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CAS No. : | 54512-75-3 | MDL No. : | MFCD00001016 |
Formula : | C5H10BrCl | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PHHNNDKXQVKJEP-UHFFFAOYSA-N |
M.W : | 185.49 | Pubchem ID : | 96070 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 0.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 38.82 |
TPSA : | 0.0 Ų |
GI absorption : | Low |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.55 cm/s |
Log Po/w (iLOGP) : | 2.34 |
Log Po/w (XLOGP3) : | 2.65 |
Log Po/w (WLOGP) : | 2.79 |
Log Po/w (MLOGP) : | 3.13 |
Log Po/w (SILICOS-IT) : | 2.65 |
Consensus Log Po/w : | 2.71 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.4 |
Solubility : | 0.746 mg/ml ; 0.00402 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.3 |
Solubility : | 0.927 mg/ml ; 0.005 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.37 |
Solubility : | 0.0786 mg/ml ; 0.000424 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.73 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #2: at -15℃; Stage #3: With hydrogenchloride In tetrahydrofuran |
(Example 1) Example 1 was carried out in a reaction apparatus 10 shown in Figure 1. A main flow channel 12 is a circular pipe made from stainless steel, and introduction points 12o and 12p are 180-degree T-shaped mixture flow channels made from stainless steel. A Grignard reagent: 1-bromomagnesium-5-chloropentane (0.45 mol/L) was diluted by a tetrahydrofuran solvent and the diluted solution was used as a raw material M2. The reagent 1-bromomagnesium-5-chloropentane was prepared by adding a magnesium powder to 1-bromo-5-chloropentane. Diethyl oxalate (7.4 mol/L) which had not been diluted by the solvent was used as a raw material M1. The raw material M2 and the raw material M1 were supplied to a flowing-type fine reaction flow channel 32, at 110 mL/min and 5.1 mL/min, respectively. Used pumps 20 and 26 were a smooth flow pump made by TACMINA CORPORATION. From the above described conditions, a mixed solution of these materials stays in the flowing-type fine reaction flow channel 32 for approximately 14 seconds. The Grignard reagent and diethyl oxalate were accommodated in a supply container and controlled at 10°C and room temperature respectively, and a thermostatic liquid tank 28 accommodated methanol as a refrigerant 30 and was controlled at -15°C. The produced liquid was collected and quenched with a dilute hydrochloric acid. The target substance of ethyl-7-chloro-2-oxalic pentane was obtained in the yield of 90percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In water; N,N-dimethyl-formamide; | PREPARATION EXAMPLE 127 Benzenethiol (3.0 g), <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (5.7 g) and potassium carbonate (4.15 g) were suspended in N,N-dimethylformamide (50 ml), and the mixture was stirred at 50 C. for 5 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. Thus, 5-phenylthiopentyl chloride was obtained. | |
With potassium carbonate; In water; N,N-dimethyl-formamide; | Preparation Example 44 Benzenethiol (3.0 g), <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (5.7 g) and potassium carbonate (4.15 g) were suspended in N,N-dimethylformamide (50 ml), and the mixture was stirred at 50C for 5 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and the solvent was evaporated under reduced pressure. Thus, 5-phenylthiopentyl chloride was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With lithium diisopropyl amide; In tetrahydrofuran; at -80℃; for 90h; | The solution of isobutyronitrile (0.7 g, 10 mmol) in THF (20 mL) was cooled to -80 C and LDA (Lithium diisopropylamide) solution (2.0 M in hexane, 6 mL, 12 mmol) was added over 10 min. The solution was stirred 30 min, and then a solution of <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (1.8 g, 10 mmol) in THF (10 mL) was added over 5 min. After stirring for 90 min, 6 N HCl (6 mL) was added slowly and the temperature allowed to rise to rt. The residue was concentrated under reduced pressure and EtOAc (20 mL) was added. The separated organic layer was washed with water (10 mL). The organic solvent was dried with Na2SO4 and concentrated in vacuo to give the crude product. Purification by column chromatography (petroleum ether (60-90 C)/EtOAc) gave 1.5 g of 2,2-dimethyl-7-chloroheptanenitrile (88%) as a colorless oil. 1H NMR (400 MHz, CDCl3) delta 3.57 (t, J = 6.6 Hz, 2H), 1.92-1.72 (m, 2H), 1.58-1.44 (m, 6H), 1.36 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.1 g (73%) | With potassium carbonate; In dimethyl sulfoxide; butanone; | A. Preparation of 2-(5-chloropentoxy)-4-(phenylmethoxy) acetophenone. A mixture of 2-hydroxy-4-(phenylmethoxy)acetophenone (15.5 g, 64.0 mmol), potassium carbonate (8.83 g, 64.0 mmol), and dimethylsulfoxide (15 mL) in 2-butanone (145 mL) was stirred at room temperature for 30 minutes. <strong>[54512-75-3]1-Bromo-5-chloropentane</strong> (11.9 g, 64.0 mmol) was added and the resulting mixture heated at reflux for 18 hours. The reaction mixture was cooled, diluted with water, and extracted with ethyl acetate. The organic layer was washed once with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo to provide a waxy solid. Purification via silica gel chromatography (ethyl acetate/hexane) provided 16.1 g (73%) of the title intermediate as a white solid: mp 76-77 C.; NMR (CDCl3) 7.85 (d, J=8.7 Hz, 1H), 7.43 (m, 5H), 6.59 (d, J=8.5 Hz, 1H), 6.53 (s, 1H), 5.11 (s, 2H), 4.05 (t, J=6 Hz, 2H), 3.61 (t, J=6 Hz, 2H), 2.60 (s, 3H), 1.90 (m, 4H), 1.69 (m, 2H); MS-FD m/e 348 (p+2, 65), 346 (p, 100); IR (CHCl3, cm-1) 3025, 1662, 1598, 1268, 1184, 1139, 1027. |
16.1 g (73%) | With potassium carbonate; In dimethyl sulfoxide; butanone; | A. Preparation of 2-(5-chloropentoxy)-4-(phenyl-methoxy)acetophenone. A mixture of 2-hydroxy-4-(phenylmethoxy)acetophenone (15.5 g, 64.0 mmol), potassium carbonate (8.83 g, 64.0 mmol), and dimethylsulfoxide (15 mL) in 2-butanone (145 mL) was stirred at room temperature for 30 minutes. <strong>[54512-75-3]1-Bromo-5-chloropentane</strong> (11.9 g, 64.0 mmol) was added and the resulting mixture heated at reflux for 18 hours. The reaction mixture was cooled, diluted with water, and extracted with ethyl acetate. The organic layer was washed once with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo to provide a waxy solid. Purification via silica gel chromatography (ethyl acetate/hexane) provided 16.1 g (73%) of the title intermediate as a white solid: mp 76-77 C.; NMR (CDCl3) 7.85 (d, J=8.7 Hz, 1H), 7.43 (m, 5H), 6.59 (d, J=8.5 Hz, 1H), 6.53 (s, 1H), 5.11 (s, 2H), 4.05 (t, J=6 Hz, 2H), 3.61 (t, J=6 Hz, 2H), 2.60 (s, 3H), 1.90 (m, 4H), 1.69 (m, 2H); MS-FD m/e 348 (p+2, 65), 346 (p, 100); IR (CHCl3, cm-1) 3025, 1662, 1598, 1268, 1184, 1139, 1027. |
16.1 g (73%) | With potassium carbonate; In dimethyl sulfoxide; butanone; | A. Preparation of 2-(5-chloropentoxy)-4-(phenylmethoxy)acetophenone. A mixture of 2-hydroxy-4-(phenylmethoxy)acetophenone (15.5 g, 64.0 mmol), potassium carbonate (8.83 g, 64.0 mmol), and dimethylsulfoxide (15 mL) in 2-butanone (145 mL) was stirred at room temperature for 30 minutes. <strong>[54512-75-3]1-Bromo-5-chloropentane</strong> (11.9 g, 64.0 mmol) was added and the resulting mixture heated at reflux for 18 hours. The reaction mixture was cooled, diluted with water, and extracted with ethyl acetate. The organic layer was washed once with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuoto provide a waxy solid. Purification via silica gel chromatography (ethyl acetate/hexane) provided 16.1 g (73%) of the title intermediate as a white solid: mp 76-77C; NMR (CDCl3) 7.85 (d, J = 8.7 Hz, 1H), 7.43 (m, 5H), 6.59 (d, J = 8.5 Hz, 1H), 6.53 (s, 1H), 5.11 (s, 2H), 4.05 (t, J = 6 Hz, 2H), 3.61 (t, J = 6 Hz, 2H), 2.60 (s, 3H), 1.90 (m, 4H), 1.69 (m, 2H); MS-FD m/e 348 (p + 2, 65), 346 (p, 100); IR (CHCl3, cm-1) 3025, 1662, 1598, 1268, 1184, 1139, 1027. |
16.1 g (73%) | With potassium carbonate; In dimethyl sulfoxide; butanone; | A. Preparation of 2-(5-chloropentoxy)-4-(phenyl-methoxy)acetophenone A mixture of 2-hydroxy-4-(phenylmethoxy)acetophenone (15.5 g, 64.0 mmol), potassium carbonate (8.83 g, 64.0 mmol), and dimethylsulfoxide (15 mL) in 2-butanone (145 mL) was stirred at room temperature for 30 minutes. <strong>[54512-75-3]1-Bromo-5-chloropentane</strong> (11.9 g, 64.0 mmol) was added and the resulting mixture heated at reflux for 18 hours. The reaction mixture was cooled, diluted with water, and extracted with ethyl acetate. The organic layer was washed once with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo to provide a waxy solid. Purification via silica gel chromatography (ethyl acetate/hexane) provided 16.1 g (73%) of the title intermediate as a white solid: mp 76-77 C.; NMR (CDCl3) 7.85 (d, J=8.7 Hz, 1H), 7.43 (m, 5H), 6.59 (d, J=8.5 Hz, 1H), 6.53 (s, 1H), 5.11 (s, 2H), 4.05 (t, J =6 Hz, 2H), 3.61 (t, J=6 Hz, 2H), 2.60 (s, 3H), 1.90 (m, 4H), 1.69 (m, 2H); MS-FD m/e 348 (p+2, 65), 346 (p, 100); IR (CHCl3, cm-1) 3025, 1662, 1598, 1268, 1184, 1139, 1027. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium nitrite; In dimethyl sulfoxide; at 20 - 25℃; | General procedure: To a solution of dry sodium nitrite (1.24 g, 18 mmol) in DMSO (100 mL), a solution of-bromochloroalkane 6 (15 mmol) in DMSO (20 mL) was added dropwise while keeping the temperature at 20-25 C. After 2-5 h, the reaction was quenched by adding ice-water (400 mL)and was repeatedly extracted with diethyl ether. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether-Et2O 5:1) to afford -chloronitroalkanes 11 as colourless oils. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; at 20℃; | General procedure: A 2.6 M methanolic solution of MeSNa (23 mL, 1.2 equiv.) was added dropwise to a stirred solution of omega-bromochloroalkane 6 (50 mmol) in dry methanol (80 mL) at room temperature (r.t.). Stirring was continued until complete consumption of the dihalide (2-3 h, GC monitoring). The mixture was concentrated in vacuo and the resulting white slurry was taken in cold water and extracted with dichloromethane. After drying the organic phase over MgSO4, filtration and concentration in vacuo, the oily residue was purified by flash chromatography using silica gel (230-400 mesh) with hexane as eluent to afford 7a-d as light yellow oils. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | t-Butyl 1-(5-chloropentyl)-1-cyclopropanecarboxylate (104c).; Under an Ar atmosphere at 0 C, BuLi (2. 5M in hexanes, 80 mL, 0.20 mol) was added dropwise to a solution of iPr2NH (27.2 mL, 194 mmol, distilled from NaOH) in dry THF (200 mL) in 30 min. The reaction mixture was stirred for 30 min, cooled to-70 C and then, t-butyl cyclopropanecarboxylate (25.0 g, 176 mmol) was added dropwise in 30 min. The resultant mixture was allowed to warm up to-35 C, cooled again to-70 C and then 1- bromo-5-chloropentane (36 mL, 50.7 g, 273 mmol) was added dropwise in 15 min. The reaction mixture was allowed to reach-5 C, stirred for 3 h, poured into a mixture of ice (100 mL), H2O (100 mL), brine (200 mL) and aqueous HCI (2 M, 200 mL) and extracted with Et20 (2 x 300 mL). The combined organic layers were washed with a mixture of brine and saturated aqueous NaHC03 (10: 1,300 mL) and dried. The remaining oil was purified by fractional distillation under reduced pressure to give 104c (31.5 g, 73%) as a colorless liquid. bp: T = 67-74C (p = 0.001 mbar).'H NMR: 3.52 (t, J = 6.6 Hz, 2H), 1.77 (quintet, J= 6.8 Hz, 2H), 1.48-1. 38 (m, 6H), 1.42 (s, 9H), 1.10 (dd, J= 6. 5 Hz, 3.8 Hz, 2H), 0.59 (dd, J= 6.6, 3.9 Hz, 2H). 13C NMR : 8 174.1, 79.9, 45.2, 34.2, 32.7, 28.2 (3x), 27.20, 27.17, 24.3, 15.4 (2x). HRMS calcd forCI3H24ClO2 (MH+) : 247.1465, found: 247.1465. | |
52.1% | With lithium diisopropyl amide; In tetrahydrofuran; at -5℃; for 4h; | At -40 C,Compound 1a (2.0 g, 14.1 mmol) was slowly added dropwise to a solution of lithium diisopropylamide (LDA, 7.1 ml, 14.1 mmol, 2 mol/L) in THF (20 ml).Then continue to add <strong>[54512-75-3]1-chloro 5-bromopentane</strong> (3.9 g, 21.1 mmol).After the addition, the reaction was continued at -5 C for 4 h.The reaction was quenched by the addition of saturated ammonium chloride (10 mL).Ethyl acetate (40 ml × 3) was extracted and the organic phases were combined.Remove the solvent,The concentrate is subjected to column separation (eluent: petroleum ether),Obtained 1.8g of a colorless liquid,The yield was 52.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | Preparation 50 : 1-(5-chloropentyl)-5-methyl-2,4(1/Y,3H)-pyrimidinedione (Prep50); 5-methyl-2,4(1H,3H)-pyrinnidinedione (commercially available, 0.55 g, 3.97mmol) was dissolved in dry DMF (15ml_) . K2CO3 (0.548g, 3.97mmol) was added and the mixture stirred at room temperature for 1 hour. <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (0.526ml , 3.97mmol) was then added and the suspension was stirred at room temperature for 4 h. The volume of solvent was reduced, then DCM was added and the organic layer was washed with water, the organic phase was evaporated and the crude purified by FC (DCM/MeOH 98/2- 95/5) to afford 0.1 g of the title compound (y = 11 %). 1H NMR (CDCI3) delta: 8.69 (1 H, bs), 6.99 (I H, s), 3.74 (2H, t), 3.56 (2H, t), 2.63 (3H, s), 1.84 (2H, m), 1.73 (2H, m), 1.53 (2H, m), | |
Preparation 11 : 1-(4-chloropentyl)-5-methyl-2,4(1H,3H)-pyrimidinedione (Prep11); A mixture of 5-methyl-2,4(1H,3H)-pyrimidinedione (thimine, 500 mg) and K2CO3 (548 g) in dry DMF(15 ml_) was stirred for 1 hour at room temperature. 1-bromo-4-chloropentane (0.548 mL) was then added and the mixture was stirred at room temperature for 4 hours. Water was then added and the resulting mixture was extracted with dichloromethane. The aqueous phase was acidified to pH 7 with aqueous 2% HCI solution and extracted with DCM. The organic phases were dried and concentrated in vacuo. The crude product was purified by a silica SPE cartridge eluting with DCM /MeOH from 98/2 to 95/5 to give the title compound (100 mg). 1H-NMR (CDCI3): delta 8.03 (bs, 1H), 6.99 (s, 1 H), 3.72 (t, 2H), 3.56 (t, 2H), 1.94 (s, 3H), 1.93-1.40 (m, 6H). MS (ES) (mlz): 231 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; for 19h; | Intermediate 4H 6-Amino-1-(4-r(5-chloropentyl)oxy1-2.6-difluorophenyl}-5-(4- fluoro-benzoyl)pyridin-2(1 H)-one; To a solution of 6-amino-5-(2,4-fluorobenzoyl)-1-(2,6-difluoro-4-hydroxyphenyl)-pyridin- 2(1/7)-one (200 mg, 0.56 mmol) in anhydrous DMF (6 ml) under an atmosphere of nitrogen was added 1 -bromo-5-chloropentane (0.088 ml, 0.67 mmol, 1.2 eq) and potassium carbonate (115 mg, 0.83 mmol, 1.5 eq). The mixture was heated at 400C for 19 hours, before being allowed to cool to room temperature and diluted with EtOAc (20 ml). The solution was washed with water (3 x 20 ml) and brine (20 ml). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (20-40 % EtOAc in heptane) afforded the title compound as a yellow solid (104 mg) which was used without further purification. LC/MS: m/z 465 [M+H]+. 1H NMR (300 MHz, CD3OD) delta: 7.60 (2H, m), 7.53 (1 H, d, J=9.4 Hz), 7.33 (2H, m), 7.05 (2H, m), 5.72 (1H, d, J=9.8 Hz), 4.11 (2H, t, J=6.3 Hz), 3.68 (2H, t, J=6.5 Hz), 1.84-1.77 (4H, m), 1.56 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 3h; | Example 2b; 5-Bromo-3-(4-chloro-phenyl)-2-piperidin-1-yl-pyrazine; To a solution of 0.5 g (0.0018 mol) 5-bromo-3-(4-chloro-phenyl)-pyrazin-2-ylamine in 10 ml dimethylformamide was added at room temperature 0.240 g sodium hydride 55% in oil (0.006 mol) and 0.49 g <strong>[54512-75-3]1-bromo-5-chloro-pentane</strong> (0.0025 mol) and the mixture was stirred at room temperature for 0.5 hours. Another 0.130 g sodium hydride 55% in oil was added and the mixture was stirred at room temperature for 2.5 h. The resulting mixture was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated, the organic phase was dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel using a gradient of 30% ethyl acetate in heptane to ethyl acetate to yield 0.043 g (83% yield) of the title compound as slightly brownish oil. MS (ISP) (M+H+)=354.1 and 356.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; In acetonitrile; at 20℃; for 26h;Heating / reflux; | While 70 g of 4-hydroxybenzonitrile (7) were added to 500 ml of acetonitrile and stirred, 85.3 g of potassium carbonate and 77.4 ml of l-bromo-5-chloropentane were added. Subsequently, the temperature was gradually increased and stirring under reflux was continued for 8 hr, and then stirring was further continued at room temperature for 18 hr. After the reaction was completed, the resultant reaction mixture was added with 500 ml of ethylacetate and then washed with water. Thereafter, the ethylacetate layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrated compound was dissolved in 280 ml of methanol, stirred at 0C for 2 hr, and then filtered, thus obtaining 118 g (yield: 90%) of a title compound as a white solid. m.p. 47C; m/z 224 [M++.] ; 1H NMR (CDCl3) delta (ppm) 1. 64 (m, 2H) , 1.82 (m, 4H) , 3.57 (t, 2H) , 4.01 (t, 2H) , 6.93 (d, 2H) , 7.57 (d, 2H) |
90.3% | With potassium carbonate; In acetonitrile; at 80 - 82℃; for 7h;Heating / reflux; | [255] 3.0 g (25.2 mmol) of 4-cyanophenol and 3.67 g (27 mmol) of potassium carbonate were sequentially added to 80 ml of acetonitrile, and then 4.67g (25.2 mmol) of l-bromo-5-chloropentane was added thereto. Subsequently, the mixture was refluxed for 7 hrs while maintaining the temperature at 80 to 820C, and then cooled to room temperature after stopping heating. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with purified water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from methanol, and then washed with methanol at - 1O0C. The resultant was dried under reduced pressure to obtain 5.09 g (yield: 90.3%) of a title compound (4). <n="31"/>[256] 1H-NMR(CDCl ) (ppm) 1.64(m, 2H), 1.82(m, 4H), 3.57(t, 2H), 4.01 (t, 2H), 6.93(d,2H), 7.57(d, 2H). |
90.3% | With potassium carbonate; In acetonitrile; at 80 - 82℃; for 7h;Heating / reflux; | 3.0 g (25.2 mmol) of 4-cyanophenol and 3.67 g (27 mmol) of potassium carbonate were sequentially added to 80 ml of acetonitrile, and then 4.67g (25.2 mmol) of l-bromo-5-chloropentane was added thereto. Subsequently, the mixture was refluxed for 7 hrs while maintaining the temperature at 80 to 820C, and then cooled to room temperature after stopping heating. The reaction solution was diluted with ethyl acetate, and washed with purified water, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from methanol, and then washed with methanol at -100C. The resultant was dried under reduced pressure to obtain 5.09 g (yield: 90.3%) of a title compound (4). 1H-NMR(CDCl3) (ppm) 1.64(m, 2H), 1.82 (m, 4H), 3.57 (t, 2H), 4.01(t, 2H), 6.93(d, 2H), 7.57(d, 2H). |
