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CAS No. : | 45767-66-6 | MDL No. : | MFCD00236025 |
Formula : | C7H5BrClF | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GAUUDQVOPUKGJD-UHFFFAOYSA-N |
M.W : | 223.47 | Pubchem ID : | 2725062 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 44.25 |
TPSA : | 0.0 Ų |
GI absorption : | Low |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.21 cm/s |
Log Po/w (iLOGP) : | 2.33 |
Log Po/w (XLOGP3) : | 3.46 |
Log Po/w (WLOGP) : | 3.64 |
Log Po/w (MLOGP) : | 4.1 |
Log Po/w (SILICOS-IT) : | 3.89 |
Consensus Log Po/w : | 3.49 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.78 |
Solubility : | 0.0368 mg/ml ; 0.000165 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.14 |
Solubility : | 0.161 mg/ml ; 0.000722 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.56 |
Solubility : | 0.0062 mg/ml ; 0.0000277 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.75 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P260-P264-P270-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501 | UN#: | 3261 |
Hazard Statements: | H302-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 |
---|---|---|
88% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 3 h; Heating / reflux | A mixture of 77.6 g (0.54 mol) of 2-chloro-4-fluorotoluene, 95.6 g(0.54 mol) of N-bromosuccinimide, 1 g of benzoyl peroxide, and 1000 ml of carbon tetrachloride were refluxed for 3 h. The resulting mixture was cooled to room temperature and then filtered through a glass frit (G3). The precipitate was additionally washed with 3 x 100 ml of carbon tetrachloride. The combined filtrate was evaporated to dryness. Fractional distillation of the residue gave pure title product, bp 97-99°C/10 mm Hg. Yield 106 g (88percent).Anal. calc. for C7H5BrClF: C, 37.62 H, 2.26 Found: C, 37.79; H, 2.34.1H NMR (CDCl3): δ 7.41 (dd, J=8.4 Hz, J=6.0 Hz, IH, 6-H), 7.13 (dd, J=8.4 Hz, J=2.6 Hz, IH, 3-H), 6.97 (dt, J=8.4 Hz, J=2.6 Hz, IH, 5-H), 4.55 (s, 2H, CH2). |
88% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane | 1-(Bromomethyl)-2-chloro-4-fluorobenzene A mixture of 77.6 g (0.54 mol) of 2-chloro-4-fluorotoluene, 95.6 g (0.54 mol) of N-bromosuccinimide, 1 g of benzoyl peroxide, and 1000 ml of carbon tetrachloride were refluxed for 3 h. The resulting mixture was cooled to room temperature and then filtered through a glass frit (G3). The precipitate was additionally washed with 3*100 ml of carbon tetrachloride. The combined filtrate was evaporated to dryness. Fractional distillation of the residue gave pure title product, bp 97-99° C./10 mm Hg. Yield 106 g (88percent). Anal. calc. for C7H5BrClF: C, 37.62 H, 2.26 Found: C, 37.79; H, 2.34. 1H NMR (CDCl3): δ 7.41 (dd, J=8.4 Hz, J=6.0 Hz, 1H, 6-H), 7.13 (dd, J=8.4 Hz, J=2.6 Hz, 1H, 3-H), 6.97 (dt, J=8.4 Hz, J=2.6 Hz, 1H, 5-H), 4.55 (s, 2H, CH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With bromine In tetrachloromethane | EXAMPLE 1 Preparation of 2-chloro-4-fluorobenzyl bromide A solution of bromine (7.10 ml) in carbon tetrachloride (70 ml) was added slowly over a period of 3 hours to a solution of 2-chloro-4-fluorotoluene (20.0 g) in carbon tetrachloride (80 ml) maintained at the reflux temperature and irradiated by light from a tungsten lamp (200 watt). After the addition was completed the mixture was heated at the reflux temperature with irradiation until the colour had been discharged (ca.1 hour). The solvent was then removed by evaporation under reduced pressure and the residual oil distilled to yield 2-chloro-4-fluorobenzyl bromide (80percent pure, 18.0 g) b.p. 110°-120° C./15 mm Hg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 3h;Heating / reflux; | A mixture of 77.6 g (0.54 mol) of <strong>[452-73-3]2-chloro-4-fluorotoluene</strong>, 95.6 g(0.54 mol) of N-bromosuccinimide, 1 g of benzoyl peroxide, and 1000 ml of carbon tetrachloride were refluxed for 3 h. The resulting mixture was cooled to room temperature and then filtered through a glass frit (G3). The precipitate was additionally washed with 3 x 100 ml of carbon tetrachloride. The combined filtrate was evaporated to dryness. Fractional distillation of the residue gave pure title product, bp 97-99C/10 mm Hg. Yield 106 g (88%).Anal. calc. for C7H5BrClF: C, 37.62 H, 2.26 Found: C, 37.79; H, 2.34.1H NMR (CDCl3): delta 7.41 (dd, J=8.4 Hz, J=6.0 Hz, IH, 6-H), 7.13 (dd, J=8.4 Hz, J=2.6 Hz, IH, 3-H), 6.97 (dt, J=8.4 Hz, J=2.6 Hz, IH, 5-H), 4.55 (s, 2H, CH2). |
106 g (88%) | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; | 1-(Bromomethyl)-2-chloro-4-fluorobenzene A mixture of 77.6 g (0.54 mol) of <strong>[452-73-3]2-chloro-4-fluorotoluene</strong>, 95.6 g (0.54 mol) of N-bromosuccinimide, 1 g of benzoyl peroxide, and 1000 ml of carbon tetrachloride were refluxed for 3 h. The resulting mixture was cooled to room temperature and then filtered through a glass frit (G3). The precipitate was additionally washed with 3*100 ml of carbon tetrachloride. The combined filtrate was evaporated to dryness. Fractional distillation of the residue gave pure title product, bp 97-99 C./10 mm Hg. Yield 106 g (88%). Anal. calc. for C7H5BrClF: C, 37.62 H, 2.26 Found: C, 37.79; H, 2.34. 1H NMR (CDCl3): delta 7.41 (dd, J=8.4 Hz, J=6.0 Hz, 1H, 6-H), 7.13 (dd, J=8.4 Hz, J=2.6 Hz, 1H, 3-H), 6.97 (dt, J=8.4 Hz, J=2.6 Hz, 1H, 5-H), 4.55 (s, 2H, CH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 3h; | [3- {2- [5-BROMO-2- (HYDROXY)-PHENYL]-5-METHYL-PYRROL-1-YL}-BENZOIC ACID ETHYL] ester (130 mg, 0.33 mmol, 1 eq) was added to DMF (1.3 [ML).] [K2CO3] (92 mg, 0.66 mmol, 2 eq) and 2- chloro-4-fluorobenzyl bromide (111.74 mg, 0.5 mmol, 1.5eq) were added to the stirred reaction mixture. After complete addition the vessel was heated to 60 [C.] After 3 hours the reaction had gone to completion. The reaction mixture was quenched with water (20 ml) and washed with EtOAc (2 x 20 [ML).] The organic extracts were combined and washed with brine (10 ml), dried over [MGS04] and the solvent was then removed in vacuo. The crude product purified by chromatography on silica gel (3% EtOAc : iso-hexane) to yield title compound (122 mg, 67%) as a colourless oil. 'H NMR [(400MHZ,] CDCl3) 1.31 (3H, t, J=7. 0Hz), 2.17 (3H, s), 4.29 (2H, q, J=7. 0Hz), 4.73 (2H, s), 6.14 (1H, d, J=3.2Hz), 6.31 (1H, d, J=3.6Hz), 6.47 (1H, d, J=8.4Hz), 6.89 (2H, m), 7.09 (1H, dd, [J=1.] 6,8. 0Hz), 7.14 (1H, br d, J=7.6Hz), 7.20 (1H, dd, J=2.4, 8.5Hz), 7.31 (1H, t, J=7.8Hz), 7.40 (1H, d, J=2. 0Hz), 7.73 (1H, t, J=1.4Hz), 7.92 (1H, br d, J=7.8Hz). LC/MS t = 4.39 mins [MH+] 541.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 65℃; for 3h; | [5- {2- [2- (HYDROXY)-PHENYL]-5-METHYL-PYRROL-1-YL}-NICOTINIC] acid ethyl ester (0. [116G,] 0. [358MM),] <strong>[45767-66-6]2-chloro-4-fluorobenzyl bromide</strong> (0.120g, 0. 