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. : | 4360-63-8 | MDL No. : | MFCD00003214 |
Formula : | C4H7BrO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CKIIJIDEWWXQEA-UHFFFAOYSA-N |
M.W : | 167.00 | Pubchem ID : | 78068 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 29.27 |
TPSA : | 18.46 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -9.65 cm/s |
Log Po/w (iLOGP) : | 1.82 |
Log Po/w (XLOGP3) : | -3.29 |
Log Po/w (WLOGP) : | 0.75 |
Log Po/w (MLOGP) : | 0.43 |
Log Po/w (SILICOS-IT) : | 1.7 |
Consensus Log Po/w : | 0.28 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 3.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 1.26 |
Solubility : | 3060.0 mg/ml ; 18.3 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 3.48 |
Solubility : | 499000.0 mg/ml ; 2990.0 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -1.21 |
Solubility : | 10.3 mg/ml ; 0.0617 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.51 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P501-P210-P264-P280-P302+P352-P370+P378-P337+P313-P305+P351+P338-P362+P364-P332+P313-P403+P235 | UN#: | N/A |
Hazard Statements: | H315-H319-H227 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.2% | Stage #1: at 20℃; for 0.5 h; Large scale Stage #2: at 0 - 3℃; for 3.5 h; Large scale |
To a reaction vessel, 10.326kg (166.3mol) of ethylene glycol was added with 3.66 Kg (83.185mol) of freshly distilled acetaldehyde and stirred slowly at room temperature for 30 mins. 14.622 Kg (91.504 mol) of bromine was added dropwise, after the dropwise addition, the reaction was carried out at 0-3°C for 3.5h, and the fraction was distilled under reduced pressure. The fractions (3.6 kPa) and 11.002 Kg (65.883 mol) of 80-82 ° C were collected and identified as bromoacetaldehyde ethylene glycol, the yield is 79.2percent, the content is more than 95percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15 g | at 140℃; | Take 20g bromoacetaldehyde dimethyl acetal, 20g ethylene glycol, 3.5g potassium hydrogen sulfate, add 120mL anisole, the temperature increased to 140 ° C for the reaction until the bromoacetaldehyde dimethyl acetal basic reaction is complete, stop Heating, cooling, vacuum distillation, the intermediate bromoacetaldehyde ethylene glycol.The mass of bromoacetaldehyde ethylene glycol was 15 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tetrabutylammomium bromide; sodium hydroxide In acetone for 6.3 h; Reflux; Large scale | To the reaction tank, 13 Kg (72.16 mol) of theophylline, 8L of acetone, 5.77 Kg of sodium hydroxide (144.32 mol) and 0.7 Kg of tetrabutylammonium bromide (2.16 mol) were added to the reaction vessel. After stirring for 10 min, 14.47 Kg of bromoacetaldehyde ethylene acetal (86.64mmol) was added. The mixture was refluxed for 6.3h and the end point of the reaction was monitored by thin layer chromatography (acetone: dichloromethane = 3: 1). After the completion of the reaction, the solvent was distilled off under reduced pressure, washed three times with saturated brine, and the residue was recrystallized from absolute ethanol to give 17.28 kg of doxofylline (64.98 mol) in a yield of 90percent, the content is above 98.5percent. |
7 g | With sodium carbonate In N,N-dimethyl-formamide at 120℃; | take 10g of theophylline, 12g bromoacetaldehyde ethylene glycol, 7.5g anhydrous sodium carbonate, added to 80ml dimethylformamide, the oil bath heated to 120 , until the basic reaction of raw materials, stop heating, The filtrate was evaporated under reduced pressure and recrystallized from ethyl acetate to give the product Doxofylline.The quality of the product Doxofylline was 7 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | for 24 h; Heating / reflux | A solution of 2-bromomethyl-[1,3]dioxolane (60.0 mmol) and triphenylphosphine (60.0 mmol) in toluene (50 mL) was refluxed for 24 hours. A solid thus formed was filtered at room temperature, washed with diethyl ether and dried under reduced pressure to yield the title compound.Yield: 3.5 g (54percent)M.P: 194-195° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15 g | With potassium bisulfite; methoxybenzene; at 140℃; | Take 20g bromoacetaldehyde dimethyl acetal, 20g ethylene glycol, 3.5g potassium hydrogen sulfate, add 120mL anisole, the temperature increased to 140 C for the reaction until the bromoacetaldehyde dimethyl acetal basic reaction is complete, stop Heating, cooling, vacuum distillation, the intermediate bromoacetaldehyde ethylene glycol.The mass of bromoacetaldehyde ethylene glycol was 15 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
280 g | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h; | Step 1. Add 160 g of diethyl malonate to 500 mL of N,N-dimethylformamide.Then 276 g of potassium carbonate was added, followed by 167 g of <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> and the mixture was heated to 60 C for 3 hours. Add 100ml of water, extract with 300ml of methyl tert-butyl ether three times, each time 100ml, after the extraction is completed, the organic phase is combined, and the methyl tert-butyl ether is evaporated under reduced pressure at 60 C under a vacuum of 0.07 MPa to give the 280 g of intermediate 1 (See the H-NMR spectrum of Fig. 1 to see that the intermediate 1 is determined to be), and the chemical reaction equation involved is: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium azide; In dimethyl sulfoxide; at 70℃; | This azide was synthesized according to an adapted Alvarez1 method. Sodium azide (2.638 g, 40.585 mmol) was suspended in DMSO and <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> was added dropwise. When heated at 70 C the azide dissolved and the clear solution was stirred overnight at the mentioned temperature, under normal atmosphere. After cooling, the reaction mixture was poured in 300 mL of an ice/water mixture. The aqueous phase was extracted with dichloromethane (3 x 100 mL). The organic phase was concentrated to a volume of 50 mL and then washed with deionised water (3 x 50mL), dried on a WA filter and concentrated to give azide 1a. Colourless oil; 1.515 g, yield: 93%. 