There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type | HazMat fee for 500 gram (Estimated) |
Excepted Quantity | USD 0.00 |
Limited Quantity | USD 15-60 |
Inaccessible (Haz class 6.1), Domestic | USD 80+ |
Inaccessible (Haz class 6.1), International | USD 150+ |
Accessible (Haz class 3, 4, 5 or 8), Domestic | USD 100+ |
Accessible (Haz class 3, 4, 5 or 8), International | USD 200+ |
Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 1462-37-9 | MDL No. : | MFCD01321307 |
Formula : | C9H11BrO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FWOHDAGPWDEWIB-UHFFFAOYSA-N |
M.W : | 215.09 | Pubchem ID : | 73833 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.33 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 49.98 |
TPSA : | 9.23 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.8 cm/s |
Log Po/w (iLOGP) : | 2.39 |
Log Po/w (XLOGP3) : | 2.55 |
Log Po/w (WLOGP) : | 2.45 |
Log Po/w (MLOGP) : | 2.64 |
Log Po/w (SILICOS-IT) : | 3.03 |
Consensus Log Po/w : | 2.61 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.92 |
Solubility : | 0.259 mg/ml ; 0.0012 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.39 |
Solubility : | 0.874 mg/ml ; 0.00406 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.21 |
Solubility : | 0.0132 mg/ml ; 0.0000615 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.76 |
Signal Word: | Danger | Class: | 9 |
Precautionary Statements: | P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P310-P362+P364-P403+P233-P501 | UN#: | 3334 |
Hazard Statements: | H315-H318-H335-H411 | Packing Group: | Ⅲ |
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 |
---|---|---|
56.2% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at -10 - 23℃; for 1 h; | Step 2: To a stirred solution of 2-(benzyloxy)ethanol (17.0 g, 1 1 1 .84 mmol) and PPh3 (35.0 g, 134.21 mmol) in DCM (170 mL) at -10 <C to -5 <C, NBS (23.88 g, 134.21 mmol) was added slowly in portions maintaining the temperature at -10 °C to -5 °C. After addition, the reaction mixture was allowed to stir at RT for 1 h until complete consumption starting material, as evidenced by TLC analysis. The reaction mixture was concentrated, the obtained crude compound was purified by CC using 5percent EtOAc in PE as eluent to afford ((2-bromoethoxy)methyl)benzene (13.5 g, 56.2percent) as pale yellow liquid (TLC solvent system: 30percent EtOAc in PE; Rf: 0.7). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With pyridine; triphenylphosphine In methanol; dichloromethane; ethyl acetate | A. To an ice-cooled mechanically stirred solution of 2-benzyloxyethanol (25 mL, 0.18 mole), triphenylphosphine (115.2 g, 0.44 mole) and pyridine (56.9 mL, 0.70 mole) in methylene chloride (1000 mL) was added, dropwise, carbon tetrabromide (61.3 g, 0.18 mole). The mixture was stirred overnight at room temperature. Methanol (130 mL) was then added and, after further stirring for 1 hour, the solvents were evaporated. The residue was triturated with hexane and the hexane solution was concentrated to yield an oil which was set aside. The residue remaining after trituration was taken up in ethyl acetate, washed with saturated sodium bicarbonate solution and brine and was concentrated to afford a brown oil. This was triturated with hexane. The resulting hexane solution was combined with the oil from the previous trituration and concentrated. The residue was chromatographed twice on silica gel eluding with hexane and then 5percent ethyl acetate/hexane to afford (2-bromoethoxymethyl)benzene as an oil (28.8 g, 76percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With carbon tetrabromide; triphenylphosphine In tetrahydrofuran at 0 - 20℃; | |
98% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at -78 - 20℃; Inert atmosphere; Darkness; | |
89% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; for 13h; |
89% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at -78 - 20℃; for 1h; | 1.ii ((2-bromoethoxy)methyl)benzene (Compound II) To a solution of NBS (17.7 g, 99.3 mol, 1 equiv.) in CH2CI2 (200 mL) was added dropwise a solution of PPfi3 (26.1 g, 99.3 mol, 1 equiv.) in CH2CI2 (140 mL) at -78 °C. The solution was stirred for 1 h, then a solution of 2-(benzyloxy)ethan-1-ol (14.4 g, 94.6 mmol, 1 equiv.) in ChhC OO mL) was added dropwise. The solution was allowed to return to rt and after one hour, the reaction was quenched using MeOH (10 mL) and PhMe (150 mL). The solution was evaporated, water was added and the aqeous phase was extracted three 24 times with EtOAc. The combined organics were washed with brine, dried over Na2S04 and evaporated. The residue was purified on silica gel column eluting with 10% EtOAc in cyclohexane to afford the desired product (18.1 g, 84.1 mol, 89%) as a light yellow oil.1H NMR (400 MHz, CDCh) d 7.41 - 7.28 (m, 5H), 4.60 (s, 2H), 3.80 (t, J = 6.2 Hz, 2H), 3.50 (t, J= 6.2 Hz, 2H); 13C NMR (101 MHz, CDCh) d 137.8, 128.5, 127.9, 127.8, 73.2, 70.0, 30.5; Rf : 0.85 (20% AcOEt in CyH) |
89% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at -78 - 20℃; for 1h; | |
89% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at -78 - 20℃; for 1h; | |
86% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane a) 1 h at r.t., b) 30 min at 35 deg C; | |
86% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane | |
77% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; for 12h; | |
56.2% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at -10 - 23℃; for 1h; | A118.2
Step 2: To a stirred solution of 2-(benzyloxy)ethanol (17.0 g, 1 1 1 .84 mmol) and PPh3 (35.0 g, 134.21 mmol) in DCM (170 mL) at -10 |
47.4% | With pyridine; phosphorus tribromide In benzene for 48h; Ambient temperature; | |
With bromine; triphenylphosphine | ||
With N-Bromosuccinimide; PS-PPh3 In dichloromethane at 20℃; for 16h; | ||
With N-Bromosuccinimide; triphenylphosphine In dichloromethane at -78℃; | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; dmap / chloroform / 5 h / 20 - 30 °C 2: lithium bromide / acetonitrile / 2.5 h / 70 - 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 68℃; for 12h; | 2-bromoethyl benzyl ether(Formula IV) (215g) was added to tetrahydrofuran (2L), and 1,8-diazabicycloundec-7-ene (DBU) (152g) was added at 68 C. After 12 hours of reaction, petroleum ether (2L) was added, filtered, and the filtrate was concentrated to dryness to obtain ethenyl benzyl ether (formula V) (130 g). Yield: 97%, purity: 99%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h; | To N-Boc-L-tyrosinemethyl ester 17 (2 g, 6.8 mmol) indry DMF (20 ml) was added 2 equiv. of 2-bromo-O-benzyl-ethanol (2.9 g, 13.6 mmol) along with 3 equiv. of K2CO3(2.8 g, 20.4 mmol) at room temperature for 1h gave the arylalkyl ether inquantitative yield. The reaction mixture was quenched with ice and extractedwith cold EtOAc (2 x 50 ml). The organic extracts were washed with cold brine(30 ml) and dried over anhydrous Na2SO4. The solvent wasremoved under reduced pressure. The resulting crude product was purified bysilica gel column chromatography using hexanes : EtOAc (9:1) as eluent to givethe 18 (2.5 g) in 87% yield.1H NMR (CDCl3300 MHz): δ7.4-7.28 (m, 5H), 7.02 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 4.99-4.91 (m, 0.5H),4.13 (t, J = 4.5Hz, 2H), 3.82 (t, J = 5.1Hz, 2H), 3.7 (s, 3H), 3.1-3.0 (m,2H), 1.42 (s, 9H). 13C NMR (CDCl3, 75 MHz) :δ172.4, 157.8, 155.0, 137.9, 130.2, 128.3, 128.0, 127.7, 127.6, 114.6, 79.8,73.3, 68.4, 67.3, 54.4, 52.1, 37.3, 28.2.IR (KBr): υ 2977, 2933, 2873, 1740,1695, 1613, 1585, 1512, 1481, 1392, 1368, 1330, 1248, 1220, 1163, 1072, 963,861, 772, 699 cm-1HRMS (ESI) m/zcalcd for C24H31NO6: 430.2208, found: 430.2224[M+H]+.[α]D25: -9.0(c = 1.0, CHCl3). |
70% | With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: ethyl cyclobutylcarboxylate With lithium diisopropyl amide In tetrahydrofuran at -78 - 0℃; for 0.25h; Stage #2: bromoethyl-2-benzyl ether In tetrahydrofuran at -78 - 20℃; for 16h; | |
Stage #1: ethyl cyclobutylcarboxylate With lithium diisopropyl amide In tetrahydrofuran at -78 - 0℃; for 0.333333h; Inert atmosphere; Stage #2: bromoethyl-2-benzyl ether In tetrahydrofuran at -78 - 21℃; for 16h; Inert atmosphere; | A Step A: Ethyl 1-(2-(benzyloxy)ethyl)cyclobutane-1-carboxylate To a solution of ethyl cyclobutanecarboxylate (5 g, 39.0 mmol) in THF (10 mL) was added LDA (21.46 mL, 42.9 mmol) in THF (40 mL) at -78 °C under N2. The mixture was stirred at -78 °C for 20 min under N2 at 0 °C. ((2-bromoethoxy)methyl)benzene (9.23 g, 42.9 mmol) in THF (10 mL) was added dropwise slowly at -78 °C under N2. Then the reaction mixture was gradually warmed to 21 °C for 16 h. The reaction was quenched by saturated NH4CI (50 mL), and extracted by EtOAc (2 x lOOmL). The organic layer was dried over Na2S04, then filtered and concentrated to give a residue which was purified by column chromatography (S1O2, PE: EtOAc = 50: 1 ~ 30: 1) to give the title compound. NMR (CD3OD, 400 MHz) 7.30-7.20 (m, 5H), 4.38 (s, 2H), 4.05-3.99 (m, 2H), 3.38 (m, J = 6.8 Hz, 2H), 2.39-2.33 (m, 2H), 2.07 (m, J = 6.7 Hz, 2H), 1.91-1.83 (m, 4H), 1.13 (m, J = 7.0 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With sodium hydride In N,N-dimethyl-formamide for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.33% | With potassium carbonate; potassium iodide; In butanone; for 16h;Heating / reflux; | 4-(2-Benzyloxyethoxy)-7H-furo[3,2-g][1]benzopyran-7-on 600 mg (2.967 mmol) of <strong>[486-60-2]5-hydroxypsoralen</strong> and 1.0 g (4.649 mmol) of benzyl-2-bromoethyl ether were refluxed in 30 ml of 2-butanone in the presence of an excess of anhydrous potassium carbonate (2.0 g) and catalytic amounts of potassium iodide for 16 hours. The progress of the reaction was monitored by thin layer chromatography. After 16 hours the reaction mixture was concentrated under reduced pressure. The oily residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and extracted with 3*50 ml of dichloromethane. The dichloromethane layer was extracted with 25 ml of 1% sodium hydroxide to separate the un-reacted <strong>[486-60-2]5-hydroxypsoralen</strong>. The dichloromethane layer was washed with 30 ml of 2% hydrochloric acid, dried over anhydrous sodium sulfate and concentrated. The resulting oily residue was dissolved in methanol, treated with charcoal and re-crystallized from 70% methanol. Yield: 123 mg (12.33%) Melting point: 90.9 C. 1H-NMR (500 MHz, CDCl3): delta [ppm]=8.19 (d, 1H, 3J=9.7 Hz, 3-H), 7.59 (d, 1H, 3J=2.2 Hz, 2'-H), 7.37 (m, 5H, 5-OCH2CH2OCH2C65), 7.19(s, 1H, 8-H), 6.95 (d, 1H, 3J=2.0 Hz, 3'-H), 6.25 (d, 1H, 3J=9.7 Hz, 4-H), 4.64 (s, 2H, 5-OCH2CH2OC2C6H5), 4.58 (t, 2H, 3J=4.62 Hz, 5-OC2CH2OCH2C6H5), 3.88 (t, 2H, 3J=4.56 Hz, 5-OCH2C2OCH2C6H5). MS (70 eV) m/z: 336 (35%, M+), 105 (5%), 91 (100%, [C7H7]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 3-methoxy-1H-pyridin-2-one With sodium hydride In hexane; N,N-dimethyl-formamide for 1h; cooling; Stage #2: bromoethyl-2-benzyl ether In hexane; N,N-dimethyl-formamide at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With caesium carbonate In N,N-dimethyl-formamide at 0 - 70℃; for 6h; | 2.a To a vigorously stirred solution of 15,2 g (100 mmol) 2-hydroxy-5-methoxy-benzaldehyde and 42.4 g (130 mmol) caesium carbonate in 350 ml DMF at 0°C was added 26.9 g (125 mmol) (2-Bromo-ethoxymethyl)-benzene (Adrich) in 50 ml DMF dropwisely. The reaction mixture was stirred vigorously at 70°C for 6h. The solvent was evaporated. 