90.3% | With potassium carbonate; In acetonitrile; at 80 - 82℃; for 7h;Heating / reflux; | Preparative Example 1 : Preparation of compound (12) in Reaction Scheme 1 1-1 : 4- (5-chloropentoxyl) -benzonitrile (4) While 3. Og(25.2mmol) of 4-hydroxybenzonitrile were added to 80 ml of acetonitrile and stirred, 3.67g(27mmol) of potassium carbonate and 4.67g(25.2mmol) of l-bromo-5- chloropentane were added. Subsequently, the temperature was gradually increased and stirring under reflux was continued for 7 hr, and then stirring was further continued to 80~82C. The temperature was decreased to room temperature, and Ethyl acetate was added, and organic layer washed with distilled water. Thereafter, the organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrated compound was recrystallized in methanol, then filtered, and washed with -10C methanol, thus obtaining 5.09 g (yield: 90.3%) of a title compound (4) . m.p. 47-490C; 1H-NMR(CDCl3) (ppm) 1.64 (m, 2H), 1.82 (m, 4H), 3.57 (t, 2H), 4.01(t, 2H), 6.93(d, 2H), 7.57 (d, 2H) |
In N-methyl-acetamide; | To a solution of 16.9 g (135 mmol) p-cyanophenol in 169 mL of dimethylformamide (DMF), cooled in an ice-bath is added in portions 6.5 g (135 mmol) sodium hydride (50% dispersion in oil). The reaction is stirred and allowed to warm-up to room temperature until no further hydrogen evolution is observed. The solution is then cooled in an ice-bath and a solution of <strong>[54512-75-3]1-bromo-5-chloro-pentane</strong> 25 g (135 mmol) in 84 mL of dimethylformamide is added. The reaction is allowed to warm up to room temperature and stirred for 18 h. The reaction is then poured onto water and the resulting solid filtered off and dried to give 4-(5-chloropentoxy) benzonitrile, m.p. 52-54 C. | |
In potassium carbonate; | A stirred solution of 4-cyanophenol (80.9 g, 0.679 mol) in 1260 mL of acetonitile is treated with potassium carbonate (93.9 g, 0.679 tool) and <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (126 g, 0.679 mmol). The reaction is refluxed overnight and potassium carbonate is filtered off. The filtrate is concentrated in vacuo to generate oil which is partitioned between ether and water. The organic layer is washed with water, dried with magnesium sulfate, and concentrated in vacuo to afford 5-(4-cyanophenoxy)pentyl chloride as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro-trimethyl-silane; lithium bromide; iodine; magnesium;copper(I) iodide; In tetrahydrofuran; water; acetic acid; | a 7alpha-(5-Chloropentyl)-11beta-fluor-estr-4-ene-3,17-dione First 20% of a solution of 39 ml of <strong>[54512-75-3]1-bromo-5-chloropentane</strong> in 300 ml of THF is added under nitrogen to a suspension of 7.2 g of magnesium chips in 100 ml of THF. After the reaction has started, which can be achieved by adding iodine and dibromomethane, the residual solution is added in drops in such a way that the internal temperature does not exceed 35 C. In a second flask, 51.2 g of lithium bromide is added to a suspension of 28.1 g of copper(I) iodide in 130 ml of THF at 0 C., whereby the internal temperature climbs to 40 C. Without cooling, 49.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one is now added and stirred for 15 minutes at 40 C. A clear solution is obtained, which was added in drops to the Grignard solution that is cooled to -50 C. Then, it is stirred for 15 more minutes at -30 C. and mixed at -70 C. drop by drop with a solution of 25 g of 11beta-fluor-estra-4,6-diene-3,17-dione in 260 ml of THF, 26 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one and 59 ml of trimethylchlorosilane in such a way that the internal temperature does not exceed -65 C. It is stirred for 30 minutes under cold conditions, then 34.7 ml of glacial acetic acid is added in drops, the cooling bath is removed and stirred for 1 more hour at room temperature. For working-up, the reaction mixture is added to 1.5 l of water, diluted with the same amount of ethyl acetate, the precipitate is separated on Celite, rewashed with ethyl acetate, the aqueous phase is extracted 3 times with ethyl acetate, washed with sodium bicarbonate and common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, 22.1 g of 7alpha-(5-chloropentyl)-11beta-fluor-estr-4-ene-3,17-dione is obtained. | |
With chloro-trimethyl-silane; lithium bromide; iodine; magnesium;copper(I) iodide; In tetrahydrofuran; acetic acid; | a 7alpha-(5-Chloropentyl)-11beta-fluoro-estr-4-ene-3,17-dione First, 20% of a solution of 39 ml of <strong>[54512-75-3]1-bromo-5-chloropentane</strong> in 300 ml of THF is added to a suspension of 7.2 g of magnesium chips in 100 ml of THF under nitrogen. After the reaction starts, which can be achieved by adding iodine and dibromomethane, the remaining solution is added in drops in such a way that the internal temperature does not exceed 35 C. In a second flask, 51.2 g of lithium bromide is added to a suspension of 28.1 g of copper(I) iodide in 130 ml of THF at 0 C., whereby the internal temperature climbs to 40 C. Without cooling, 49.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one is now added and stirred for 15 minutes at 40 C. A clear solution is obtained, which is added in drops to the Grignard solution that is cooled to -50 C. Then, it is stirred for 15 more minutes at -30 C. and mixed at -70 C. drop by drop with a solution of 25 g of 11beta-fluoro-estra-4,6-diene-3,17-dione in 260 ml of THF, 26 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one and 59 ml of trimethylchlorosilane in such a way that the internal temperature does not exceed -65 C. It is stirred for 30 minutes cold, then 34.7 ml of glacial acetic acid is added in drops, the cooling bath is removed, and it is stirred for 1 more hour at room temperature. For working-up, the reaction mixture is added to 1.51 of water, diluted with the same amount of ethyl acetate, the precipitate is separated on Celite, rewashed with ethyl acetate, the aqueous phase is extracted 3 times with ethyl acetate, washed with sodium bicarbonate and common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, 22.1 g of 7alpha-(5-chloropentyl)-11beta-fluoro-estr-4-ene-3,17-dione is obtained. |
Yield | Reaction Conditions | Operation in experiment |
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In N-methyl-acetamide; water; | PREPARATION EXAMPLE 98 60% Sodium hydride (1.16 g) was suspended in dimethylformamide (40 ml), and a solution of cyclohexanemethanol (0.3 g) in dimethylformamide (10 ml) was dropwise added under ice-cooling with stirring, which was followed by stirring at room temperature for 1 hr. The mixture was again ice-cooled, and a solution of 1-bromo-5-chloropentane (4.88 g) in dimethylformamide (10 ml) was dropwise added, which was followed by stirring at room temperature for 2.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 2.9 g of 5-(cyclohexylmethoxy)pentyl bromide. 1 H-NMR (CDCl3,ppm) delta: 0.83-1.94(17 H,m), 3.19(2 H,d,J=6.6 Hz), 3.39(2 H,t,J=6.6 Hz), 3.54(2 H,t,J=7.3 Hz) | |
In N-methyl-acetamide; water; | Preparation Example 15 60% Sodium hydride (1.16 g) was suspended in dimethylformamide (40 ml), and a solution of cyclohexanemethanol (3 g) in dimethylformamide (10 ml) was dropwise added under ice-cooling with stirring, which was followed by stirring at room temperature for 1 hr. The mixture was again ice-cooled, and a solution of 1-bromo-5-chloropentane (4.88 g) in dimethylformamide (10 ml) was dropwise added, which was followed by stirring at room temperature for 2.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 2.9 g of 5-(cyclohexylmethoxy)pentyl bromide. 1H-NMR (CDCl3,ppm)delta:0.83-1.94(17H,m), 3.19(2H,d,J=6.6Hz), 3.39(2H,t,J=6.6Hz), 3.54(2H,t,J=7.3Hz) |
Yield | Reaction Conditions | Operation in experiment |
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94% | In water; acetone; | EXAMPLE 48 Synthesis of 4-[3-(5-chloropentyloxy)phenyl]-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran STR37 4-(3-Hydroxyphenyl)-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (283 mg, 0.6 mmol), <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (598 mg, 3.2 mmol) and aqueous 2N-NaOH solution (1 ml) were dissolved in acetone (3 ml) and then refluxed for 6 hours. The reaction mixture was cooled to room temperature and then water was added thereto. The reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=8:1) to obtain 307 mg (yield: 94%) of the title compound as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
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97% | With sodium hydroxide; In water; acetone; | EXAMPLE 16 Synthesis of 4-[4-(5chloropentyloxy)phenyl]-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran 4-(4-Hydroxyphenyl)-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (180 mg, 0.4 mmol), <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (0.39 ml, 2 mmol) and 2N aqueous sodium hydroxide solution (70 mul, 2 mmol) were dissolved in acetone (4 ml) and then refluxed for 6 hours. The reaction mixture was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to remove the organic solvent. The concentrate was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 247 mg (yield: 97%) of the title compound as a colorless oil. 1 H-NMR(300 MHz, CDCl3): delta 7.10(m, 1H), 6.78(m, 5H), 6.70(dd, 3H), 6.63(s, 1H), 6.45(dd, 1H), 5.23(s, 2H), 5.14(s, 2H), 4.65(t, 1H), 4.22(dd, 1H), 3.83(m, 2H), 3.72(t, 2H), 3.43(s, 6H), 1.82(m, 2H), 1.48(m, 2H), 1.17(t, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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85% | With potassium carbonate; In N,N-dimethyl-formamide; | Reference Example 21 A mixture of <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (10.0 g), thiophenol (5.94 g), potassium carbonate (7.45 g) and N,N-dimethylformamide (DMF) (50 ml) was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then concentrated to dryness. Potassium phthalimide (11.0 g) and N,N-dimethylformamide (100 ml) were added to the residue and the resultant was stirred at 90 C. for 2 hours. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then concentrated to dryness. The crystals were collected by filtration and recrystallized from isopropyl ether to obtain N-(5-phenylthiopentyl)phthalimide (14.9 g, 85%) as colorless prisms, m.p. 87-88 C. |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 36 7-[5-(4-Hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one The compound was prepared by a method similar to Example 3 from <strong>[6665-86-7]7-hydroxyflavone</strong>, 1-bromo-5-chloropentane, and 4-hydroxypiperidine: mp 94-95 C. |