1H NMR (300 MHz, CDCl3): delta = 5.10 (t, 1H, J = 3.5 Hz; CH), 4.15-3.85 (m, 4H; CH2CH2), 3.33 ppm (d, 2H, J = 3.5 Hz; CH2N). The 1H NMR spectrum is in accordance with the one described in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | l -[(1.3-Dioxolan-2-yl)methyl]-lH-imidazole hydrochloride (QC-202). Under an atmosphere of N2, a mixture of imidazole (1.22 g, 18.00 mmol, 1.5 equiv) and sodium hydroxide (0.72 g, 18.00 mmol. 1.5 equiv) in DMSO (3 mL) was heated at 70-80 0C with stirring for 1 h. To this was slowly added a solution of 2-bromomethyl-l ,3-dioxolane (2.00 g, 12.00 mmol, 1 equiv) in DMSO (2 mL), and the mixture heated at 70-80 0C with stirring for 26 h. Heating was slightly elevaled and the DMSO was removed by blowing a stream of air over the reaction mixture. High-vacuum drying left a residue that was diluted with H2O; the mixture was extracted with benzene (3 x 25 mL) and also with EtOAc (2 x 25 mL). The combined organic extracts were dried (MgSO4) and concentrated to give the free base (814 mg, 5.28 mmol, 44%) as a golden oil. To a solution of this free base in hot 2-propanol (3 mL) was added a solution of 37% aqueous HCl (546 mg, 5.54 mmol, 1.05 equiv) in 2-propanol (3 mL). The solution was concentrated and dried under high vacuum. The residue was recrystallized from EtOH-2-propanol to give QC-202 (613 mg, 3.22 mmol, 27%) as a white solid: mp 173-174 0C; 1H NMR (400 MHz, CD3OD): delta 3.73-3.82 (m, 2 H), 3.85-3.93 (m, 2 H), 4.51 (d, J= 2.4 Hz, 2 H), 5.23 (t, J= 2.6 Hz, 1 H), 7.56 (s, 1 H), 7.61 (s, 1 H), 8.94 (s, 1 H); '3C NMR (100 MHz, CD3OD): delta 51.7, 66.6, 101.2, 120.4, 125.1 , 137.7; HRMS (EI) [M-HCl]+ Calcd. for C7Hi0N2O2: 154.0742. Found: 154.0742; Anal. Calcd. for C7HnClN2O2: C, 44.10, H, 5.82, N, 14.70. Found: C, 44.22, H, 5.60, N, 14.75. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With 18-crown-6 ether; In N,N-dimethyl-formamide; at 140℃; for 1.5h;Microwave irradiation; | Stage 1 - Synthesis of 2-[(2,6-dimethoxy-4-nitrophenoxy)methyl]-1 ,3-dioxolane; To a mixture of 2,5-dimethoxy-3-hydroxynitrobenzene (2.Og, 8.43mmol), 18-crown-6 (2.97g, 8.43mmol) and bromomethyl dioxolane (4.22g, 25.3mmol) was added DMF (60ml). The solution was then heated for a total of 1.5 h in the CEM microwave at <n="38"/>140 0C, initial voltage = 300W. The solution was poured on to a mixture of sat. NaHCO3 and Et2O, the layers separated and the aqueous extracted with Et2O. The combined organic layers were washed with water (4 x 50ml), 1 M HCI (50ml) and brine (2 x 50ml), dried over MgSO4 filtered and evaporated. Hexanes were added to the solid residue and the resulting suspension stirred for 1 h. The product was isolated by filtration and dried in a vacuum oven to afford the title compound (1.45g, 57%). m/z 286 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃; for 3.5h; | A 2-quinolone derivative (0.20 g, 0.75 mmol) obtained from 2-phenoxyaniline by the same processes as in Reference Examples 5, 6 and 7 was dissolved in N,N'-dimethylformamide (10 ml), and cesium carbonate (0.49 g, 1.51 mmol) and <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (0.16 ml, 1.51 mmol) were added thereto at room temperature. After the reaction solution was stirred at 80C for 1.5 hours, <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (0.20 ml, 1.89 mmol) and cesium carbonate (0.49 g, 1.51 mmol) were further added thereto. After 2 hours, water and ethyl acetate were added thereto to effect separation and extraction. The organic layer was washed with water, dried and then concentrated, and the residue was purified by the use of a silica gel column (ethyl acetate : hexane = 1 : 3 to 1 : 1) to obtain the desired compound (0.12 g, 44%) and its O-alkyl derivative (0.09 g, 34%). 1H-NMR (CDCl3) delta 3.80-3.93(m, 4H), 4.40(d, J=4.4Hz, 2H), 5.22(t, J=4.4Hz, 1H), 6.91(dd, J=8.8, 2.2Hz, 1H), 7.11-7.16(m, 3H), 7.26(m, 1H), 7.42-7.48(m, 2H), 7.65(d, J=8.8Hz, 1H), 8.34(s, 1H), 10.42(s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With lithium diisopropyl amide; In tetrahydrofuran; DMF (N,N-dimethyl-formamide); at 20℃; for 14h;Heating / reflux; | Scheme III, step B: To a stirred lithium diisopropyl amide solution (6.2 mmol in 10 mL of THF) was added deoxybenzoin (1.10 g, 5.6 mmol) in DMF (10 mL), at 0 C. under an atmosphere of nitrogen. The mixture was stirred at room temperature for 2 hours and then heated to reflux for 12 hours. The title compound was isolated by standard work-up and purified by purified by flash chromatography to provide 1.17 g (74%). |
57% | With potassium iodide; In tetrahydrofuran; N-methyl-acetamide; diethyl ether; water; ethyl acetate; | A. Preparation of 2-(2'-benzoyl-2'-phenyl)ethyl-1,3-dioxolane: To a stirred suspension of sodium hydride (61.25 mmol) in 150 mL of dimethylformamide at 0 C. under nitrogen was added dropwise a solution of deoxybenzoin (50.96 mmol) in 150 mL of tetrahydrofuran. The mixture was stirred at 0 C. for 1 hour and room temperature for 1 hour. To the mixture <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (60.55 mmol) and catalyst potassium iodide (6.0 mmol) were added. The mixture was heated to reflux for 13 hours. After cooling, diethyl ether (300 mL) and water (300 mL) were added. The organic layer was separated and washed with water (150 mL*2). Purification by flash chromatography using hexanes and ethyl acetate gave 2-(2'-benzoyl-2'-phenyl)ethyl-1,3-dioxolane (8.18 g; 57%). |