200 ml water and 200 ml ethyl acetate were added. The organic phase was separated. The aqueous phase was extracted three times with 100 ml ethyl acetate each. The combined organic phases were washed with 50 ml water and 50 ml brine. The organic phase was dried with magnesium sulphate and evaporated. The crude product was purified by silica column chromatography (gradient ethylacetate : hexane 1:3 → 1:2). The desired product 2a was obtained in 86% yield (24.6 g, 86 mmol) as yellow oil. MS-ESI: 287 (M+ + I , 100). Elementary analysis: C 71.31 % H 6.34% Determined: C 71.29% H 6.35% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: 77 percent / K2CO3; KI / dimethylformamide / 8 h / 90 °C 2.1: tetrahydrofuran / 8 h / 20 °C 2.2: p-ABSA; DBU / tetrahydrofuran / 8 h / 20 °C 2.3: 70 percent / aq. LiOH / tetrahydrofuran / 3 h / 20 °C 3.1: 88 percent / Rh2(OAc)4 / CH2Cl2 / 0.25 h / 20 °C 4.1: 74 percent / CF3COOH / 2 h / 40 - 50 °C 5.1: 78 percent / LiAlH4 / tetrahydrofuran / 4 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1.) NaH / 1.) 0 deg C; 2.) reflux, 5h 2: 84 percent / LiAlH4 / diethyl ether / Ambient temperature | ||
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0 - 20 °C 1.2: 20 °C / Reflux 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 12 h / Reflux | ||
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0 °C 1.2: 5 h / 75 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C |
Multi-step reaction with 2 steps 1: sodium hydride / tetrahydrofuran; mineral oil / 5 h / 90 °C / Inert atmosphere 2: lithium aluminium tetrahydride / tetrahydrofuran / 12 h / 20 °C / Inert atmosphere; Cooling with ice | ||
Multi-step reaction with 2 steps 1: sodium hydride / tetrahydrofuran / 5 h / 90 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 12 h / 20 °C / Cooling with ice | ||
Multi-step reaction with 2 steps 1: sodium methylate 2: lithium aluminium tetrahydride | ||
Multi-step reaction with 2 steps 1.1: sodium methylate / ethanol / 2 h / Reflux 1.2: Heating 2.1: lithium aluminium tetrahydride / toluene / 3 h / Reflux | ||
Multi-step reaction with 2 steps 1: sodium hydride / tetrahydrofuran 2: lithium aluminium tetrahydride / tetrahydrofuran | ||
Multi-step reaction with 2 steps 1: sodium hydride / tetrahydrofuran 2: lithium aluminium tetrahydride / tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hexamethylsilazane; In tetrahydrofuran; toluene; | Step 1: Using <strong>[4630-82-4]Methyl cyclohexanecarboxylate</strong> (5. 55g), KHMDS (100mi of a 0.5M solution in toluene), anhydrous THF (100ml) and benzyl 2-bromoethyl ether (10. 09g) and the procedure set forth previously (Example 108, Step1), the desired intermediate benzyl ether (6. 83g) was obtained after silica gel column chromatography (EtOAc: Hexanes: 15: 85). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With pyridine; triphenylphosphine In methanol; dichloromethane; ethyl acetate | 1.A 4-(1,3-dioxo-1,3-dihydrobenzo[f]isoindol-2-yl)-2-{1-›2-(4-methoxyphenyl)-1-(methylcarbamoyl)[ethylcarbamoyl]cyclohexylmethyl}butyric acid (diastereomer A) A. To an ice-cooled mechanically stirred solution of 2-benzyloxyethanol (25 mL, 0.18 mole), triphenylphosphine (115.2 g, 0.44 mole) and pyridine (56.9 mL, 0.70 mole) in methylene chloride (1000 mL) was added, dropwise, carbon tetrabromide (61.3 g, 0.18 mole). The mixture was stirred overnight at room temperature. Methanol (130 mL) was then added and, after further stirring for 1 hour, the solvents were evaporated. The residue was triturated with hexane and the hexane solution was concentrated to yield an oil which was set aside. The residue remaining after trituration was taken up in ethyl acetate, washed with saturated sodium bicarbonate solution and brine and was concentrated to afford a brown oil. This was triturated with hexane. The resulting hexane solution was combined with the oil from the previous trituration and concentrated. The residue was chromatographed twice on silica gel eluding with hexane and then 5% ethyl acetate/hexane to afford (2-bromoethoxymethyl)benzene as an oil (28.8 g, 76% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In acetonitrile for 24h; Heating / reflux; | 26.i Example 26; 5-{(li?)-2-[({l-[2-(Benzyloxy)ethyl]-4-hydroxypiperidin-4-yl}methyl)amino]-l- hydroxyethyl}-8-hydroxyquinoIin-2(lH)-one; i) l-(2-Benzyloxy-ethyl)-piperidin-4-one4-Piperidinone hydrate hydrochloride (0.714g), potassium iodide (50mg), benzyl 2- bromoethyl ether (0.8 g) were stirred and refluxed in MeCN (20 mL) in the presence of K2CO3 (1.28 g) for 24 h. The mixture was poured into water (150 mL) and extracted into EtOAc. Drying (MgSO4) and evaporation left an oil (880 mg) which was chromatographed on silica gel eluting with 3:2 EtOAc-isohexane to give the sub-titled compound as a colourless oil. Yield: 550 mg.IH NMR (300Mz, CDCl3) δ 7.40 - 7.32 (4H, m), 7.33 - 7.28 (IH, m), 4.57 (2H, s), 3.63 (2H, t), 2.82 (4H, t), 2.75 (2H, t), 2.47 (4H, t) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 20 - 80℃; | Reference example 14-1 Methyl 4-(2-benzyloxyethoxy)-2-chlorobenzoate To a stirred mixture of <strong>[104253-44-3]methyl 2-chloro-4-hydroxybenzoate</strong> (0.959 g), cesium carbonate (2.51 g), sodium iodide (0.847 g) and N,N-dimethylformamide (15 mL) was added (2-bromoethoxymethyl)-benzene (0.975 mL) at room temperature, and the reaction mixture was stirred at 80C overnight. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated. The organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and after filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by column chromatography on aminopropylsilylated silica gel (eluent:ethyl acetate-hexane) to give methyl 4-(2-benzyloxyethoxy)-2-chlorobenzoate (1.66 g). 1H-NMR(CDCl3) delta ppm: 3.80-3.85 (2H, m), 3.89 (3H, s), 4.15-4.25 (2H, m), 4.62 (2H, s), 6.84 (1H, dd, J=8.8, 2.5Hz), 7.00 (1H, d, J=2.5Hz), 7.25-7.40 (5H, m), 7.87 (1H, d, J=8.8Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In propyl alcohol for 4h; Reflux; | 21; 2 Example 21: Preparation of umeclidinium bromide The compound of formula I prepared in Example 16 (5.0 g, 0.017 mol), 50 mL of n-propanol, and benzyl-2-bromoethyl ether (4.28 g, 0.020 mmol) were added to the reaction flask, and stirred to dissolve.Warm to reflux for 4 hours.Cool to room temperature for crystallization, and filter to obtain the crude product. The crude product is recrystallized from a mixed solvent of acetonitrile and water to obtain 7.8 g of umeclidinium bromide in a yield of 90%. The chemical purity detected by HPLC is 99.70%. |
89% | In propyl alcohol at 82 - 87℃; for 4h; Reflux; | 6 Example 6: Preparation of 4-[hydroxy(diphenyl)methyll-1-{2-[(phenylmethyl)oxylethyl}-1-azoniabicyclo[2.2.2loctane bromide (Intermediate Grade) Example 6: Preparation of 4-[hydroxy(diphenyl)methyll-1-{2-[(phenylmethyl)oxylethyl}-1-azoniabicyclo[2.2.2loctane bromide (Intermediate Grade) A solution of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (445.6 g, for example, as preparaed by Example4) and benzyl 2-bromoethyl ether (360.9 g) in n-propanol (4456 ml) was refluxed for 3 hours. The solutionwas cooled to 87°C, seeded with umeclidinium bromide (Form 1)(0.44g), cooled further to 82°C and aged for1 hour. The slurry was cooled to 0-5°C over 2.5 hours and aged for 1 hour. The product was filtered andwashed with n-propanol (2 x 900 ml). Drying under vacuum at 50°C gave a white solid (690 g, 89%). El-MS m/z 428 (Mj Rt (4.7 mm).‘H NMR (400MHz; DMSO-d6): 7.57 (4H, d), 7.40-7.30 (9H, m), 7.26 (2H, t), 5.94 (1H, s), 4.52 (2H, s), 3.84 (2H, m), 3.49 (6H, t), 3.38 (2H, m), 2.02 (6H, t). |
87% | In propyl alcohol for 13h; Reflux; | 7 The WD1 (6.34g, 21 . 61mmol) and WD7 (5.14g, 23 . 90mmol) in n-propanol (25 ml) of the solution in a reflux 13 hours, for not less than 1 hour the solution is cooled to 50 - 55 °C, stirring 40 minutes, inducing crystallization. Not less than 1 hour the mixed cooling to the 17 - 23 °C, and stirring 60 minutes, continue to not less than 1 hours the mixture is cooled to 0 - 5 °C, thermal insulation 2 hours, filtering the product, and are used for propanol washing twice, in 50 °C lower vacuum drying to obtain the white solid bromine ammonium (9.56g, 87.0%): |
85.3% | In propyl alcohol for 4h; Reflux; | 3.2.2. General procedure for umeclidinium bromide (1) To a solution of 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol 6 (5.0 g, 17.1 mmol) in n-propanol was added 2-bromoethyl phenylmethyl ether (4.4 g, 20.5 mmol). The solution was refluxed for 4 h. The reaction was cooled down to room temperature and the solid separated out. This solid was filtered off and recrystallized from acetonitrile and water to give the title compound (7.4 g, 85.3%). 1H NMR (400 MHz, DMSO-d6) 7.58-7.52 (m, 4H), 7.37-7.28 (m, 9H), 7.27-7.20 (m, 2H), 5.92 (s, 1H), 4.50 (s, 2H), 3.86-3.78 (m, 2H), 3.49 (t, J = 7.2 Hz, 6H), 3.42-3.35 (m, 2H), 2.01 (t, J = 7.2 Hz, 6H). HRMS (ESI): m/z calcd. For C29H34NO2Br: 507.1733. Found: 428.2584 [M-Br]+. |
84% | In lithium hydroxide monohydrate for 24h; Reflux; | |