537mmol) and potassium carbonate (0.099g, 0. [716MMOL)] were heated in DMF [(1 ML)] at [65C] in a nitrogen atmosphere for 3 hours. Upon cooling the mixture was diluted with EtOAc and water. The organic layer was extracted and the aqueous layer washed with 3xEtOAc. The combined organics were then washed with brine and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 15% EtOAc/iso-hexane. This yielded the title compound as a yellow oil (0.035g, 30%). 'H-NMR [(400MHZ,] CDCl3) 1.33 (3H, t, J=7Hz), 2.18 (3H, s), 4.32 (2H, q, J=7Hz), 4.78 (2H, s), 6.18 (1H, d, J=3Hz), 6.32 (1H, d, J=3Hz), 6.65 (1H, d, 9Hz), 6.89-7. 01 (3H, m), 7.07- 7.18 (2H, m), 7.29 (1H, d, J=2Hz), 7.93 (1H, t, J=2Hz), 8.40 (1H, d, J=2Hz), 9.03 (1H, d, J=2Hz). LC/MS t = 3.96 min [[MH+]] 465 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 16h; | 2-Chloro-4-fluoro-benzyl bromide (47mg, 0.21 [MMOL)] was added to 5- {2- [5-Chloro-2- [(HYDROXY)-PHENYL]-5-METHYL-PYRROL-1-YL} NICOTINIC] acid ethyl ester (50mg, 0. 14mmol) and [K2CO3] (43mg, 0.31 [MMOL)] in DMF [(1 ML)] and the reaction mixture was heated at [60C] for 16 hours. Upon cooling the reaction mixture was diluted with EtOAc, washed with water, brine, dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel with isohexane/EtOAc (15%) as eluant, to give the title compound (39mg, 56%). 'H NMR [(400MHZ,] [CDC13)] 1.35 (3H, t, J=7Hz), 2.17 (3H, s), 4.34 (2H, q, J=7Hz), 4.73 (2H, s), 6.17 (1H, dd, [J=1,] 3.5Hz), 6.32 (1H, d, J=3.5Hz), 6.57 (1H, d, J=9Hz), 6.88-6. 94 (2H, m), 7.07-7. 14 (2H, m), 7.30 (1H, d, J=3Hz), 7.92 (1H, t, J=2Hz), 8.40 (1H, d, 2Hz), 9.06 (1H, d, J=2Hz). LC/MS t=4.14 min [MH+] 499/501/503. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 16h; | [2-CHLORO-4-FLUORO-BENZYL] bromide (168mg, 0. [75MMOL)] was added to [3- {2- [5-] methanesulfonyl-2-(hydroxy)-phenyl]-5-methyl-pyrrol-1-yl}-benzoic acid ethyl ester (200mg, 0. [50MMOL)] and [K2CO3] (138mg, [1.] 0mmol) in DMF (2ml) and the reaction mixture was heated at [60C] for 16 hours. Upon cooling the reaction mixture was diluted with EtOAc, washed with water, brine, dried [(MGS04), FILTERED] and concentrated. The residue was purified by chromatography on silica gel with isohexane/EtOAc (30%) as eluant, to give the title compound (248mg, 91 %). ['H-NMR] [(400MHZ,] CDCI3) 1.31 (3H, t, J=7Hz), 2.18 (3H, s), 2.89 (3H, s), 4.29 (2H, q, J=7Hz), 4.93 (2H, s), 6.16 (1H, d, J=3Hz), 6.42 (1H, d, J=3Hz), 6.79 (1H, d, J=9Hz), 6.94 (1H, ddd, J=2Hz, 8Hz), 7.00-7. 16 (1H, m), 7.13 (1H, dd, J=2Hz, 8Hz), 7.18-7. 22 (1H, m), 7.34 (1 H, t, J=8Hz), 7.67-7. 73 (3H, m), 7.93 (1H, d, J=8Hz). LC/MS t=3.84 min [[MNH4+]] = 559/561. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 65℃; for 3.5h; | [3- {2- [5-TRIFLUOROMETHYL-2- (HYDROXY)-PHENYL]-5-METHYL-PYRROL-1-YL}-BENZOIC] acid ethyl ester (0.085g, 0. 219mmol), <strong>[45767-66-6]2-chloro-4-fluorobenzyl bromide</strong> (0.073g, 0. [329MMOL)] and potassium carbonate (0. [061G,] 0. [438MMOL)] were heated in DMF (2ml) at [65C] in a nitrogen atmosphere for 3.5 hours. Upon cooling the mixture was diluted with EtOAc and washed with 2 x water. The organic layer was extracted and the aqueous layer washed with 3 x EtOAc. The combined organics were then washed with brine and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 8% EtOAc/iso- hexane. This yielded the title compound as a clear oil (0. [091G,] 78%). 'H-NMR [(400MHZ,] [CDCI3)] 1.29 (3H, t, J=7Hz), 2.18 (3H, s), 4.28 (2H, q, J=7Hz), 4.85 (2H, s), 6.17 (1H, d, J=3Hz), 6.37 (1H, d, J=3Hz), 6.67 (1H, d, J=9Hz), 6.86-6. 97 (2H, m), 7.11 (1H, dd, J=2Hz, 9Hz), 7.15 (1H, broad d, J=9Hz), 7.31 (1H, t, J=8Hz), 7.37 (1H, dd, J=2Hz, 9Hz), 7.50 (1H, d, J=2Hz), 7.12 (1H, t, [J=1HZ),] 7.93 (1H, dt, J=0.5Hz, 8Hz). LC/MS t=4.34 min [MH+] 532/534. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 16h; | 2-Chloro-4-fluoro-benzyl bromide (25mg, 0. [11 MMOL)] was added to [2- {2- [5-CHLORO-2-] [(HYDROXY)-PHENYL]-5-METHYL-PYRROL-1-YL}-ISONICOTINIC] acid ethyl ester (40mg, 0. 11mmol) and [K2C03] (31 mg, 0. [31 MMOL)] in DMF [(1] ml) and the reaction mixture was heated at [60C] for 16 hours. Upon cooling the reaction mixture was diluted with EtOAc, washed with water, brine, dried [(MGS04),] filtered and concentrated. The residue was purified by chromatography on silica gel with isohexane/EtOAc (10%) as eluant, to give the title compound (46mg, 82%). ['H] NMR [(400MHZ,] CDCl3) 1.31 (3H, t, J=7Hz), 2.31 (3H, s), 4.30 (2H, q, J=7Hz), 4.68 (2H, s), 6.14 (1H, dd, [J=1,] 3.5Hz), 6.33 (1H, d, J=3.5Hz), 6.57 (1H, d, J=9Hz), 6.90 (1H, ddd, J=2.5, 9Hz), 7.03-7. 11 (3H, m), 7.30 (1H, d, J=2.5Hz), 7.40 (1H, broad s), 7.67 (1H, dd, J=1.5, 5Hz), 8.50 (1H, d, J=5Hz). LC/MS t=4.20 min [MH+] 499/501/503 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 65℃; for 2.5h; | [5- [2- (5-BROMO-2-HYDROXY-PHENYL)-5-METHYL-PYRROL-1-YL]-NICOTINIC] acid ethyl ester (0.06g, 0. [125MMOL), 2-CHLORO-4-FLUORO-BENZYL] bromide (0.042g, 0. 187mmol) and potassium carbonate (0. 034g, 0. [249MMOL)] were heated in DMF [(1] ml) at [65C] in a nitrogen atmosphere for 2.5 hours. Upon cooling the mixture was diluted with EtOAc and water. The organic layer was extracted and the aqueous layer washed with 3xEtOAc. The combined organics were then washed with brine and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 15% EtOAc/iso-hexane. This yielded the title compound as a clear oil (0.079g, 98%). 'H-NMR [(400MHZ,] [CDCI3)] 1.35 (3H, t, J=7Hz), 2.17 (3H, s), 4.34 (2H, q, J=7Hz), 4.72 (2H, s), 6.18 (1H, d, J=3Hz), 6.31 (1H, d, J=3Hz), 6.51 (1H, d, 9Hz), 6.91 (2H, dd, J=1Hz, 7Hz), 7.09 (1H, dt, J=1Hz, 9Hz), 7.25 (1H, d, J=3Hz), 7.45 (1H, d, J=3Hz), 7.91 (1H, t, J=2Hz), 8.40 (1H, d, J=3Hz), 9.06 (1 H, d, J=2Hz). [LC/MS T = 4. 14 MIN [MH+]] 545 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 3h; | 3-{2-[2-(Hydroxy)-phenyl]-5-methyl-pyrrol-1-yl}-benzoic acid ethyl ester (200 mg, 0.62 [MMOL,] 1 eq) was added to DMF (2 [ML). K2CO3] (172 mg, 1.25 [MMOL,] 2 eq) and 2-chloro-4- [FLUOROBENZYL] bromide (208.9 mg, 0.93 mmol, 1.5eq) were added to the stirred reaction mixture. After complete addition the vessel was heated to 60 [C.] After 3 hours the reaction had gone to completion. The reaction mixture was quenched with water (20 [ML)] and washed with EtOAc (2 x 20 ml). The organic extracts were combined and washed with brine (10 [ML),] dried over [MGS04] and the solvent was then removed in vacuo. The crude product was purified by chromatography on silica gel (5% EtOAc : iso-hexane) to yield title compound (189 mg, 65%) as a colourless oil. 'H NMR [(400MHZ,] [CDCI3)] 1.30 (3H, t, J=7. [1HZ),] 2.18 (3H, s), 4.28 (2H, q, J=7. [0HZ),] 4.79 (2H, s), 6.15 (1H, d, J=3.4Hz), 6.31 (1H, d, J=3.4Hz), 6.61 (1H, d, J=8. [0HZ),] 6.88 (2H, m), [6. 