Yield | Reaction Conditions | Operation in experiment |
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99.1% | Step 1. Under dry N2 protection, add 7.3 g of diethyl oxalate, 9.3 g of 1-bromo-5-chloropentane and a four-necked flask equipped with a condenser, a thermometer, a stirrer and a 50 ml constant pressure dropping funnel. a mixture of 30 ml of tetrahydrofuran;Step 2, at -25 ° C,Quickly add 1.0g PSIM-MgBr,During the dropwise addition reaction, the reaction temperature is kept at about -10 ° C, and after the completion of the dropwise addition, the reaction is continued for 1 h;Step 3. Hydrolyze with 15 ml of 4 M hydrochloric acid, and ensure the reaction temperature is below 0 °C during acid hydrolysis. The organic layer was separated, and the aqueous layer was extracted with dichloromethane, and washed with a saturated sodium chloride solution, and shaken with a NaHS03 saturated solution;Step 4: After the shaking is completed, the organic layer and the aqueous layer are neutralized with a saturated NaHC03 solution, and the organic layer is rotated to evaporate the tetrahydrofuran. The organic layer is combined, neutralized with saturated NaHC03, washed with NaHS03, then washed with NaCl until neutral, and evaporated.Evaporation under reduced pressure gave ethyl 7-chloro-2-oxoheptanoate. | |
90% | (Example 1) Example 1 was carried out in a reaction apparatus 10 shown in Figure 1. A main flow channel 12 is a circular pipe made from stainless steel, and introduction points 12o and 12p are 180-degree T-shaped mixture flow channels made from stainless steel. A Grignard reagent: 1-bromomagnesium-5-chloropentane (0.45 mol/L) was diluted by a tetrahydrofuran solvent and the diluted solution was used as a raw material M2. The reagent 1-bromomagnesium-5-chloropentane was prepared by adding a magnesium powder to 1-bromo-5-chloropentane. Diethyl oxalate (7.4 mol/L) which had not been diluted by the solvent was used as a raw material M1. The raw material M2 and the raw material M1 were supplied to a flowing-type fine reaction flow channel 32, at 110 mL/min and 5.1 mL/min, respectively. Used pumps 20 and 26 were a smooth flow pump made by TACMINA CORPORATION. From the above described conditions, a mixed solution of these materials stays in the flowing-type fine reaction flow channel 32 for approximately 14 seconds. The Grignard reagent and diethyl oxalate were accommodated in a supply container and controlled at 10°C and room temperature respectively, and a thermostatic liquid tank 28 accommodated methanol as a refrigerant 30 and was controlled at -15°C. The produced liquid was collected and quenched with a dilute hydrochloric acid. The target substance of ethyl-7-chloro-2-oxalic pentane was obtained in the yield of 90percent. | |
l-bromo-5-chloropentane (29 lg, 1.57 mol) was reacted with diethyl oxalate (206.5g) through Grignard reaction to obtain ethyl 7-chloro-2-oxo-heptanoate (3) and the compound (3) was reacted with (S)-2,2-dimethylcyclopropanecarboxamide to obtain ethyl (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptanoate (237g, 0.79 mol). The above-described step was performed by the procedure according to the procedure disclosed in EP 48301 (Bl). |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; In n-heptane; | Example 14 A mixture of 205 g (1.11 mol) of <strong>[54512-75-3]1-bromo-5-chloropentane</strong>, 121 g (0.93 mol) of ethyl 3-oxobutanoate, and 109 g of n-heptane was heated to 100C, and after the addition of 72 g (0.52 mol) of potassium carbonate, was stirred at the same temperature for 22 hours. In the middle of the stirring, more potassium carbonate was added at 72 g (0.52 mol) on 2 and 8.4 hours later, respectively, and at 26 g (0.18 mol) on 18 hours later. The reaction mixture was cooled to room temperature, after which inorganic salts were filtered off and the filtered solid was washed with 148 g of n-heptane. The combined filtrates were concentrated under reduced pressure to give 230 g of the crude product of ethyl 7-chloro-2-(1-oxoethyl)heptanoate. | |
With potassium carbonate; In ethyl acetate; at 20 - 80℃; for 6.5h; | At room temperature, 16.7g (0.09mol) 1- bromo-5-chloro pentane, 13.0g (0.10mol) of ethyl acetoacetate and 6.4g (0.025mol) of polyethylene glycol -400 (PEG-400) was dissolved in 100ml of ethyl acetate, mix well, the reaction solution was added 20.8g (0.15mol) of anhydrous potassium carbonate.After addition, the temperature was raised to 75 ~ 80 , the reaction was stirred for maintaining the temperature, HPLC monitoring the progress of the reaction, about 6.5h the reaction was complete.After completion of the reaction, heating was stopped, the reaction mixture was cooled to room temperature, the solid insolubles were removed by filtration, the solid residue was washed with a small amount of ethyl acetate, filtrate was collected, concentrated under reduced pressure recovering ethyl acetate (next batch reaction can be applied) to give a pale yellow oil, is the desired product.Gas chromatography (GC) detection of 78.3% purity, 18.6 g of an amount of external standard, a yield of 88.3%. |
Yield | Reaction Conditions | Operation in experiment |
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With nitrosylsulfuric acid; sulfuric acid; In water; toluene; | Then, 230 g (0.62 mol) of the crude product of ethyl 7-chloro-2-(1-oxoethyl)heptanoate thus obtained was cooled to 5°C, to which 228 g (0.81 mol) of 44percent nitrosylsulfuric acid/sulfuric acid solution was added dropwise over 6 hours, and the mixture was further stirred at the same temperature for 4 hours. In another flask, 113 g (1.39 mol) of 37percent aqueous formalin solution and 291 g of toluene were placed and then cooled to 10°C, to which the above reaction solution was added dropwise at the same temperature over 2 hours, and the mixture was further stirred at the same temperature for 30 minutes. The reaction mixture was subjected to phase separation, and the oil layer was washed with 107 g of 5percent aqueous sodium carbonate solution and then with 107 g of water to give 508 g of a toluene solution containing <strong>[78834-75-0]ethyl 7-chloro-2-oxoheptanoate</strong>. In the toluene solution, 18.1percent by weight (72percent yield) of <strong>[78834-75-0]ethyl 7-chloro-2-oxoheptanoate</strong> and 5.4percent by weight of 1-bromo-5-chloropentane were contained. |
Yield | Reaction Conditions | Operation in experiment |
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92% | With potassium carbonate; In acetone; at 20℃; for 60h; | A solution of tetrahydropthalimide (1 equiv.), l-bromo-5-chloropentane (7 equiv.) and potassium carbonate (3 equiv.) in acetone (25 mL/g) was stirred for about 60 hours at room temperature. The reaction mixture was then filtered washed with acetone. The filtrate was evaporated under reduced pressure to form an oily residue. The oily residue was then stirred in hexane and the solid separated out was dried under vacuum to yield the title product. EPO <DP n="29"/>Yield: 92 % |
Yield | Reaction Conditions | Operation in experiment |
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73% | With hydrogenchloride; sodium hydroxide; n-butyllithium; IPr2NH; In tetrahydrofuran; water; | t-Butyl 1-(5-chloropentyl)-1-cyclopropanecarboxylate (104c). Under an Ar atmosphere at 0 C., BuLi (2.5M in hexanes, 80 mL, 0.20 mol) was added dropwise to a solution of iPr2NH (27.2 mL, 194 mmol, distilled from NaOH) in dry THF (200 mL) in 30 min. The reaction mixture was stirred for 30 min, cooled to -70 C. and then, t-butyl cyclopropanecarboxylate (25.0 g, 176 mmol) was added dropwise in 30 min. The resultant mixture was allowed to warm up to -35 C., cooled again to -70 C. and then <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (36 mL, 50.7 g, 273 mmol) was added dropwise in 15 min. The reaction mixture was allowed to reach -5 C., stirred for 3 h, poured into a mixture of ice (100 mL), H2O (100 mL), brine (200 mL) and aqueous HCl (2 M, 200 mL) and extracted with Et2O (2*300 mL). The combined organic layers were washed with a mixture of brine and saturated aqueous NaHCO3 (10:1, 300 mL) and dried. The remaining oil was purified by fractional distillation under reduced pressure to give 104c (31.5 g, 73%) as a colorless liquid. bp: T=67-74 C. (p=0.001 mbar). 1H NMR: 3.52 (t, J=6.6 Hz, 2H), 1.77 (quintet, J=6.8 Hz, 2H), 1.48-1.38 (m, 6H), 1.42 (s, 9H), 1.10 (dd, J=6.5 Hz, 3.8 Hz, 2H), 0.59 (dd, J=6.6, 3.9 Hz, 2H). 13C NMR: delta 174.1, 79.9, 45.2, 34.2, 32.7, 28.2 (3*), 27.20, 27.17, 24.3, 15.4 (2*). HRMS calcd for C13H24ClO2 (MH+): 247.1465, found: 247.1465. |
Yield | Reaction Conditions | Operation in experiment |