82.2% | In tetrahydrofuran at 60℃; for 24h; | 12 Example 12 Preparation of 4-[hydroxyl(diphenyl)methyl]-1 -[2(phenylmethyl)oxy]ethyl}-1 - azoniabicyclo[2.2.2] octane bromide (I) To a solution of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (IV, 0.20 g, 0.69 mmol) in THF (30.0 mL) was added ((2-bromoethoxy)methyl)benzene (0.16 mL, 1.03 mmol). The solution was stirred for 24h at 60°C. Then the solution was cooled down to 25°C and concentrated under vacuum, forming a white solid. The product was filtered and washed with ethyl acetate (5x20.0 mL) and n-hexane (5x20.0 mL) under vacuum. The white solid was then dried under vacuum (0.30 g, 82.2%). 4-[hydroxyl(diphenyl)methyl]-1 -[2(phenylmethyl)oxy]ethyl}-1 -azoniabicyclo[2.2.2] octane bromide (I): -N R (300 MHz, DMSO-de) δ 7.54 (d, J = 6.0 Hz, 4H), 7.35 - 7.20 (m, 11 H), 5.97 (s, 1 H), 4.49 (s, 2H), 3.81 (b, 2H), 3.49 - 3.46 (m, 6H), 3.31 (s, 2H), 1.99 (bt, J=6.0 Hz, 6H).MS (ESI) m/z calcd for -Hs-iNO,: 428, found 428 [M + H]+. |
75% | In propyl alcohol for 2h; Reflux; | 11 4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azabicyclo[2,2,2]octan-1-ium bromide Preparation of compound 5 Compound 4 (3.30g, 11.2mmol) and benzyl 2-bromoethyl ether (2.31ml, 14.6mmol) were refluxed in 50ml n-propanol for 2h, cooled at room temperature, a large amount of solid precipitated out and filtered, and the filter cake was recrystallized in acetonitrile Obtained 4.26 g of umeclidinium bromide with a yield of 75.00%. |
23.8% | In chloroform; acetonitrile at 60℃; for 16 - 24h; | 84.A; 84.B Example 84 Preparation of 4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane bromide Method A: 1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.020 g, 0.068 mmol) was diluted in CHCl3 (1.8 mL) and dispensed directly into a 1 dram vial containing 2-bromoethyl phenylmethyl ether (0.022 g, 0.102 mmol). CH3CN (1.2 mL) was added; the vial was fitted with a stirring bar and capped. The reaction was stirred and heated at 60° C. for 24 h. The contents of the vial were transferred (after removal of stirring bar) into a polypropylene tube and concentrated under Nitrogen. The crude product was collected on a polypropylene tube frit. Excess bromide was removed by washing the crude product with EtOAc (5*2 mL) and Hexane (5*2 mL). The product was then dried under vacuum to give the title compound (0.008 g, 23.8%). |
2.47 g | In chloroform; acetonitrile at 60℃; for 16h; | |
In chloroform; acetonitrile at 20℃; Reflux; | 2 Example 2: Quaternary salt formation To an intermediate (3) (1 equiv}. mixture of acetonitrile and chloroform (10 ml , 2 3) dud ((2hwmoethox methl)henzene 4) xas added Hi mixtute was stirred at room temperature for 35 to 48h. The solvents, acetonitrile and chloroform were evaporated, and the iesulting- residue was washed with diethyl ether to obtain a pure form of quatemary sah of(S) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: 5'-O-(4-4'-dimethoxytrityl)thymidine With sodium hydride In N,N-dimethyl-formamide for 0.166667h; Stage #2: bromoethyl-2-benzyl ether In N,N-dimethyl-formamide at 20℃; for 3h; | To a round bottom flask containing 50 (4 g, 7.35 mmol) in DMF (75 mL), NaH (1.76 g, 44.1 mmol) was added and stirred for 10 min. To this, BnO(CH2)2Br (5.8 mL, 34.75 mmol) was added and stirred for 3 hrs at RT. The reaction mixture was then poured into water (500 mL) and extracted with EtOAc (100x3 mL). The combined organics were washed with water (50 mL), brine (50 mL) and dried over MgSO4. Purification of the residue by silica gel flash chromatography gave the product (2.9 g, 58%) as yellow oil. This was dissolved in MeOH (50 mL), IM HCl (10 mL) was added and stirred for 2 hrs. After the reaction was done, solvent evaporated to dryness and repeatedly washed with Et2O:Hexanes (1:1) to give the compound 52 (100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium hydride In N,N-dimethyl-formamide at 0 - 60℃; | |
60% | Stage #1: ethyl phenylcyanoacetate With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: bromoethyl-2-benzyl ether In N,N-dimethyl-formamide at 60℃; | 8.B1 step Bl - Ethyl phenylcyanoacetate (22, 18.3 mL, 0.1054 mol, Ar1 = Ph) was added dropwise to a suspension of NaH (4.85 g, 0.1213 mol, 60% dispersion in oil) in DMF (200 mL) cooled to 0 C. The resulting mixture was stirred at 0 C for 30 min then benzyl 2-bromoethyl ether (20 mL, 0.1265 mmol) was added. The reaction mixture was then stirred at 60 C overnight, cooled to RT and partitioned between EtOAc and a saturated aqueous NH4Cl. The aqueous layer was thrice back- extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by Si?2 chromatography eluting with a EtOAc/hexane gradient (5 to 95% EtOAc) to afford 20 g (60%) of 24a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: Methyl 4-hydroxyphenylacetate With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere; Stage #2: bromoethyl-2-benzyl ether In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | Methyl 2-{4-[2-(benzyloxy)ethoxy]phenyl}acetate (8a; ZHAWOC7100): Under an argon atmosphere,methyl 2-(4-hydroxyphenyl)acetate (3.51 g, 21.14 mmol) and caesium carbonate (13.78 g, 42.28 mmol)were suspended in dimethylformamide (130 mL), the mixture was stirred at ambient temperaturefor 2 h. Benzyl-2-bromoethylether (5.00 g, 23.25 mmol) was added and it was stirred at ambienttemperature for further 12 h. Water (250 mL) and ethyl acetate (250 mL) were added and the resultingphases separated. The organic phase was dried over sodium sulfate and concentrated in vacuum.Purification by chromatography on silica gel (gradient: 0-100% ethyl acetate in cyclohexane) affordedthe title compound 8a as a white solid (5.30 g, 84% yield): 1H-NMR (DMSO-d6): δ = 7.38-7.26 (m, 5H),7.19-7.15 (m, 2H), 6.92-6.88 (m, 2H), 4.55 (s, 2H), 4.13-4.10 (m, 2H), 3.78-3.74 (m, 2H), 3.60 (s, 3H), 3.59(s, 2H) ppm. 13C-NMR (DMSO-d6): δ = 172.33, 157.88, 138.78, 130.83, 128.70, 127.99, 127.89, 126.83,114.83, 72.55, 68.71, 67.53, 52.06, 39.72 ppm. MS (m/z): 301 [M + H]+. |
75% | With caesium carbonate In N,N-dimethyl-formamide at 50℃; for 2h; | 192 To a solution of methyl 4-hydroxyphenylacetate (500 mg, 3.01 mmol) in N,N-dimethylformamide (2.0 ml), cesium carbonate (1.00 g, 3.07 mmol) and benzyl 2-bromoethyl ether (0.5 ml, 3.2 mmol) were added, and the mixture was stirred at 50°C for 2 hours and then cooled to room temperature. Distilled water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water, dried, and then concentrated under a reduced pressure. The residue was purified via flash chromatography (silica gel, n-hexane/ethyl acetate) to give a title compound (679 mg, 2.26 mmol, 75 %) as a colorless liquid. 1H-NMR (400 MHz, CDCl3) δ: 3.56 (2H, s), 3.68 (3H, s), 3.82 (2H, t, J = 4.88 Hz), 4.14 (2H, t, J = 4.88 Hz), 4.63 (2H, s), 6.88 (2H, d, J = 8.5 Hz), 7.18 (2H, d, J = 8.5 Hz), 7.27-7.39 (5H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1: To a solution of sodium hydride 60% in oil (5.93 g, 148 mmol) in DMSO (124 mL) previously stirred for 10 minutes at room temperature was added dropwise diethyl 2- isopropylmalonate (25.3 mL, 124 mmol). The reaction was allowed to stir for 1 hour at RT, then, ((2-bromoethoxy)methyl)benzene (19.55 mL, 124 mmol) was added, and the reaction mixture was allowed to stir at room temperature for about 15 hours and at 60C for 2 hours. The reaction mixture was quenched with saturated aqueous H4CI solution and extracted with Et20. The organic layer was washed with deionized water, dried over MgS04, filtered, and concentrated in vacuo. The crude residue obtained was purified using flash chromatography on silica gel (hexane/EtOAc: 90/10) to provide the product as oil. LC/MS: [(M+l)]+ = 337.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10.0 g of <strong>[40463-28-3]2-methoxy-5,7,8,9-tetrahydrobenzocyclohepten-6-one</strong> were dissolved in 180 ml of THF at 0 C. Addition of 6.02 g of potassium hydride was followed by warming to RT and stirring at RT for 2 h. The reaction mixture was again cooled to 0 C., and 8.30 ml of (2-bromoethoxymethyl)benzene were added dropwise. The mixture was warmed to RT and stirred at RT for 2 h. After addition of H2O, the reaction mixture was concentrated in vacuo, and the resulting residue was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered, concentrated and dried in vacuo. Purification by column chromatography on silica gel resulted in 5-(2-benzyloxyethyl)-<strong>[40463-28-3]2-methoxy-5,7,8,9-tetrahydrobenzocyclohepten-6-one</strong>: C21H24O3: MH+=325 m/e (6.5 g, as approx. 30% mixture with <strong>[40463-28-3]2-methoxy-5,7,8,9-tetrahydrobenzocyclohepten-6-one</strong>). This mixture was directly reacted further. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | To a stirred solution of <strong>[501-00-8]3-fluorophenylacetonitrile</strong> (1.0 ml, 8.6 mmol) in toluene (20 ml) at 60 0C was added 50% sodium amide ("NaNH2", 1.0 ml, 13 mmol) in one portion. The resulting solution was stirred for 10 min and then a solution of 2- benzyloxyethyl bromide (1.2 ml, 8.0 mmol) in toluene (20 ml) was added drop wise over a 0.5 h period. Upon completion of addition, the reaction mixture was stirred for an additional 1 h. At the conclusion of this period, the reaction mixture was cooled to ambient temperature and then quenched by adding a few drops of aq. IN hydrochloric EPO <DP n="94"/>acid ("HCl"). The reaction mixture was then diluted with EtOAc (100 ml) and washed with brine (20 ml x 2). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure to provide an oily mixture. The oily mixture was purified on silica eluting with 0 - 50% EtOAc/hexanes to provide Intermediate 30 (0.78 g, 2.9 mmol, 36%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 65℃; | 12 To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (6.84 g, 0.0455 mol) in anhydrous DMF (15 mL) was added NaH in mineral oil (60%, 2.23 g, 0.0558 mol). (2-Bromo-ethyoxymethyl)-benzene (10.0 g, 0.0465 mol) was added and the reaction was kept at 65° C. overnight. The reaction mixture was poured into water and extracted with dichloromethane to yield (4-(2-benzyloxy-ethoxy)-3,5-dimethylbenzaldehyde (10.5 g, 81%), which was used for next step reaction without further purification |
