,4-dioxane; water at 20℃; for 10h; Stage #2: With hydrogenchloride In water | 35.1 Allylglycine (10.11 g) was dissolved in a mixed solvent of 2N aqueous sodium hydroxide solution (176 ml) and dioxane (175 ml), and 2,6-dichlorobenzoyl chloride (15.10 ml) was added dropwise thereto, followed by stirring the resulting mixture at room temperature for 10 hours. After concentrating the reaction solution to remove dioxane, water (150 ml) was added thereto and the resulting solution was washed with ether. Aqueous layer was acidified by adding 3N hydrochloric acid in small portions thereto, and extracted 3 times with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate mixed solvent to obtain 2-(2,6-dichlorobenzamido)pent-4-enoic acid (23.48 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Reference Example 37 2-(2,6-Dichlorobenzamido)pent-4-ynoic acid methyl ester [Show Image] (1) Propargylglycine (5.00 g) was dissolved in a mixed solvent of 2N aqueous sodium hydroxide solution (100 ml) and dioxane (100 ml), and 2,6-dichlorobenzoyl chloride (9.45 ml) was added dropwise thereto at 0C, followed by stirring the resulting mixture at room temperature overnight. Water was added to the reaction solution, and the solution was washed with ether. Aqueous layer was acidified by adding 3N hydrochloric acid in small portions thereto and extracted with ethyl acetate, and organic layer was dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to dryness to obtain 2-(2,6-dichlorobenzamido)pent-4-ynoic acid. | ||
Reference Example 37 2-(2,6-Dichlorobenzamido)pent-4-ynoic acid methyl ester [Show Image] (1) Propargylglycine (5.00 g) was dissolved in a mixed solvent of 2N aqueous sodium hydroxide solution (100 ml) and dioxane (100 ml), and 2,6-dichlorobenzoyl chloride (9.45 ml) was added dropwise thereto at 0C, followed by stirring the resulting mixture at room temperature overnight. Water was added to the reaction solution, and the solution was washed with ether. Aqueous layer was acidified by adding 3N hydrochloric acid in small portions thereto and extracted with ethyl acetate, and organic layer was dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to dryness to obtain 2-(2,6-dichlorobenzamido)pent-4-ynoic acid. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In 1,4-dioxane; at 20℃; for 5h; | Preparation IX; Synthesis of 4-C2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid2,6-dichlorobenzoyl chloride (8.2 g, 39.05 mmol) was added cautiously to a solution of <strong>[360056-45-7]4-amino-1H-pyrazole-3-carboxylic acid methyl ester</strong> (prepared in a manner analogous to Preparation VIII) (5 g; 35.5 mmol) and triethylamine (5.95 ml; 42.6 mmol) in dioxane (50 ml) then stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate treated with methanol (50 ml) and 2M sodium hydroxide solution (100 ml), heated at 50 C for 4 hours, and then evaporated. 100 ml of water was added to the residue then acidified with concentrated hydrochloric acid. The solid was collected by filtration, washed with water (100 ml) and sucked dry to give 10.05 g of 4-(2,6-dichloro-benzoylamino)- lH-pyrazole-3-carboxylic acid as a pale violet solid. (LC/MS: Rt 2.26, [M+H]+ 300 / 302). | |
With triethylamine; In 1,4-dioxane; at 18 - 25℃; for 16h; | Stage 3: Preparation of 4-f2,6-dichlorobenzoylamino)-l//-pyrazole-3-carboxylic acid methyl ester EPO <DP n="75"/>C12H9CI2N3O3 FW: 314.13A solution of 4-amino-l//-pyrazole-3-carboxylic acid methyl ester (0.634 Kg, 4.49 mol, 1 wt) in 1,4-dioxane (8.90 L, 9 vol) under nitrogen was treated with triethylamine (0.761 L, 5.46 mol, 1.2 vol) followed by 2,6-dichlorobenzoyl chloride (0.710 L, 4.96 mol, 0.72 vol) such that the internal temperature was maintained in the range 20 to 25 0C. Residual 2,6-dichlorobenzoyl chloride was washed in with a line rinse of 1 ,4-dioxane (0.990 L, 1 vol) and the reaction mixture stirred at 18 to 25 C until complete (16 hours) by TLC analysis (eluent: ethyl acetate: heptanes 3:1; Rf amine 0.25, Rf product 0.65). The reaction mixture was filtered, the filter-cake washed with 1,4-dioxane (2x 0.990 L, 2x 1 vol) and the combined filtrates (red) progressed to Stage 4 without further isolation. | |
With triethylamine; In 1,4-dioxane; at 18 - 25℃; for 16h; | A solution of 4-amino-1 H-pyrazole-3-carboxylic acid methyl ester (0.634 Kg, 4.49 mol, 1 wt) in 1 ,4-dioxane (8.90 L, 9 vol) under nitrogen was treated with triethylamine (0.761 L, 5.46 mol, 1.2 vol) followed by 2,6- dichlorobenzoyl chloride (0.710 L, 4.96 mol, 0.72 vol) such that the internal temperature was maintained in the range 20 to 25 C. Residual 2,6-dichlorobenzoyl chloride was washed in with a line rinse of 1 ,4-dioxane (0.990 EPO <DP n="213"/>L, 1 vol) and the reaction mixture stirred at 18 to 25 C until complete (16 hours) by TLC analysis (eluent: ethyl acetate: heptanes 3:1 ; Rfamine 0.25, Rf product 0.65). The reaction mixture was filtered, the filter-cake washed with 1 ,4-dioxane (2x 0.990 L, 2x 1 vol) and the combined filtrates (red) progressed to Stage 4 without further isolation. |
With triethylamine; In 1,4-dioxane; at 18 - 25℃; for 16h; | A solution of 4-amino-1 H-pyrazole-3-carboxylic acid methyl ester (0.634 Kg, 4.49 mol, 1 wt) in 1 ,4-dioxane (8.90 L, 9 vol) under nitrogen was treated with triethylamine (0.761 L, 5.46 mol, 1.2 vol) followed by 2,6- dichlorobenzoyl chloride (0.710 L, 4.96 mol, 0.72 vol) such that the internal temperature was maintained in the range 20 to 25 C. Residual 2,6-dichlorobenzoyl chloride was washed in with a line rinse of 1 ,4-dioxane (0.990 EPO <DP n="213"/>L, 1 vol) and the reaction mixture stirred at 18 to 25 C until complete (16 hours) by TLC analysis (eluent: ethyl acetate: heptanes 3:1 ; Rfamine 0.25, Rf product 0.65). The reaction mixture was filtered, the filter-cake washed with 1 ,4-dioxane (2x 0.990 L, 2x 1 vol) and the combined filtrates (red) progressed to Stage 4 without further isolation. | |