57% | With potassium iodide; In tetrahydrofuran; N-methyl-acetamide; diethyl ether; water; ethyl acetate; | A. Preparation of 2-(2'-benzoyl-2'-phenyl)ethyl-1,3-dioxolane: To a stirred suspension of sodium hydride (61.25 mmol) in 150 mL of dimethylformamide at 0 C. under nitrogen was added dropwise a solution of deoxybenzoin (50.96 mmol) in 150 mL of tetrahydrofuran. The mixture was stirred at 0 C. for 1 hour and room temperature for 1 hour. To the mixture <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (60.55 mmol) and catalyst potassium iodide (6.0 mmol) were added. The mixture was heated to reflux for 13 hours. After cooling, diethyl ether (300 mL) and water (300 mL) were added. The organic layer was separated and washed with water (150 mL*2). Purification by flash chromatography using hexanes and ethyl acetate gave 2-(2'-benzoyl-2'-phenyl)ethyl-1,3-dioxolane (8.18 g; 57%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With lithium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃; for 0.666667h; | 2-bromomethyl-1, 3-DIOXOLANE (12. 94ML, 125. 0MMOLE) was added to a solution of 1- INDANECARBONITRILE (16. 27g, 113.6mmole) in 100MUT of THF and cooled to 0 C. After the dropwise addition of 1 M LHMDS (125MI) the solution was stirred at 0 C for 20min then at room temperature for 20min. After the removal of solvent the residue was flashed of silica using 15% EtOAc and Hexanes to afford 19. 23g of 1- (1, 3-DIOXOLAN-2- YLMETHYL)-1-INDANECARBONITRILE (74% yield) as a thick oil. 1 H NMR (300 MHz, DMSO-D6) 8 ppm 2.0 (dd, J=14.3, 5.8 Hz, 1 H) 2.5 (m, 3 H) 3.0 (t, J=7. 2HZ, 2H) 3.8 (m, 2 H) 3.9 (m, 2 H) 5.0 (m, 1 H) 7.3 (m, 3H) 7.5 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 0 - 55℃; for 2h; | To 9 (1.03 g, 4.01 mmol) in anhydrous DMF (10 ML) at 0 C. was added <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (2.49 ML, 24.0 mmol), followed by Cs2CO3 (4.57 g, 14.0 mmol).The ice bath was removed and the reaction was heated for 2 h at 55 C. After cooling to ambient temperature the reaction mixture was diluted with distilled water (60 ML), then extracted with EtOAc (150 ML).The organic layer was washed with distilled water (3*60 ML), then concentrated and chromatographed on silica (10-50% CH2Cl2 in hexanes) to give 10 contaminated with <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong>.The <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> was removed by stirring the mixture in a 50 C. oil bath at reduced pressure (0.5 MmHg) for several hours to give 10 (1.06 g, 77%) as a colorless oil. 1H-NMR (CDCl3) delta 1.30 (t, J=7.3 Hz, 3H), 2.91 (q, J=7.3 Hz, 2H), 3.95-4.10 (m, 4H), 4.13 (d, J=3.9 Hz, 2H), 5.47 (t, J=3.9 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 7.20 (dd, J=8.3, 7.8 Hz, 1H), 7.36 (d, J=8.3 Hz, 1H); ESIMS m/e 79Br 343.0 and 81Br 345.0 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With ammonium chloride; zinc; In tetrahydrofuran; water; at 0℃; | The present example utilizes 2-bromomethyl-[1,3]dioxolane instead of allyl bromide, as used in Example 13, which eliminates the need for ozonolysis and subsequent reduction of intermediate 3. See J. S. Yadav, and C. Srinivas, Tetrahedron Lett. 2002, 43, 3837-3839; and T. Harada, and T. Mukaiyama, Chem. Lett. 1981, 1109-1110. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With triethylamine; In DMF (N,N-dimethyl-formamide); at 60℃; | REFERENTIAL EXAMPLE 1 4-[(5,6-Dimethoxy-1-indanon)-2-yl]methyl-1-(1,3-dioxolan-2-yl)methylpiperdine 4-[(5,6-Dimethoxy-1-indanon)-2-yl]methylpiperidine (1.00 g, 3.46 mmol) was dissolved in N,N-dimethylformamide (DMF) (10 ml), followed by adding triethylamine (0.96 ml, 6.92 mmol) and <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (0.43 ml, 4.13 mmol) thereto. The mixture was stirred overnight at 60 C. and then allowed to cool to room temperature. After adding water (50 ml) thereto, the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with brine (50 ml*2), dried (MgSO4) and then evaporated. The resulting residue was purified by silica gel column chromatography (NH-silica gel; n-hexane/ethyl acetate system) and then recrystallized from ethyl acetate/n-hexane, to give the title compound (0.48 g, yield: 37%) as white crystals. Melting point: 125-126 C. 1H-NMR (400Mz, CDCl3); delta (ppm) 1.27-1.56(4H, m), 1.64-1.78(2H, m), 1.91(1H, ddd, J=4Hz, J=8Hz, J=13.6Hz), 2.09(1H, ddt, J=2.8Hz, J=5.6Hz, J=11.6Hz), 2.58(2H, d, J=4.4Hz), 2.67-2.75(2H, m), 3.02(1H, bdt, J=3.2Hz, J=7.2Hz), 3.24(1H, dd, J=8Hz, J=17.6Hz), 3.84-4.00(4H, m), 3.91(3H, s) 3.97(3H, s), 5.02(1H, t, J=4.4Hz), 6.86(1H, s), 7.17(1H, s). ESI-MS: m/z=376(M+H+). |
With triethylamine; In N,N-dimethylformamide (DMF); water; | Referential Example 1 : 4-[(5,6-Dimethoxy-1-indanon)-2-yl]methyl-1 - (1,3-dioxolan-2-yl)methylpiperidine 4-[(5,6-Dimethoxy-1-indanon)-2-yl]methylpiperidine (1.00 g, 3.46 mmol) was dissolved in N,N-dimethylformamide (DMF) (10 ml), followed by adding triethylamine (0.96 ml, 6.92 mmol) and <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (0.43 ml, 4.13 mmol) thereto. The mixture was stirred overnight at 60C and then allowed to cool to room temperature. After adding water (50 ml) thereto, the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with brine(50mlx2), dried (MgSO4) and then evaporated. The resulting residue was purified by silica gel column chromatography (NH-silica gel; n-hexane/ethyl acetate system) and then recrystallized from ethyl acetate/n-hexane, to give the title compound (0.48 g, yield: 37%) as white crystals. Melting point: 125-126C. 1H-NMR (400Mz, CDCl3); delta(ppm) 1.27-1.56(4H,m), 1.64-1.78(2H,m), 1.91(1H,ddd,J=4Hz,J=8Hz,J=13.6Hz), 2.09(1H,ddt,J=2.8Hz,J=5.6Hz,J=11.6Hz), 2.58(2H,d,J=4.4Hz), 2.67-2.75(2H,m), 3.02(lH,bdt,J=3.2Hz,J=7.2Hz), 3.24(1H,dd,J=8Hz,J=17.6Hz), 3.84-4.00(4H,m), 3.91(3H,s), 3.97(3H,s), 5.02(1H,t,J=4.4Hz), 6.86(1H,s), 7.17(1H,s). ESI-MS: m/z=376(M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;18-crown-6 ether; potassium iodide; In acetonitrile; for 6h;Heating / reflux; | 1.88 g (8 mmol) of 6-hydroxy-5-trifluoromethyl-pyridine-2-carboxylic acid ethyl ester and 1.47 g (8 mmol) of 2-bromomethyl-1, 3-dioxolane in 30 ml of acetonitrile are heated at reflux temperature in the presence of 1.22 g (8.8 mmol) of potassium carbonate and catalytic amounts of potassium iodide and 18-crown-6 for 6 hours. The reaction mixture is then extracted with ethyl acetate against water and dilute acid at pH 3, dried over sodium sulfate and concentrated by evaporation. After chromatographic separation of the residue (eluant : ethyl acetate/hexane 15: 85), 6- ( [1, 3] dioxolan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2- carboxylic acid ethyl ester is obtained in the form of an oil ; 1H NMR (CDCI3) : 8.00, d, 1 H; 7.76, d, 1 H; 1.40, t, 1 H; 4.61, d, 2H; 4.42, q, 2H; 4.09, m, 2H; 3.93, m, 2H; 1.42, t, 3H. | |