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 65℃; | 13 Example 13. Preparation of 2-(4-(2-(benzyloxy)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one [0196] A mixture of dimethyl acetone-1,3-dicarboxylate (200 g 1.148 mol), cyanamide (48.3 g, 1.148 mol), and Ni(acac)2 (14.75 g, 0.0574 mol) in dioxane (200 mL) was heated to reflux in a 1-L flask with a reflux condenser. The reaction mixture was heated at reflux for 16 hours and then cooled to room temperature. The precipitate was filtered off, and the solid was mixed with methanol (200 mL), stirred for 30 minutes, and filtered again to give methyl 2-amino-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (93 g, 44%). [0197] In a 1-L flask with a reflux condenser was added methyl 2-amino-4- hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (93.0 g, 0.505 mol) and POCI3 (425 ml_) and the reaction mixture was heated to reflux for 35 minutes. About 300 ml_ POCI3 was evaporated under vacuum. The residue was poured into ice and water (400 ml_), which was further neutralized with KOH to pH approximately 6-7. The precipitate was filtered off and extracted with ethyl acetate (2 x 300 ml_). The organic solution was concentrated and passed through a column, eluting with hexane:ethyl acetate 4:1 , to give methyl 2-amino-4,6-dichloropyridine-3-carboxylate (22.5 g, 20.1%).[0198] In a 500-mL flask with a reflux condenser was added methyl 2- amino-4.6-dichloropyridine-3-carboxylate (22.5 g, 0.101 mol) and 25 wt% sodium methoxide in methanol (88 mL, 0.407 mol), together with methanol (20 ml_). The mixture was heated to reflux for 5 hours, then cooled to room temperature. Acetic acid (15 mL) was added to the mixture and pH was adjusted to approximatley 7. Methanol was removed and the residue was poured into water (100 mL). The precipitated solid was filtered and further rinsed with water (3 * 200 mL) to give methyl 2-amino-4, 6-dimethoxypyridine-3-carboxylate (18.5 g, 86.4%).[0199] In a 500-mL flask with a reflux condenser was added methyl 2-amino-4,6-dimethoxypyridine-3-carboxylate (18.5 g, 0.0872 mol), potassium hydroxide (19.5 g, 0.349 mol) in water (80 mL) and ethanol (100 mL). The mixture was heated to 800C for 16 hours. The solvent was removed and aqueous HCI was used to adjust the pH to 6. The water was removed by freeze drying. The obtained solid was extracted with methanol to yield 2-amino-4,6-dimethoxy-nicotinic acid (17.2 g, 100%).[0200] 2-Amino-4,6-dimethoxy-nicotinic acid (17.2 g, 0.0872 mol) was added to THF (110 mL). 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (21.73 g, 0.113 mol), 1-hydroxybenzotriazole hydrate (12.96 g, 0.0959 mol) and 4-methyl morpholine (9.7 g, 0.0959 mol) were then added to the suspension. After stirring for 10 minutes at room temperature, 50% v/v ammonium hydroxide (18.3 g, 0.262 mol) was added. The reaction mixture was kept at room temperature for 16 hours. THF was removed and the residue was poured into cold water (100 mL). The precipitate was filtered off and washed with cold water to yield 2-amino-4,6-dimethoxy-nicotinamide (10.8 g, 62.3%). [0201] To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (6.84 g, 0.0455 mol) in anhydrous DMF (15 ml_) was added NaH in mineral oil (60%, 2.23 g, 0.0558 mol). (2-Bromo-ethyoxymethyl)-benzene (10.0 g, 0.0465 mol) was added and the reaction was kept at 65°C overnight. The reaction mixture was poured into water and extracted with dichloromethane to yield (4-(2-benzyloxy-ethoxy)-3,5-dimethylbenzaldehyde (10.5 g, 81%), which was used for next step reaction without further purification.[0202] To a solution of 2-amino-4,6-dimethoxy-nicotinamide (2.55 g, 12.9 mmol) and 4-(2-benzyloxy-ethoxy)-3,5-dimethylbenzaldehyde (3.68 g, 12.9 mmol) in N,N-dimethyl acetamide (20 ml_), were added NaHSO3 (2.52 g, 14.2 mmol) and p-TSA (1.98 g, 10.4 mmol). The reaction mixture was heated at 1500C for 14 hours. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and the solid was collected and further washed with methanol. The crude product was purified by column chromatography (silica gel 230-400 mesh; 2% methanol in CH2CI2 as eluent) to give the title compound as an off-white solid (0.88 g, 14.7%). MP 204.5-205.90C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.22% | With potassium carbonate; In acetonitrile; at 90℃; for 4h;Inert atmosphere; | To a stirred solution of 3,5-dimethyl lH-pyrazole-3,5-dicarboxylate (10 g, 54.30 mmol, 1 equiv.) and [(2-bromoethoxy)methyl] benzene (12.8 g, 59.51 mmol, 1.096 equiv.) in MeCN (200 mL) was added K2CO3 (11.3 g, 81.46 mmol, 1.5 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 90 C. The mixture was allowed to cool down to room temperature and then quenched with water. The resulting mixture was extracted with EtOAc and the combined organic layers were dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with PE/EtOAc (10: 1) to afford the title compound as a yellow oil in 96.22% yield. |
96.22% | With potassium carbonate; In acetonitrile; at 90℃; for 4h;Inert atmosphere; | To a stirred solution of 3, 5 -dimethyl lH-pyrazole-3,5-dicarboxylate (10 g, 54.30 mmol, 1 equiv.) and [(2-bromoethoxy)methyl]benzene (12.8 g, 59.51 mmol, 1.096 equiv.) in MeCN (200 mL) was added K2CO3 (11.3 g, 81.46 mmol, 1.5 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 90 C. The mixture was allowed to cool down to room temperature and then quenched with water. The resulting mixture was extracted with EtOAc and the combined organic layers were dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with PE/EtOAc (10: 1) to afford the title compound as a yellow oil in 96.22% yield. |
With potassium carbonate; In acetonitrile; at 85℃; for 1.5h; | First step When n is 1, The compound (89) (10.0 g) was dissolved in acetonitrile (200 ml), benzyl 2-bromoethyl ether (9.5 ml) and potassium carbonate (11.3 g) were added, and the mixture was stirred at 85C for 1.5 hours. After allowed to cool to room temperature, the solvent was evaporated under reduced pressure, and water was added. The mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to afford the compound (90) (17.0 g). 1H-NMR (CDCl3) delta: 3.84 (3H, d, J = 2.5 Hz), 3.86 (2H, t, J = 5.8 Hz), 3.94 (3H, s), 4.47 (2H, s), 4.90 (2H, t, J = 5.8 Hz), 7.19 -7.36 (6H m).When n is 2 The compound (89) (10.0 g) was dissolved in acetonitrile (100 ml), benzyl 3-bromopropyl ether (11.2 ml) and potassium carbonate (11.3 g) were added, and the mixture was stirred at 85C for 1.5 hours. After allowed to cool to room temperature, the solvent was evaporated under reduced pressure, and water was added. The mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to afford the compound (90) (18.0 g). 1H-NMR (CDCl3) delta: 2.16-2.23 (2H, m), 3.50 (2H, t, J = 6.1 Hz), 3.87 (3H, s), 3.93 (3H, s), 4.48 (2H, s), 4.77 (2H, t, J = 7.4 Hz), 7.26-7.35 (6H, m). |
With potassium carbonate; In acetonitrile; for 4.5h;Inert atmosphere; Reflux; | Step 2 To an acetonitrile (250 mL) solution of crude product 2 (24.5 g) obtained from Step 1, benzyl-2-bromoethylether A (27.3 mL, 173 mmol) and potassium carbonate (27.5 g, 199 mmol) were added, under nitrogen atmosphere, followed by heating at reflux for 4 hours and a half. The reaction solution was filtered and then the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed sequentially with water and saturated brine, then dried with anhydrous magnesium sulfate and concentrated in vacuo to yield crude product 3 (54.6 g). LC/MS (Method A): 1.97 min, [M+H]+ = 319. | |
With potassium carbonate; In acetonitrile; for 4.5h;Reflux; Inert atmosphere; | Step 2; To an acetonitrile (250 mL) solution of crude product 15 (24.5 g) obtained from Step 1, benzyl-2-bromoethyl ether A (27.3 mL, 173 mmol) and potassium carbonate (27.5 g, 199 mmol) were added. The solution was then heated at reflux under flow of nitrogen for 4 hours and a half. The reaction mixture was filtered and then the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed sequentially water and saturated brine, then dried over anhydrous magnesium sulfate and concentrated in vacuo to yield crude product 16 (54.6 g). LC/MS (Method A): 1.97 min, [M+H]+ = 319. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; In N,N-dimethyl-formamide; | Example 38d methyl 3-(2-(benzyloxy)ethoxy)-5-methoxybenzoate To a solution of <strong>[19520-74-2]methyl 3-hydroxy-5-methoxybenzoate</strong> (Chakraporty, T. K. and Reddy, G. V. J. Org. Chem., 57, 1992, 5462) (3.3 g, 18.1 mmol) in dry DMF (30 mL) was added K2CO3 (6.3 g, 45.3 mmol) at room temperature. The reaction was stirred at room temperature for 10 minutes then ((2-bromoethoxy)methyl)benzene (3.4 mL, 21.7 mmol) was added and the mixture stirred at 160 C. for 2 hrs. The reaction was cooled down to room temperature and diluted with EtOAc, washed with water and brine, and dried over MgSO4, filtered and concentrated to give the crude product (90%) which was used in the next step without further purification. |
90% | With potassium carbonate; In N,N-dimethyl-formamide; | Example 38d methyl 3-(2-(benzyloxy)ethoxy)-5-methoxybenzoate To a solution of <strong>[19520-74-2]methyl 3-hydroxy-5-methoxybenzoate</strong> (Chakraporty, T. K. and Reddy, G. V. J. Org. Chem., 57, 1992, 5462.) (3.3 g, 18.1 mmol) in dry DMF (30 mL) was added K2CO3 (6.3 g, 45.3 mmol) at room temperature. The reaction was stirred at room temperature for 10 minutes then ((2-bromoethoxy)methyl)benzene (3.4 mL, 21.7 mmol) was added and the mixture stirred at 160 C. for 2 hrs. The reaction was cooled down to room temperature and diluted with EtOAc, washed with water and brine, and dried over MgSO4, filtered and concentrated to give the crude product (90%) which was used in the next step without further purification. |
To a solution of <strong>[19520-74-2]methyl 3-hydroxy-5-methoxybenzoate</strong> (Chakraporty, T. K. and Reddy, G. V. J. Org. Chem, 57, 1992, 5462.) (3.3 g, 18.1 mmol) in dry DMF (30 mL) was added K2CO3 (6.3 g, 45.3 mmol) at room temperature. The reaction was stirred at room temperature for 10 minutes then ((2-bromoethoxy)methyl)benzene (3.4 mL, 21.7 mmol) was added and the mixture stirred at 160 C. for 2 hrs. The reaction was cooled down to room temperature and diluted with EtOAc, washed with water and brine, and dried over MgSO4, filtered and concentrated to give the crude product (90%) which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium iodide In acetone Reflux; | |
85% | With sodium iodide In acetone for 48h; Reflux; | |
73% | With sodium iodide In acetone for 3h; Reflux; |
60% | With sodium iodide In acetone for 16h; Reflux; | C2.1 Step 1. ((2-iodoethoxy)methyl)benzene (1-444) A mixture of ((2-bromoethoxy)methyl)benzene (cas: 1462-37-9, 10 g, 46.7 mmol) and sodium iodide (10.5 g, 1.5 equiv.) in acetone (250 mL) was heated to reflux for 16 hours. The reaction mixture was concentrated, and the residue was dissolved into EtOAc (200 mL) and diluted with water (100 mL). The organic layer was washed with brine (50 mL x 3), dried over anhydrous Na2S04 and concentrated to afford the crude product, which was purified by silica gel chromatography (Petroleum ether: EtOAc= 20: 1) to afford iodide I- 444 as a brown liquid (7 g, yield: 60%). |