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38% | Example A9; a. Preparation of intermediate 32; In a three-neck flask under N2 flow were introduced magnesium (4.8 g, 0.202 mol) in 15 ml of THF and a catalytic amount of I2. A few drops of l-bromo-5-chloropentane were added to initiate the reaction. After the solution had lost its color, more l-bromo- 5-chloropentane (26.6 ml, 0.2 mol) in 75 ml of THF were added dropwise keeping the temperature at about 10 0C. The mixture was stirred for 1 hour at this temperature. Then the solution of 3-bromobenzaldehyde (15.8 ml, 1.35 mol) in 75 ml of THF was added dropwise at 10 0C and the mixture was stirred half a day at room temperature. The reaction was quenched with aqueous ammonium chloride (10 % solution), diluted with ethyl acetate and filtered on Celite. The organic layer was then washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel (cyclohexane/EtOAc 80/20). Yield: 15 g of intermediate 32 (38 %). |
Yield | Reaction Conditions | Operation in experiment |
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70%; 6.9% | EXAMPLES 7alpha-(5-Chloropentyl)-11-beta-fluoroestr-4-ene-3,17-dione; 3.38 g (138.72 mmol) magnesium chips were suspended in 100 ml THF. 1.86 ml of a 20% solution of DIBAH in toluene was added (20C) to activate the magnesium. A solution of 25.74 g (138.72 mmol) <strong>[54512-75-3]1-bromo-5-chloropentane</strong> in 80 ml of THF was prepared separately. Approx. 10% of this solution was added drop-wise to the magnesium chips under vigorous stirring. Following the initiation of the reaction (duration approx. 5 to 10 minutes, may be determined by development of heat), the remaining bromide solution was continuously added over 30 minutes at 25C to 30C within 30 minutes. Subsequently, the mixture was stirred for 1.5 h at 23C (whereby the magnesium was completely dissolved). In order to carry out the 1,6 addition, 20 g (69.36 mmol) of 11-beta-fluoroestra-4,6-diene-3,17-dione was suspended in 180 ml THF. 2.94 g (69.36 mmol) of LiCl and 6.6 g (34.68 mmol) of Cul were mixed with 25 ml of THF and stirred for 1 hour at room temperature. The steroid solution was cooled to -10C and the catalyst solution was added to the steroid solution. Subsequently, 44 ml (346.79 mmol) of trimethylsilyl chloride was added, and the mixture was cooled to -70C to -60C. 80% of the Grignard solution prepared above was added drop-wise to this solution over 3 hours. After completing the reaction, the reaction mixture was quenched by adding 40 ml of 2M HCl and the reaction mixture was heated to room temperature. Subsequently, 80 ml of water was added, and the layers were separated. The aqueous phase was extracted once with 100 ml of toluene, and the combined organic phases were washed once with a mixture of 70 ml of an ammonia solution and 70 ml of water. Subsequently, the organic phase was washed twice with a solution of 18 g of ammonium chloride and 16 ml of ammonia solution in 100 ml of water. The solvent was subsequently evaporated, and the residue was separated chromatographically to determine the yield. 19,2 g (70% of theory) of 7alpha-(5-Chloropentyl)-11-beta-fluoroestr-4-ene-3,17-dione was obtained. Likewise, 1,9 g (6,9% of theory) of 7beta-(5-Chloropentyl)-11-beta-fluoroestr-4-ene-3,17-dione was obtained. Thus, the obtained ratio between the alpha and the beta isomer was 10:1. |
Yield | Reaction Conditions | Operation in experiment |
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90% | To a suspension of NaH (60% suspension in oil, 0.72 g, 30 mM) in 20 ml dry DMF was added 6, 7-dihydro-12H-benzothiepino [5,4-b] indole (5.02 g, 20 mM, dissolved in 30 ml diy DMF) at 0C under nitrogen atmosphere with stirring. After 15 min, 1-bromo-5- chloro pentane (5.5 g, 30 mM, dissolved in 30 ml DMF) was added dropwise and continued stirring at room temperature for 1.5 hr. The reaction mixture was poured into water, extracted with ethyl acetate and dried over sodium sulphate. The concentrate was chromatographed on silica gel using ethyl acetate/hexane (1: 20) to yield an oil, 6.40 g, (90 %).'H NMR (CDC13) 8 : 1.29 (m, 2H), 1.63 (m, 4H), 2.99 (bs, 2H), 3. 18 (t, 2H), 3.55 (bs, 2H), 4.29 (t, 2H), 7.15-7. 25 (m, 3H), 7. 38 (m, 3H), 7.62 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H). FABMS: m/z 356 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
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85% | To a suspension of NaH (60% suspension in oil, 0. 36 g, 15 mM) in 10 ml dry DMF was added 3-methoxy-6, 7-dihydro-12H-benzothiepino [5,4-b] indole (2.81 g, 10 mM, dissolved in 20 ml dry DMF) at 0C under nitrogen atmosphere with stirring. After 15 min, l-bromo-5-chloro pentane (2.77 g, 15 mM, dissolved in 20 ml DMF) was added dropwise and continued stirring at room temperature for 1.5 hr. On completion, the reaction mixture was poured into water, extracted with ethyl acetate and dried over sodium sulphate. The concentrate was chromatographed on silica gel using ethyl acetate/hexane (1: 20) to yield an oil, 3.26 g (85 %).'H NMR (CDC13) 8 : 1.25 (111, 2H), 1.57 (m, 4H), 2.99 (bs, 2H), 3.36 (t, 2H), 3.56 (bs, 2H), 3.81 (s, 3H), 4.49 (t, 2H), 6.97 ( dd, J = 2.66, 8.56 Hz, 1H), 7.19 (m, lH), 7.25 (dd, 1H), 7.32 (m, 1H), 7.34 (m, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7. 55 (d, J = 7.6 Hz, 1H). EIMS: m/z 385 (M+). |
Yield | Reaction Conditions | Operation in experiment |
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90% | To a suspension of NaH (60% suspension in oil, 0.36 g, 15 mM) in 10 ml dry DMF was added 9-methoxy-6, 7-dihydro-12H-benzothiepino [5, 4-b] indole (2. 81 g, 10 mM, dissolved in 20 ml dry DMF) at 0C under nitrogen atmosphere with stirring. After 15 min, 1-bromo-5-chloro pentane (2.77 g, 15 mM, dissolved in 20 ml DMF) was added dropwise and continued stirring at room temperature for 1.5 hr. The reaction mixture was poured into water, extracted with ethyl acetate and dried over sodium sulphate. The concentrate was chromatographed on silica gel using ethyl acetatc/hcxane (1: 20) to yield an oil, 3.46 g (90 %).'H NMR (CDCl3) 8 : 1.16 (m, 2H), 1.63 (m, 4H), 2.99 (bs, 2H), 3.35 (t, 2H), 3.54 (bs, 2H), 3.88 (s, 3H, OCH3), 4.25 (t, 2H), 6.90 (dd, J = 2.36, 8.8 Hz, 1H), 7.04 (d, J = 2. 26 Hz, 1H), 7. 27 (m, 2H), 7.39 (m, 2H), 7. 78 (d, J = 7.56 Hz, 1H). EIMS: m/z 385 (M+). |
Yield | Reaction Conditions | Operation in experiment |
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90% | To a suspension of NaH (60% suspension in oil) (0.48 g, 20 mM) in 10 ml dry DMF was added 3, 9-dimethoxy-6, 7-dihydro-12H-benzothiepino [5, 4-b] indole (3.11 g, 10 mM, dissolved in 20 ml dry DMF) at 0C under nitrogen atmosphere with stirring. After 15 min, 1-bromo-5-cliloro pentane (2.77 g, 15 mM, dissolved in 20 ml DMF) was added dropwise and continued stirring at room temperature for 1.5 hr. The reaction mixture was poured into water, extracted with ethyl acetate and dried over sodium sulphate. The concentrate was chromatographed on silica gel using ethyl acetate/hexane (1: 20) to yield an oil, 3.74 g (90 %). 1H NMR (CDCI3) 8 : 1.16 (m, 2H), 1.63 (m, 4H), 2.99 (bs, 2H), 3.35 (t, 2H), 3.54 (bs, 2H), 3.87 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.18 (t, 2H), 6. 87 (dd, J = 2. 36,8. 8 Hz, 1H), 6.97 (d, J = 2.6 Hz, 1H), 7.01 (m, 2H), 7.24 (s, 1H), 7. 33 (dd, J = 2. 4,8. 8 Hz 1H). FABMS : m/z 416 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
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90% | To a suspension of NaH (60% suspension in oil, 0.48 g, 20 mM) in 20 ml dry DMF was added 6, 7-dihydro-12H-benzoxepino [5,4-b] indole (2.35 g, 10 mM, dissolved in 20 ml dry DMF) at 0C under nitrogen atmosphere with stirring. After 15 min, 1-brom-5- chloro pentane (3.7 g, 20 mM, dissolved in 20 ml DMF) was added dropwise and continued stirring at room temperature for 1.5 hr. The reaction mixture was poured into water and extracted with ethyl acetate, dried over sodium sulphate. The concentrate was chromatographed on silica gel using ethyl acetate/hexane (1: 20) to yield an oil, 3.50 g (90 %).'H NMR (CDC13) 5 : 1.29 (m, 2H), 1.63 (m, 4H), 3.07 (t, 2H), 3.37 (t, 2H), 4.53 (t, 2H), 4.61 (t, 2H), 7.15-7. 22 (m, 5H), 7.44 (d, J = 7.6 Hz, 1H), 7.62 (m, 2H). EIMS: m/z 390 (M+). |
Yield | Reaction Conditions | Operation in experiment |
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Intermediate 35: 9-(5-ChloropentylV2-{r(1 SV1-methylbutylloxy>-8-(methyloxyV9H- purin-6-amine; 2-[(1 S)-1-Methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (600mg, 1.642 mmol) and potassium carbonate (567mg, 4.11 mmol) were stirred at 600C in DMF (10ml) for 1 hour under nitrogen. The reaction was cooled to room temperature when <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (0.216ml, 1.642mmol) and triethylamine (0.343ml, 2.464mmol) were added and the mixture stirred at 200C under nitrogen for 16 hours. The mixture was then diluted with water (10ml) and brine (10ml) and extracted with DCM (2 x 10ml). The combined organic extracts were evaporated and the residue dissolved in DCM and purified by column chromatography using the Flashmaster Il (7Og aminopropyl cartridge) with a 0-100% ethyl acetate in cyclohexane gradient over 40 minutes. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow gum (430mg). LCMS (System D): tRET = 4.15min; MH+ = 356/358 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 15: 2-(Butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (2g, 5.69mmol) and potassium carbonate (1.967g, 14.23 mmol) were suspended in DMF (20ml) and heated to 5O0C, under nitrogen for 1 hour. The mixture was cooled to room temperature, <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (0.75ml, 5.69mmol) was added and stirring was continued at room temperature for 18 hours. The reaction mixture was partitioned between DCM (40ml) and water (40ml) and the layers were separated using a hydrophobic frit. The aqueous layer was extracted again with DCM (10ml) and the combined organics were washed with saturated lithium chloride solution, separated (hydrophobic frit) and concentrated in vacuo to give the title compound as a yellow oil (1.946g). LCMS (System B): tRET = 2.58min; MH+ = 342, 344 | ||
Intermediate 17: 2-(Butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine; 2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (2g, 5.69mmol) and potassium carbonate (1.967g, 14.23 mmol) were suspended in DMF (20ml) and heated to 5O0C, under nitrogen for 1 hour. The mixture was cooled to room temperature, <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (0.75ml, 5.69mmol) was added and stirring was continued at room temperature for 18 hours. The reaction mixture was partitioned between DCM (40ml) and water (40ml) and the layers were separated using a hydrophobic frit. The aqueous layer was extracted again with DCM (10ml) and the combined organics were washed with saturated lithium chloride solution, separated (hydrophobic frit) and concentrated in vacuo to give the title compound as a yellow oil (1.946g). LCMS (System B): tRET = 2.58min; MH+ = 342/344 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 21 : 9-(5-ChloropentylV2-{r(1 SV1-methylbutylloxy>-8-(methyloxyV9H- purin-6-amine; 2-[(1 S)- 1 -Methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (600mg, 1.642 mmol) and potassium carbonate (567mg, 4.11 mmol) were stirred at 600C in DMF (10ml) for 1 hour under nitrogen. The reaction was cooled to room temperature when <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (0.216ml, 1.642mmol) and triethylamine (0.343ml, 2.464mmol) were added and the mixture stirred at 200C under nitrogen for 1 6hours. The mixture was then diluted with water (10ml) and brine (10ml) and extracted with DCM (2 x 10ml). The combined organic extracts were evaporated and the residue dissolved in DCM and purified by column chromatography using the Flashmaster Il (7Og aminopropyl cartridge) with a 0-100% ethyl acetate in cyclohexane gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow gum (430mg). LCMS (System D): tRET = 4.15min; MH+ = 356/358 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.6% | With caesium carbonate; In toluene; at 60℃; for 18h; | Example 32A Methyl 4-{(4E)-5-{2-[(5-chloropentyl)oxy]phenyl}-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate (racemate) 1.84 g (9.9 mmol) of <strong>[54512-75-3]1-bromo-5-chloropentane</strong> [CAS Reg. No. 586-78-7] and 6.45 g (19.8 mmol) of anhydrous cesium carbonate are added to a solution of 1.1 g (2.47 mmol) of methyl 4-{(4E)-5-(2-hydroxyphenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate (racemate; Example 18A) in 16.5 ml of dry toluene, and the mixture is then stirred at 60 C. for 18 h. The mixture is then filtered, and the filtrate is evaporated to dryness. The crude product obtained is taken up in ethyl acetate and washed twice with saturated sodium bicarbonate solution, and the organic phase is dried over sodium sulfate and concentrated. The crude product is then purified by flash chromatography on silica gel (mobile phase: dichloromethane). This gives 1.00 g (1.82 mmol, 73.6% of theory) of a colorless oil. LC-MS (Method 10): Rt=3.08 min; m/z=549 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate; In acetone; for 8h;Reflux; | General procedure: Compound 11 (0.5 g, 1.5 mmol) was dissolved in acetone (30 mL) and anhydrous K2CO3 (0.2 g, 1.5 mmol) and 1-bromo-3-chloropropane (0.15 mL, 1.5 mmol) were added. After refluxing for 8 h, the mixture was hot filtered, the solvent was removed under reduced pressure and the crude was purified by flash column chromatography using CH2Cl2/CH3OH (97.5:2.5) as eluant, to afford 12 as an oil (0.5 g, 82%); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate; potassium iodide; In acetonitrile; for 20h;Reflux; | General procedure: Compound 9 (1.00 g, 5.28 mmol) was dissolved in acetonitrile (14 mL). Successively, potassium carbonate (2.19 g, 15.85 mmol), 1-bromo-3-chloropropane (2.08 g, 13.21 mmol) and potassium iodide (0.10 g, 0.60 mmol) were added. The reaction mixture was heated under reflux for 20 h. After being cooled, it was concentrated under reduced pressure. Then, water and ethyl acetate were added. The organic layer was separated and dried over anhydrous sodium sulphate. After filtration, solvents were eliminated under reduced pressure to give 17 (0.80 g, 57%) as a white solid. This crude product was used without further purification: mp 83-85 C; IR (KBr) cm-1 1724, 1667 (CO); 1H NMR (DMSO-d6) delta 7.40-7.20 (m, 5H, aromatic), 3.79 (t, J = 6.8 Hz, 2H, CONCH2), 3.60 (t, J = 6.4 Hz, 2H, CH2Cl), 3.58-3.30 (m, 1H, CH), 2.92 (dd, 2J = 16.2 Hz, 3J = 10.6 Hz, 2H, CHCHAHB), 2.80 (dd, 2J = 16.2 Hz, 3J = 4.6 Hz, 2H, CHCHAHB), 1.98-1.81 (m, 2H, CH2CH2Cl). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate salt (for example, as prepared for Intermediate 6) (2 g, 5.69 mmol) and potassium carbonate (1 .967 g, 14.23 mmol) were suspended in DMF (20 mL) and heated to 50 C, under nitrogen for 1 hour. The mixture was cooled to room temperature, <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (commercially available, for example, from Aldrich) (0.75 mL, 5.69 mmol) was added and stirring was continued at room temperature for 18 hours. The reaction mixture was partitioned between DCM (40 mL) and water (40 mL) and the layers were separated using a hydrophobic frit. The aqueous layer was extracted again with DCM (10 mL) and the combined organics were washed with saturated lithium chloride solution, separated (hydrophobic frit) and concentrated in vacuo to give the title compound as a yellow oil (1.946 g).LCMS (System B): tRET = 2.58min; MH+ = 342/344 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2-[(1 S)-1-Methylbutyl]oxy}-8-(methylxy)-9H-purin-6-amine, trifluoroacetate salt (600 mg, 1.642 mmol) (for example, as prepared for Intermediate 7) and potassium carbonate (567 mg, 4.1 1 mmol) were stirred at 60 C in DMF (10 mL) for 1 hour under nitrogen. The reaction was cooled to room temperature when <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (commercially available, for example, from Aldrich) (0.216 mL, 1.642 mmol) and triethylamine (0.343 mL, 2.464 mmol) were added and the mixture stirred at 20 C under nitrogen for 16 hours. The mixture was then diluted with water (10 mL) and brine (10 mL) and extracted with dichloromethane (2 x 10 mL). The combined organic extracts were evaporated and the residue dissolved in dichloromethane and purified by columnchromatography using the Flashmaster II (70 g aminopropyl cartridge) with a 0-100% ethyl acetate in cyclohexane gradient over 40 minutes. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow gum (430 mg).LCMS (System D): tRET = 4.15min; MH+ = 356, 358 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Sodium hydroxide (2M, 2.52 L, 2.3 eq.) was added to a solution of 2-[(1 S)-1 -methylbutyl]oxy}-8- (methyloxy)-9H-purin-6-amine, trifluoroacetate salt (800 g, 1 .0 eq.) in NMP (3.08 L). 1-Bromo-5- chloropentane (432 mL, 1.5 eq.) was added. The reaction mixture was heated to 50 C for 6 h. The reaction mixture was cooled to 20-25 C. Ethyl acetate (8.0 L) was added, followed by water (1.6 L). After stirring for 10 minutes, the phases were separated and the organic phase was then washed with water (1.6 L). The ethyl acetate phase was further diluted with ethyl acetate (4.0 L) and heated to 50 C. Sulfuric acid (1 17 mL, 1 eq.) was added dropwise. The reaction mixture was cooled to 10 C over 1.5 hours and aged for half an hour. The product was isolated by filtration as a white solid, washed on the filter with ethyl acetate (2.4 L) and dried under reduced pressure at 40C (570 g, 57% theoretical yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | Example 7; Scheme 7 shows a method for making radiolabeled compounds of formula (I) for preparation of 2-(5-(4-(6-fluoropyridin-2-yl)piperazin-l-yl)pentyl)-4-methyl-l,2,4- triazine-3,5(2H,4H)-dione Scheme 7Preparation of 2-(5-chloropentyl)-4-methyl-l,2,4-triazine-3,5(2H,4H)-dioneTo a suspension of 60% NaH (200 mg, 5 mmol) in DMF (5 mL) was added 4-methyl- l,2,4-triazine-3,5(2H,4H)-dione (508 mg, 4 mmol) in DMF (20 mL) dropwiswe at 0 C. After one hour a yellow/orange suspension had formed and to this was added 1 -bromo- 5-chloropentane (740 mg, 4 mmol) in DMF (15 mL) dropwise. The reaction mixture was allowed to warm to room temperature and then stirred for 18 hours. The raction was quenched with water (100 mL) and partitioned with EtOAc (100 mL x 2). The organics were dried over magnesium sulfate, filtered and concentrated. The yellow oil was purified on silica (50 g) eluting with EtOAc/petrol (5 to 100% EtOAc over 14 CV at a flow of 40 mL/min). The porduct eluted between 5-8 CV and this was concentrated to give a white solid (390 mg, 34%). *H NMR (300 MHz, CDC13): delta 1.46 (2H, p, J = 7.4 Hz, CH2), 1.70-1.83 (4H, 2 x CH2), 1.73 (2U, p, J = 7.7 Hz, CH2), 2.31 (2H, t, J = l.l Hz, CH2), 3.30 (3H, s, NCH3), 3.51 (2H, t, J = 6.7 Hz, CH2), 3.95 (2H, t, J = 7.4 Hz, CH2), 7.17-7.31 (5H, m, ArH), and 7.36 (1H, s, N=CH); 13C NMR (75 MHz, CDC13): delta 23.6, 26.9, 27.3, 31.9, 44.6, 51.5, 133.7, 148.7, and 156.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium carbonate; In acetone; for 24h;Reflux; | General procedure: A stirred mixture of 4-benzofuran-2-yl-phenol [11] (1 g, 4.7 mmol), 1-bromo-3-chloropropane (0.94 mL, 9.5 mmol) and K2CO3 (1.2 g) was refluxed in acetone (100 mL) for 20 h. The suspension was filtered while hot and the solvent was removed under reduced pressure. After adding petroleum ether, the residue was kept in the freezer overnight and the white solid that formed was filtered off, affording 26 (0.93 g, 69%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Example 1 Synthesis of 2-(5-Chloropentyloxy)benzo[d]thiazole (K23) To a solution of 2-hydroxybenzothiazole (0.2 g, 1.32 mmol) in 10 mL of acetonitrile was added K2CO3 (0.274 g, 1.98 mmol), followed by stirring at 50?55 C. for 30 min. Then, <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (0.245 g, 1.32 mmol) was added to and reacted with the solution of 2-hydroxybenzothiazole at 80?90 C. for 3 hours. The reaction was cooled to room temperature, diluted with 10 mL of EtOAc, and washed with distilled water and a saturated NaCl aqueous solution. It was dried over MgSO4 and the solvent was removed by concentration under reduced pressure to afford K23 (0.333 g, 98%). Transparent oil; 1H NMR (400 MHz, Acetone-d6) delta 7.579 (d, J=7.8, 1H), 7.393?7.295 (m, 2H), 7.194 (t, J=7.5, 1H), 4.015 (t, J=7.2, 2H), 3.602 (t, J=6.6, 2H), 1.869?1.743 (m, 4H), 1.574?1.496 (m, 2H); HR-FABMS Calcd for C12H15ClNOS (M++H): 256.0563. Found: 256.0565. | |