98 (1H,] dd, J=7.0, 8.2Hz), 7.08 (1H, dd, J=2.0, 8. 0Hz), 7.12 (2H, m), 7.26 (2H, m), 7.77 [(1 H, BR S),] 7.89 [(1 H, BR D,] J=7.6Hz). LC/MS t = 4.23 mins [[MH+]] 464.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 18h; | 3- {2- [5-Chloro-2- (hydroxy)-phenyl]-5-methyl-pyrrol-1-yl}-benzoic acid ethyl ester (0.148g, 0. 41mmol), 2-chloro-4-fluoro-benzyl bromide (0.139g, 0. [62MMOL)] and potassium carbonate (0. [12G,] 0. [82MMOL)] were heated in DMF at [60C] in a nitrogen atmosphere for 18 hours. Upon cooling the mixture was diluted with EtOAc and water. The organic layer was extracted and the aqueous layer washed with EtOAc. The combined organics were then washed with brine and concentrated in vacuo. This yielded the title compound as a clear oil (0.149g, 72%). The residue was purified by chromatography on silica gel eluting with 5% EtOAc/iso-hexane. 1H-NMR [(400MHZ,] CDCI3) 1.31 (3H, t, 7Hz), 2.17 (3H, s), 4.29 (2H, q, 7Hz), 4.73 (2H, s), 6.13 (1H, dd, J=0.5Hz, 3Hz), 6.31 (1H, d, 3Hz), 6.52 (1H, d, 9Hz), 6.85-6. 91 (2H, m), 7.05- 7.10 (2H, m), 7.15 (1H, m), 7.25 (1H, d, J=3Hz), 7.30 (1H, t, J=8Hz), 7.74 (1H, t, [J=0.] 5Hz), 7.92 (1H, dt, J=0.5Hz, 8Hz). LC/MS t = 4.36 min [MH+] 498/500/502. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dimethoxyethane; at 70℃; for 6h; | Example 68: 2-Chloro-1-[1-[(4-chlorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]-4-fluorobenzene sodium 4-chlorobenzenesulfinate (197 mg, 0.992 mmol) and <strong>[45767-66-6]2-chloro-4-fluorobenzyl bromide</strong> (222 mg, 0.992 mmol) were added to dimethoxyethane (5 ml).. The resulting mixture was stirred at 70C for 6 hours.. After cooling to room temperature, the solvent was concentrated under reduced pressure.. The residue was added with ethyl acetate and from the resulting mixture, the insoluble matter was filtered off.. The residue obtained by concentrating the filtrate under reduced pressure was washed with hexane to yield a white powder (225 mg). Then, a toluene (10 ml) solution of the resulting white powder (61 mg), 4-(methylsulfonyl)-1-butanol (59 mg, 0.394 mmol) obtained in Referential Example 3 and cyanomethylenetri-n-butylphosphorane (93 mg, 0.384 mmol) was heated under reflux for 15 hours under an argon atmosphere.. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure.. The residue was subjected to medium-pressure chromatography on a silica gel column, whereby from the fraction eluted with hexane:ethyl acetate(=1:1), the title compound was obtained as a white solid (38 mg). Melting point: 124.0-125.0C. IR (ATR) nu: 2969, 2933, 1604, 1575, 1492, 1475, 1461, 1396, 1315, 1276, 1230, 1130, 1085, 1049, 1014, 973, 902, 850, 823, 782, 748, 659, 630, 588, 549, 501, 457 cm-1.1H-NMR (400MHz, CDCl3) delta: 1.30-1.50(2H,m), 1.79-1.98(2H,m), 2.10-2.25(1H,m), 2.48-2.60(1H,m), 2.87(3H,s), 2.95(2H,t,J=7.7Hz), 4.79(1H,dd,J=11.1,4.0Hz), 6.98(1H,dd,J=8.3,2.7Hz), 7.05-7.15(1H,m), 7.38(2H,d,J=8.3Hz), 7.48(2H,d,J=8.5Hz), 7.60-7.70(1H,m). MS (m/z): 453 (M++H). Elemental Analysis for C18H19Cl2FO4S2 Calculated: C 47.69%; H 4.22%; Cl 15.64%; F 4.19%; S 14.55%. Found: C 47.44%; H 4.20%; Cl 15.37%; F 4.07%; S 14.33%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium carbonate; In acetone;Heating / reflux; | A mixture of 1- [1- (5-chloro-2-hydroxy-phenyl]-ethyl]-5-methyl-1 H-pyrazole-3-carboxylic acid ethyl ester (100mg, 0. 32mol), K2CO3 (112mg, 0.81 mmol) and 2-chloro-4- fluorobenzyl bromide (79mg, 0. 36mmol) in acetone (3ml) was refluxed overnight under nitrogen. After cooling the solid was filtered off and the solvent removed in vacuo. Purification was carried out on a SPE using iso-hexane containing a gradient of ethyl acetate (5-10%) to yield the title compound (120mg, 74%). t = 3.95, [MH+] 451,454. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.7% | With potassium carbonate; In acetonitrile; for 1h;Heating / reflux; | A suspension of 2-amino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (93.2 mg, 0.40 mmol), 2-chloro-4-fluoro-benzylbromide (89.2 mg, 0.40 mmol) and K2CO3 (83.01 mg, 0.60 mmol) in acetonitrile (10 mL) was heated to reflux under argon for 1 hr. Cooled to r.t. and the reaction mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated to give a residue which was triturated with EtOAc and filtered to give 2-(2-chloro-4-fluoro-benzylamino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester as a white solid (73.0 mg, 48.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With hydrogenchloride; In N,N-dimethyl-formamide; | Reference Example 125 To a solution of ethyl 3-(3-isopropoxy-1H-pyrazol-5-yl)propionate (1.00 g) in N,N-dimethylformamide (20 ml) was added sodium hydride (190 mg, 60% in oil) at room temperature, and the mixture was stirred for 10 min. To the reaction mixture was added <strong>[45767-66-6]2-chloro-4-fluorobenzyl bromide</strong> (1.55 g), and the mixture was stirred at room temperature for 4 hr. 1N Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:49 to 1:4, v/v) to give ethyl 3-[1-(2-chloro-4-fluorobenzyl)-3-isopropoxy-1H-pyrazol-5-yl]propionate (790 mg, yield 48%) as a colorless oil. 1H-NMR (300 MHz, CDCl3) delta:1.24 (3 H, t, J = 7.2 Hz), 1.32 (6 H, d, J = 6.0 Hz), 2.53 - 2.59 (2 H, m), 2.74 - 2.80 (2 H, m), 4.12 (2 H, q, J = 7.2 Hz), 4.63 - 4.75 (1 H, m), 5.18 (2 H, s), 5.51 (1 H, s), 6.61 (1 H, dd, J = 6.0, 8.7 Hz), 6.85 - 6.91 (1 H, m), 7.10 (1 H, dd, J = 2.5, 8.3 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro-trimethyl-silane; ammonium chloride; magnesium; In water; ethyl acetate; butanone; | Example 27 1-(2-chloro-4-fluorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride 0.38 g (15.6 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.79 g (15.6 mmole) of <strong>[45767-66-6]2-chloro-4-fluorobenzyl bromide</strong> dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 3.0 g (13.0 mmole) of the 2-(dimethyl-aminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 60 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 4.52 g of crude base (92.8% of theory) were obtained. The crude base was dissolved in 45 ml of 2-butanone and some ethyl acetate, 0.11 ml (6.0 mmole) of water and 1.52 ml (12.0 mmole) of chlorotrimethylsilane were added in succession, and the reaction mixture was kept for 15 hours at RT. The solvents were distilled off on a rotary evaporator (500 to 10 mbar), the residue was taken up in 20 ml of ether, the remaining solids were filtered off, washed with small portions of ether, and dried to constant weight in an oil pump vacuum. 4.45 g of 1-(2-chloro-4-fluorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride (83.2% of theory) were obtained in this way. The hydrochloride decomposes on heating above 100 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In N,N-dimethyl-formamide; for 18h; | Example 111; JV-[(2-chloro-4-fluorophenyl)methyl]-2,3-dimethyl-6-(li?