With sodium iodide In acetone for 6h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetra-(n-butyl)ammonium iodide; sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 80℃; | A solution of 1.29 g of <strong>[95656-88-5]benzyl 3-hydroxypyrrolidine-1-carboxylate</strong> in 80 ml of THF is cooled to 0 C., 0.245 g of 60% NaH in oil is added and then 1.26 g of [(2-bromoethoxy)methyl]benzene and 0.108 g of tetrabutylammonium iodide and it is heated at 80 C. for 3 hours. 0.28 g of NaH and 0.40 g of [(2-bromoethoxy)methyl]benzene are added and it is heated at 80 C. for 2 hours. The reaction mixture is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with 0.1M HCl solution, with a saturated solution of NaHCO3, it is dried and the solvent is evaporated under vacuum. The product thus obtained is purified by preparative HPLC and 0.46 g of the expected compound is obtained. | |
With tetra-(n-butyl)ammonium iodide; sodium hydride; In tetrahydrofuran; oil; at 80℃; for 5h; | Preparation 7.92-(Pyrrolidin-3-yloxy)ethanol.Step 1 : Benzyl 3-(2-benzyloxyethoxy)pyrrolidine-1 -carboxylate.A solution of 1 .29 g of benzyl 3-hydroxypyrrolidine-1 -carboxylate in 80 ml of THF is cooled to 0C, 0.245 g of 60% NaH in oil is added and then 1 .26 g of [(2- bromoethoxy)methyl]benzene and 0.108 g of tetrabutylammonium iodide and it is heated at 80C for 3 hours. 0.28 g of NaH and 0.40 g of [(2- bromoethoxy)methyl]benzene are added and it is heated at 80C for 2 hours. The reaction mixture is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with 0.1 M HCI solution, with a saturated solution of NaHC03, it is dried and the solvent is evaporated under vacuum. The product thus obtained is purified by preparative HPLC and 0.46 g of the expected compound is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 6h; | Preparation 104-(2-Benzyloxy-ethoxy)-2-fluoro-benzonitrileScheme 2, Step Jc)A mixture of <strong>[82380-18-5]2-fluoro-4-hydroxy-benzonitrile</strong> (4.57 g, 33.3 mmol), K2C03 (13.8 g, 99.9 mmol) and benzyl 2-bromoethyl ether (5.79 ml, 36.6 mmol) in dry DMF (15 ml) was stirred at 70C for 6h. The reaction mixture was cooled to r.t., poured into 300 ml of water and extracted with EtOAc (2X100 ml). The organic layers were combined, dried over sodium sulfate and evaporated to dryness. The crude residue was purified by chromatography (Biotage SP1 Flash Purification system) on a silica gel cartridge (Biotage SNAP 100 g) eluting with a gradient from hexane / EtOAc 100:0 to 60:40 over 20 CV, affording 8.79 g (yield: 97%) of the title compound as a colourless oil.1H-NMR (400 MHz), delta (ppm, DMSO-de): 7.75 - 7.90 (m, 1 H) 7.26 - 7.38 (m, 5 H) 7.19 (dd, J=11.96, 2.44 Hz, 1 H) 6.99 (dd, J=8.79, 2.32 Hz, 1 H) 4.55 (s, 2 H) 4.22 - 4.34 (m, 2 H) 3.65 - 3.87 (m, 2 H)ESI (+) MS m/z 272 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With sodium hydride In N,N-dimethyl-formamide at 0 - 23℃; for 16h; | A118.4 Step 4: To a stirred solution of (4-bromo-2-fluorophenyl)methanol( 5 g, 24.509 mmol) in DMF (50 mL) at 0 °C NaH (60% suspension in mineral oil, 1 .96 g, 49.01 8 mmol) was added in portions. To the resulting suspension ((2-bromoethoxy)methyl)benzene (6.32 g, 29.41 mmol) was added at 0 °C, and the reaction mixture was allowed to stir at RT for 16 h until complete consumption of (4-bromo-2-fluorophenyl)methanol, as evidenced by TLC analysis. The reaction mixture was quenched with MeOH (5 mL), diluted with ice cold water (50 mL) and was extracted with EtOAc (3x 1 00 mL). The combined EtOAc layer was washed with water (50 mL), brine (50 mL), dried over anhydrous NaS04, filtered and concentrated. The obtained crude compound was purified by CC using 5% EtOAc in PE as eluent to afford 1 -((2-(benzyloxy)ethoxy)methyl)-4-bromo-2-fluorobenzene (4.2 g, 51 %) as yellow liquid (TLC solvent system: 30% EtOAc in PE; Rf: 0.6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 15.5h;Inert atmosphere; | Step A: Ethyl 1-(2-benzyloxyethyl)-2-methyl-pyrrole-3-carboxylate Ethyl 2-methyl-1H-pyrrole-3-carboxylate (10 g, 65.3 mmol) is dissolved in 100 mL of dimethylformamide under argon cooled to 0 C., and then 2-bromoethoxymethylbenzene (28.1 g, 130.6 mmol) is added all at once. The reaction mixture is placed under stirring. There is then added thereto, at 0 C., in three portions, NaH (1.72 g, 71.83 mmol) over a period of 15 minutes. The reaction mixture is stirred for 15 minutes at 0 C., and then for 15 hours at ambient temperature. It is then poured into an ice bath and then extracted 3 times with ethyl acetate. The organic phase is washed 3 times with saturated aqueous lithium chloride solution, dried over MgSO4, filtered and then evaporated to dryness. The residue thereby obtained is purified by chromatography over silica gel using petroleum ether and ethyl acetate as eluants. The expected compound is obtained in the form of an oil. 1H NMR (400 MHz, dmso-d6) delta ppm: 7.32 (t, 2H), 7.3 (t, 1H), 7.23 (d, 2H), 6.72 (d, 1H), 6.35 (d, 1H), 4.48 (s, 2H), 4.15 (quad., 2H), 4.1 (t, 2H), 3.7 (t, 2H), 2.45 (s, 3H), 1.25 (t, 3H) IR (ATR) cm-1: 1689 nu -C=O |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 2.25h; | A solution of <strong>[876379-22-5]benzyl (3S)-3-[(2-methylpropan-2-yl)oxycarbonylamino]piperidine-1-carboxylate</strong> (150 mg, 0.449 mmol) in DMF (0.9 ml) was cooled to 0C, followed by addition of sodium hydride (>60% oil, 26.9 mg, 0.673 mmol), and it was stirred for 15 minutes. 2-Bromoethoxymethylbenzene (0.213 ml, 1.35 mmol) was added, and the mixture was stirred at room temperature for two hours. Sodium hydride (>60% oil, 27 mg, 0.675 mmol) was added, followed by two hours of further stirring. Water was added to the reaction mixture, followed by extraction with a mixed solvent of ethyl acetate and hexane. The organic layer was washed three times with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane) to yield benzyl (3S)-3-[(2-methylpropan-2-yl)oxycarbonyl-(2-phenylmethoxyethyl)amino]piperidine-1-carboxylate (123 mg, 58%) as a colorless oily substance. LCMS: m/z 469 [M+H]+ HPLC retention time: 1.05 min (analysis condition F) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 16h; | A solution of <strong>[496-69-5]2-bromo-4-fluorophenol</strong> (1 .91 g, 10 mmol), ((2- bromoethoxy)methyl)benzene (2.6 g, 12 mmol) and K2C03 (2.76 g, 20 mmol) in 40 mL of DMF was stirred at 25 C for 16 h. Then the mixture was poured into 300 mL of water, extracted with ethyl acetate (200 mL), washed with water (200 mL) and brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated at 40 C under reduced pressure and the residue was purified by silica gel chromatography eluting with ethyl acetate and petroleum ether (1 :5) to afford the product (3.1 g, 95%) as a colorless oil. 1H NMR (300 MHz, DMSO-d6): delta 7.55 (dd, 1 H), 7.36-7.15 (m, 7H), 4.60 (s, 2H), 4.22-4.19 (m, 2H), 3.80- 3.77 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
760 mg | In N,N-dimethyl-formamide; at 60℃; for 2h;Inert atmosphere; | A mixture of <strong>[348-27-6]2-fluoro-4-hydroxybenzaldehyde</strong> (400mg) and benzyl 2-bromoethyl ether (0.677 mL) in DMF (10 mL) was stirred at 60C for 2h. The mixture was diluted at rt with water and DCM, the layers were separated and the aq. layer was washed with DCM. The combined org. layers were dried over MgS04, filtrated off and evaporated in vacuo. The crude was purified by CC (Buchi Sepacore, 20g cartridge, solvent A: Heptane, solvent B: EA, gradient in %B: 5 to 10, flow rate: 8 imL/min) to afford 760mg of a colourless oil. LC-MS (A) tR = 0.91 min; [M+H]+: 275.13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium carbonate; In acetone; for 15h;Reflux; | To a solution of <strong>[29415-97-2]methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong></strong> (1.00 g, 4.33 mmol) in acetone (50 mL) was added ((2-bromoethoxy) methyl) benzene (1.40 g, 6.49 mmol), and K2CO3 (0.90 g, 6.49 mmol). The mixture was heated to gentle reflux and stirred for 15 h. Acetone was removed under vacuum. The residue was dissolved into dichloromethane (150 mL), washed with NaOH (1 M) (50 mL × 2) and brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated to give the crude product as a pale yellow oil. To this residue was added hexane (50 mL) and stirred for 30 min. The resulting precipitate was filtered to give desired product 48 (0.80 g, 50% yield) as a white solid.1H NMR (500 MHz, CDCl3) delta ppm 8.24 (d, J = 2.5 Hz, 1H), 7.95 (dd, J = 2.0, 9.0 Hz, 1H), 7.38-7.28 (m, 5H), 6.91 (d, J = 8.5 Hz, 1H), 4.69 (s, 2H), 4.27(t, J = 4.5 Hz, 2H), 3.91 (t, J = 4.5 Hz, 2H), 3.89 (s, 3H).13C NMR (125 MHz, CDCl3): delta ppm 165.91, 159.12, 138.22, 135.09, 130.71, 128.68, 127.97, 127.93, 124.11, 112.31, 112.11, 73.79, 69.31, 68.26, 52.36. MS (ESI) m/z = 365.0 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In toluene; for 20h;Reflux; | A mixture of 2 g of <strong>[1708-40-3]cis-1,3-O-benzylideneglycerol</strong>, 3.51 ml of benzyl 2-bromoethyl ether, 1.25 g of KOH powder and 30 ml of toluene was stirred under reflux for about 20 hours. After cooling to room temperature, the insoluble material was removed by filtration and the filtrate concentrated. The residue was distilled at 140 C. under reduced pressure to remove benzyl 2-bromoethyl ether. After distillation, the residue dissolved in 20 ml of methanol containing 2 ml of conc.HCl and refluxed for 4 hours. 100 ml of water was added and the pH was adjusted to 5-6 with solid NaOH. NaCl was added to 10% and the product was extracted with dichloromethane (50 ml-3). The combined dichloromethane extracts were dried over Na2SO4, filtered and evaporated. The residue was dried under vacuum and the product was purified by chromatography on a silica gel column (80 g) eluted with ethyl acetate. The combined fractions were evaporated and dried under vacuum |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In N,N-dimethyl-formamide; at 60℃; for 12h; | To a mixture of ( (2-bromoethoxy) methyl) benzene (4.54 g 21.11 mmol) in DMF (40 mL) was added <strong>[286946-77-8]5-bromo-2-chloropyridin-3-ol</strong> (4 g 19.19 mmol) which was stirred at 60 for 12 hrs. The mixture was diluted with water (50 mL) . The mixture was extracted with EtOAc (50 mL x3) and concentrated to give crude product which was purified by column (PE/EtOAc 101 Rf 0.5) to give 3- (2- (benzyloxy) ethoxy) -5-bromo-2-chloropyridine (6.5 g 17.36 mmol 90yield) as a yellow solid1HNMR(400 MHz METHANOL-d4) delta 8.01 (s 1H) 7.73 (s 1H) 7.43-7.15 (m 5H) 4.61 (s 2H) 4.30-4.27 (m 2H) 3.91-3.82 (m 2H) ES-LCMS m/z 342.0 344.0 (M +H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.6 g | With caesium carbonate In acetonitrile at 80℃; for 16h; | 94.1 Step 1: Preparation of 1 -(2-benzyloxyethoxy)-5-bromo-2,3-difluoro-benzene A mixture of 5-bromo-2,3-difluoro-phenol (1.5 g, 7.21 mmol), 2- bromoethoxymethylbenzene (1.85 g, 8.65 mmol) and Cs2CO3 (3.53 g, 10.82 mmol) in MeCN(15 mL) was heated with stirring at 80 °C for 16 hrs. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with DCM (100 mL), washed with H20 (30 mL) and brine (30 mL), dried over anhydrous Na2504 and concentrated in vacuo to give 1-(2-benzyloxyethoxy)-5-bromo-2,3-difluoro-benzene (1.6 g), which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: 2-benzylamino-1H-benzimidazole With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.333333h; Inert atmosphere; Cooling with ice; Stage #2: bromoethyl-2-benzyl ether In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h; Inert atmosphere; Cooling with ice; | 5 EXAMPLE 5 N-Benzyl-1 -(2-(benzyloxy)eth-y1Hl)-1 -benzo[d|imidazol-2-amine (SC175) was prepared according to Route 3. To an ice-cooled solution of N-benzyl--11H -benzo[d|imidazol-2-amine (225 mg, 1 .01 mmol) in anhydrous DMF (5 imL) under argon was added NaH (60% w/w dispersion in mineral oil; 44.0 mg, 1 .10 mmol). After 20 min a solution of (2-bromoethyl) benzyl ether (240 mg, 1 .12 mmol) in DMF (5 imL) was added. The mixture was stirred and allowed to come ambient temperature over the course of 1 h. TLC analysis (100% EtOAc) indicated complete consumption of the benzimidazole substrate (Rf 0.30) and formation of a product (Rf 0.83). The reaction mixture was evaporated to dryness (70 °C, 12 mbar) and the resulting residue diluted with EtOAc (50 imL). This solution was then washed with brine (3 χ 20 imL), dried (Na2S04), filtered and evaporated to afford a viscous oil that was subjected to chromatography over a Strata SI-1 silica cartridge (20 g Giga Tube), eluting with 100% DCM followed by 100% EtOAc. Fractions containing the product were combined and evaporated to afford N-benzyl-1 -(2- (benzyloxy)ethyl-1)H-1 -benzo[d|imidazol-2-amine (308 mg, 861 μmοΙ; 86%) as a yellow oil: δΗ (300 MHz, CDCI3) 7.57 (1 H, ddd, J 7.7, 1 .2 and 0.6), 7.23-7.34 (8 H, m), 7.14- 7.20 (3 H, m), 7.09 (1 H, td, J 7.4 and 1 .2), 7.04 (1 H, ddd, J 7.7, 1 .6 and 0.7), 5.69 (1 H, br t, J 5.5), 4.63 (2 H, d, J 5.6), 4.45 (2 H, s), 4.12-4.17 (2 H, m), 3.81 -3.86 (2 H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | The indole (5) (0.5 g, 1.2 mmol) dissolved in THF (10 mL) wasadded to a slurry of NaH (0.1 g, 2.4 mmol) suspended in THF(20 mL) and was the suspension was allowed to stir for 10 min at 0 C under a nitrogen atmosphere, after which alkylbromide 59(0.24 g, 1.2 mmol) was added dropwise. The mixture was left tostir at 0 C for a further 30 min before being refluxed for 2 h. Themixture was then evaporated under reduced pressure till all theTHF had been removed. The brown oil was dissolved in EtOAc(20 mL) and washed with water (20 mL 2), brine (40 mL) anddried over Na2SO4. The solvent was evaporated in vacuo to afforda brown resin. Column chromatography over silica gel (DCM/EtOAc, gradient 4:1 to 2:1) afforded the product as a yellow solid(0.285 g, 43%); Mp 69-71 C. IR: mmax (KBr) cm1: 2935.8, 1614.5,1594.6, 1508.3, 1450.4, 1331.6, 1236.2, 1125.0, 998.4, 839.9. 1HNMR 400 MHz (CDCl3): d 7.24-7.57 (m, 10H, Ar-H), 7.13-7.19(m, 4H, Ar-H), 7.07 (d, J = 8.53 Hz, 2H, Ar-H), 6.99 (dd, J = 2.26,8.78 Hz, 1H, Ar-H), 6.51-6.80 (m, 5H, Ar-H), 5.17 (d, J = 12.05 Hz,4H, 2 CH2), 4.76 (s, 2H, CH2) 4.22 (t, J = 6.27 Hz, 2H, CH2), 3.82(t, J = 6.27 Hz, 2H, CH2), 2.20 (s, 3H, CH3). 13C NMR 100 MHz(CDCl3): d; 158.1 (COH), 152.7 (COH), 137.5, 137.4, 136.4, 131.5,128.5, 128.2, 128.1, 127.9, 127.8, 127.7, 127.4, 127.3, 127.2,127.1, 124.2 (CC), 114.2, 111.7, 110.0, 108.1 (CC), 102.0, 72.6(CH2), 70.6 (CH2), 69.6 (CH2), 68.3 (CH2), 43.3 (CH2), 8.9 (CH3).HRMS (EI): Found 554.2683 (M+H)+, C38H36NO3 requires 554.2695. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.0% | In 0 °C lower, the <strong>[7748-36-9]oxetan-3-ol</strong> 28a of (1g, 13.5mmol) N, N-dimethyl formamide (5 ml) solution is dropped to sodium hydride (0.65g, 27mmol, 60percent) of N, N-dimethyl formamide (5 ml) in suspension, stirring reaction reaction system for 15 minutes, then adding 2- animal pen oxygen radical bromine ethane (2.7g, 13mmol), heating the resulting mixture to room temperature, stirring for 6 hours. After the reaction, cooling to 0 °C, adding 25mL50percent quenching reaction aqueous solution of ammonium chloride, extracted with ethyl acetate (20 ml × 2). The combined organic phase is washed with a saturated salt water (30 ml), anhydrous sodium sulfate for drying, filtering, the filtrate concentrated under reduced pressure, the residue is purified by silica gel column chromatography [petroleum ether/ethyl acetate (v/v)=10/1)], to obtain a target compound 28b (1.2g, pale yellow liquid), yield: 43.0percent. | |
With lithium hexamethyldisilazane; In tetrahydrofuran; 1,4-dioxane; at 20℃; for 2h; | 1.0 M Lithium bis(trimethylsilyl)amide in THF (31.1 mL, 31.1 mmol, 1.2 equiv) was added dropwise at RT to a solution of <strong>[7748-36-9]oxetan-3-ol</strong> (1.92 g, 25.9 mmol) and ((2- bromoethoxy)methyl)benzene (6.13 g, 28.5 mmol, 1.1 equiv) in dioxane (15 mL). The mixture was stirred at ambient temperature for 2 hours. DMF (20 mL) was added along with sodium iodide, and the reaction mixture was stirred at ambient temperature overnight, then stirred at 70 °C for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and aqueous citric acid. The organic layer was washed twice with brine, then dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane and ethyl acetate) to give 3-(2-(benzyloxy)ethoxy)oxetane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3 g | With potassium carbonate In N,N-dimethyl-formamide at 40℃; | 8.1 8.1 4′-Hydroxy-biphenyl-4-carboxylic acid 2-benzyloxy-ethyl ester 4′-Hydroxy-biphenyl-4-carboxylic acid 2-benzyloxy-ethyl ester is prepared from commercially available 4′-hydroxy-biphenyl-4-carboxylic acid. To a solution of 4′-hydroxy-biphenyl-4-carboxylic acid (4.28 g, 20 mmol) in DMF (30 ml) is added potassium bicarbonate (2.40 g, 24.0 mmol). To the resulted suspension (2-bromo-ethoxymethyl)-benzene (6.45 g. 30.0 mmol) is added. The reaction mixture is stirred at 40° C. overnight. After cooling to room temperature, the reaction mixture is poured into 100 ml ice-water mixture and extracted with 60 ml MTBE. The organic phase is washed with sat. aq. NaCl solution and dried over sodium sulfate. After removing solvent in vacuo, the crude product is purified by recrystallization from heptane to afford 4′-hydroxybiphenyl-4-carboxylic acid 2-benzyloxy-ethyl ester as white crystals (3.0 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38 g | With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 3h; | To a solution of <strong>[188815-32-9]3-bromo-5-iodo-benzoic acid</strong> (25.00 g, 76.5 mmol) in DMF (70 ml) is added potassium carbonate (12.68 g, 91.8 mmol). To the resulted suspension (2-bromo-ethoxymethyl)-benzene (13.30 ml, 84.12 mmol) is added. The reaction mixture is stirred at 70 C. for 3 hours. After cooling to room temperature, the reaction mixture is added into 1000 ml water and extracted with 3×300 ml methyl-t-butyl ether (MTBE). The organic phase is washed with sat. aq. NaCl solution, dried over sodium sulfate. After removing solvent in vacuo, <strong>[188815-32-9]3-bromo-5-iodo-benzoic acid</strong> 2-benzyloxy-ethyl ester is obtained as brown oil (38.0 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.1 g | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 4h; | 4a 4a: 4a: Potassium carbonate (27.24 g, 197.1 mmol) is added to the solution of 4- bromo -isophthalic acid (21.00 g, 85.7 mmol) in DMF (200 ). (2- bromo- ethoxymethyl) - benzene (40.00 g, 186.00 mmol) is subsequently added to thegenerated suspension. At 70, thereaction mixture is stirred for 4 hours. After it is cooled to roomtemperature, the reaction mixture is added to 1,000 water and extracted with 3×300 methyltert-butyl ether (MTBE). The organic phase is washed with saturated aqueoussolution of NaCl and it is dried over sodium sulfate. After the solvent isremoved in a vacuum, the milky residue is refined by a column chromatographyabove the silica gel using heptane /ethyl acetate 3:2 as an eluent to produce 4a as colorless oil (36.1 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22.1 g | With caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 3h; | 6a: cesium carbonate (33.84 g,103.9 mmol) is added to the solution of 4- bromo -3- hydroxybenzoic acid (9.8g, 45.2 mmol) in DMF (140 ). (2- bromo - ethoxymethyl) - benzene (21.37 g, 99.3 mmol) isadded to the generated suspension. At 110, the reaction mixture is stirred for 3hours. After it is cooledto room temperature, the reaction mixture is added to 800 water and extracted with 3×250 ethyl acetate. The organic phaseis washed with a saturated aqueous solution of NaCl and it is dried over thesodium sulfate. After the solvent is removed in a vacuum, the milky residue isrefined by a column chromatography above the silica gel using heptane / ethyl acetate 7:3 as an eluent and 6a is obtainedas colorless oil (22.1 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