With 18-crown-6 ether; potassium carbonate;potassium iodide; In acetonitrile; for 6h;Heating / reflux; | Example P8: Preparation of 6-([1,3]dioxolan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2- carboxylic acid ethyl ester:; 1.88 g (8 mmol) of 6-hydroxy-5-trifluoromethyl-pyridine-2-carboxylic acid ethyl ester and 1.47 g (8 mmol) of 2-bromomethyl-1, 3-dioxolane in 30 ml of acetonitrile are heated at reflux temperature in the presence of 1.22 g (8.8 mmol) of potassium carbonate and catalytic amounts of potassium iodide and 18-crown-6 for 6 hours. The reaction mixture is then extracted with ethyl acetate against water and dilute acid at pH 3, dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel (eluant : ethyl acetate/hexane 15: 85), yielding 6- ( [1, 3] dioxolan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2- carboxylic acid ethyl ester in the form of an oil ;'H NMR (CDCI3) : 8.00, d, 1 H; 7.76, d, 1 H; 5.40, t, 1H ; 4.61, d, 2H; 4.42, q, 2H; 4.09, m, 2H; 3.93, m, 2H; 1.42, t, 3H |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;sodium iodide; In dimethyl sulfoxide; at 95 - 120℃; for 6h; | 30 g of 2- (4-hydroxyphenylthio) pyridine, 27.1 g of 2-bromomethyl-1, 3-dioxolane, 31 g of potassium carbonate, and 120 mL of dimethylsulfoxide were mixed. A catalytic amount of sodium iodide was added to the mixture, and then the resultant mixture was caused to react on an oil bath of 95 to 100C temperature for 4 hours. Further, the temperature of the oil bath was raised to 120C, to continue the reaction for 2 hours. After the completion of the reaction, the system was cooled, and then 800 mL of water was added thereto, to precipitate a crystal. This crystal was collected by filtration, washed with water, and dried. Then, the dried crystal was dissolved into methanol, and subjected to natural filtration. Then, water was added to the filtrate, to precipitate a crystal. The resultant crystal was filtrated and washed with water, to yield 39 g of the target compound (yield 91.1 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; tetra-(n-butyl)ammonium iodide; In tetrahydrofuran; DMF (N,N-dimethyl-formamide); at 0 - 70℃; for 14h; | Reference Example 33 Under ice cooling, 18 ml of 2-(bromomethyl)-1,3-dioxolane, 9.87 g of potassium tert-butoxide and 6.57 g of tetrabutylammonium iodide were added to a solution of 14.0 g of <strong>[25504-47-6]methyl 2-oxopiperidine-4-carboxylate</strong> in 300 ml of tetrahydrofuran and 50 ml of dimethylformamide, and the mixture was stirred at 70°C for 14 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4.50 g of yellow oil. This oil was dissolved in 90 ml of tetrahydrofuran and 1.00 g of lithium borohydride was added to the solution under ice cooling, followed by stirring at ambient temperature for 4 hours. After saturated aqueous ammonium chloride solution was added to the reaction mixture, the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give 2.60 g of colorless oil. This oil was dissolved in 30 ml of dimethylsulfoxide, and 5.14 g of triethylamine and 4.04 g of sulfur trioxide-pyridine complex were added to the solution, followed by stirring at ambient temperature for 1.5 hour. The reaction mixture was poured into water, followed by extraction with chloroform. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 2.36 g of 1-(1,3-dioxolan-2-ylmethyl)-2-oxopiperidine-4-carbaldehyde. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium iodide; In tetrahydrofuran; water; | Preparation of 1-Cycloheptyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl)propan-1-one Scheme III, step B: 1-cycloheptyl-2-(2-pyridyl)ethan-1-one (5.0 g, 23.0 mmol, prepared above in Scheme III, step A) was dissolved in anhydrous THF (50 mL) was added dropwise to a suspension of sodium hydride (1.29 g of a 60% dispersion, 32.2 mmol) in anhydrous DMF cooled to 0 C. The reaction mixture was then warmed to room temperature and stirred for one hour. Then <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (3.58 mL, 34.5 mmol) and potassium iodide (0.5 g, crushed) were added and the reaction mixture was heated at reflux for 16 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography (ethyl acetate/hexane, 3/7, silica gel) to provide 1-cycloheptyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl)propan-1-one (4.52 g, 65%). |
65% | Scheme III, step B: 1-cycloheptyl-2-(2-pyridyl)ethan-1-one (5.0 g, 23.0 mmol, prepared above in Scheme III, step A) was dissolved in anhydrous THF (50 mL) was added dropwise to a suspension of sodium hydride (1.29 g of a 60% dispersion, 32.2 mmol) in anhydrous DMF cooled to 0 C. The reaction mixture was then warmed to room temperature and stirred for one hour. Then <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (3.58 mL, 34.5 mmol) and potassium iodide (0.5 g, crushed) were added and the reaction mixture was heated at reflux for 16 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography (ethyl acetate/hexane, 3/7, silica gel) to provide 1-cycloheptyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl) propan-1-one (4.52 g, 65%). | |
65% | Scheme III step B: 1-cycloheptyl-2-(2-pyridyl)ethan-1-one (5.0 g, 23.0 mmol, prepared above in Scheme III, step A) was dissolved in anhydrous THF (50 ML) was added dropwise to a suspension of sodium hydride (1.29 g of a 60% dispersion, 32.2 mmol) in anhydrous DMF cooled to 0 C. The reaction mixture was then warmed to room temperature and stirred for one hour.. Then <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (3.58 ML, 34.5 mmol) and potassium iodide (0.5 g, crushed) were added and the reaction mixture was heated at reflux for 16 hours.. water was added, and the mixture was extracted with ethyl acetate.. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.. The residue was purified by flash chromatography (ethyl acetate/hexane, 3/7, silica gel) to provide 1-cycloheptyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl)propan-1-one (4.52 g, 65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium iodide; In tetrahydrofuran; water; N,N-dimethyl-formamide; | Preparation of 1-Cyclopentyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl)propan-1-one Scheme III, step B: A 500 round bottom flask was charged with 60% sodium hydride (1.27 g, 31.9 mmol) and anhydrous DMF (50 mL). The suspension was cooled to 0 C. and 1-cyclopentyl-2-(2-pyridyl)ethan-1-one (4.30 g, 22.8 mmol, prepared above in Scheme III, step A) dissolved in anhydrous THF (50 mL) was added dropwise to the suspension. The reaction mixture was warmed to room temperature and stirred for one hour. Then <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (3.54 mL, 34.2 mmol) and potassium iodide (0.2 g, crushed) were added and the reaction mixture was heated at reflux for 6 hours. The reaction mixture was then cooled to room temperature and stirred for 16 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography (ethyl acetate:hexane, 3:7, silica gel) to provide 1-cyclopentyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl)propan-1-one (1.43 g). | |
Scheme III, step B: A 500 round bottom flask was charged with 60% sodium hydride (1.27 g, 31.9 mmol) and anhydrous DMF (50 mL). The suspension was cooled to 0 C. and 1-cyclopentyl-2-(2-pyridyl)ethan-1-one (4.30 g, 22.8 mmol, prepared above in Scheme III, step A) dissolved in anhydrous THF (50 mL) was added dropwise to the suspension. The reaction mixture was warmed to room temperature and stirred for one hour. Then <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (3.54 mL, 34.2 mmol) and potassium iodide (0.2 g, crushed) were added and the reaction mixture was heated at reflux for 6 hours. The reaction mixture was then cooled to room temperature and stirred for 16 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography (ethyl acetate:hexane, 3:7, silica gel) to provide 1-cyclopentyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl) propan-1-one (1.43 g). | ||
Scheme III, step B: A 500 round bottom flask was charged with 60% sodium hydride (1.27 g, 31.9 mmol) and anhydrous DMF (50 ML).. The suspension was cooled to 0 C. and 1-cyclopentyl-2-(2-pyridyl)ethan-1-one (4.30 g, 22.8 mmol, prepared above in Scheme III, step A) dissolved in anhydrous THF (50 ML) was added dropwise to the suspension.. The reaction mixture was warmed to room temperature and stirred for one hour.. Then <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (3.54 ML, 34.2 mmol) and potassium iodide (0.2 g, crushed) were added and the reaction mixture was heated at reflux for 6 hours.. The reaction mixture was then cooled to room temperature and stirred for 16 hours.. water was added, and the mixture was extracted with ethyl acetate.. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.. The residue was purified by flash chromatography (ethyl acetate:hexane, 3:7, silica gel) to provide 1-cyclopentyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl)propan-1-one (1.43 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | NaH (1.5 eq., 60 % dispersion in mineral oil) was added to a solution of methyl 2-bromo-3-cyclohexyl- lH-indole-6-carboxylate (prepared as described in published International patent application WO 2004/065367) in DMF (0.1 M) and once effervescence had subsided the solution was allowed to stir at RT for a further 30 min. 2-bromomethyl-l,3-dioxolane (4 eq.) and catalytic (0.025 eq) potassium iodide were then added and the mixture heated at 50 0C for 36 h. The reaction mixture was allowed to cool to RT, quenched with aqueous HCl (1 N) and extracted with EtOAc. The organics were washed with aqueous HCl (1 N) (3 x), water and brine before being dried over Na2SO4, filtered and the solvent evaporated in vacuo. Purification was by flash chromatography (10 % EtOAc/PE) to give a pale yellow solid that was triturated with Et2O/PE to afford the title compound as a white solid (69 %). 1H NMR (400 MHz, DMSO-fi?6, 300 K) delta 1.35-1.45 (m, 3H), 1.68-1.80 (m, 3H), 1.8-2.0 (m, 4H), 2.83-2.89 (m, IH), 3.78 (s, 4H), 3.88 (s, 3H), 4.45-4.46 (m, 2H), 5.13-5.18 (m, IH) 7.65 (d, J8.5, IH), 7.81 (d, J8.5, IH), 8.14 (s, IH); MS (ES+) m/z All (M+H)+, m/z AlA (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 90 - 120℃; for 2h; | Example 35; 2-amino-3-(l,3-dioxolan-2-ylmethyl)-6-[2-(lH-indol-6-yl)ethyl]pyrimidin-4(3H)-one; To a stirred solution of 2-amino-6-[2-(lH-indol-6-yl)ethyl]pyrimidin-4(3H)-one (1.0 g, 3.9 mmol) in DMF (20 mL) was added potassium carbonate (0.82 g, 5.91 mmol) and 2-bromomethyl-l,3-dioxolane (0.57 mL, 5.51 mmol). The reaction was heated at 90 C for 2 h, sodium iodide was added (0.03 g, 0.2 mmol), then the mixture was heated at 100C overnight. The temperature was increased to 11O0C for 2 h, then to 120 0C for another 2 h. The temperature was then lowered to 100 0C and additional portions of 2-bromomethy 1-1,3 -dioxolane (0.08 mL, 0.8 mmol) and potassium carbonate (0.11 g, 0.8 mmol) were added. The reaction was stirred 8 h, cooled, then concentrated under reduced pressure. It was diluted with ethyl acetate, washed with water, and again concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (60-100% ethyl acetate/hexanes, 1% methanol/ethyl acetate) to afford the desired product as a solid (370 mg, 28%). |