-l,2,4- triazoI-l-yl)imidazo[l,2-alpha]pyridin-8-amineA mixture of 2,3 -dimethyl-6-(lH- 1 ,2,4-triazol- 1 -yl)imidazo[ 1 ,2-alpha]pyridin-8-amine (Description 54;150mg, 0.66mmol), l-(bromomethyl)-2-chloro-4-fluorobenzene (176mg, 0.79mmol) and sodium carbonate (220mg, 2.1mmol) were stirred in dimethylformamide (5ml) for 48 hours, further l-(bromomethyl)-2-chloro-4- fluorobenzene (147mg, 0.66mmol) was added and the reaction stirred for 18 hours and partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried (MgSO4), evaporated, purified by chromatography on silica gel (ethyl acetate/hexane) and evaporated to give the title compound. MS (ES+ve): [M+H]+ at m/z 371 and 373 (C18H16ClFN6 requires [M+H]+ at m/z 371 and 373). EPO <DP n="106"/>The following compounds were prepared by reaction of 2,3-dimethyl-6-(lH-l,2,4- triazol-l-yl)imidazo[l,2-alpha]pyridin-8-amine (Description 54) with the appropriate benzyl bromide (as indicated) in an analogous manner to that described for Example 111 altering reaction temperatures, times, solvents and drying agents as appropriate: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In N,N-dimethyl-formamide; at 60℃; for 16h; | Example 43; - iV-[(2-Chloro-4-fluorophenyl)methyl]-2,3-dimethyl-6-(lJ?-pyrazol- 1 -yl)imidazo [1 ,2-alpha] py ridin-8-amineA mixf°re of2,3-dimethyl-6-(lH-pyrazol-l-yl)imidazo[l,2-alpha]pyridin-8-amine (Description 20, lOOmg, 0.44mmol), l-(bromomethyl)-2-chloro-4-fluorobenzene (295mg, 1.32mmol), sodium carbonate (148mg, 1.40mmol) and dimethylformamide (5mL) were stirred at 6O0C for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried over magnesium sulphate and evaporated. The product was purified by chromatography on silica gel and eluted with 0-50% ethyl acetate in hexane. The solvent was then evaporated to give the title compound. MS (ES+ve): [M+H]+ at m/z 370/372 (C19H17FN5Cl requires [M+H]+ at m/z 370/372). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With bromine; In tetrachloromethane; | EXAMPLE 1 Preparation of 2-chloro-4-fluorobenzyl bromide A solution of bromine (7.10 ml) in carbon tetrachloride (70 ml) was added slowly over a period of 3 hours to a solution of <strong>[452-73-3]2-chloro-4-fluorotoluene</strong> (20.0 g) in carbon tetrachloride (80 ml) maintained at the reflux temperature and irradiated by light from a tungsten lamp (200 watt). After the addition was completed the mixture was heated at the reflux temperature with irradiation until the colour had been discharged (ca.1 hour). The solvent was then removed by evaporation under reduced pressure and the residual oil distilled to yield 2-chloro-4-fluorobenzyl bromide (80% pure, 18.0 g) b.p. 110-120 C./15 mm Hg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In diethyl ether; acetone; | EXAMPLE 2 Preparation of 2-chloro-4-fluorobenzyl(+-)-cis-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylate A mixture of (+-)-cis-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylic acid (1.20 g), anhydrous potassium carbonate (2.0 g), <strong>[45767-66-6]2-chloro-4-fluorobenzyl bromide</strong> (1.10 g), and dry acetone (30 ml) was stirred for a period of 2 hours at the ambient temperature (ca 25 C.) and kept at that temperature for a further 18 hours. After diluting the mixture with diethyl ether (300 ml) the resultant mixture was washed with dilute aqueous sodium carbonate solution and dried over anhydrous magnesium sulphate. The solvents were evaporated and the residual oil purified by preparative thick layer chromatography using silica gel plates and chloroform eluent, to give 2-chloro-4-fluorobenzyl(+-)-cis-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylate (1.31 g) as a colourless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N-methyl-acetamide; hexane; | Step C Synthesis of 2-[(2-chloro-4-fluorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone A solution of 0.52 grams (0.005 mole) of 4,4-dimethyl-3-isoxazolidinone, 1.0 gram (0.005 mole) of <strong>[45767-66-6](2-chloro-4-fluorophenyl)methyl bromide</strong> and 0.62 gram (0.005 mole) of potassium carbonate in 40 ml of dimethylformamide was stirred at ambient temperature for 18 hours. The dimethylformamide was removed under high vacuum with mild heat. The residue was extracted with methylene chloride. The extract was filtered and dried with sodium sulfate. The mixture was refiltered and the filtrate concentrated under reduced pressure to give an oil residue. The residue was slurried in warm hexane and a solid was removed by filtration. The filtrate was concentrated under reduced pressure to give 0.39 gram of 2-[(2-chloro-4-fluorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; | Step A Synthesis of N-methyl-N-(2-chloro-4-fluorobenzyl)methylsulfonamide By the method of Example 6, Step B, 10.0 g (0.045 mole) of <strong>[45767-66-6]2-chloro-4-fluorobenzyl bromide</strong>, prepared by the method of Example 8, Step A, 4.88 g (0.045 mole) of N-methylmethylsulfonamide, 6.18 g (0.045 mole) of potassium carbonate, and 0.50 g (0.0019 mole) of 1,4,7,10,13,16-hexaoxacyclooctadecane Were reacted in 125 ml of acetonitrile. This mixture was refluxed overnight. The solid product, N-methyl-N-(2-chloro-4-fluorobenzyl)methylsulfonamide, weighed 6.95 g, m.p. 88-90 C. The nmr and ir spectra were consistent with the proposed structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; | Step B Synthesis of 2-[(2-chloro-4-fluorophenyl)-methyl]-4,4-dimethyl-3-isoxazolidinone By the method of Example 6, Step B, 95.6 g (0.83 mole) of 4,4-dimethyl-3-isoxazolidinone, 186 g (0.83 mole) of <strong>[45767-66-6]2-chloro-4-fluorobenzyl bromide</strong>, 114.7 g (0.83 mole) of potassium carbonate, and 2.2 g (0.008 mole) of 1,4,7,10,13,16-hexaoxacyclooctadecane were reacted at room temperature in 1500 ml of acetonitrile, yielding 230 g of impure 2-[(2-chloro-4-fluorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone. The nmr spectrum was consistent with the proposed structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; | Step A Synthesis of 2-chloro-4-fluorobenzyl bromide By the method of Example 7, Step C, 141.4 g (0.978 mole) of <strong>[452-73-3]2-chloro-4-fluorotoluene</strong>, 175.8 g (0.978 mole) of N-bromosuccinimide, and 5.0 g of benzoyl peroxide in 15 liters of carbon tetrachloride were reacted, yielding 165 g of 2-chloro-4-fluorobenzyl bromide as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; diethyl ether; n-heptane; ethyl acetate; | Step A Synthesis of N-(2-chloro-4-fluorobenzyl)-N-methoxyacetamide To a stirred mixture of 1.95 g (0.0219 mole) of N-methoxyacetamide, 1.23 g 0.022 mole) of powdered potassium hydroxide, and a small amount (~0.05 g) of 18-crown-6 