285 mg | To a stirred solution of benzo[cf]thiazol-5-amine (250 mg, 1.66 mmol) in acetonitrile (5 mL) were added the K2CO3 (276 mg, 2.00 mmol) in portion wise over the period of 10 min at 0 °C and the reaction mixture heated at 65 °C for 30 min. Then the temperature was brought to 30 °C, ((2-bromoethoxy)methyl)benzene (0.290 mL, 1.83 mmol) was added the resulting reaction mixture was refluxed for 24h. The reaction mixture was concentrated to dryness; the crude material dissolved in water (30 mL), washed with ether (2 x 30 mL) to remove organic impurities and the aqueous layer neutralized with 1.5N HC1 to pH 7 and extracted with ether (3 x 50 mL). The combined organic layer was washed with water (30 mL), brine (30 mL), dried (Na2S04), filtered, concentrated and the crude product was purified by silica gel chromatography (24 g Redisep® column, eluting with 30percent EtOAc in n-hexane) to afford the title compound (285 mg) as light brown solid. LC-MS Retention Time = 2.56 min; m/z = 285.2 [M+H]+. Column: KINETIX XB-C18, 75x3 mm, 2.6 muiotaeta; Flow rate: 1 mL/min; Mobile Phase A: 10 mM HCOONH4 in 98percent Water/ 2percent ACN; Mobile Phase B: 10 mM HCOONH4 in 2percent Water/ 98percent ACN; 20percent B to 100percent B over 4 min, then hold for 0.6 min at 100percent B with flow rate of 1.5 mL/min; Detection: UV at 220 nm. 1H NMR (400 MHZ, CDCl3) delta 8.90 (s, 1H), 7.70 (d, J=8 Hz, 1H), 7.36 -7.25 (m, 6H), 6.83 (dd, J=8.8, 2.0 Hz, 1H), 4.57 (s, 2H), 4.24 (br s, 1H), 3.76 (t, J=5.2 Hz, 2H), 3.42 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 2,3;4,5-di-O-isopropylidene-β-D-fructopyranose With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.333333h; Inert atmosphere; Stage #2: bromoethyl-2-benzyl ether In tetrahydrofuran; mineral oil at 20℃; for 168h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: 5-bromoindoline; bromoethyl-2-benzyl ether With potassium carbonate In N,N-dimethyl-formamide; acetonitrile at 100 - 120℃; for 2.25h; Microwave irradiation; Stage #2: With tetrabutyl ammonium fluoride at 120℃; for 1h; Microwave irradiation; | 1a.1 Step 1 5-bromo-2,3-dihydro-1 H-indole (700 mg, 3.53 mmol) was dissolved indry acetonitrile (10 mL). K2003 (1.47 g, 10.60 mmol) was added to the solutionfollowed by [(2-bromoethoxy)methyl]benzene (616 pL, 3.89 mmol). Themicrowave vial was sealed and the reaction was heated at 100°C for 15 mmunder microwave irradiation. After TLC, no conversion was observed. Thereaction was heated for additional 1 h at 120°C under microwave irradiation. TheTLC showed only starting material. Dry DMF (1 mL) was added and the reactionwas heated at 120°C for lh under microwave irradiation. After TLC, smallconversion was observed. A catalytic amount of tetrabutylammonium bromidewas added and the reaction was heated at 120°C for lh under microwaveirradiation. The TLC showed complete conversion. The solution wasdecomposed into water. The aqueous layer was extracted with EtOAc. Thecombined organic layers were dried over Mg504, filtered and the solution wasconcentrated under reduced pressure. The crude material was purified by silicagel column chromatography eluting with cyclohexane/EtOAc (90:10). Thedesired fractions were combined and concentrated to dryness to afford 1-[2-(benzyloxy)ethyl]-5-bromo-2,3-dihydro-1H-indole Ex.41a (620 mg, 53%) ascolourless oil. 1H NMR (300 MHz, DMSO-d6, d in ppm): 2.85 (t, 2H, J=8.5Hz),3.25 (t, 2H, J=5.6Hz), 3.41 (t, 2H, J=8.5Hz), 3.62 (t, 2H, J=5.6Hz), 4.50 (s, 2H),6.43 (d, 1H, J=8.3Hz), 7.07 (dd, 1H, J=8.3Hz, J=2.lHz), 7.13 (m, 1H), 7.22-7.35(m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | General procedure: alpha-Monosubstituted malonic diester 1 was synthesized according to the reported procedure as follows.3 tert-Butyl methyl malonate was purchased from Kanto Chemical, and used without further purification. The physical properties and spectral data of the new compounds, 2-(2-methylbenzyl)malonate 1g, 2-prenylmalonate 1l, and 2-(2-benzyloxyethyl)malonate 1o, are listed below. A 100 mL round-bottom flask equipped with a stirring bar was charged with <strong>[42726-73-8]tert-butyl methyl malonate</strong> (846 muL, 5.0 mmol) and DMF (10 mL). To the solution, sodium hydride (60percent oil suspension, 200 mg, 5.0 mmol) was added. The reaction was allowed to stir at 0 °C for 30 min. To the mixture, corresponding alkyl halide (5.0 mmol) was added at 0 °C and the mixture was stirred at room temperature for 24 h. To the reaction mixture, H2O was added, and the mixture was extracted with CH2Cl2 (3 * 20 mL), dried over MgSO4, and concentrated in vacuo. The remaining residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford the desired product 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide at 70℃; for 18h; | Intermediate 80a: (2R,3R)-3-(2-(Benzyloxy)ethoxy)butan-2-ol Intermediate 80a: (2R,3R)-3-(2-(Benzyloxy)ethoxy)butan-2-ol Tetrabutylammonium hydrogen sulfate (0.565 g, 1.66 mmol) was added in one portion to ((2-bromoethoxy)methyl)benzene (3.86 mL, 24.4 mmol) and (2R,3R)-butane-2,3-diol (1.01 mL, 11.1 mmol) in 50% sodium hydroxide solution (6 mL) at 20° C. The resulting mixture was stirred at 70° C. for 18 hours. The cooled reaction mixture was separated and the organics were washed with water (20 mL), saturated brine solution (20 mL), dried with MgSO4, filtered and evaporated to afford crude product as a yellow oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in heptane to afford the title compound (0.970 g, 39%) as a yellow oil; 1H NMR (400 MHz, CDCl3, 30° C.) 1.12 (6H, t), 3.15-3.25 (2H, m), 3.52-3.67 (4H, m), 3.8-3.87 (1H, m), 4.57 (2H, s), 7.26-7.39 (5H, m); m/z: ES+ [M+H]+ 225.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide; at 70℃; for 72h; | Intermediate 82a: (2S,3S)-3-(2-(Benzyloxy)ethoxy)butan-2-ol Tetrabutylammonium hydrogen sulfate (0.565 g, 1.66 mmol) was added in one portion to ((2-bromoethoxy)methyl)benzene (2.10 mL, 13.3 mmol) and <strong>[19132-06-0](2S,3S)-butane-2,3-diol</strong> (1.0 g, 11 mmol) in 50% sodium hydroxide solution (9 mL) at 20 C. under air. The resulting mixture was stirred at 70 C. for 3 days. The cooled reaction mixture was diluted with EtOAc (50 mL) separated and the organics were washed with water (20 mL), saturated brine solution (20 mL), dried (MgSO4), filtered and evaporated to afford crude product as a yellow oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane to afford the title compound (0.800 g, 32%) as a yellow oil; 1H NMR (400 MHz, CDCl3, 30 C.) 1.13 (6H, t), 3.16-3.24 (2H, m), 3.54-3.66 (4H, m), 3.8-3.88 (1H, m), 4.57 (2H, s), 7.27-7.4 (5H, m); m/z: ES+ [M+H]+225.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.87% | In water; acetonitrile for 3h; Reflux; | 7 Example 7 Preparation of 4-[hydroxy(diphenyl)methyl]-1-[2-[(benzyl)oxy]ethyl]-1-azabicyclo[2.2.2]octane bromide In a 250ml four-neck bottle, add (1-azabicyclo[2.2.2]octane-4-yl)(diphenyl)methanol sulfate (II) 4g, benzyl-2-bromoethyl ether (III) 2.64g, The reaction was refluxed for 3 h in acetonitrile/water (44 ml) (volume: acetonitrile: water = 1:2). Cooling down, crystallization, filtration, wash with acetonitrile: water = 1:3 (2 x 4 ml), dry, the white solid was 4.84 g, the yield was 92.87%, and the purity was 99.52%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.05% | In isopropyl alcohol for 2.5h; Reflux; | 9 Example 9 Preparation of 4-[hydroxy(diphenyl)methyl]-1-[2-[(benzyl)oxy]ethyl]-1-azabicyclo[2.2.2]octane bromide In a 250ml four-neck bottle, add (1-azabicyclo[2.2.2]octane-4-yl)(diphenyl)methanol formate (II) 4g, benzyl-2-bromoethyl ether (III) 2.80g, the reaction was refluxed in 44 ml of isopropanol for 2.5 h. Cool down, crystallize, filter, wash with isopropyl alcohol (2 × 4 ml), Dry, giving a white solid 5.31g, The yield was 92.05% and the purity was 99.48%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.85% | In 1,4-dioxane for 2h; Reflux; | 10 Example 10 Preparation of 4-[hydroxy(diphenyl)methyl]-1-[2-[(phenylmethyl)oxy]ethyl]-1-azabicyclo[2.2.2]octane bromide In a 250ml four-neck bottle, add (1-azabicyclo[2.2.2]octane-4-yl)(diphenyl)methanol nitrate (II) 4g, benzyl-2-bromoethyl ether (III) 2.66 g, the reaction was refluxed in 46 ml of dioxane for 2 h. Cooling down, crystallization, filtration, washing with dioxane (2 × 4 ml), Dry to give a white solid 5.19g. The yield was 90.85%, and the purity was 99.41%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.01% | In propan-1-ol; water for 2h; Reflux; | 5; 8 Example 5 Preparation of 4-[hydroxy(diphenyl)methyl]-1-[2-[(benzyl)oxy]ethyl]-1-azabicyclo[2.2.2]octane bromide In a 250ml four-neck bottle, Add (1-azabicyclo[2.2.2]octane-4-yl)(diphenyl)methanol hydrochloride (v) 4g, Benzyl-2-bromoethyl ether (III) 2.87 g, The reaction was refluxed for 2 h in n-propanol/water (32 ml total) (volume ratio n-propanol: water = 1:1). Cooling down, crystallization, filtration, washing with n-propanol: water = 1:1 (2 × 4 ml), Dry to give a white solid 5.80 g, The yield was 94.01% and the purity was 99.82%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.25% | In 2-methyltetrahydrofuran; water for 2.5h; Reflux; | 6 Example 6 Preparation of 4-[hydroxy(diphenyl)methyl]-1-[2-[(phenylmethyl)oxy]ethyl]-1-azabicyclo[2.2.2]octane bromide In a 250 ml four-necked flask, (1-azabicyclo[2.2.2]octane-4-yl)(diphenyl)methanol hydrobromide (II) 4 g, benzyl-2-bromide ether (III) 2.42g, in 2-methyltetrahydrofuran/water (40 ml total)(volume ratio 2-methyltetrahydrofuran: water = 1:4) reflux reaction for 2.5h, cooling down, crystallization, filtration, Wash with 2-methyltetrahydrofuran: water = 1:5 (2 x 4 ml), Drying gave 5.08 g of a white solid, yield 93.25%, purity 99.63%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.3% | With lithium bromide In acetonitrile at 70 - 80℃; for 2.5h; | 3; 6; 9 Preparation of 2-benzyloxybromoethane 38.6 g of ethyl 2-benzyloxy p-toluenesulfonate (0.126 mol), 32.83 g of lithium bromide (0.378 mol) and 386 mL of acetonitrile were added to a 1000 mL four-necked flask, and the reaction was carried out at 70 ° C - 80 ° C for 2.5 h. The completion of the reaction was monitored by TLC, 300 mL of water was added, the reaction solution was extracted with 200 mL of chloroform three times, the organic phase was combined, washed once with 200 mL of water, and the organic phase was evaporated to give 25.6 g of colorless transparent oil, yield: 94.3%; HPLC purity: 99.9%. The GC purity was 99.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.5% | With sodium bromide; In dimethyl sulfoxide; at 80 - 100℃; for 1h; | 37.5 g of Purified ethyl 2-benzyloxymethanesulfonate (0.1628 mol), 34.60 g of sodium bromide (0.3362 mol), and 257.5 mL of DMSO were added to a 1000 mL four-necked flask, and the mixture was kept at 80 C - 100 C for 1 h. The completion of the reaction was monitored by TLC, the heating was turned off, 300 mL of water was added, the reaction liquid was extracted three times with 200 mL of isopropyl ether, the organic phase was combined, washed once with 200 mL of water, and the organic phase was evaporated to give 32.7 g of colorless transparent oil, yield 93.5%. HPLC purity 99.7%, GC purity 99.