With triethylamine; In 1,4-dioxane; at 15 - 25℃; for 14 - 24h; | A solution of 4-amino-1 H-pyrazole-3-carboxylic acid methyl ester (0.634 Kg, 4.49 mol, 1 wt) in 1 ,4-dioxane (8.90 L, 9 vol) under nitrogen was treated with triethylamine (0.761 L, 5.46 mol, 1.2 vol) followed by 2,6-dichlorobenzoyl chloride (0.710 L, 4.96 mol, 0.72 vol) such that the internal temperature was maintained in the range 20 to 25 0C. Residual 2,6- dichlorobenzoyl chloride was washed in with a line rinse of 1 ,4-dioxane (0.990 L, 1 vol) and the reaction mixture stirred at 18 to 25 C until complete (16 hours) by TLC analysis (eluent: ethyl acetate: heptanes 3:1 ; Rf amin80.25, Rf product 0.65). The reaction mixture was filtered, the filter-cake washed with 1 ,4-dioxane (2x 0.990 L, 2x 1 vol) and the combined filtrates (red) progressed to Stage 4 without further isolation.Triethylamine (1.42L, 10.20 MoI, 1.2 vol) was added to solution of 4-amino-1H-pyrazole-3- carboxylic acid methyl ester (1.184Kg, 8.39 MoI, 1.0 wt) in 1,4-dioxane (10.66L, 9.0 vol) at 15 to 25C under nitrogen. 2,6-Dichlorobenzoyl chloride (1.33L, 9.28 MoI, 1.12 vol) was charged at 15 to 250C followed by a line rinse of 1 ,4-dioxane (1.18L, 1.0 vol) and the reaction mixture stirred at 15 to 25C for 14 to 24 hours. Reaction completion was determined by 1H NMR analysis2. The reaction mixture was filtered, the filter-cake washed with 1 ,4-dioxane (2x 1.18L, 2x 1.0 vol) and the combined filtrates progressed to Stage 4 without further isolation. | |
With triethylamine; In 1,4-dioxane; at 15 - 25℃; for 14 - 24h; | Triethylamine (1.42L, 10.20 MoI, 1.2 vol) was added to solution of 4-amino-1H-pyrazole-3- carboxylic acid methyl ester (1.184Kg, 8.39 MoI, 1.0 wt) in 1 ,4-dioxane (10.66L, 9.0 vol) at 15 to 25C under nitrogen. 2,6-Dichlorobenzoyl chloride (1.33L, 9.28 MoI, 1.12 vol) was charged at 15 to 25C followed by a line rinse of 1,4-dioxane (1.18L, 1.0 vol) and the reaction mixture stirred at 15 to 250C for 14 to 24 hours. Reaction completion was determined by 1H NMR analysis1. The reaction mixture was filtered, the filter-cake washed with 1 ,4-dioxane (2x 1.18L, 2x 1.0 vol) and the combined filtrates progressed to Stage 4 without further isolation. | |
With triethylamine; In 1,4-dioxane; at 20 - 25℃; for 16h; | A solution of 4-amino-1/-/-pyrazole-3-carboxylic acid methyl ester (0.634 Kg, 4.49 mol, 1 wt) in 1 ,4-dioxane (8.90 L1 9 vol) under nitrogen was treated with triethylamine (0.761 L, 5.46 mol, 1.2 vol) followed by 2,6-dichlorobenzoyl chloride (0.710 L, 4.96 mol, 0.72 vol) such that the internal temperature was maintained in the range 20 to 25 0C. Residual 2,6- dichlorobenzoyl chloride was washed in with a line rinse of 1 ,4-dioxane (0.990 L, 1 vol) and the reaction mixture stirred at 18 to 25 C until complete (16 hours) by TLC analysis (eluent: ethyl acetate: heptanes 3:1 ; Rf amjne 0.25, Rf product 0.65). The reaction mixture was filtered, the filter-cake washed with 1 ,4-dioxane (2x 0.990 L, 2x 1 vol) and the combined filtrates (red) progressed to Stage 4 without further isolation. | |
With triethylamine; In 1,4-dioxane; | Preparation of 4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid methyl ester A solution of <strong>[360056-45-7]4-amino-1H-pyrazole-3-carboxylic acid methyl ester</strong> (0.634 Kg, 4.49 mol, 1 wt) in 1,4-dioxane (8.90 L, 9 vol) under nitrogen was treated with triethylamine (0.761 L, 5.46 mol, 1.2 vol) followed by 2,6-dichlorobenzoyl chloride (0.710 L, 4.96 mol, 0.72 vol) such that the internal temperature was maintained in the range 20 to 25 C. Residual 2,6-dichlorobenzoyl chloride was washed in with a line rinse of 1,4-dioxane (0.990 L, 1 vol) and the reaction mixture stirred at 18 to 250 C until complete (16 hours) by TLC analysis (eluent: ethyl acetate: heptanes 3:1; Rf amine 0.25, Rf product 0.65). The reaction mixture was filtered, the filter-cake washed with 1,4-dioxane (2*0.990 L, 2*1 vol) and the combined filtrates (red) progressed to Stage 4 without further isolation. | |
With triethylamine; In 1,4-dioxane; | Preparation of 4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid methyl ester Triethylamine (1.42 L, 10.20 Mol, 1.2 vol) was added to solution of <strong>[360056-45-7]4-amino-1H-pyrazole-3-carboxylic acid methyl ester</strong> (1.184 Kg, 8.39 Mol, 1.0 wt) in 1,4-dioxane (10.66 L, 9.0 vol) at 15 to 25 C. under nitrogen. 2,6-Dichlorobenzoyl chloride (1.33 L, 9.28 Mol, 1.12 vol) was charged at 15 to 25 C. followed by a line rinse of 1,4-dioxane (1.18 L, 1.0 vol) and the reaction mixture stirred at 15 to 25 C. for 14 to 24 hours. Reaction completion was determined by 1H NMR analysis1. The reaction mixture was filtered, the filter-cake washed with 1,4-dioxane (2*1.18 L, 2*1.0 vol) and the combined filtrates progressed to Stage 4 without further isolation. 1 A sample of the reaction mixture was filtered, the filtrates dissolved in d6-DMSO and a 1H NMR spectrum obtained | |
With triethylamine; In 1,4-dioxane; at 15 - 25℃; for 14 - 24h; | A solution of 4-amino-1/-/-pyrazole-3-carboxylic acid methyl ester (0.634 Kg, 4.49 mol, 1 wt) in 1 ,4-dioxane (8.90 L, 9 vol) under nitrogen was treated with triethylamine (0.761 L, 5.46 mol, 1.2 vol) followed by 2,6-dichlorobenzoyl chloride (0.710 L, 4.96 mol, 0.72 vol) such that the internal temperature was maintained in the range 20 to 25 0C. Residual 2,6- dichlorobenzoyl chloride was washed in with a line rinse of 1 ,4-dioxane (0.990 L, 1 vol) and the reaction mixture stirred at 18 to 25 C until complete (16 hours) by TLC analysis (eluent: ethyl acetate: heptanes 3:1 ; Rfamine0.25, Rf product0.65). The reaction mixture was filtered, the filter-cake washed with 1 ,4-dioxane (2x 0.990 L, 2x 1 vol) and the combined filtrates (red) progressed to Stage 4 without further isolation. Stage 3: Preparation of 4-(2,beta-dichlorobenzoylamino)-1 H-pyrazole-3-carboxvlic acid methyl esterTriethylamine (1.42L, 10.20 MoI, 1.2 vol) was added to solution of 4-amino-1H-pyrazole-3- carboxylic acid methyl ester (1.184Kg, 8.39 MoI, 1.0 wt) in 1 ,4-dioxane (10.66L, 9.0 vol) at 15 to 250C under nitrogen. 2,6-Dichlorobenzoyl chloride (1.33L1 9.28 MoI1 1.12 vol) was charged at 15 to 25C followed by a line rinse of 1 ,4-dioxane (1.18L, 1.0 vol) and the reaction mixture stirred at 15 to 25C for 14 to 24 hours. Reaction completion was determined by 1H NMR analysis1. The reaction mixture was filtered, the filter-cake washed with 1 ,4-dioxane (2x 1.18L, 2x 1.0 vol) and the combined filtrates progressed to Stage 4 without further isolation. | |