in 10 ml of tetrahydrofuran was added a solution of 5.05 g (0.0226 mole) of <strong>[45767-66-6]4-fluoro-2-chlorobenzyl bromide</strong> in 15 ml of tetrahydrofuran. This mixture was heated at reflux for approximately 17 hours and then was allowed to cool to room temperature. The mixture was diluted with 125 ml of diethyl ether and was washed with an aqueous, saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving a yellow oil. This oil was purified by column chromatography on silica gel, eluding with ethyl acetate:n-heptane (25:75) followed by ethyl acetate:n-heptane (50:50), to yield 1.7 g of N-(2-chloro-4-fluoro-benzyl)-N-methoxyacetamide as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; ethanol; | Step A Synthesis of 2-chloro-4-fluorobenzyl ethyl ether Tetrahydrofuran (50 ml) was added to stirred sodium hydride (1.26 g, 0.053 mole) under a nitrogen atmosphere while being cooled in an ice-water bath. Absolute ethanol (5 ml) was then added dropwise and the reaction stirred until hydrogen evolution ceased. A solution of <strong>[45767-66-6]2-chloro-4-fluorobenzyl bromide</strong> (10.62 g, 0.0475 mole) in tetrahydrofuran (10 ml) was then added to the reaction mixture. The reaction mixture was allowed to stir at ambient temperature overnight. Ethanol and tetrahydrofuran were removed under reduced pressure. The reaction mixture was diluted with diethyl ether (200 ml), washed with water (4*75 ml), dried (magnesium sulfate) and concentrated under reduced pressure to remove solvent. The residue was distilled at low pressure yielding 5.27 g of 2-chloro-4-fluorobenzyl ethyl ether, b.p. 67-68 C./10 mm Hg. The nmr spectrum was consistent with the proposed structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.18% | With sodium borohydrid; potassium carbonate; triethylamine; In titanium(IV) isopropylate; methanol; water; dimethyl sulfoxide; acetonitrile; | Example 293 N-[1-(2-Chloro-4-fluorobenzyl)-3-piperidyl]-N-(1H-5-indazolyl)amine 3-Hydroxypiperidine (1 g) and potassium carbonate (2.76 g) were dissolved in acetonitrile (10 ml), and <strong>[45767-66-6]2-chloro-4-fluorobenzyl bromide</strong> (2.23 g) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr and was then filtered through Celite, and the filtrate was concentrated to give an intermediate. This intermediate and triethylamine (1.78 g) were dissolved in anhydrous dimethyl sulfoxide (7.55 ml), and a sulfur trioxide-trimethylamine complex (2.45 g) was added to the solution under an argon atmosphere at room temperature. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution was then added thereto, andthe mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and was concentrated to give an intermediate. This intermediate (317 mg) and 5-aminoindazole (139 mg) were dissolved in titanium tetraisopropoxide (1.6 g), and the mixture was stirred at room temperature for 18 hr. A minor amount of methanol and sodium borohydride (100 mg) were then added to the reaction solution, and the mixture was stirred for 18 hr. The reaction solution was diluted with ethyl acetate (40 ml), and a minor amount of water was added thereto, and the mixture was then filtered under the reduced pressure. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel [chloroform/methanol] to give the title compound (150 mg, yield 4.18%). 1H-NMR (CDCl3, 400 MHz): 1.56 - 1.74 (m, 5H), 2.42 - 2.49 (m, 2H), 2.73 - 2.76 (m, 1H), 3.56 (s, 2H), 3.59 - 3.62 (m, 1H), 6.79 - 6.83 (m, 1H), 6.94 (dt, J = 2.7, 8.3 Hz, 1H), 7.12 (dd, J = 2.7, 8.5 Hz, 2H), 7.27 - 7.30 (m, 1H), 7.39 - 7.42 (m, 1H), 7.86 (d, J = 1.0 Hz, 1H) Mass spectrum (ESI-MS, m/z): 359 (M++1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A suspension of potassium fert-butoxide (1.6 g) in anhydrous tetrahydrofuran (25 mL) at 00C was treated with a mixture of terf-butanol (1.0 mL) and 3-oxopentanoic acid methyl ester (1.5 g). After stirring at 00C for 45 minutes a solution of 1 -bromomethyl- 2-chloro-4-fluorobenzene (2.6 g) in tetrahydrofuran (5.0 mL) was added and the resulting mixture stirred at room temperature for 3 days. The mixture was diluted with water and the tetrahydrofuran removed under reduced pressure. The mixture was extracted with ethyl acetate and the combined extracts dried over magnesium sulfate and the solvent removed under reduced pressure to afford the title compound, 3.2 g.MS: ESI (+ve) (Method B): 273 (MH-H)+, Retention time 3.8 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33.4 g (84%) | With potassium hydroxide; thionyl chloride; sodium ethanolate;AlCl3; In ethanol; dichloromethane; water; | 4-Chloro-6-fluoro-2-methylindan-1-one To a solution of sodium ethoxide in ethanol obtained from 4.80 g (0.21 mol) of sodium and 120 ml of anhydrous ethanol, a solution of 36.5 g (0.21 mol) of diethyl methylmalonate in 50 ml of ethanol was added dropwise, while vigorously stirring, over 15 min. Then, 44.7 g (0.20 mol) of <strong>[45767-66-6]1-(bromomethyl)-2-chloro-4-fluorobenzene</strong> was added dropwise with such a rate, so the reaction mixture would be slowly refluxing. The resulting mixture was additionally refluxed for 4 h, then, cooled to room temperature, and a solution of 40 g of potassium hydroxide in 100 ml of water was added. This mixture was refluxed for 3 h, and then ethanol was distilled off at atmospheric pressure. The solution obtained was cooled to ambient temperature and acidified by saturated hydrochloric acid to pH 1. The precipitate formed was filtered off, washed with 2*200 ml of cold water, and dried in air. The dibasic acid obtained was then decarboxylated by heating it at 160 C. for 2 h. To the viscous oil obtained 40 ml of dichloromethane and 60 ml of SOCl2 were added, and the resulting mixture was refluxed for 2 h. Dichloromethane and the excess of SOCl2 were distilled off, and the residue was dissolved in 50 ml of anhydrous dichloromethane. The solution obtained was added dropwise to a suspension of 25.3 g (0.19 mol) of AlCl3 in 260 ml of dichloromethane for 1 h at 0 C. The reaction mixture was refluxed for 3 h, then cooled to room temperature, poured on 500 cm3 of ice, and finally acidified by saturated HCl to pH 3. The organic layer was separated, and the aqueous layer was washed with 3*300 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The title product was isolated fractional distillation in vacuum, bp 121-123 C./3 mm Hg. Yield 33.4 g (84%). Anal. calc. for C10H8ClFO: C, 60.47; H, 4.06. Found: C, 60.29; H, 4.21. 1H NMR (CDCl3): delta 7.08 (dd, J=8.4 Hz, J=2.5 Hz, 1H, 7-H), 7.02 (dd, J=7.0 Hz, J=2.5 Hz, 1H, 5-H), 3.13 (ddd, J=17.6 Hz, J=8.0 Hz, J=1.5 Hz, 1H 3-H), 2.53-2.62 (m, 1H, 2-H), 2.43 (ddd, J=17.6 Hz, J=4.0 Hz, J=1.9 Hz, 1H, 3'-H), 1.12 (d, J=7.4 Hz, 3H, 2-Me). 