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | To a solution of <strong>[109-11-5]morpholin-3-one</strong> (cas: 109-11-5, 2 g, 19.8 mmol) in anhydrous DMF (25 mL) was added NaH (60% dispersion in mineral oil, 1.98 g, 2.5 equiv.) at 0 C under N2. The reaction mixture was stirred for 30 minutes and then ((2- bromoethoxy)methyl)benzene (cas: 1462-37-9, 1.98 g, 2.5 equiv.) was added to the reaction mixture, which was then allowed to warm to ambient temperature. After 12 hours, analysis by LC-MS indicated completion of the reaction. The reaction mixture was quenched with H20 (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic extracts were concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (Petroleum ether: EtOAc = 1 :4) to provide morpholinone 1-339 as a pale oil (2.3 g, 49% yield). MS (ESI, pos. ion) m/z: 236(M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 2,2,2-trifluoroethoxyethanol With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere; Stage #2: bromoethyl-2-benzyl ether In N,N-dimethyl-formamide at 20℃; for 20h; | 35.1 Step 1: Synthesis of 2-[2-(2,2,2-trifluoroethoxy)ethoxy]ethoxymethylbenzene: To a slurry of sodium hydride (12.49 g, 520.5 mmol) in DMF (150 mL) was added 2-(2,2,2-trifluoroethoxy)ethanol (5 g, 34.7 mmol) in DMF (10 mL) under N2 atmosphere at 0 C. The mixture was stirred for 1h then 2-bromoethoxymethylbenzene (18.66 g, 86.75 mmol) was added dropwise. The mixture was stirred at room temperature for 20 h then quenched with water (50 mL) and extracted with EtOAc (80 mL). The organic layer was washed with water (50 mL x 3), brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography (PE:EA = 25:1 to 20:1) to provide 2-[2- (2,2,2-trifluoroethoxy)ethoxy]ethoxymethylbenzene (8.1 g, 84% yield) as a colorless liquid. 1H NMR (400MHz, CDCl3): d 7.37- 7.26 (m, 5H), 4.57 (s, 2H), 3.90 (q, J = 8.8 Hz, 2H), 3.79 (dd, J = 5.6, 3.5 Hz, 2H), 3.71- 3.61 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | To a solution of 2-(hydroxymethyl)propane-1,3-diol (2 g, 18.85 mmol) in THF (30 mL) at 0 C was added sodium hydride (9.05 g, 376.93 mmol). and the reaction heated to 50C for 1 h then cooled to rt.2-bromoethoxymethylbenzene (40.54 g, 188.47 mmol) was then added and the mixture heated to 65 oC for 17 h. The reaction was quenched with ice-water (50 mL), then this was extracted with EtOAc (50 mL × 2). The combined organicc layers were washed with brine (100 mL), dried, filtered, concentrated and then purified by silica gel chromatography (PE:EtOAc = 20:1) to afford 2-[3-(2-benzyloxyethoxy)-2-(2- benzyloxyethoxymethyl)propoxy]ethoxymethylbenzene (5 g, 52% yield) as a colorless liquid. ESI-MS (EI+, m/z): 509.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; In tetrahydrofuran; at -78 - 20℃; | A solution of I-16A (2.362 mL, 24.96 mmol) in THF (50 mL) was cooled to -78 C. To the chilled solution was added nBuLi (10.98 mL, 27.5 mmol) dropwise, followed by dropwise addition of benzyl-2-bromoethyl ether (3.99 mL, 25.2 mmol). The resulting solution was allowed to slowly warm to RT. Upon completion of the reaction, the mixture was cooled to 0 C. and quenched with H2O. The aqueous mixture was diluted with EtOAc. The phases were separated and the organic layer was washed with 2 M HCl and brine, dried over sodium sulfate, and concentrated under reduced pressure. The oily residue was purified by column chromatography (SiO2, 0-50% EtOAc/heptane) to afford I-16B as a colorless oil. LCMS m/z: 255 (M+1). 1H NMR (400 MHz, CDCl3) delta ppm 1.73-1.90 (m, 2H) 2.02-2.13 (m, 1H) 2.14-2.39 (m, 3H) 2.94-3.03 (m, 1H) 3.11-3.24 (m, 2H) 3.59-3.71 (m, 2H) 4.46-4.59 (m, 2H) 7.27-7.41 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.1% | To a solution of di -tert- butyl phosphonate (1.0 g, 5.1 mmol) in DMF (12 mL) was added NaH (0.62 g, 15 mmol, 60% purity) at 0 C. The mixture was stirred at 0 C for 10 min. Then ((2- bromoethoxy)methyl)benzene (1.7 g, 7.7 mmol, 1.2 mL) in DMF (12 mL) was added to the mixture. The mixture was stirred at 25 C for 16 hr. The reaction mixture was quenched by addition water 30 (mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (10 mL c 3), dried over NaiSCri, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, petroleum ethenethyl acetate, 100: 1 to 40: 1) to give 1 (0.98 g, 52.16% yield, 90% purity) as a white solid. LCMS: tR = 0.965 min., (ES+) m/z (M+H)+ = 329.2. - NMR (DMSO-i 400 MHz): d 7.34 - 7.27 (m, 5H), 4.47 (s, 2H), 3.62 - 3.53 (m, 2H), 1.99 - 1.90 (m, 2H), 1.41 - 1.39 (m, 18H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With salicylidene-4-anisidine; potassium methanolate; cobalt(II) chloride In N,N-dimethyl acetamide at 60℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | Stage #1: 1-diphenylmethyl-3-hydroxymethylazetidine With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Stage #2: bromoethyl-2-benzyl ether In tetrahydrofuran; mineral oil at 0 - 25℃; for 2h; | 24.1 Step 1: To a solution of (1-benzhydrylazetidin-3-yl)methanol (2.5 g, 9.9 mmol, 1 eq) in THF (25 mL) was added NaH (0.79 g, 20 mmol, 60% purity, 2 eq) in portions at 0° C. The mixture was stirred at 0° C. for 1 hr. Then 2-bromoethoxymethylbenzene (2.4 g, 11 mmol, 1.8 mL, 1.1 eq) was added dropwise at 0° C. The mixture was stirred at 25° C. for 2 hrs. The residue was quenched by water (20 mL), then extracted with EA (50 mL×3). The combined organic layers were washed with saturated brine (30 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=20/1 to 1/1) to give 24-1 (1.6 g, 41% yield) as a yellow oil. LCMS: (ES+) m/z (M+H)+=388.3. 1H NMR (400 MHz, CDCl3) δ 7.35-7.30 (m. 1H), 7.33 (d, J=7.2 Hz, 3H), 7.27 (br d, J=3.24 Hz, 3H), 7.23-7.16 (m, 5H), 7.15-7.07 (m, 3H), 4.50 (s, 2H), 4.29-4.25 (m, 1H), 3.58-3.51 (m, 6H), 3.28-3.16 (m, 2H), 2.90-2.76 (m, 2H), 2.73-2.59 (m, 1H). |
41% | Stage #1: 1-diphenylmethyl-3-hydroxymethylazetidine With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Stage #2: bromoethyl-2-benzyl ether In tetrahydrofuran; mineral oil at 0 - 25℃; for 2h; | 24.1 Step 1: To a solution of (1-benzhydrylazetidin-3-yl)methanol (2.5 g, 9.9 mmol, 1 eq) in THF (25 mL) was added NaH (0.79 g, 20 mmol, 60% purity, 2 eq) in portions at 0° C. The mixture was stirred at 0° C. for 1 hr. Then 2-bromoethoxymethylbenzene (2.4 g, 11 mmol, 1.8 mL, 1.1 eq) was added dropwise at 0° C. The mixture was stirred at 25° C. for 2 hrs. The residue was quenched by water (20 mL), then extracted with EA (50 mL×3). The combined organic layers were washed with saturated brine (30 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=20/1 to 1/1) to give 24-1 (1.6 g, 41% yield) as a yellow oil. LCMS: (ES+) m/z (M+H)+=388.3. 1H NMR (400 MHz, CDCl3) δ 7.35-7.30 (m. 1H), 7.33 (d, J=7.2 Hz, 3H), 7.27 (br d, J=3.24 Hz, 3H), 7.23-7.16 (m, 5H), 7.15-7.07 (m, 3H), 4.50 (s, 2H), 4.29-4.25 (m, 1H), 3.58-3.51 (m, 6H), 3.28-3.16 (m, 2H), 2.90-2.76 (m, 2H), 2.73-2.59 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11 g | With norborn-2-ene; bis(acetonitrile)palladium(II) chloride; Potassium bicarbonate In N,N-dimethyl acetamide at 100℃; for 24h; | 17 Reference Example 17: Ethyl 5-[2-(benzyloxy)ethyl]-1H-pyrrole-2-carboxylate Potassium bicarbonate (80 g), 2-bromoethoxymethylbenzene (, 57 g) and bis(acetonitrile)dichloropalladium (II) (3.5 g) were added to a solution of ethyl 1H-pyrrole-2-carboxylate (37 g) and norbornene (50 g) in DMA (265 mL), and the resultant solution was stirred at 100°C for 24 hours. Water was added to the reaction solution, the resultant solution was filtrated through Celite (trade name), and the filtrate was extracted with ethyl acetate. An organic layer was washed with water and saturated saline, and was then dried over sodium sulfate anhydride, and a dried product was concentrated under a reduced pressure. The resultant residue was purified by silica gel column chromatography (hexane : (ethyl acetate) = 8 : 1 →- 6 : 1). The resultant residue was dissolved in heptane, the resultant solution was washed with a methanol/water (1 : 1) mixed solution, a heptane layer was dried over sodium sulfate anhydride, and a dried product was concentrated under a reduced pressure. The resultant residue was purified by silica gel column chromatography (hexane : (ethyl acetate) = 99 : 1 →- 6 : 4). In this manner, the title compound (11 g) having the following physical property values was produced. TLC: Rf0.34 (hexane : (ethyl acetate) = 5 : 1); HPLC retention time (min): 1.04; MS(ESI, Pos.): 274(M+H)+. |
11 g | With norborn-2-ene; bis(acetonitrile)palladium(II) chloride; Potassium bicarbonate In N,N-dimethyl acetamide at 100℃; for 24h; | 17 Reference Example 17: Ethyl 5-[2-(benzyloxy)ethyl]-1H-pyrrole-2-carboxylate Potassium bicarbonate (80 g), 2-bromoethoxymethylbenzene (, 57 g) and bis(acetonitrile)dichloropalladium (II) (3.5 g) were added to a solution of ethyl 1H-pyrrole-2-carboxylate (37 g) and norbornene (50 g) in DMA (265 mL), and the resultant solution was stirred at 100°C for 24 hours. Water was added to the reaction solution, the resultant solution was filtrated through Celite (trade name), and the filtrate was extracted with ethyl acetate. An organic layer was washed with water and saturated saline, and was then dried over sodium sulfate anhydride, and a dried product was concentrated under a reduced pressure. The resultant residue was purified by silica gel column chromatography (hexane : (ethyl acetate) = 8 : 1 →- 6 : 1). The resultant residue was dissolved in heptane, the resultant solution was washed with a methanol/water (1 : 1) mixed solution, a heptane layer was dried over sodium sulfate anhydride, and a dried product was concentrated under a reduced pressure. The resultant residue was purified by silica gel column chromatography (hexane : (ethyl acetate) = 99 : 1 →- 6 : 4). In this manner, the title compound (11 g) having the following physical property values was produced. TLC: Rf0.34 (hexane : (ethyl acetate) = 5 : 1); HPLC retention time (min): 1.04; MS(ESI, Pos.): 274(M+H)+. |
[ 54314-84-0 ]
((3-Bromopropoxy)methyl)benzene
Similarity: 0.91
[ 91273-58-4 ]
((3-Bromo-2-methylpropoxy)methyl)benzene
Similarity: 0.85
[ 54314-84-0 ]
((3-Bromopropoxy)methyl)benzene
Similarity: 0.91
[ 91273-58-4 ]
((3-Bromo-2-methylpropoxy)methyl)benzene
Similarity: 0.85
[ 1402667-16-6 ]
4-Bromo-1,3-dihydroisobenzofuran
Similarity: 0.71
[ 54314-84-0 ]
((3-Bromopropoxy)methyl)benzene
Similarity: 0.91
[ 91273-58-4 ]
((3-Bromo-2-methylpropoxy)methyl)benzene
Similarity: 0.85
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :