Structure of 3-Chlorophenethyl bromide
CAS No.: 16799-05-6
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CAS No. : | 16799-05-6 |
Formula : | C8H8BrCl |
M.W : | 219.51 |
SMILES Code : | ClC1=CC(CCBr)=CC=C1 |
MDL No. : | MFCD04117465 |
InChI Key : | LKPWGXCMVLJRIK-UHFFFAOYSA-N |
Pubchem ID : | 140140 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H302-H318-H412 |
Precautionary Statements: | P264-P270-P273-P280-P301+P312+P330-P305+P351+P338+P310-P501 |
Class: | 9 |
UN#: | 3082 |
Packing Group: | Ⅲ |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 0.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 49.1 |
TPSA ? Topological Polar Surface Area: Calculated from |
0.0 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.56 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.17 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.28 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.98 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.8 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.36 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.51 |
Solubility | 0.0678 mg/ml ; 0.000309 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.84 |
Solubility | 0.317 mg/ml ; 0.00144 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.68 |
Solubility | 0.00457 mg/ml ; 0.0000208 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
Yes |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.39 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.68 |
* 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 |
---|---|---|
71% | With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃; for 5h; | Add triphenylphoshpine (3.90 g, 14.9 mmol) to a stirred solution of 3- chlorophenethyl alcohol (2.0 mL, 14.8 mmol), carbon tetrabromide (4.91 g, 14.8 mmol) and anhydrous dichloromethane (100 mL). Stir for 5 h under nitrogen at room temperature, and then wash with water (100 mL) and brine (100 mL). Dry the dichloromethane layer over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 100% hexanes to yield 2. 30 g (71%) of 1- (2- bromo-ethyl) -3-chloro-benzene: TLC: Rf in 100% hexanes : 0.27 ; LH NMR (CDC13) : 7.26-7. 11 (m, 3H), 7.09-7. 07 (m, 1H), 3.54 (t, 2H), 3.12 (t, 2H). |
64.6% | Production Example 5 Synthesis of 3-chlorophenethyl bromide 3-Chlorophenethyl alcohol (1.0 ml) was treated as in Production Example 1 to give the title compound (1.417 g) as a pale yellow oil (yield: 64.6%). 1H-NMR (400 MHz, CDCl3): delta(ppm) 3.14(2H, t, J=8.6Hz), 3.56(2H, t, J=8.6Hz), 7.11(1H, m), 7.21(1H, s), 7.45(2H, m). | |
With bromotriphenylphosphonium bromide; In acetonitrile; for 24h; | According to Scheme 11, a solution of 3-chlorophenethyl alcohol (5 g, 32 mmol) in 50 mL of dry MeCN was treated with dibromotriphenylphosphorane (13.54 g, 32 mmol) for 24 h. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was triturated with hexane and filtered. Evaporation of the solvent provided 6.5 g of 3-chlorophenethyl bromide |
22.4 g | With phosphorus tribromide; at 0 - 80℃; for 2.16667h; | Specific operations are as follows: 20g of m-chlorophenylacetic acid was added to 200ml of tetrahydrofuran, cooled to 0 C with stirring,At the beginning of batch addition of 8.9g of lithium aluminum hydride, the temperature was raised to 25 ~ 30 after the addition, the reaction 4h after the addition of water 300ml, dichloromethane400 ml of the mixture was separated, and the organic phase was added with 20 g of anhydrous sodium sulfate and dried under reduced pressure at 30-35 C. to obtain a pale yellow oil (S1-1): 18.3 g; Dropping phosphorus tribromide, the dropping temperature during the control at 0 ~ 10 C, dropping completed,After stirring for 10min, the temperature was raised to 75-80 C,After stirring for 2h, 30ml of saturated sodium bicarbonate solution, 200ml of ethyl acetate,The mixture was stirred for 20 minutes, and the filtrate was concentrated under reduced pressure at 40-45 C. to give a yellow liquid (intermediate S2): 22.4 g. Yield: 87.