98% | K2CO3 (0.274 g, 1.98 mmol) was added to a solutionof 2-hydroxybenzothiazole (0.2 g, 1.32 mmol) in 10 mL ofacetonitrile, followed by stirring at 50-55 C for 30 min.<strong>[54512-75-3]1-Bromo-5-chloropentane</strong> (0.245 g, 1.32 mmol) was addedto the reaction mixture and reacted at 80-90 C for 3 h. Thereaction mixture was cooled to room temperature, anddiluted with 10 mL of EtOAc, washed with distilled waterand saturated with NaCl aqueous solution. It was dried overMgSO4 and the solvent was removed by concentration underreduced pressure to yield compound 1 (0.333 g, 98 %).Transparent oil; 1H NMR (400 MHz, acetone-d6) delta7.579 (d, J = 7.8, 1H), 7.393-7.295 (m, 2H), 7.194 (t,J = 7.5, 1H), 4.015 (t, J = 7.2, 2H), 3.602 (t, J = 6.6,2H), 1.869-1.743 (m, 4H), 1.574-1.496 (m, 2H); HRFABMSCalcd for C12H15ClNOS (M++H): 256.0563,Found: 256.0565. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium carbonate; In acetone; for 48h;Inert atmosphere; Reflux; | General procedure: 4 (20.1 g, 0.1 mol) and anhydrous K2CO3 (55.3 g, 0.4 mol) were added into dry acetone (300 mL) under N2 atmosphere, and then appropriate alkyl dihalides (0.3 mol) was added. The reaction mixture was refluxed for 48 h. After cooling, the mixture was quenched with water (100 mL), and extracted with CH2Cl2 (3×30 mL), the organic layers were collected, dried over anhydrous Na2SO4, filtered and concentrated to dryness, crystallized from CH2Cl2/PE to obtain 5a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride; In benzene; at 80℃; under 60804.1 Torr; for 3h; | General procedure: Typical procedure for radical/ionic three-component coupling reaction leading to cyanohydrin derivatives 1-cyanononyl ethyl carbonate (3a) [34] (Table 1, entry 1): A mixture of 1-bromooctane (1a, 96.6 mg, 0.5 mmol), ethyl cyanoformate (2a, 79.3 mg, 0.8 mmol), tributyltin hydride (174.6 mg, 0.6 mmol), triethylamine (13.2 mg, 0.13 mmol), and AIBN (24.6 mg, 0.15 mmol) in C6H6 (17 mL) were placed in a 100 mL stainless steel autoclave. The reaction mixture was degassed 3 times with 10 atm of CO and charged with 90 atm of CO at -40 C (MeCN-dry ice bath). Then the autoclave was allowed to warm to room temperature, which caused the pressure gauge to indicate 120 atm. Then the reaction was conducted at 80 C for 3 h. After cooling to room temperature, the reaction mixture was concentrated and purified by silica gel flash chromatography (hexane/EtOAc 97:3) to afford 3a (95.3 mg, 79%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With tetrabutylammomium bromide; potassium carbonate; In acetonitrile; for 5h;Reflux; | To 100 ml of acetonitrile were added 2.5 g (11 mmol) of 4-methyl-3-(2,2,2-trifluoroethylthio)phenol, 2.5 g (13 mmol) of <strong>[54512-75-3]1-bromo-5-chloropentane</strong>, 1.9 g (14 mmol) of potassium carbonate and 0.35 g (1.1 mmol) of tetra-n-butylammonium bromide. The mixture was refluxed for 5 hours under heating and then allowed to cool to room temperature. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent : a mixed solvent of n-hexane : ethyl acetate = 10 : 1), to obtain 2.9 g (yield: 79%) of an intended product. 1H-NMR (300 MHz, CDCl3/TMS delta (ppm)) 1.56-1.66 (2H, m), 1.74-1.93 (4H, m), 2.38 (3H, s), 3.36 (2H, q), 3.56 (2H, t), 3.94 (2H, t), 6.74 (1H, d), 7.00 (1H, s), 7.09 (1H, d) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | General procedure: Intermediates 19-26 were prepared following literature procedures, with slight modifications [50]. A solution of 10-14 (6.6mmol) in acetone (20mL) was mixed with K2CO3 (10mmol) and stirred at room temperature for 10min. After addition of the appropriate 1-bromo-omega-chloroalkane or 1,omega-dibromoalkane (7.3mmol), the mixture was stirred for further 24h. Inorganic materials was removed by filtration, then the solvent was removed in vacuum to obtain a residue which was used without any further purification for the next step. For analytical purpose, crude 23-26 were purified by flash chromatography or by recrystallization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | General procedure: Intermediates 19-26 were prepared following literature procedures, with slight modifications [50]. A solution of 10-14 (6.6mmol) in acetone (20mL) was mixed with K2CO3 (10mmol) and stirred at room temperature for 10min. After addition of the appropriate 1-bromo-omega-chloroalkane or 1,omega-dibromoalkane (7.3mmol), the mixture was stirred for further 24h. Inorganic materials was removed by filtration, then the solvent was removed in vacuum to obtain a residue which was used without any further purification for the next step. For analytical purpose, crude 23-26 were purified by flash chromatography or by recrystallization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.0% | With tetrabutylammomium bromide; sodium hydroxide; In water; at 60℃; for 2.08333h; | The benzotriazole (11.9 g, 0.10 mol) was dissolved in 100mL of 30 wt% sodium hydroxide aqueous solution and then was added with bromo-5-chloro-pentane (36.8 g, 0.20 mol), tetrabutylammonium bromide (0.8 g, 0.0025 mol); it is then mixed and stirred for 5 minutes. Heat slowly to 60C and allow to react for 2 hours under stirring. The reaction solution was cooled to room temperature, and extracted with 100 mL of dichloromethane and the liquid was separated; and 100 mL of dichloromethane was then added to aqueous phase, and then the organic phases were combined and washed with 100 mL of saturated saline solution and the liquid was separated; and the organic phase was evaporated to obtain oily substance. The oily substance was then purified by chromatography separation using neutral Al2O3 to obtain 15.8 g of 1-(5-chloro-pentyl)-1H-benzotriazole, with a yield of 71.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.5% | With tetrabutylammomium bromide; sodium hydroxide; In water; at 60℃; for 2.08333h; | The 2-Chloro-1H-benzimidazol(15.2 g, 0.10 mol) was dissolved in 200mL of 20 wt% sodium hydroxide aqueous solution and then was added with Bromo-5-chloro-pentane (36.8 g, 0.20 mol), tetrabutylammonium bromide (1.0 g, 0.003 mol); it is then mixed and stirred for 5 minutes, heated to 60C and react for 2 hours under stirring. The reaction solution was cooled to room temperature, and extracted with 100 mL of dichloromethane and the liquid was separated; and 100 mL of dichloromethane was then added to aqueous phase, and then the organic phases were combined and washed with 100 mL of saturated saline solution and the liquid was separated; and the organic phase was evaporated to obtain oily substance. The oily substance was then purified by chromatography separation using neutral Al2O3 to obtain 16.0 g of 1-(5-chloro-pentyl)-2-chloro-1H-benzimidazol, with a yield of 62.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a solution of 5 in anhydrous DMF was cooled to 0C. 60% NaH (1.1 eq.) was added and stirred for 30 min. Haloalkane(2.0 eq.) was added dropwise. The mixture was stirred at room temperature for 2 h., and then water was added and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was chromatographed by silicagel column (EtOAc/petroleum ether = 1/1) to afford 6a-6c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | 2.55 g (105 mmol) of metallic magnesium (20 to 50 mesh) and 200 g of tetrahydrofuran (THF) were charged in a 200 mL flask purged with a nitrogen atmosphere, and the reaction solution was cooled to 0 C. with stirring. After cooling, 18.55 g (100 mmol) of <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (solvent / dihaloalkane weight ratio 10.78) was added over about 2 hours and aged at the same temperature for 2 hours to obtain a Grignard reagent It was. Analysis of this reaction solution by gas chromatography (GC) revealed that the yield of the Grignard reagent was 85 area% and the selectivity was 85%.0.16 g (1.0 mmol) of ferric chloride was added to the solution of the Grignard reagent obtained by the above operation, 6.25 g (100 mmol) of vinyl chloride was bubbled in over 2 hours while maintaining the temperature at 0 C., And aged at a temperature for 1 hour. After completion of the reaction, a 10% ammonium chloride aqueous solution and methylene chloride were added, and the resultant salt was dissolved and separated. After fractionation of the organic layer, this was quantitatively analyzed by gas chromatography (GC). As a result, 7-chloro-1-heptene as a target product was produced with a yield of 76%. The results are shown in Table 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53%; 10% | With potassium carbonate; potassium iodide; In acetone; for 9.0h;Reflux; | Acetone was added (30 mL) to a mixture of pyrimidinone 1(2.90 mmol), 1-bromo-5-chloro-pentane (5.80 mmol), potassiumcarbonate (4.34 mmol), and of a catalytic amount of potassiumiodide and the mixture was refluxed under stirring for 9 h. Afterbeing cooled, the solid was removed by filtration and the solutionwas concentrated to dryness. Recrystallization with cyclohexanegave pure compound 2. From the solution compound 3 was isolatedby flash chromatography using a mixture of cyclohexane/ethyl acetate (9:1, v/v).Compound 2: yield 53%, mp 103.9-104.5 C. IR (KBr, selectedlines) cm1 2944, 2361, 1673, 1593, 1450, 691. 1H NMR (DMSOd6)d 1.30-1.50 (m, 2H, CH2), 1.60-1.85 (m, 2H + 2H, CH2CH2),3.65 (t, J = 6.6 Hz, 2H, CH2Cl), 3.92 (t, J = 7.2 Hz, 2H, CONCH2),6.97 (s, 1H, NCH), 7.40-7.58 (m, 3H, aromatic), 7.98-8.15 (m, 2H,aromatic), 8.59 (s, 1H, CCH). Anal. (C15H17ClN2O) C, H, N.Compound 3: yield 10%, mp 41.0-44.0 C. IR (KBr, selectedlines) cm1 2956, 1592, 1541, 1466, 1219, 868, 696. 1H NMR(DMSO-d6) d 1.44-1.65 (m, 2H, CH2), 1.70-1.90 (m, 2H + 2H, CH2CH2),3.67 (t, J = 6.6 Hz, 2H, CH2Cl), 4.39 (t, J = 6.4 Hz, 2H, OCH2),7.45-7.60 (m, 3H + 1H, aromatic + NCH), 8.15-8.25 (m, 2H,aromatic), 8.84 (d, J = 1.2 Hz, 1H, CCH). Anal. (C15H17ClN2O) C, H, N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.4% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h; | Brought 6-(4-chlorophenyl)-1-methyl-8-(1H-pyrazol-4- yl)spiro[benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-4,1 (59-2) (0.1g, 0.2494 mmol) and cesium carbonate (121 mg, 0.3741 mmol) up in DMF (831 muL ) at r.t. Added <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (39.2 0.2992 mmol) and stirred at r.t. for 16 hours before concentrating from toluene onto celite. Purified by isco 0-10% MeOH/DCM to give 8-(1-(5-chloropentyl)-1H-pyrazol-4-yl)-6-(4- chlorophenyl)-1-methylspiro[benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-4,1'-cyclopropane] (77-1) (85.0 mg, 0.2494 mmol, 67.4 % yield) as an oil. LCMS (ES+): m/z 507 [M + H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.6% | Brought 6-(4-chlorophenyl)-1-methyl-8-(1H-pyrazol-4- yl)spiro[benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-4,1'-cyclopropane] (0.1 g, 0.2494 mmol) and cesium carbonate (121 mg, 0.3741 mmol) up in DMF (2.49 mL ) and added 1-bromo-5- chloropentane (39.3 muL, 0.2992 mmol). Stirred reaction at r.t. for 5 hours and added sodium azide (32.4 mg, 0.4988 mmol). Heated reaction up to 70C and stirred for 16 hours. Concentrated from toluene onto celite and purified by isco 0-10% MeOH/DCM to give 8-(1-(5-azidopentyl)-1H- pyrazol-4-yl)-6-(4-chlorophenyl)-1-methylspiro[benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine- 4,1'-cyclopropane] (110 mg, 0.2148 mmol, 86.6 %) as an oil. LCMS (ES+): m/z= 512 [M + H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; | General procedure: To a suspension of corresponding cyclic imide 1a-1k (4mmol), potassium carbonate (4.4mmol) in DMF (5mL), 1-bromo-4-chlorobutane (1,2-dibromoethane (5 eq) for 2l, 1-bromo-3-chloropropane for 2m, <strong>[54512-75-3]1-bromo-5-chloropentane</strong> for 2n) (4.4mmol) was added dropwise at 0C. The mixture was stirred at room temperature overnight and then partitioned between ethyl acetate (EA, 20mL) and water (30mL). The organic layer was washed successively with water (3×30mL), saturated brine, and dried over anhydrous Na2SO4. The solvent was evaporated under vacuum and the residue was purified by column chromatography using petroleum ether(PE): EA (8:1) as eluent to give 2a-2n. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of compound MM2c-1 (40 g, 219 mmol) in tetrahydrofuran (400 mL) there was added dropwise sec-butyllithium (1.4 mol/L, 187 mL, 262 mmol) at -75 C. under a nitrogen gas atmosphere. The obtained solution was stirred for 2 hours and added dropwise to a solution of <strong>[54512-75-3]1-bromo-5-chloropentene</strong> (36.9 g, 198.7 mmol) in tetrahydrofuran (300 mL) at -75 C. The solution was raised to room temperature and stirred overnight, and then quenched with 2 mol/L hydrochloric acid (50 mL) The oil layer separated after standing was separated out from the aqueous layer and combined with the dichloromethane-extracted portion of the aqueous layer. The oil layer was concentrated under reduced pressure to remove the solvent and obtain an oil. The HPLC-area percent value of the obtained oil (MM2c-2, 84 g) measured under analysis conditions 2 was 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With caesium carbonate; In N,N-dimethyl-formamide; at 18℃; for 16h; | As shown in Figure 2B, 1 -Bromo-5-chloropentane (25 ml_, 35 mmol) was added to a stirred solution of 2-nitroimidazole (1) (200 mg, 1.75 mmol) in anhydrous DMF (30 ml_), and then caesium carbonate (1.14 g, 3.5 mmol) was added. The reaction was stirred at 18C for 16 h. The reaction mixture was partitioned between ethyl acetate (200 mL) and H20 (50 ml_) three times. The organic phase was washed with H20 and brine three times, followed by solvent evaporation. The crude product was purified by column chromatography, eluting with petroleum ether first, to extract the l-bromo-5-chloropentane, and then eluting with ethyl acetate, to give 1-(5-chloropentyl)-2-nitro-1H-imidazole (11) (75%) as an oil. 1H NMR (300 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 10h; | General procedure: To a solution of 14b (2.00 g, 16 mmol) in acetonitrile (100 ml) was added K2CO3 (5.20 g, 37.6 mmol) and 1-bromo-4-chlorobutane or <strong>[54512-75-3]1-bromo-5-chloropentane</strong> or 1-bromo-6-chlorohexane (24 mmol) and then stirred at 60 oC for 10 h. After cooling to ambient temperature, the reaction mixture was filtrated. The filtrate was condensed and the crude product was purified by flash chromatograph eluting with ethyl acetate/petroleum ether (1:15, v: v) to afford 17l-17n as light yellow oils. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | Compound 2 (518g, 1.88mol) was dissolved in 3.5L DMF necked flask fitted with a solvent, was added cesium carbonate (797.4g, 2.45mol), was added compound 3 (364.7g, 1.98mol), N2 protected, stirred at room temperature overnight.TLC showed disappearance of compound 2.The reaction solution was slowly added to 4L of ice water, extracted with ethyl acetate, the combined organic phases, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 711g of compound 4 as a yellow oil (yield: 100 %), the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate; In acetone; for 10h;Reflux; | General procedure: To a solution of 4-hydroxybenzoate (1.00g, 6.02mmol, 1.0 eq) in acetone (25mL), 1-bromo-2-chloroethane (1.29g, 9.036mmol, 1.5 eq) and K2CO3 (2.49g, 3.0 eq) were added. The reaction was refluxed and stirred for 10h, then it was hot filtered and concentrated under vacuum. The obtained crude 20 was purified via flash column chromatography, mobile phase toluene to give 1.60g of neat compound as colorless oil, yield 86%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.1% | Example 3 Preparation of (9E,11Z)-1-chloro-9,11-hexadecadiene (1-2: X=Cl) To a reactor were charged magnesium (13.1 g, 0.540 gram atom) and tetrahydrofuran (146 g), and the resulting mixture was stirred at 60 to 65 C. for 30 minutes. Then, (4E,6Z)-1-chloro-4,6-undecadiene (4-1: X1=Cl) (91.7 g, 0.491 mol) was added dropwise at 60 to 70 C., and then the resulting mixture was stirred at 70 to 75 C. for 6 hours to prepare (4E,6Z)-4,6-undecadienyl magnesium chloride. To another reactor were charged cuprous iodide (0.98 g, 0.0049 mol), triethyl phosphite (1.96 g, 0.0118 mol), <strong>[54512-75-3]1-bromo-5-chloropentane</strong> (105 g, 0.565 mol) and tetrahydrofuran (48.7 g), and the resulting mixture was stirred at 0 to 5 C. for 30 minutes. Then, the solution of (4E,6Z)-4,6-undecadienyl magnesium chloride in tetrahydrofuran as prepared above was added dropwise at 5 to 15 C. After completion of the dropwise addition, the resulting reaction mixture was stirred at 5 to 10 C. for 3 hours, and then the reaction was stopped by the addition of ammonium chloride (4.63 g), 20 wt % aqueous hydrogen chloride (7.46 g) and water (130 g) to the reaction mixture. After removal of the aqueous layer by liquid-liquid separation, the organic layer was concentrated by evaporating the solvent under vacuum, and the resulting concentrate was subjected to distillation under vacuum to obtain (9E,11Z)-1-chloro-9,11-hexadecadiene (1-2: X=Cl) (106 g, 0.412 mol) with a yield of 84.1%. |
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
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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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P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
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P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
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P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
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P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
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P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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