With triethylamine; In 1,4-dioxane; at 15 - 25℃; for 14 - 24h;Industry scale; | Stage 3: Preparation of 4-(2,6-dichlorobenzoylamino)-lH-pyrazole-3-carboxylic acid methyl ester <n="73"/>C5H7N3O2 C7H3CI3O C12H9CI2N3O3 FW: 141.13 FW: 209.46 FW: 314.13Triethylamine (1.42L, 10.20 MoI, 1.2 vol) was added to solution of 4-amino-lH"- pyrazole-3-carboxylic acid methyl ester (1.184Kg, 8.39 MoI5 1.0 wt) in 1,4-dioxane (10.66L, 9.0 vol) at 15 to 25C under nitrogen. 2,6-Dichlorobenzoyl chloride (1.33L, 9.28 MoI, 1.12 vol) was charged at 15 to 250C followed by a line rinse of 1,4-dioxane (1.18L, 1.0 vol) and the reaction mixture stirred at 15 to 250C for 14 to 24 hours. Reaction completion was determined by 1HNMR analysis1. The reaction mixture was filtered, the filter-cake washed with 1,4-dioxane (2x 1.18L, 2x 1.0 vol) and the combined filtrates progressed to Stage 4 without further isolation. | |
In tetrahydrofuran; 1,4-dioxane; dichloromethane; at 0 - 20℃; for 1h;Alkaline conditions; | <strong>[360056-45-7]methyl 4-amino-1H-pyrazole-3-carboxylate</strong> (1.0 g, 7.09 mmol) and triethylamine (1.5 mL, 8.5 mmol) were stirred in dioxane (10 mL) at 0C. A solution of 2,6-dichlorobenzoyl chloride (1.5 g, 7.17 mmol) in THF (5 mL) was added dropwise until the starting material was consumed. The reaction was filtered, and the resultant solid washed with dioxane (3 x 20 mL). The filtrates were combined and used directly in the next reaction. MS (ESI) m/z 315 (M + H)+. Expected mass from chemical formula C12H9N3O3: 314.12 Da. | |
With triethylamine; In tetrahydrofuran; 1,4-dioxane; at 0℃; | <strong>[360056-45-7]methyl 4-amino-1H-pyrazole-3-carboxylate</strong> (1.0 g, 7.09 mmol) and triethylamine (1.5 mL, 8.5 mmol) were stirred in dioxane (10 mL) at 0C. A solution of 2,6- dichlorobenzoyl chloride (1.5 g, 7.17 mmol) in THF (5 mL) was added dropwise until the starting material was consumed. The reaction was filtered, and the resultant solid washed with dioxane (3 x 20 mL). The filtrates were combined and used directly in the next reaction. MS (ESI) m/z 315 (M + H)+. Expected mass from chemical formula C12H9N3O3: 314.12 Da |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In dichloromethane; | 1) A solution of 2,6-dichlorobenzoylchloride (0.68 mL) in CH2Cl2 (5 mL) was added to a solution of an ice-cold solution of D-tyrosine methyl ester HCl salt (1.0 g) and DIEA (2.26 mL) in CH2Cl2 (15 mL). The mixture was stirred at room temperature for 24 h. The mixture was diluted with CH2Cl2 (50 mL) and washed successively with H2O, 1 N HCl and brine. The organic layer was dried (MgSO4) and evaporated, and the residue was recrystallized from EtOAc and hexanes to yield 1.46 g of N-(2,6-dichlorobenzoyl)-D-tyrosine methyl ester. ESMS: m/z 369 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine In ethanol; ISOPROPYLAMIDE; water | 4.1 Example 4 (1) A mixture of 8-amino-4-hydroxyquinoline (300 mg), 2,6-dichlorobenzoyl chloride (432 mg), triethylamine (569 mg) and catalytic amount of dimethylaminopyridine in dimethylacetamide (3 ml) was stirred for 1 hour under ice-cooling. To the mixture was added water (3 ml) and the resulting precipitate was collected by filtration. The residue was suspended in hot ethanol (10 ml) with stirring. The resulting precipitate was collected by filtration, and the residue was purified by flash chromatography (ethyl acetate-dichloromethane) to give 8-amino-4-(2,6-dichlorobenzoyloxy)quinoline (240 mg). NMR (CDCl3, δ): 5.03 (2H, br s), 6.95 (1H, d, J=7.5 Hz), 7.30-7.52 (6H, m), 8.79 (1H, d, J=5 Hz) |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In 1,2-dichloro-ethane; | Example 1 A mixture of <strong>[90-52-8]8-amino-6-methoxyquinoline</strong> (121 mg), 2,6-dichlorobenzoyl chloride (175 mg) and triethylamine (91.4 mg) in ethylene chloride (3 ml) was refluxed for 3 hours. After cooling, the mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate:n-hexane, 1:2, v/v) to give 8-(2,6-dichlorobenzoylamino)-6-methoxyquinoline (164.5 mg). mp: 180-182 C. NMR (CDCl3, delta): 3.97 (3H, s), 6.88 (1H, s), 7.30-7.50 (4H, m), 8.06 (1H, d, J=8 Hz), 8.60 (1H, m), 8.70 (1H, s) its hydrochloride mp: 236-244 C. NMR (DMSO-d6, delta): 3.93 (3H, s), 7.22 (1H, s), 7.40-7.70 (4H, m), 8.34 (1H, d, J=8 Hz), 8.43 (1H, s), 8.73 (1H, d, J=8 Hz) |
Yield | Reaction Conditions | Operation in experiment |
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With sodium chloride; ammonia In dichloromethane; ethyl acetate; benzene | R.1 2,6-dichlorobenzamide STR1147 Reference Example 1 2,6-dichlorobenzamide STR1147 To a solution of 2,6-dichlorobenzoyl chloride(10 g) in dichloromethane (3 ml) was added 28 % aqueous solution of ammonia (25 ml) at 0° C. The reaction mixture was stirred at room temperature for 2 h. To the reaction mixture was added benzene, and the mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was filtered. The filtrate was washed with a saturated aqueous solution of sodium hydrocarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate and concentrated. The residue was washed with hexane, and dried to give the title compound (7.05 g) having the following physical data. TLC: Rf 0.60 (hexane:ethyl acetate=1:1). |
Yield | Reaction Conditions | Operation in experiment |
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In toluene; | EXAMPLE 34 2,6-DICHLORO-N-(3-BENZISOXAZOLYL)BENZAMIDE 3-Aminobenzisoxazole (2 gram), 2,6-dichlorobenzoylchloride (2 gram), and 50 ml. of toluene are heated at reflux for 16 hours. After evaporation of the solvent at reduced pressure, the resultant oily semi-solid is triturated with ether. The solid so formed is then washed with ether and water and constitutes the desired product. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide In ethanol; chloroform | 27 2,6-DICHLORO-N-(3-(4-CHLOROPHENYL)-5-ISOXAZOLYL)BENZAMIDE EXAMPLE 27 2,6-DICHLORO-N-(3-(4-CHLOROPHENYL)-5-ISOXAZOLYL)BENZAMIDE 3-(4-Chlorophenyl)-5-aminoisoxazole (1 gram) and 2,6-dichlorobenzoylchloride (5 grams) were placed in a 100 ml. reaction vessel and heated to near reflux for 11/2 hours. The mixture was then cooled to room temperature and treated with 25 ml. of 2 N NaOH and 25 ml. ethanol. After refluxing for 2 hours, the ethanol was slowly removed at reduced pressure. A solid precipitate was collected by filtration. The remaining solution was treated with activated charcoal, filtered, and cooled to room temperature. The aqueous solution was extracted with chloroform. The chloroform was washed with water and dried (Na2 SO4). Removal of the solvent afforded an oily product which was recrystallized from ether/hexane, m.p. 208°-209° C. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride In 1,4-dioxane; sodium hydroxide; water | R.37.1 2-(2,6-Dichlorobenzamido)pent-4-ynoic acid methyl ester (1) Propargylglycine (5.00 g) was dissolved in a mixed solvent of 2N aqueous sodium hydroxide solution (100 ml) and dioxane (100 ml), and 2,6-dichlorobenzoyl chloride (9.45 ml) was added dropwise thereto at 0°C, followed by stirring the resulting mixture at room temperature overnight. Water was added to the reaction solution, and the solution was washed with ether. Aqueous layer was acidified by adding 3N hydrochloric acid in small portions thereto and extracted with ethyl acetate, and organic layer was dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to dryness to obtain 2-(2,6-dichlorobenzamido)pent-4-ynoic acid. | |
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; | 37.1 Propargylglycine (5.00 g) was dissolved in a mixed solvent of 2N aqueous sodium hydroxide solution (100 ml) and dioxane (100 ml), and 2,6-dichlorobenzoyl chloride (9.45 ml) was added dropwise thereto at 0°C, followed by stirring the resulting mixture at room temperature overnight. Water was added to the reaction solution, and the solution was washed with ether. Aqueous layer was acidified by adding 3N hydrochloric acid in small portions thereto and extracted with ethyl acetate, and organic layer was dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to dryness to obtain 2-(2,6-dichlorobenzamido)pent-4-ynoic acid. |
Yield | Reaction Conditions | Operation in experiment |
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Step 1: Synthesis of Nalpha-(2,6-dichlorobenzoyl)-<strong>[1991-81-7]4-iodo-L-phenylalanine</strong>: Water (21 mL), acetone (9.80 mL) and a 6M sodium hydroxide aqueous solution (5.20 mL) were added to 7.50 g of <strong>[1991-81-7]4-iodo-L-phenylalanine</strong> and the resulting mixture was stirred at 10°C to thus give a uniform solution. To this solution, there were alternatively added 4.05 mL of 2,6-dichlorobenzoyl chloride and 4.50 mL of a 6M sodium hydroxide aqueous solution while taking care to maintain the pH value of not less than 13 and the temperature of not higher than 15°C. After confirming the completion of the reaction, 6.50 mL of a 6M hydrochloric acid aqueous solution was added to the reaction system to thus precipitate the desired product. The solid thus separated was isolated through filtration under reduced pressure, washed with 15 mL of water and dried at 70°C for 4 hours under reduced pressure to thus give 12.42 g of the intended product. 1H-NMR (400MHz, DMSO-d6): delta 9.06 (d, 1H, J=8.3Hz), delta 7.63 (d, 2H, J=8.2Hz), delta 7.48-7.35 (m, 3H), delta 7.11 (d, 2H, J=8.2Hz), delta 4.68 (ddd, 1H, J=10.0, 8.4, 4.8Hz), delta3.11 (dd, 1H, J=14.0, 4.8Hz), delta2.87 (dd, 1H, J=14.0, 10.0Hz); MS (ESI+): m/z 463.9 (MH+) and 485.9 (M+Na), (ESI-): m/z 461.8 (M-H-). |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 21; (S)-3-[4-(2-tert-Butyl-3-oxo-5-p-tolyloxy-2,3-dihydro-pyridazin-4-yl)-phenyl]-2-(2,6-dichloro-benzoylamino)-propionic acid, Cpd 196; To a suspension of Compound 1a (13.6 mg, 65.1 mumol) in a mixture of aqueous sodium carbonate (2M, 0.25 mL) and acetonitrile (0.25 mL) was added Compound 1e (10.3 muL, 71.9 mumol). The mixture was stirred at 50 C. for 30 min prior to the addition of trans-dichloro(bistriphenylphosphine) palladium (II) (2.3 mg, 3.3 mumol) and Compound 21a (21.0 mg, 71.7 mumol). The resulting suspension was heated by microwave irradiation (CEM Explorer, 150 C., 6 min). The resulting mixture was acidified to pH 2 by addition of TFA and was concentrated and resuspended in a mixture of 1% HOAc-CH2Cl2 (500 muL) and water (100 muL). The resulting mixture was filtered through a plug of Celite (Varian Chem Elut), which was washed with 1% HOAc-CH2Cl2 (4×1.2 mL). The filtrate was concentrated and the residue was purified by reverse-phase HPLC, affording Compound 196 as a colorless oil (9.3 mg). (MS ES+) m/z 594.6 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
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HMPB-BHA resin (5.00 g, substitution level = 0.80 mmol/g) was placed in a 200 mL Advanced ChemTech reaction vessel and swollen by washing with DMF (3 x 50 mL). A solution of Fmoc-Hphe-OH (4.85 g, 12.1 mmol) in DMF (50.0 mL) was added to the vessel and the mixture shaken for 0.25 hours. Pyridine (1.62 mL, 20.0 mmol) followed by 2,6-dichlorobenzoyl chloride (1.72 mL, 12.0 mmol) in DMF (50.0 mL) were added and the mixture shaken for 8 hours at 22 C. The resin was washed with DMF, CH2Cl2, methanol, CH2Cl2 and DMF (3 x 90 mL each) then treated with DMF (50.0 mL), pyridine (1.62 mL, 20.0 mmol) and benzoyl chloride (1.40 mL, 12.1 mmol) and the vessel shaken for 3 hours. Final washing was then performed with DMF, CH2Cl2, methanol and CH2Cl2 (3 x 50 mL each) and the loading (0.60 mmol/g) determined by fulvene-piperidine assay. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | A solution of <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (0.74 g, 4.3 mmol) in DMF (5 mL) was added to a cooled (0 C.) mixture of NaH (0.31 g, 7.82 mmol, 60% in mineral oil) in DMF (15 mL). The resulting mixture was stirred for 20 minutes at 0 C. and then a solution of 2,6-dichlorobenzoyl chloride (0.82 g, 3.91 mmol) in DMF (5 mL) was added dropwise. The reaction was stirred at 0 C. for 4 hours and then poured onto ice-water (20 mL). The precipitate was collected and filtrate was extracted by EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The resulting solid was combined with the precipitate to afford N-(2-bromopyridin-4-yl)-2,6-dichlorobenzamide (1.0 g, Yield: 74%). 1HNMR (DMSO-d6, 400 MHz): delta 11.41 (s, 1H), 8.33 (d, J=5.6 Hz, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.64-7.54 (m, 4H). LCMS (ESI) m/z: 345.0 [M+H+]. | |
To a round-bottom flask was added sodium hydride (0.31g, 7.82mmol, 60% in mineral oil) and N,N-dimethylformamide (15mL). The resulting suspension was cooled to 0C under nitrogen and then <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (0.74g, 4.3mmol) was added. The mixture was stirred at 0C for 20min and then 2,6-dichlorobenzoyl chloride (0.82g, 3.91mmol) was added dropwise. The reaction was warmed to room temperature, stirred for 12h, and then poured into ice-water (20mL). The mixture was extracted with ethyl acetate (2×50mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to afford crude desired product (1.0g, 74% yield) that could be used without further purification. 1H NMR (DMSO-d6, 400MHz): delta 11.41 (s, 1H), 8.33 (d, J=5.6Hz, 1H), 7.99 (d, J=1.6Hz, 1H), 7.64-7.54 (m, 4H). LCMS (ESI) m/z=345.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tri-n-propylamine; dmap; In toluene; at 20 - 25℃; | Example 2; Step b; Formation of Compound (5); 45.8 g of the compound (4) as obtained according to Example 1 were suspended in600 ml toluene. Water as contained in the suspension was removed at a temperature between 60-80 C. and under reduced pressure of 450-400 mbar. Subsequently,200 ml toluene were newly added and the suspension was cooled to 20-25 C. Then, a solution of1.22 g dimethylaminopyridine in20 ml toluene was added, prior to the addition of15.8 g n-tripropylamine. Subsequently,22.0 g 2,6-dichlorobenzoylchloride were slowly added via a dropping funnel over approximately 15 minutes while the mixture was kept between 20 and 25 C.The reaction mixture was stirred for about 1-2 hours at a temperature between 20-25 C., whereby the color of the mixture turned into brown.The brownish reaction mixture as obtained by the last step above, was diluted with275 ml water and subsequently with29.6 g hydrochloric acid (37%). The resulting two phase mixture was heated to 65-70 C. The two phases were allowed to separate after about 10 minutes. The toluene phase was washed at a temperature between 65 and 70 C., first with300 ml of an aqueous solution containing 10% sodium hydrogencarbonate, and then with300 ml water. The organic (toluene) phase was concentrated by evaporation at temperatures between 55 and 60 C. and at reduced pressure (200-80 mbar) to a volume of about 200 ml. During this procedure the crude product (5) precipitated due to crystallization. The resulting suspension was then slowly cooled down (within about 5 h) to -5 to 0 C. and further stirred at that temperature for 1 h. The crude product was separated by filtration, washed twice with30 ml toluene (0 C.), and was subsequently dried at 50-55 C. and 26-13 mbar.Yield: 57 g (90%) of compound of formula (5). |
74% | With dmap; triethylamine; In tetrahydrofuran; at 0 - 20℃; for 0.5h; | General procedure: To a solution of 1 eq. 1 H-pyrrolo[2,3-0]pyridine derivative (1), prepared according to Example 3, in THF (0.1 M), triethylamine (1.05 eq.) was added. The resulting solution was cooled to 0C, 2,6-dichlorobenzoyl chloride (1.01 eq.) was added dropwise followed by the addition of 0.1 eq. 4-DMAP. The ice bath was removed and the reaction was stirred at RT until TLC showed complete consumption of the starting material (about 30min). The crude material was poured on water and extracted with EtOAc three times. The combined organic layers were dried over sodium sulfate, the solvent was removed in vacuo and the product was purified via flash chromatography (Si02, PE/EtOAc 15 - 25%). |
36% | With N-ethyl-N,N-diisopropylamine;dmap; In toluene; at 20℃;Inert atmosphere; | Into a reaction flask under nitrogen, propane- 1 -sulfonic acid [3-(5-bromo- 1 H-pyrrolo[2,3- b]pyridine-3-carbony.)-2,4-difluoro-phenyl]-amide (9, 8.40 g, 18.3 mmol) is combined with 100 mL of toluene, 4-dimethylaminopyridine (447 mg, 3.7 mmol), diisopropylethylamine (4.74 g, 36.7 mmol) and 2,6-dichloro-benzoyl chloride (10, 4.34 g, 20.7 mmol). The reaction is stirred at room temperature overnight, then diluted with 300 mL of dichloromethane and washed with 200 mL of saturated aqueous sodium bicarbonate, then 200 mL of brine. The organic layer is dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of ethyl acetate: hexane. Appropriate fractions are combined to provide crude material that is further purified with additional chromatography, eluting with 1 : 1 hexane:dich.oromethane up to 100 % dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (11, 4.15 g, 36%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: 2-Chloro-4-nitrobenzoic acid (201 mg, 1.0 mmol) and cyanuric chloride (368 mg, 2 mmol) in 2 mL CH2Cl2 were treated with pyridine (79 mg, 1.0 mmol) and irradiated in the microwave for 15 min at 50 C. Then, the resulting mixture was treated with FeCl3 (324 mg, 2.0 mmol) and irradiated in the microwave for 5 min at 30 C. Finally, 3 mL of toluene was added to the solution and irradiated in the microwave for 15 min at 70 C. Then the reaction mixture was filtered from Celite. The filtrate was washed with sodium thiosulphate followed by brine solution. The separated organic layer was dried on Na2SO4 and concentrated under reduced pressure to give pure product 6a (269.5 mg, 93% yield). Mp 110-112 C (lit. 1 111.2 C). 1H NMR (500 MHz, CDCl3): delta 2.39 (s, 3H), 7.26 (d, J = 7.45 Hz, 2H), 7.54 (d, J = 7.45 Hz, 1H), 7.61 (d, J = 6.85 Hz, 2H), 8.26 (dd, J = 6.85, 2.7 Hz, 1H), 8.30 (d, J = 7.4 Hz, 1H); 13C NMR (500 Hz, CDCl3): delta 21.4 (CH3), 122.0 (CH), 125.1 (CH), 129.6 (CH), 129.7 (CH), 130.15 (CH), 132.2 (C), 144.6 (C), 146.2 (C), 148.9 (C), 193.5 (CO); IR (cm-1): 638.3, 740.8, 801.5, 836.3, 863.0, 1000.7, 1025.9, 1052.5, 1005.1, 1133.9, 1158.3, 1180.7, 1272.5, 1294.3, 1315.8, 1349.1, 1403.2, 1449.5, 1461.2, 1528.8, 1573.3, 1595.7, 1607.9, 1673.9, 3087.5; GC/MS: 275 [M+]; HRMS: calcd for C14H10ClNO3: 275.0349. Found: 275.0467. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: glycine ethyl ester hydrochloride With sodium hydrogencarbonate In 2-methyltetrahydrofuran; water for 0.5h; Cooling; Stage #2: 2,6-Dichlorobenzoyl chloride In 2-methyltetrahydrofuran; water at 10℃; for 3h; Cooling; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | To a mixture of <strong>[39217-08-8]2-chloropyridine-3,4-diamine</strong> (2.0 g, 13.93 mmol), diisopropylethylamine (7.29 mL, 41.79 mmol) in CH2C12 (100 mL) and C¾CN (10 niL) cooled to 0 C, was added 2,6-dichlorobenzoyl chloride (2.92 g, 13.93 mmol) portionwise.Then 50 mL of CH3CN was added to dissolve the reaction mixture and the reaction was warmed to 23 C overnight. Monitoring the reaction by LC-MS showed complete conversion.The mixture was concentrated to dryness via rotavap to give a brown residue, which was then treated with POCI3 (10.68 g, 69.65 mmol). The reaction mixture was heated at 120 C overnight. Then the reaction mixture was cooled to 23 C, concentrated via rotavap, and carefully poured onto ice slowly. After neutralization with a saturated aqueous NaHC03 solution to pH 7.0, the mixture was extracted with EtOAc (2 x 100 mL), washed with brine, and dried over anhydrous Na2S04. Crude mixture was purified by column chromatography on silica gel with 0-10% CH2Cl2/MeOH to give desired product (2.9 g, 70% yield). ¾ NMR (DMSO- , 500 MHz): delta 13.75 (s, 1H), 8.20 (m, 1H), 7.73 - 7.65 (m, 5H). LCMS(ESI) m/z:298.0 [M+H+] | |
70% | To a cooled (0 C) mixture of <strong>[39217-08-8]2-chloropyridine-3,4-diamine</strong> (2.0 g, 13.93 mmol), diisopropylethylamine (7.29 mL, 41.79 mmol) indichloromethane (100 mL) and CH3CN (10 mL), was added2,6-dichlorobenzoyl chloride (2.92 g, 13.93 mmol) portionwise. Then 50 mL of CH3CNwas added to dilute the reaction mixture and the reaction was warmed to 23 Covernight. The next morning, monitoring the reaction by LC-MS showed completeconversion. The mixture was concentrated todryness via rotavap to give a brown residue, which was then treated with POCl3(10.68 g, 69.65 mmol). The reaction mixture was heated at 120 C overnight.Then the reaction mixture was cooled to 23 C, concentrated via rotavap, andcarefully and slowly poured onto ice. After neutralization with a saturatedaqueous NaHCO3 solution, the mixture was extracted with EtOAc (2 x100 mL), washed with brine, and dried over anhydrous Na2SO4.The crude mixture was purified by column chromatography on silica gel with0-10% dichloromethane/MeOH to give desired product (2.9 g, 70% yield). 1HNMR (DMSO-d6, 500 MHz): delta 13.75 (s,1H), 8.20 (m, 1H), 7.73 - 7.65 (m, 5H). LCMS(ESI)m/z: 298 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | A mixture of <strong>[4316-98-7]6-chloropyrimidine-4,5-diamine</strong> (200 mg, 1.4 mmol), 2,6-dichlorobenzoyl chloride (288 mg, 1.4 mmol), ammonium chloride (0.44 g, 8.4 mmol) in POCl3 (10 niL) was heated at 100 C for 15 hours. The mixture was cooled to room temperature and carefully poured into ice/water slowly, neutralized with NH4OH (25%) to basic (pH 7-8). The mixture was extracted with EtOAc (3 x50 mL) and the organic layer was washed with brine (3 x20 niL), dried with Na2S04 and concentrated by vacuum. The residue was purified by column chromatography on silica gel with EtOAc and petroleum ether (1 : 5) to afford the desired product (96 mg, 22% yield). NMR (DMSO- 6, 500 MHz): delta 14.46 (s, 1H), 8.83 (s, 1H),7.68 - 7.76 (m, 3H). LCMS(ESI) m/z: 299.4 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium hydrogencarbonate In diethyl ether; water at 20℃; Cooling with ice; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; at 3 - 20℃; for 3.16667h;Inert atmosphere; | 2,6-Dichlorobenzoyl chloride (13.7 mL,95.6 mmol) was added dropwise, over 10 minutes, to a solution of <strong>[159783-22-9]3,5-difluoropyridin-4-ylamine</strong> (10.37 g,79.7 mmol) in pyridine (160 mL) at a temperature of between 3 and 5 C, under argon. The reaction mixture was allowed to warm to room temperature over 1 hour and then stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure and the resultant residue was treated with HC1 (IN, 120 mL). The resultant suspension was stirred at room temperature for 45 minutes and the precipitate was collected by filtration, washing with water. A mixture of 2,6-dichloro-N-(3,5-difluoropyridin-4-yl)-benzamide and of 2,6- dichloro-N-(2,6-dichlorobenzoyl)-N-(3,5-difluoropyridin-4-yl)-benzamide (22.0 g) was obtained.A suspension of this mixture (22.0 g) in IN NaOH (200 mL) and MeOH (200 mL) was heated at 65 C for 7 hours then slowly cooled to room temperature. The pH of the mixture was adjusted to 4-5 by dropwise addition of 12N HC1, controlling the exotherm by the use of an ice-bath. The residue was left standing at room temperature for 18 hours and then the resultant solid was collected by filtration, washing with water, to afford the title compound as an off-white solid (14.65 g, 61% yield over two steps). LCMS (Method D): RT = 2.93 min, m/z: 303 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | To a solution of 6- chloro-5-fluoropyrimidin-4-amine (1.21 g, 8.2 mmol) in DMF (25 mL) at 0 C was added NaH (60% in mineral oil, 0.46 g, 11.5 mmol). The reaction mixture was stirred at 0 C for 20 minutes. 2,6-dichlorobenzoyl chloride (2.06 g, 9.8 mmol) was then added dropwise over 5 minutes. The reaction mixture was warmed to room temperature and stirred under nitrogen overnight. The reaction was quenched with saturated NH4C1 solution (100 mL), and extracted with EtOAc (3 x 100 mL). The combined organics layer was dried over Na2S04 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-25% EtOAc in hexane gradient to give the desired compound as a white solid (1.32 g, 50% yield). ¾ NMR (400 MHz, CDC13) delta 8.39 (s, 1H), 8.10 (s, 1H), 7.39-7.35 (m, 3H). LCMS (ESI) m/z: 320.0 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine; In 1,4-dioxane; for 18h;Reflux; | A mixture of 2-chloro- 3-fluoropyridin-4-ylamine (660 mg, 4.5 mmol), 2,6-dichlorobenzoyl chloride (1.43 mL, 2.10 g, 10.0 mmol) and triethylamine (1.53 mL, 1.11 g, 11.0 mmol) in dioxane (12 mL) was heated under reflux for 18 hours then cooled to ambient temperature. The resultant mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was separated, washed with brine, dried over Na2S04 and concentrated under reduced pressure. The residue was triturated with diethyl ether, filtered, dried and further purified by silica gel flash chromatography (0-25 % EtOAc in pentane) to afford the title compound as a pink solid (1.17 g, 81 % yield). NMR (300 MHz, CDC13): delta 8.50 (t, J = 5.3 Hz, 1H), 8.22 (d, J = 5.5 Hz, 1H), 7.83 (br s, 1H), 7.40-7.39 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
pyridine; at 1℃; for 150h; | ExamplesExample 14-(l-(2,6-dichlorobenzoyl H-indazol-3-yl)benzoic acidi) A solution of 3-bromo-4-azaindole (100 mg, 0.508 mmol) and 2,6-dichlorobenzoyl chloride (159 mg, 0.761 mmol) in 4 ml of pyridine was stirred for 1 h at 150 C in a microwave reactor. After cooling to room temperature the reaction mixture was diluted with water and the product was extracted into CH2CI2. The organic layer was washed with water, dried over a phase separation filter and concentrated under reduced pressure. The residue was purified on S1O2, using 10% ethylacetate in heptane as the eluent, to give (3-bromo-7H-indazol- 1 -yl)(2,6- dichlorophenvDmethanone (140 mg) as a yellow solid. | |
With pyridine; at 150℃; for 1h;Microwave; | A solution of 3-bromo-4-azaindole (100 mg, 0.508 mmol) and 2,6-dichlorobenzoyl chloride (159 mg, 0.761 mmol) in 4 ml of pyridine was stirred for 1 h at 150 C in a microwave reactor. After cooling to room temperature the reaction mixture was diluted with water and the product was extracted into CH2Cl2. The organic layer was washed with water, dried over a phase separation filter and concentrated under reduced pressure. The residue was purified on SiO2, using 10% ethylacetate in heptane as the eluent, to give (3-bromo-1H-indazol-1-yl)(2,6-dichlorophenyl)methanone (140 mg) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethyl potassium malonate With triethylamine; magnesium chloride In acetonitrile at 10 - 15℃; for 2.5h; Stage #2: 2,6-Dichlorobenzoyl chloride In acetonitrile at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 0 °C / Inert atmosphere 1.2: 12 h / 0 - 20 °C / Inert atmosphere 2.1: tris-(dibenzylideneacetone)dipalladium(0); DavePhos; lithium hexamethyldisilazane / tetrahydrofuran; 1,4-dioxane / 5 h / 100 °C / Microwave irradiation; Inert atmosphere; Sealed tube 3.1: pyridine / 4 h / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; acetonitrile; at 20℃; for 4h; | To a round-bottom flask was added <strong>[74420-00-1]1H-pyrrolo[2,3-b]pyridin-4-amine</strong> (1.00 g, 7.51 mmol), dichloromethane (50 mL), acetonitrile (10 mL) and DIPEA (1.96 mL, 11.27 mmol). 2,6-Dichlorobenzoyl chloride (1.57 g, 7.51 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 4 hours. The mixture was poured into the ice-water and extracted with dichloromethane (3 x 30 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (30 mL), and then dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (0-10% MeOH/DCM) to afford a crude product, which was further purified by rpHPLC to afford the desired product (0.24 g, 10% yield). 1H NMR (DMSO-d6, 400 MHz,) delta 7.90 (d, J = 0.8 Hz, 1H), 7.82 - 7.62 (m, 3H), 7.52 (d, J = 0.8 Hz, 1H), 6.92 (s, 2H), 6.45 (s, 2H). LCMS (ESI) m/z = 307.2 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: (4-ethoxyphenyl)hydrazine hydrochloride With triethylamine In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: 2,6-Dichlorobenzoyl chloride In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine In acetonitrile at 20℃; Reflux; | 2-Methoxy-N'-(2,6-dichlorobenzoyl)benzohydrazide (2b) General procedure: 2 mL of triethylamine and 0.73 g (0.004 mol) of 2,6-dichlorobenzoyl chloride in 15 mL of anhydrous acetonitrile were added to a stirred solution of 0.39 g (0.003 mol) of salicylic acid hydrazide 1a in 20 mL of anhydrous acetonitrile. The reaction mixture was incubated at room temperature overnight and then refluxed during 10 h. The solvent was removed in vacuum; the oily residue was washed with water (2 ×10 mL), dried, and purified by chromatography on silica gel (0.063-0.200 μm; ethyl acetate-petroleum ether, 1 : 5 as eluent) collecting the fraction with Rf=0.70. After distilling off the solvent, the product was recrystallized from propan-2-ol. Yield 0.73 g (85%), colorless crystals, mp 139-140 °C. IR spectrum, ν, cm-1: 763, 792, 855, 1005, 1010, 1156, 1158, 1236, 1249, 1360, 1467, 1466, 1491, 1499, 1564, 1594, 1598(C=C); 1668, 1701 (C=O); 3037 (NH), 3280 (OH). 1H NMR spectrum (CDCl3), δ, ppm: 7.08-7.12 m (2H, HAr), 7.23-7.39 m (4H, HAr), 7.57 and 7.61 d.d (1H, HAr, J1 = 7.5, J2 = 7.6 Hz), 10.40 d (1H, NH, J =7.6 Hz), 11.21 d (H, NH, J = 7.6 Hz). 13C NMR spectrum (DMSO-d6), δ, ppm: 116.15, 116.46, 118.84, 128.63, 129.37, 132.02, 132.38, 133.79, 133.99, 159.69, 160.15 (C=O), 161.35 (C=O). Found, %: C 51.80; H 3.06; N 8.60. C14H10Cl2N2O3. Calculated, %: C 51.72; H 3.10; N 8.62. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | To a mixture of <strong>[89182-17-2]6-chloropyridine-3,4-diamine</strong> (2.0 g, 14mmol) anddiisopropylethylamine(5.4 g, 42mmol) indichoromethane(100 mL) and acetonitrile (50 mL) at 0 C, was added 2,6-dichlorobenzoyl chloride (2.92 g, 13.9mmol)portionwise. The reaction mixture was stirred at room temperature overnight. The mixture was then concentrated to dryness to give a brown residue, which was then treated with POCl3(11 g, 70mmol) and was stirred at 120 C overnight. The mixture was cooled to room temperature and carefully concentrated and then poured slowly, after which the reaction mixture was neutralized with sat. NaHCO3. The mixture was extracted withEtOAc, washed with brine and then concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluting withMeOH/dichloromethane(0-10%) to give the title compound (1.0 g, 24% yield) as a brown solid. LCMS (ESI) m/z: 298 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; triethylamine; In tetrahydrofuran; at 90℃; for 4h; | To a solution of <strong>[271-73-8]1H-<strong>[271-73-8]pyrazolo[3,4-b]pyridine</strong></strong> (500 mg, 4.20 mmol) in THF (8 mL) was added 2,6-dichlorobenzoyl chloride (879 mg, 4.20 mmol), TEA (1.755 mL, 12.59 mmol) and DMAP (256 mg, 2.099 mmol). The reaction was stirred at 90° C. for 4 hours. LCMS show no starting material and the desired product formed. The reaction mixture was concentrated and purified by silica gel column chromatography (SiO2, EtOAc/PE=0percent to 50percent) to give (2,6-dichlorophenyl)(1H-pyrazolo[3,4-b]pyridin-1-yl)methanone. MS: 292 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1.0h; | To a mixture of methyl (2S)-2-amino-3-(3- hydroxyphenyl)propanoate hydrochloride (100. mg, 0.4300mmol) in DCM (2.1581mL) at r. t. was added diisopropylethylamine (0.38mL, 2.16mmol) followed by 2,6-dichlorobenzoyl chloride (0.06mL, 0.4300mmol) dropwise. The resulting mixture was stirred at r. t. for 1 hr. The reaction was concentrated, the residue was then partitioned between EtOAc (5.0 mL) and 1N HCl (2.0 mL). the layers were separated and the organic layer was washed with saturated sodium bicarbonate (2.0 mL) followed by brine (2.0 mL), dried over sodium sulfate, filtered and concentrated to give 37a-int. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With aluminum (III) chloride at 0 - 110℃; for 15h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With triethylamine; In dichloromethane; at 20℃; for 1h;Cooling with ice; | Comparative Example 3 2,6-Dichloro-N-(4-fluoro-3-methoxybenzyl)benzamide To a mixture of <strong>[123652-95-9]3-fluoro-4-methoxybenzylamine</strong> (28.9 mg, 0.19 mmol) and dichloromethane (1 mL) was added triethylamine (0.040 mL, 0.29 mmol) followed by 2,6-dichlorobenzoyl chloride (0.021 mL, 0.14 mmol) under ice cooling and the resultant was stirred at room temperature for 1 hour. The reaction mixture was filtered through celite(tm) and the filtrate was evaporated to remove the solvent under a reduced pressure. The residue was triturated with heptane/ethyl acetate (1:1) to give the title compound (47 mg, 60% yield). 1H-NMR Spectrum (DMSO-d6) delta (ppm): 3.78 (s, 3H), 4.37 (d, J=6.11 Hz, 2 H), 7.07-7.14 (m, 1 H), 7.14-7.20 (m, 1 H), 7.37-7.43 (m, 1 H), 7.47 (s, 1 H), 7.48 (s, 1 H), 9.07-9.17 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3h;Cooling with ice; | Comparative Example 2 2,6-dichloro-N-[(2,3-dihydro-1,4-benzodioxin-6-yl)methyl]benzamide To a mixture of 2,3-dihydro-1,4-benzodioxin-6-yl)methylamine (50 mg, 0.30 mmol) and dichloromethane (1 mL) were added N,N-diisopropylethylamine (0.11 mL, 0.61 mmol) and 2,6-dichlorobenzoyl chloride (0.043 mL, 0.30 mmol) under ice cooling and the resultant was stirred at room temperature for 3 hours. The reaction mixture was purified by column chromatography on silica gel (heptane:ethyl acetate=2:1) to give the title compound (94 mg, 92% yield), 1H-NMR Spectrum (CDCl3) delta (ppm): 4.24 (s, 4 H), 4.57 (d, J=5.47 Hz, 2 H), 5.94 (br. s, 1 H), 6.81-6.92 (m, 3 H), 7.21 -7.33 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminium trichloride; at 40℃; | Hereinafter there are listed examples of ketones obtainalbe or obtained by the process of the invention: hexanone-3 decanone-4 ... o-chloropropiophenone m-chloroacetophenone 3-chloro-5-methylpropiophenone 2,6-dichloroacetophenone m-bromopropiophenone p-bromoacetophenone p-bromopropiophenone ... |
Tags: 4659-45-4 synthesis path| 4659-45-4 SDS| 4659-45-4 COA| 4659-45-4 purity| 4659-45-4 application| 4659-45-4 NMR| 4659-45-4 COA| 4659-45-4 structure
[ 116070-31-6 ]
2,6-Dichloro-4-methylbenzaldehyde
Similarity: 0.85
[ 116070-31-6 ]
2,6-Dichloro-4-methylbenzaldehyde
Similarity: 0.85
[ 25784-91-2 ]
2-Chloro-5-nitrobenzoylchloride
Similarity: 0.62
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Code | Phrase |
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P102 | Keep out of reach of children. |
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Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
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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. |
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P243 | Take precautionary measures against static discharge. |
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P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
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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. |
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P285 | In case of inadequate ventilation wear respiratory protection. |
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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: |
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P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
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P333 | If skin irritation or rash occurs: |
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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. |
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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. |
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P362 | Take off contaminated clothing and wash before reuse. |
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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. |
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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. |
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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. |
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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. |
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P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
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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. |
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P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
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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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