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dimethyl sulfoxide; at 100℃; | A solution of the bromide (6.5 g, 29.6 mmol) in 50 mL of dry DMSO containing NaCN (2.17 g, 44 mmol) was heated to 100 C. overnight. The reaction mixture was diluted with water and extracted with ether. The ether layer was washed with water, dried and the solvent was removed in vacuo. Chromatography (silica gel, hexane:ethyl acetate, 4:1) provided 3.7 g of nitrile 89 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃; for 18h;Product distribution / selectivity; | To a solution of 2- (3-chlorophenyl) ethanol (1.06 g, 6.0 mmol) in CH2CL2 (50 mL) at RT under nitrogen was added CBr4 (1.98 g, 5.8 mmol) and PPh3 (1.57 g, 5.8 mmol). After stirring at RT for 18 h the reaction mixture was concentrated and the residue diluted with ETZO (30 mL) resulting in precipitation of triphenylphosphine oxide. The ethereal solution was decanted, evaporated and purified via flash chromatography (silica, hexane) to provide 2- (3-CHLORO) phenylethyl bromide as a clear oil (57%). 1H NMR (400 MHz, DMSO-d6) 8 7.39-7. 22 (m, 3 H), 7.18-7. 09 (m, 1 H), 3.63-3. 51 (m, 2 H), 3.25-3. 17 (m, 2 H); 13C NMR (100.6 MHz, DMSO-d6) B 141.2, 134.6, 130.7, 129.3, 127.6, 127.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | a tert-Butyl {9-[2-(3-Chlorophenyl)ethyl]-4-methyl-1-methylthio-carbazol-2-yl}acetate Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and <strong>[16799-05-6]2-(3-chlorophenyl)ethyl bromide</strong> as starting materials, the title compound was obtained in a yield of 73% as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 16 Preparation of 1-(3-chlorophenyl)-3-(3-ethyl-4-pyridyl)-propane 1.13 g (9.35 mmol) of 3-ethyl-4-methylpyridine and 2.05 g (9.35 mmol) of <strong>[16799-05-6]m-chlorophenethyl bromide</strong> were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.23 g of the desired compound (yield: 50.7%). The resulting compound was identified as 1-(3-chlorophenyl)-3-(3-ethyl-4-pyridyl)-propane (hereinafter referred to as compound 16) by the following analytical results. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 3 Preparation of 1-(3-chlorophenyl)-3-(4-pyridyl)-butane 1.0 g (9.35 mmol) of 4-ethylpyridine and 2.05 g (9.35 mmol) of <strong>[16799-05-6]3-chlorophenethyl bromide</strong> were reacted in the same manner as in Example 1. The reaction product was purified to obtain 0.65 g of the desired compound (yield: 28.2%). The resulting compound was identified as 1-(3-chlorophenyl)-3-(4-pyridyl)-butane (hereinafter referred to as compound 3) by the following analytical results. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In ethanol; water; toluene; | The starting material can be manufactured, for example, as follows: 50 ml of ethanol, 50 g of potassium hydroxide and 8.8 ml of water are added to 39.8 g of 1-ethoxycarbonyl-4-[2-(3-chlorophenyl)-ethyl]-piperazine, obtainable by reacting 17.7 g of 1-ethoxycarbonylpiperazine and 24.6 g of 2-(3-chlorophenyl)-ethyl bromide while heating at 120-125 under nitrogen, and the whole is heated under reflux for 3 hours. The whole is then allowed to cool, is diluted with 300 ml of water and 300 ml of toluene and shaken thoroughly, and then the organic phase is separated off, washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to dryness by evaporation under reduced pressure. 1-[2-(3-chlorophenyl)-ethyl]piperazine is obtained and can be purified via the hydrochloride (m.p. 260) from which it can then be freed again by treatment with sodium hydroxide solution, separation with diethyl ether and evaporation of the latter. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | To a stirred solution of the product from step (c) above (30.0 mg, 0.05 mmol) in DMSO (0.5 mL) at RT was added NaBH4 (5.6 mg, 0.125 mmol). Once effervescence had ceased, the product from step (d) above was added (20 mg, 0.09 mmol). The reaction was complete after 18 h at RT. Purification was achieved using preparative HPLC to give a white solid (90%). H NMR (400 MHz, DMSO-d6) 8 7.38-7. 02 (m, 5 H), 6.08 (br s, 1 H), 4.29 (br s, 1 H), 3.60 (dd, 1 H), 3.49 (dd, 1 H), 3.26-3. 18 (m, 2 H), 2.92 (t, 2 H), 1.63-1. 55 (m, 1 H), 1.46- 1.31 (m, 2 H), 0.82 (d, 3 H), 0.81 (d, 3 H) ; MS (ESI+) M/Z 439 [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; at 80℃; for 4h; | Example 57; (3R)-1-[2-(3-Chlorophenyl)ethyl]-3-[2-piperidin-1-yl-2-(2-thienyl)propanoyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide (Isomer 1); (3R)-1-Azabicyclo[2.2.2]oct-3-yl 2-piperidin-1-yl-2-(2-thienyl)propanoate (Example 57b, Isomer 1, 0.5 g) in acetonitrile (3 mL) was treated with <strong>[16799-05-6]1-(2-bromoethyl)-3-chlorobenzene</strong> (0.35 g) and the mixture stirred and heated at 80 C. for 4 h. The mixture was concentrated to dryness, and the residue purified on silica gel eluting with 5% methanol in dichloromethane. The product from the column was triturated with ether to afford title compound as a colourless solid (160 mg).m/e 487 [M]30 1H NMR (400 MHz, DMSO) delta 7.51 (1H, dd), 7.48-7.44 (1H, m), 7.41-7.32 (2H, m), 7.32-7.27 (1H, m), 7.10 (1H, dd), 6.97 (1H, dd), 5.17-5.13 (1H, m), 3.95-3.88 (1H, m), 3.65-3.56 (1H, m), 3.50-3.40 (4H, m), 3.33-3.26 (1H, m), 3.24-3.16 (1H, m), 3.04-2.97 (2H, m), 2.51-2.42 (2H, m), 2.41-2.32 (2H, m), 2.31-2.23 (1H, m), 2.04-1.83 (4H, m), 1.62 (3H, s), 1.56-1.38 (6H, m).; Preparation of Example 57 Bromide; (3R)-1-[2-(3-Chlorophenyl)ethyl]-3-[2-piperidin-1-yl-2-(2-thienyl)propanoyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide (Isomer 1) Crystalline Form A; (3R)-1-Azabicyclo[2.2.2]oct-3-yl 2-piperidin-1-yl-2-(2-thienyl)propanoate (Example 57b, Isomer 1, 0.5 g) in acetonitrile (3 mL) was treated with <strong>[16799-05-6]1-(2-bromoethyl)-3-chlorobenzene</strong> (0.35 g) and the mixture stirred and heated at 80 C. for 4 h. The mixture was concentrated to dryness, and the residue purified on silica gel eluting with 5% methanol in dichloromethane. The product from the column was triturated with diethyl ether to afford title compound as a colourless solid (160 mg).m/e 487 [M]+ 1H NMR (400 MHz, DMSO) delta 7.51 (1H, dd), 7.48-7.44 (1H, m), 7.41-7.32 (2H, m), 7.32-7.27 (1H, m), 7.10 (1H, dd), 6.97 (1H, dd), 5.17-5.13 (1H, m), 3.95-3.88 (1H, m), 3.65-3.56 (1H, m), 3.50-3.40 (4H, m), 3.33-3.26 (1H, m), 3.24-3.16 (1H, m), 3.04-2.97 (2H, m), 2.51-2.42 (2H, m), 2.41-2.32 (2H, m), 2.31-2.23 (1H, m), 2.04-1.83 (4H, m), 1.62 (3H, s), 1.56-1.38 (6H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; for 2h;Reflux; | General procedure: Thiourea (7 mmol) was dissolved in 13.5 mL ethanol and the appropriate alkylbromide (7 mmol) was added. The mixture was stirred and heated under reflux for 2 h after which the reaction became homogenous. The reaction was allowed to cool to room temperature and the ethanol solvent was removed under reduced pressure. A solution of NaOH (10.5 mmol) in 8.75 mL water was added to the residue, and the reaction mixture was heated under reflux (120 C) for 2 h. The reaction was subsequently cooled to room temperature and aqueous H2SO4 (15%) was added. The mercaptan separated as oil droplets and was extracted to diethylether (30 mL). The organic phase was washed twice with water, dried over anhydrous Na2SO4 and removed under reduced pressure. This yielded the desired mercaptans which were used without further purification for the synthesis of 1, 3 and 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 1.5h;Microwave irradiation; | Example 15: Preparation of 8-[2-(3-chlorophenyl)ethyl]-3-methyl-4-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)-1-oxa-8-azaspiro[4.5]dec-3-en-2-one [Show Image] A mixture of 3-methyl-4-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)-1-oxa-8-azaspiro[4.5]dec-3-en-2-one dihydrochloride (Example 1, 200 mg, 0.40 mmol), anhydrous potassium carbonate (180 mg, 1.30 mmol) and 1-(2-bromo-ethyl)-3-chlorobenzene (0.07 mL, 0.22 mmol) in anhydrous N,N-dimethylformamide (3 mL) was heated at 90C for 1.5 hours under microwave irradiation. The reaction mixture was concentrated under vacuum. The residue was taken up in dichloromethane (20 mL), washed with water (20 mL) and brine (20 mL), dried (MgSO4) and concentrated under vacuum. After purification by flash chromatography (silica), the title compound was obtained as a white solid (44 mg, 20%). 1H NMR (DMSO-d6, 400 MHz): delta 7.46-7.42 (m, 1 H), 7.30-7.17 (m, 6H), 7.11 (d, J = 7.5 Hz, 1H), 3.79-3.78 (m, 1H), 3.68-3.67 (m, 1H), 3.55 (s, 3H), 3.55 (d, J = 4.9 Hz, 2H), 2.89-2.88 (m, 3H), 2.73-2.71 (m, 2H), 2.49-2.48 (m, 2H), 2.23-2.21 (m, 3H), 1.82-1.81 (m, 1H), 1.75 (s, 3H), 1.67-1.66 (m, 1H), 1.51-1.49 (d, J = 7.3 Hz, 1H). LCMS (Method D): Mass found (M+ 562), Rt (min): 4.75, Area (%): 99.6 (Max), 99.5 (254 nm). HPLC (Method A): Rt (min): 4.72, Area (%): 99.3 (Max), 99.2 (254 nm). |
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 1.5h;microwave irradiation; | Example 15: Preparation of 8-r2-(3-chlorophenyl)ethvn-3-methyl-4-((4-r3- (trifluoromethyl)phenvnpiperazin-1-yl}carbonyl)-1-oxa-8-azaspiror4.5ldec-3-en-2-oneA mixture of 3-methyl-4-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)-1 -oxa-8- azaspiro[4.5]dec-3-en-2-one dihydrochloride (Example 1 , 200 mg, 0.40 mmol), anhydrous potassium carbonate (180 mg, 1.30 mmol) and <strong>[16799-05-6]1-(2-bromo-ethyl)-3-chloro-benzene</strong> (0.07 mL, 0.22 mmol) in anhydrous Nu,Nu-dimethylformamide (3 mL) was heated at 90C for 1.5 hours under microwave irradiation. The reaction mixture was concentrated under vacuum. The residue was taken up in dichloromethane (20 mL), washed with water (20 mL) and brine (20 mL), dried (MgS04) and concentrated under vacuum. After purification by flash chromatography (silica), the title compound was obtained as a white solid. 1H NMR (DMSO-d6, 400 MHz): delta 7.46-7.42 (m, 1 H), 7.30-7.17 (m, 6H), 7.11 (d, J = 7.5 Hz, 1H), 3.79-3.78 (m, 1H), 3.68-3.67 (m, 1H), 3.55 (s, 3H), 3.55 (d, J = 4.9 Hz, 2H), 2.89-2.88 (m, 3H), 2.73-2.71 (m, 2H), 2.49-2.48 (m, 2H), 2.23-2.21 (m, 3H), 1.82-1.81 (m, 1 H), 1.75 (s, 3H), 1.67-1.66 (m, 1 H), 1.51-1.49 (d, J = 7.3 Hz, 1H). LCMS (Method D): Mass found (M+ 562), Rt (min): 4.75, Area (%): 99.6 (Max), 99.5 (254 nm). HPLC (Method A): Rt (min): 4.72, Area (%): 99.3 (Max), 99.2 (254 nm). |
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