28% | Example 35: 2-amino-3-(l,3-dioxolan-2-ylmethyl)-6-[2-(lH-indol-6-yl)ethyl]pyrimidin-4(3H)-one; H To a stirred solution of 2-amino-6-[2-(lH-indol-6-yl)ethyl]pyrimidm-4(3H)-one (1.0 g, 3.9 mmol) inDMF (20 mL) was added potassium carbonate (0.82 g, 5.91 mmol) and 2-bromomethyl-l,3-dioxolane (0.57 mL, 5.51 mmol). The reaction was heated at 90 C for 2 h, sodium iodide was added (0.03 g, 0.2 mmol), then the mixture was heated at 100C overnight. The temperature was increased to 110C for 2 h, then to 120 C for another 2 h. The temperature was then lowered to 100 C and additional portions of 2-bromomethy 1-1,3-dioxolane (0.08 mL, 0.8 mmol) and potassium carbonate (0.11 g, 0.8 mmol) were added. The reaction was stirred 8 h, cooled, then concentrated under reduced pressure. It was diluted with ethyl acetate, washed with water, and again concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (60-100% ethyl acetate/hexanes, 1% methanol/ethyl acetate) to afford the desired product as a solid (370 mg, 28%). JH NMR (300 MHz, MeOH-d4) 8 7.42 (d, J = 8.1 Hz, 1H), 7.19 (s, 1H), 7.13 (d, J = 3.1 Hz, 1H), 6.87 (mult, 1H), 6.35 (mult, 1H), 5.66 (s, 1H), 5.09 (t, J = 4.1 Hz, 1H), 4.18 (d, J = 4.0 Hz, 2H), 3.93 (mult, 4H), 3.00 (t, J = 7.8 Hz, 2H), 2.69 (t, J = 7.8 Hz, 2H); m/z (APCI) 341 (MH+), HRMS (ES) M+, found 341.1595; Ci8H20N4O3 requires 341.1613. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With sodium hydroxide; tetra-(n-butyl)ammonium iodide; lithium hexamethyldisilazane; In tetrahydrofuran; water; | Preparation 10 4-Cyano-4-(3,4-difluorophenyl)-5-(1,3-dioxolan-2-yl)pentanoic acid A solution of <strong>[658-99-1]3,4-difluorobenzyl cyanide</strong> (20g, 0.13mol) in tetrahydrofuran (20ml) was added dropwise to a solution of lithium bis(trimethylsilyl)amide (1.0M, 144ml, 0,14mol) in tetrahydrofuran at 0C under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours, after which time it was cooled to 0C and a solution of 2-bromomethyl-1,3-dioxolane (15ml, 0.14mol) in tetrahydrofuran (15ml) was added followed by tetra-n-butylammonium iodide (2g, 5.4mmol). The reaction mixture was warmed to room temperature and stirred for 18 hours. A further portion of solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 144ml, 0.14mol) was added dropwise to the reaction mixture at 0C and then the mixture was allowed to warm to room temperature over 5 hours. The reaction mixture was cooled to 0C and a solution of ethyl 3-bromopropionate (18ml, 0.14mol) in tetrahydrofuran (20ml) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. A solution of sodium hydroxide (7.8g, 0.20mol) in water (50ml) was added to the crude reaction mixture at 0C and the mixture then allowed to warm to room temperature. The reaction mixture was stirred for 36 hours. The reaction mixture was partitioned between water and diethyl ether, the organic layer re-extracted with water and the combined aqueous layers were acidified to pH 1.0 with aqueous hydrochloric acid (2N). The aqueous layer was extracted with ethyl acetate (x2), dried over Na2SO4and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluding with a gradient system of dichloromethane gradually changing to dichloromethane: methanol: acetic acid (95: 5: 1, by volume) to afford the title compound as a brown oil (15.0g, 37%) which solidified on standing. 1H-NMR (CDCl3): delta = 7.30 (1H, m), 7.20 (2H, m), 4.80 (1H, m), 3.95 (2H, m), 3.80 (2H, m), 2.50 (2H, m), 2.30 (2H, m), 2.20 (2H, m). m/z: 312 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With tetra-(n-butyl)ammonium iodide; In tetrahydrofuran; mineral oil; | Preparation 3 2-(4-Chlorophenyl)-3-(1,3-dioxolan-2-yl)propanenitrile A solution of 4-chlorobenzyl cyanide (10g, 66.0mmol) in tetrahydrofuran (45ml) was added dropwise to a suspension of sodium hydride (60 % w/w dispersion in mineral oil, 2.91g, 72.75mmol) in tetrahydrofuran (25ml) at 0C. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. <strong>[4360-63-8]2-Bromomethyl-1,3-dioxolane</strong> (12.1g, 72.75mmol) was added to the reaction mixture followed by tetra-n-butylammonium iodide (1g, 2.7mmol) and then the mixture heated under reflux for 4 hours. The reaction mixture was cooled and partitioned between ethyl acetate and water, the layers were separated and aqueous layer re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluding with a solvent system of hexane: ethyl acetate (11: 2, by volume) to afford the title compound as an orange oil (11.6g, 74%). 1H-NMR (CDCl3): delta = 7.30 (4H, m), 4.95 (1H, m), 4.00 (3H, m), 3.95 (2H, m), 2.30 (1H, m), 2.10 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Methyl 2-bromo-3-cvclohexyl-l-(2,2-dimethoxyethyl)-lH-indole-6-carboxylate To a stirred solution of methyl 2-bromo-3-cyclohexyl-lH-indole-6-carboxylate (prepared as described in published International patent application WO2004/087714) (0.2 M, 1 eq.) in DMF at RT was added NaH (60 % dispersion in mineral oil, 1.75 eq). After 1 h, KI (8 mol %) and bromoacetaldehyde dimethyl acetal (2.5 eq) were added and the reaction heated at 80 0C for 17 h. After cooling to RT, the reaction was quenched by addition of aqueous HCl (IN) and extracted into EtOAc (x3). The combined organics were washed with HCl (IN), H2O and brine before being dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography (Biotage, 5-10 % EtOAc/PE gradient) gave the title compound as a white solid (79 %). 1H NMR (300 MHz, ^DMSO, 300 K) delta 1.51-1.68 (m, 3H), 1.67- 1.72 (m, 3H), 1.82-1.99 (m, 4H), 2.81-2.89 (m, IH), 3.25 (s, 6H), 3.87 (s, 3H), 4.35-4.37 (m, 2H), 4.46- EPO <DP n="16"/>4.59 (m, IH), 7.64 (d, J8.4, IH), 7.80 (d, J8.4, IH), 8.10 (s, IH); MS (ES+) m/z 446 (M+H)+, 448 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 24h; | Example 29; Preparation of 7-(4-chlorophenyl)-2-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)pyrrolo [1,2-a]pyrazin-1(2H)-one trifluoroacetic acid salt; Step A. Preparation of N-((1,3-dioxolan-2-yl)methyl)-3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)aniline; A suspension of K2CO3 (235 mg, 1.70 mmol), 2-(bromomethyl)-1,3-dioxolane (400 mg, 1.70 mmol), and 3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (3.0 g, 14.5 mmol), preparation described in Patent: WO2002/101146, in DMSO (17 mL) was heated at 80 C. for 24 hr. After removal of any precipitate by filtration, the filtrate was partitioned between EtOAc/H2O (100/20 mL). The organic layer was washed with brine and dried over MgSO4. After removal of the solvent under vacuum, the residue was chromatographed on silica gel using 0%-20% gradient EtOAc/Hexanes to elute the title compound as a yellow brownish oil (150 mg, 27%) MS (ESI) 323 