13C NMR (CDCl3): delta 206.3 (d, J=2.9 Hz), 161.7 (d, J=251.8 Hz), 146.1 (d, J=3.0 Hz) 138.8 (d, J=8.1 Hz), 132.9 (d, J=9.6 Hz), 121.5 (d, J=26.5 Hz), 108.0 (d, J=21.3 Hz), 42.1, 32.9, 15.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 151-[(2-Chloro-4-fluorophenyl)methyl]-4-[(2,3-dichlorophenyl)carbonyl]-2- piperazinone (E15); 4-[(2,3-Dichlorophenyl)carbonyl]-2-piperazinone (200 mg, 0.73 mmol, prepared as described below) and sodium hydride (60% dispersion in mineral oil) (35.1 mg, 0.88 mmol) were added together in N,N-dimethylformamide (3 ml) at O0C. After 15 minutes, <strong>[45767-66-6]1-(bromomethyl)-2-chloro-4-fluorobenzene</strong> (327 mg, 1.47 mmol) was added. The mixture was left under argon and in an icebath and allowed to return to room temperature whilst being stirred constantly overnight. The reaction was quenched by the addition of methanol and saturated aqueous ammonium chloride and then the solvents were evaporated in vacuo. The residue was dissolved in dichloromethane and saturated aqueous sodium hydrogen carbonate, and then extracted into dichloromethane (x3). The combined organic extracts were washed with water (x1 ), then brine (x1 ), and dried with magnesium sulphate. The solvent was evaporated in vacuo and the crude product was purified by flash-silica gel chromatography, eluting with 30-70% ethyl acetate in isohexane, to give 1-[(2-chloro- 4-fluorophenyl)methyl]-4-[(2,3-dichlorophenyl)carbonyl]-2-piperazinone (165 mg) as a clear/white solid. LC/MS [M+H]+ = 417, retention time = 2.88 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.50 g | To a solution of DIPA (4 mL) in dehydrated THF (100 mL), n-butyllithium (1.6 N solution in hexane, 17 mL) was added at 0C. After stirring at 0C for 30 minutes, a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (5 g) in dehydrated THF (30 mL) was added to the reaction solution. In an argon atmosphere, the mixture was stirred at 0C for 1 hour. 1-(Bromomethyl)-2-chloro-4-fluorobenzene (5.31 g) was added to the reaction solution at -78C. The temperature of the mixture was gradually raised to room temperature, and the mixture was stirred overnight at room temperature. The completion of the reaction was confirmed by TLC. The mixture was poured to a saturated aqueous solution of ammonium chloride (100 mL) at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and then concentrated. The residue was purified by column chromatography (ethyl acetate/hexane) to obtain the title compound (7.50 g). 1H NMR (300 MHz, CDCl3) delta 1.46 (9H, s), 1.55-1.71 (2H, m), 1.80-1.94 (2H, m), 2.82-3.15 (4H, m), 3.96-4.42 (2H, m), 6.96-7.07 (1H, m), 7.12-7.21 (1H, m), 7.39-7.51 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 42 : methyl (4S)-2-(2-chloro-4-fluorobenzyl)-5-[(2,6-dichlorophenyl)amino]-4-methyl-5-oxopentanoate To a solution of the compound prepared in Example 41 (4.56 g)in tetrahydrofuran (70 mL) was added dropwise 1M lithium hexamethyl disilazide / tetrahydrofuran solution (31.5 mL) at -78 C and the solution was stirred for 20 minutes. 2-Chloro-4-fluorobenzyl bromide (4.02 g) in tetrahydrofuran (5 mL) was added dropwise thereto and the solution was stirred at -78 C for 30 minutes. The reaction solution was risen to 0 C gradually. An aqueous saturated ammonium chloride solution was added to the reaction solution and the solution was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The obtained residue was purified by preparative medium pressure liquid chromatograph : W-prep 2XY (column : main column 4L, inject column L ; auto condition setting : hexane : ethyl acetate = 2:1, Rf 0.65, separation mode GR) to give the title compound (5.75 g) having the following physical data. TLC : Rf 0.20 (ethyl acetate: hexane =1:4); 1H-NMR : delta 7.37 (d, J=8.1Hz, 2H), 7.25-7.03 (m, 4H), 6.90 (td, J=8.4, 2.7Hz, 1H), 3.62 (s, 3H), 3.10-2.90 (m, 3H), 2.60-2.42 (m, 1H), 2.40-2.22 (m, 1H), 1.80-1.60 (m, 1H), 1.27 (d, J=7.2Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of sodium ethoxide in ethanol obtained from 4.80 g(0.21 mol) of sodium and 120 ml of anhydrous ethanol, a solution of 36.5 g (0.21 mol) of diethyl methylmalonate in 50 ml of ethanol was added dropwise, while vigorously stirring, over 15 min. Then, 44.7 g (0.20 mol) of 1 -(bromomethyl)-2- chloro-4-fluorobenzene was added dropwise with such a rate, so the reaction mixture would be slowly refluxing. The resulting mixture was additionally refluxed for 4 h, then, cooled to room temperature, and a solution of 40 g of potassium hydroxide in 100 ml of water was added. This mixture was refluxed for 3 h, and then ethanol was distilled off at atmospheric pressure. The solution obtained was cooled to ambient temperature and acidified by saturated hydrochloric acid to pH 1. The precipitate formed was filtered off, washed with 2 x 200 ml of cold water, and dried in air. The dibasic acid obtained was then decarboxylated by heating it at 16O0C for 2 h. To the viscous oil obtained 40 ml of dichloromethane and 60 ml of SOCl2 were added, and the resulting mixture was refluxed for 2 h. Dichloromethane and the excess of SOCl2 were distilled off, and the residue was dissolved in 50 ml of anhydrous dichloromethane. The solution obtained was added dropwise to a suspension of 25.3 g (0.19 mol) Of AlCl3 in 260 ml of dichloromethane for 1 h at O0C. The reaction mixture was refluxed for 3 h, then cooled to room temperature, poured on 500 cm3 of ice, and finally acidified by saturated HCl to pH 3. The organic layer was separated, and the aqueous layer was washed with 3 x 300 ml of methyl-terZ-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The title product was isolated fractional distillation in vacuum, bp 121-123C/3 mm Hg. Yield 33.4 g (84%).Anal. calc. for C10H8ClFO: C, 60.47; H, 4.06. Found: C, 60.29; H, 4.21.1H NMR (CDCl3): delta 7.08 (dd, J=8.4 Hz, J=2.5 Hz, IH, 7-H), 7.02 (dd, J=7.0 Hz, J=2.5 Hz, IH, 5-H), 3.13 (ddd, J=17.6 Hz, J=8.0 Hz, J=1.5 Hz, IH, 3- H), 2.53-2.62 (m, I H, 2-H), 2.43 (ddd, J=I 7.6 Hz, J=4.0 Hz, J=I .9 Hz, IH, 3'-H), 1.12 (d, J=7.4 Hz, 3H, 2-Me). <n="118"/>13C NMR (CDCl3): delta 206.3 (d, J=2.9 Hz), 161.7 (d, J=251.8 Hz), 146.1 (d, J=3.0 Hz) 138.8 (d, J=8.1 Hz), 132.9 (d, J=9.6 Hz), 121.5 (d, J=26.5 Hz), 108.0 (d, J=21.3 Hz), 42.1, 32.9, 15.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of zinc powder (208 mg) and ethylene glycol dimethyl ether (10 mL) were added 1,2-dibromoethane (20 mg) and <strong>[45767-66-6]2-chloro-4-fluorobenzyl bromide</strong> (473 mg) and the mixture was stirred at 75 C for 1 hour. The compound prepared in Example 5 and tetrakis(triphenylphosphine)-palladium (123 mg) were added hereto and the reaction mixture was stirred at same temperature for 15 minutes. The reaction mixture was added by hydrochloric acid (1 mol/L) and ethyl acetate, then the water layer was extracted with ethyl acetate. The obtained extract was dried with anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 2 : 1) to give the title compound (171 mg) having the following physical data. TLC : Rf 0.36 (hexane:ethyl acetate=3:2); NMR : delta 4.18 (s, 2H), 6.73 (dd, J=9.61, 0.82Hz, 1H), 6.93-7.04 (m, 1H), 7.16 (dd, J=8.42, 2.56Hz, 1H), 7.20-7.29 (m, 1H), 7.38-7.48 (m, 1H), 7.50-7.58 (m, 2H), 7.98-8.09 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 1191-[(2-Chloro-4-fluorophenyl)methyl]-4-(2-methyl-3-pyridinyl)-2,3- piperazinedione (E119)1-(2-Methyl-3-pyridinyl)-2,3-piperazinedione (0.11 g, 0.53 mmol) was dissolved in N,N-dimethylformamide (5 ml) and cooled to O0C. Sodium hydride (0.025 g, 0.63 mmol) was added and the mixture stirred for 10 minutes, until the fizzing stopped. 1- (bromomethyl)-2-chloro-4-fluorobenzene (0.18 g, 0.79 mmol) was added and the reaction warmed to room temperature, before being heated to 500C with stirring for 3 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane (15ml) and water (10ml). The organic layer was separated using a hydrophobic frit and the aqueous layer washed with further dichloromethane (10ml). The combined organic layers were concentrated in vacuo and purified by mass-directed automated HPLC. The product was dissolved in methanol (~15ml) and passed down a pre-conditioned 10g aminopropyl cartridge. The cartridge was washed with methanol (40 ml) and the solution concentrated under vacuum to yield 1-[(2-chloro-4-fluorophenyl)methyl]-4-(2-methyl-3-pyridinyl)-2,3-piperazinedione (0.043 g) as a yellow solid. LC/MS [M+H]+ = 348, retention time = 1.83 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium hydride; In N,N-dimethyl-formamide; for 2h; | General procedure: To a stirred solution of alcohol (4) (1.0 mmol), benzyl bromide (1.1 mmol) in DMF (10 vol) at 0 C slowly added sodium hydride (1.2 mmol) and stirred the reaction mass for 2 h at 25-30 C. Added water and ethyl acetate separated the layers. Organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated the volatiles. The crude compound was purified by column chromatography (10% EtOAc/Hexanes). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium hydride; In N,N-dimethyl-formamide; for 2h; | General procedure: To a stirred solution of alcohol (4) (1.0 mmol), benzyl bromide (1.1 mmol) in DMF (10 vol) at 0 C slowly added sodium hydride (1.2 mmol) and stirred the reaction mass for 2 h at 25-30 C. Added water and ethyl acetate separated the layers. Organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated the volatiles. The crude compound was purified by column chromatography (10% EtOAc/Hexanes). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium hydride; In N,N-dimethyl-formamide; for 2h; | General procedure: To a stirred solution of alcohol (4) (1.0 mmol), benzyl bromide (1.1 mmol) in DMF (10 vol) at 0 C slowly added sodium hydride (1.2 mmol) and stirred the reaction mass for 2 h at 25-30 C. Added water and ethyl acetate separated the layers. Organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated the volatiles. The crude compound was purified by column chromatography (10% EtOAc/Hexanes). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium hydride; In N,N-dimethyl-formamide; for 2h; | General procedure: To a stirred solution of alcohol (4) (1.0 mmol), benzyl bromide (1.1 mmol) in DMF (10 vol) at 0 C slowly added sodium hydride (1.2 mmol) and stirred the reaction mass for 2 h at 25-30 C. Added water and ethyl acetate separated the layers. Organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated the volatiles. The crude compound was purified by column chromatography (10% EtOAc/Hexanes). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In tetrahydrofuran; at -78 - 20℃;Inert atmosphere; | [000228] 5,7-Dichloro-l-(4-methoxybenzyl)-lH-benzo[e][l,4]diazepin-2(3H)-one (0.85 g, 3.82 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) and cooled to -78 C under nitrogen. Potassium tert-butoxide (0.48 g, 3.82 mmol) was dissolved in anhydroustetrahydrofuran (4 mL) and added to the benzodiazepine via syringe. After 2 minutes, a solution of the <strong>[45767-66-6]2-chloro-4-fluorobenzyl bromide</strong> (1.27 g, 3.64 mmol) in anhydroustetrahydrofuran (3 mL) was added. The reaction mixture was stirred at -78 C for 2 then allowed to warm to room temperature over 1 h. The reaction was quenched with water and the layers partitioned. The organic layer was evaporated onto silica gel and chromatographed eluting with 10-35% ethyl acetate in hexanes to obtain 5,7-dichloro-3-(2-chloro-4- fluorobenzyl)-l-(4-methoxybenzyl)-lH-benzo[e][l,4]diazepin-2(3H)-one (0.6 g, 1.22 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.7% | With sodium hydroxide; In isopropyl alcohol; at 70℃; | To a suspension of sodium 4-hydroxybenzenesulfonate dihydrate (1.3 g, 5.6 mmol) in isopropanol (25 mL), containing 5.6 mL of NaOH 1 N freshly prepared, <strong>[45767-66-6]2-chloro-4-fluorobenzyl bromide</strong> (2.5 g, 11.2 mmol) was added. The reaction was refluxed (70 C) overnight. Isopropanol was evaporated and the precipitate was collected by filtration and washed with isopropanol. The solid was dried in vacuo. White solid (1.93 g, 91.7% yield). 1H NMR (DMSO-d6) delta: 5.13 (s, 2H); 6.92-6.97 (m, 2H); 7.26 (dt, J1 = 10 Hz, J2 = 2.6 Hz, 1H); 7.49-7.54 (m, 3H); 7.64 (dd, J = 6.4 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 20℃; | A mixture of the portion of above residue (42.0 mumol), and <strong>[45767-66-6]1-(bromomethyl)-2-chloro-4-fluorobenzene</strong> (18.8 mg, 84.0 mumol) and DBU (12.7 muL, 84.0 mumol) in DMF (250 muL) was stirred at the room temperature overnight. The reaction mixture was directly purified by preparative HPLC (column: Gemini Sum C18 110A 75*30 mm. mobile phase: water (0.05% Et3N): acetonitrile 70:30% to 5:95%. WL: 300 nm Flow: 30 mL/min.) to afford the title compound as light-yellow solid (8.3 mg, 49%). MS (m/e): 405.4 (MH+). |
8.3 mg | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 20℃; | A mixture of the portion of above residue (42.0 muiotaetaomicron?), and l-(bromomethyl)-2-chloro-4- fluorobenzene (18.8 mg, 84.0 mupiiotaomicron?) and DBU (12.7 mu?, 84.0 muiotaetaomicron?) in DMF (250 mu?,) was stirred at the room temperature overnight. The reaction mixture was directly purified by preparative HPLC (column: Gemini 5um CI 8 110A 75 x 30mm. mobile phase: water (0.05% Et3N): acetonitrile 70:30% to 5:95%. WL: 300 nm Flow: 30 mL/min.) to afford the title compound as light-yellow solid (8.3 mg, 49%). MS(m/e): 405.4 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere; | To a solution of Example 77 (40 mg, 0.17 mmol) in DMF (1.7 mL) was added cesium carbonate (226 mg, 0.70 mmol) and <strong>[45767-66-6]2-chloro-4-fluorobenzyl bromide</strong> (58 mg, 0.26 mmol) and the reaction mixture was stirred for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried with Na2SO4, filtered, concentrated and purified by flash column chromatography (0-20% iPrOH in EtOAc) to provide the desired compound (41 mg, 65%). MS (ESI): mass calcd. for C17H14ClFN6O, 372.8; m/z found, 373.1 [M+H]+. 1H NMR (400 MHz, DMSO) delta 9.47 (d, J=1.3 Hz, 1H), 8.84-8.80 (m, 2H), 7.61-7.55 (m, 1H), 7.55-7.50 (m, 1H), 7.26-7.19 (m, 1H), 5.10 (d, J=15.9 Hz, 1H), 5.01-4.89 (m, 1H), 4.70 (dd, J=13.9, 4.6 Hz, 1H), 4.48 (d, J=16.0 Hz, 1H), 4.13-4.03 (m, 1H), 1.18 (d, J=6.7 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.35 g | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 0.666667h; | To a flask containing (i?)-fert-butyl 3-((3-bromo-6-cyclopropyl-[l ,2,4]triazolo- [4,3 -a]pyridin-7-yl)oxy)piperidine-l -carboxylate (0.75 g, 1.72 mmol) was added a 4 M solution of hydrochloric acid in 1,4-dioxane (2.4 mL). The clear reaction solution was stirred to form a precipitate. Distilled water (1 mL) was added to dissolve the precipitate and stirring continued at ambient temperature for 1 h. The reaction mixture was neutralized with an aqueous saturated solution of sodium bicarbonate and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine (1 x 25 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue obtained was redissolved in anhydrous dimethylformamide (18 mL) to which potassium carbonate (0.44 g, 3.21 mmol) and l-(bromomethyl)-2-chloro-4-fluorobenzene (0.36 g, 1.60 mmol) in anhydrous DMF (4 mL) were added. The reaction mixture was stirred at ambient temperature for 40 minutes then poured into distilled water (100 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 0 to 10% methanol (with 0.4% ammonium hydroxide) in dichloromethane to afford the title compound (0.35 g, 50% yield over two steps): (ES+) m/z 479.1, 481.1 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In toluene; for 12h;Reflux; | The compound 2 - chloro -4 - fluorine bromine animal pen (2.24 g, 10 mmol), triphenylphosphine (2.86 g, 11 mmol, 1.1 eq) and toluene (12 ml) mixture of reflux reaction for 12 hours, cooling to room temperature, filtered, the solid for PE (10 ml) washing, to obtain the title compound as a white powder (4.60 g, 95%), without further purification, directly used for the next step reaction. |
In toluene; for 12h;Reflux; | A mixture of l-(bromomethyl)-2-chloro-4-fluorobenzene (2.24 g, 10 mmol) and triphenylphosphine (2.86 g, 1 1 mmol) in toluene (12 mL) was refluxed with vigorous stirring for 12 hours, then cooled to rt, and filtered. The solid was washed with PE (10 mL) to give the title compound as white powder (4.60 g, 95%>). The crude product was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With ruthenium(III) chloride trihydrate; sodium nitrite; In N,N-dimethyl-formamide; at 40℃; for 6h;Green chemistry; | General procedure: RuCl3*3H2O (0.075 mmol) was added to a solution of indole (0.50 mmol), alkyl bromide (0.7 mmol), and NaNO2 (1.0 mmol) in DMF (1mL) under atmosphere and the mixture was stirred at 40 C for 8-26 h (monitored by thin-layer chromatography, TLC). The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: EtOA/PE 1:4) to yield the corresponding product. |
With ruthenium(III) chloride trihydrate; sodium nitrite; In N,N-dimethyl-formamide; at 40℃; | General procedure: To a solution of indole (0.50mmol), alkyl bromide (0.7mmol) and NaNO2 (1.0mmol) in DMF (1mL) was added RuCl3·3H2O (0.075mmol) under atmosphere and the mixture was stirred at 40C for 8-26h (monitored by TLC). The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluant: EtOAc/PE=1:4) to yield the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With ruthenium(III) chloride trihydrate; sodium nitrite; In N,N-dimethyl-formamide; at 40℃; for 7h;Green chemistry; | General procedure: RuCl3*3H2O (0.075 mmol) was added to a solution of indole (0.50 mmol), alkyl bromide (0.7 mmol), and NaNO2 (1.0 mmol) in DMF (1mL) under atmosphere and the mixture was stirred at 40 C for 8-26 h (monitored by thin-layer chromatography, TLC). The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: EtOA/PE 1:4) to yield the corresponding product. |
With ruthenium(III) chloride trihydrate; sodium nitrite; In N,N-dimethyl-formamide; at 40℃; | General procedure: To a solution of indole (0.50mmol), alkyl bromide (0.7mmol) and NaNO2 (1.0mmol) in DMF (1mL) was added RuCl3·3H2O (0.075mmol) under atmosphere and the mixture was stirred at 40C for 8-26h (monitored by TLC). The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluant: EtOAc/PE=1:4) to yield the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | To a mixture of 1-Boc-4-hydroxypiperidine (2.00 g, 10.00 mmol) in anhydrous dimethylformamide (20 mL) was added sodium hydride (60dispersion in mineral oil, 0.40 g, 10.10 mmol) at 0 . The reaction mixture was allowed to warm to ambient temperature and stirred for 1 hour. To this reaction mixture was added <strong>[45767-66-6]2-chloro-4-fluorobenzylbromide</strong> (2.45 g, 11.00 mmol) and tetrabutylammonium iodide (0.37 g, 1.00 mmol) and the reaction mixture was stirred for 48 hours at ambient temperature. After addition of water (20 mL) and dilution with ethyl acetate (200 mL) , the organic phase was washed with water (3 × 20 mL) , brine (20 mL) , and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo provided the title compound as yellowish oil (3.50 g, quant. yield) , which was used without further purification: MS (ES+) m/z 288.1, 290.1 (M-55) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 20h; | Intermediate b (50mg) and 2-chloro-4-fluoro compound (38mg) was dissolved in 1mL of dimethylformamide was added 70mg of potassium carbonate, stirred for 20 hours at room temperature. 20mL water was added, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and spin dry, through the column, to give a white solid 23 (45mg), yield 60%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; In methanol; at 50℃; for 2h;Inert atmosphere; | To a stirred solution of 1-(bromomethyl)-2-chloro-4-fluorobenzene (1 g, 1 equiv.) in DMF (5 mL) was added NH3(g) in MeOH (5 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 50 degrees celsius under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was monitored by LCMS. The resulting mixture was used in the next step(E00848-157) directly without further purification |
Tags: 45767-66-6 synthesis path| 45767-66-6 SDS| 45767-66-6 COA| 45767-66-6 purity| 45767-66-6 application| 45767-66-6 NMR| 45767-66-6 COA| 45767-66-6 structure
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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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