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodium methylate; In methanol; afford_thioacetic acid S-[1,3]dioxolan-2-ylmethyl ester; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; N,N-dimethyl-formamide; | 1a) Sodium [1,3]dioxolan-2-ylmethanethiolate 2-Bromomethyl[1,3]dioxolane (101.2 g, 0.606 mol) and potassium thioacetate (70.8 g, 0.620 mol) in DMF (700 mL) are stirred at 40C for 70 h under nitrogen. The reaction mixture is cooled to RT and filtered. The solvent is removed under reduced pressure. The residue is dissolved in DCM (400 mL) and washed with water (400 mL). The aqueous layer is extracted again with DCM (2 x 100 mL). The combined extracts are washed with brine (2 x 100 mL), dried over sodium sulfate, and concentrated in vacuo. The residue is filtered through silica (eluent: DCM) and concentrated in vacuo to afford_thioacetic acid S-[1,3]dioxolan-2-ylmethyl ester (97.1 g, 99%). Thioacetic acid S-[1,3]dioxolan-2-ylmethyl ester (63.4 g, 0.391 mol) and sodium methoxide (21.6 g, 0.400 mol) in anhydrous methanol (1 L) are stirred at RT for 12 h. The solvent is removed under reduced pressure to yield the product as a yellow solid (37.5 g, 67%): 1H NMR as expected. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To 5 mL of an N,N-dimethylformamide solution containing 0.50 g of <strong>[64495-55-2]6-nitroquinolin-2(1H)-one</strong>, 0.32 g of 60% sodium hydride was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. Thereto was added 2.2 g of 2-bromomethyl-1,3-dioxolane, and the mixture was stirred at 90C for 36 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and 1 mol/L hydrochloric acid were added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Chromatorex-NH, manufactured by Fuji Silysia Chemical Ltd., eluent; hexane : ethyl acetate = 4 : 1] to obtain 0.24 g of a pale yellow solid, 1-(1,3-dioxolan-2-ylmethyl)-<strong>[64495-55-2]6-nitroquinolin-2(1H)-one</strong>. 1H-NMR (CDCl3) delta: 3.87-3.90 (2H, m), 4.00-4.04 (2H, m), 4.58 (2H, d, J=4.1 Hz), 5.23 (1H, t, J=4.1 Hz), 6.84 (1H, d, J=9.2 Hz), 7.73 (1H, d, J=9.2 Hz), 7.78 (1H, d, J=9.6 Hz), 8.37 (1H, dd, J=9.6, 2.8 Hz), 8.46 (1H, d, J=2.8 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 6-methylquinolin-2(1H)-one With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 2-bromomethyl-1,3-dioxolane In N,N-dimethyl-formamide at 90℃; for 8h; | 162 Into 5 mL of N,N-dimethylformamide, 297 mg of 6-methylquinolin-2(1H)-one was dissolved, thereto was added 282 mg of 60% sodium hydride, and the mixture was stirred at room temperature for 1 hour. Thereto was added 1.0 mL of 2-bromomethyl-1,3-dioxolane, and the mixture was stirred at 90°C for 8 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and 1 mol/L hydrochloric acid were added thereto. The organic layer was separated, washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60 manufactured by Kanto Chemical Co., Inc., eluent; ethyl acetate : hexane= 3 : 1] to obtain 253 mg of a white solid, 1-(1,3-dioxolan-2-ylmethyl)-6-methylquinolin-2(1H)-one. 1H-NMR (CDCl3) δ: 2.41 (3H, s), 3.85-3.91 (2H, m), 3.99-4.08 (2H, m), 4.53 (2H, d, J=4.8 Hz), 5.26 (1H, t, J=4.8 Hz), 6.69 (1H, d, J=9.7 Hz), 7.30-7.40 (2H, m), 7.42-7.53 (1H, m), 7.62 (1H, d, J=9.7 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To 15 mL of an N,N-dimethylformamide solution containing 920 mg of <strong>[99465-09-5]5-bromoquinolin-2(1H)-one</strong>, 530 mg of 60% sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. Thereto was added 2.13 mL of 2-bromomethyl-1,3-dioxolane, and the mixture was stirred at 90C for 11 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and 1 mol/L hydrochloric acid were added thereto. The organic layer was separated, the resultant solution was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60 manufactured by Kanto Chemical Co., Inc., eluent; ethyl acetate : hexane 1:4] to obtain 484 mg of a pale yellow solid, 1-(1,3-dioxolan-2-ylmethyl)-<strong>[99465-09-5]5-bromoquinolin-2(1H)-one</strong>. 1H-NMR (CDCl3) delta: 3.86-3.90 (2H, m), 4.01-4.05 (2H, m), 4.55 (2H, d, J=4.1 Hz), 5.22-5.26 (1H, m), 6.79 (1H, d, J=9.6 Hz), 7.37 (1H, dd, J=8.7, 7.8 Hz), 7.48 (1H, dd, J=7.8, 0.9 Hz), 7.55-7.60 (1H, m), 8.13-8.18 (1H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To 20 mL of an N,N-dimethylformamide solution containing 540 mg of <strong>[20146-59-2]4-chloroquinolin-2(1H)-one</strong>, 376 mg of 60% sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. Thereto was added 3.2 mL of 2-bromomethyl-1,3-dioxolane, and the mixture was stirred at 90C for 16 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and 1 mol/L hydrochloric acid were added thereto. The organic layer was separated, the resultant solution was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60 manufactured by Kanto Chemical Co., Inc., eluent; ethyl acetate : hexane = 1 : 1] to obtain 165 mg of a white solid, 1-(1,3-dioxolan-2-ylmethyl)-<strong>[20146-59-2]4-chloroquinolin-2(1H)-one</strong>. 1H-NMR (CDCl3) delta: 3.84-3.92 (2H, m), 3.99-4.05 (2H, m), 4.54 (2H, d, J=4.4 Hz), 5.25 (1H, t, J=4.4 Hz), 6.91 (1H, s), 7.24-7.37 (1H, m), 7.60-7.68 (2H, m), 8.02 (1H, d, J=7.9 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To 70 mL of an N,N-dimethylformamide solution containing 1.40 g of <strong>[607-66-9]4-methylquinolin-2(1H)-one</strong>, 1.06 g of 60% sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. Thereto was added 7.34 g of 2-bromomethyl-1,3-dioxolane, and the mixture was stirred at 90C for 5 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate, toluene and 1 mol/L hydrochloric acid were added thereto. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60N manufactured by Kanto Chemical Co., Inc., eluent; ethyl acetate] to obtain 0.75 g of a white solid, 1-(1,3-dioxolan-2-ylmethyl)-<strong>[607-66-9]4-methylquinolin-2(1H)-one</strong>. 1H-NMR (CDCl3) delta: 2.47 (3H, s) 3.86-3.89 (2H, m) 4.03-4.07 (2H, m) 4.55 (2H, d, J=4.6 Hz) 5.27 (1H, t, J=4.6 Hz) 6.61 (1H, s) 7.23-7.25 (1H, m) 7.53-7.57 (1H, m) 7.59-7.61 (1H, m) 7.68-7.71 (1H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To 30 mL of an N,N-dimethylformamide solution containing 1.5 g of <strong>[101382-55-2]7-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde</strong>, 0.32 g of 60% sodium hydride was added, and the mixture was stirred at 50C for 30 minutes. Thereto was added 1.53 mL of 2-bromomethyl-1,3-dioxolane, and the reaction mixture was stirred at 80 to 90C for 2 hours. Thereto was added 1.53 mL of 2-bromomethyl-1,3-dioxolane, and the reaction mixture was stirred for 3 hours and 30 minutes. Water and ethyl acetate were then added thereto, and the reaction mixture was adjusted to pH 1.5 with 6 mol/L hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was added with a mixed solution of diethyl ether and ethyl acetate, and a solid substance collected by filtration, and then purified by silica gel column chromatography [eluent; chloroform] to obtain 0.35 g of a yellow solid, 1-(1,3-dioxolan-2-ylmethyl)-<strong>[101382-55-2]7-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde</strong>. 1H-NMR (CDCl3) delta: 3.88-3.93 (2H, m), 3.95 (3H, s), 4.00-4.10 (2H, m), 4.56 (2H, d, J=4.3 Hz), 5.26 (1H, t, J=4.3 Hz), 6.88 (1H, dd, J=8.8, 2.2 Hz), 7.09 (1H, d, J=2.2 Hz), 7.63 (1H, d, J=8.8 Hz), 8.32 (1H, s), 10.42 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To 70 mL of an N,N-dimethylformamide solution containing 1.00 g of <strong>[1810-66-8]6-bromoquinolin-2(1H)-one</strong>, 0.54 g of 60% sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. Thereto was added 3.73 g of 2-bromomethyl-1,3-dioxolane, and the mixture was stirred at 90C for 5 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate, toluene and 1 mol/L hydrochloric acid were added thereto. The organic layer was separated, washed sequentially with water, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60N manufactured by Kanto Chemical Co., Inc., eluent; ethyl acetate] to obtain 0.56 g of a white solid, 1-(1,3-dioxolan-2-ylmethyl)-<strong>[1810-66-8]6-bromoquinolin-2(1H)-one</strong>. 1H-NMR (CDCl3) delta: 3.86-3.91 (2H, m), 4.00-4.05 (2H, m), 4.49-4.53 (2H, m), 5.21-5.24 (1H, m), 6.72-6.75 (1H, m), 7.47-7.51 (1H, m), 7.57-7.60 (1H, m), 7.60-7.63 (1H, m), 7.66-7.68 (1H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Scheme III, step B: A 250 mL round bottom flask was charged with anhydrous DMF (30 mL) and sodium hydride (0.56 g of a 60% dispersion, 14.0 mmol). The suspension was cooled to 0 C. and 1-cyclohexyl-2-(2-pyridyl) ethan-1-one (2.03 g, 10 mmol) in THF (30 mL) as added dropwise to the suspension. After addition was complete, the reaction was stirred for 2.5 hours at room temperature. Then <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (1.55 mL, 15 mmol) was added and the reaction was heated at reflux for 16 hours. The reaction mixture was then quenched with water and extracted with diethyl ether (4×50 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate:hexane, 3:7, silica gel) to provide 1-cyclohexyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl) propan-1-one (1.79 g, 62%) as a yellow oil | |
62% | Scheme III, step B: A 250 ML round bottom flask was charged with anhydrous DMF (30 ML) and sodium hydride (0.56 g of a 60% dispersion, 14.0 mmol).. The suspension was cooled to 0 C. and 1-cyclohexyl-2-(2-pyridyl)ethan-1-one (2.03 g, 10 mmol) in THF (30 ML) was added dropwise to the suspension.. After addition was complete, the reaction was stirred for 2.5 hours at room temperature.. Then <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (1.55 ML, 15 mmol) was added and the reaction was heated at reflux for 16 hours.. The reaction mixture was then quenched with water and extracted with diethyl ether (4*50 ML).. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum.. The residue was purified by column chromatography (ethyl acetate:hexane, 3:7, silica gel) to provide 1-cyclohexyl-3-(2-(1,2-dioxolane))-2-(2-pyridyl)propan-1-one (1.79 g, 62%) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 1.2 g of <strong>[10261-82-2]1,5-naphthyridin-2(1H)-one</strong> in 24 mL of N,N-dimethylformamide, 0.82 g of 60% sodium hydride was added at 60C, and the mixture was stirred at the same temperature for 20 minutes, and then stirred at 55 to 80C for 30 minutes. Thereto was added 1.3 mL of 2-bromomethyl-1,3-dioxolan at 60C, the temperature of the reaction mixture was increased to 100C over 4 hours, and to the reaction mixture, 2.3 g of potassium carbonate was added, and the mixture was stirred at the same temperature for 3 hours. After leaving overnight, 0.85 mL of 2-bromomethyl-1,3-dioxolan and 0.33 g of 60% sodium hydride were added thereto, and the mixture was stirred at 70 to 75C for 1 hour 30 minutes. The reaction mixture was cooled to room temperature, water, sodium chloride and chloroform were then added thereto, and the organic layer was separated. The aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol = 49:1 to obtain 1.1 g of 1-(1,3-dioxolan-2-ylmethyl)-<strong>[10261-82-2]1,5-naphthyridin-2(1H)-one</strong> as a light yellow solid. 1H-NMR (CDCl3) delta: 3.82-3.94 (2H, m), 3.96-4.05 (2H, m), 4.52 (2H, d, J = 4.2 Hz), 5.22 (1H, t, J = 4.2 Hz), 6.94 (1H, d, J = 9.8 Hz), 7.45 (1H, dd, J = 8.6, 4.5 Hz), 7.90-7.98 (2H, m), 8.54 (1H, dd, J = 4.5, 1.2 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3.2 g of <strong>[15944-34-0]7-chloro-1,8-naphthyridin-2(1H)-one</strong> in 32 mL of N,N-dimethylformamide, 3.7 g of potassium carbonate was added, and the mixture was stirred at 50 to 60C for 23 minutes, and then, thereto was added 2.2 mL of 2-bromomethyl-1,3-dioxolan, and the mixture was stirred at 60 to 78C for 25 minutes. Thereto were added 16 mL of N,N-dimethylformamide and 1.1 mL of 2-bromomethyl-1,3-dioxolan, the mixture was stirred at 90 to 95C for 2 hours 15 minutes, 3.7 g of potassium carbonate was added thereto, and the mixture was stirred for 20 minutes. The reaction mixture was cooled to room temperature, water and ethyl acetate were then added thereto, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate = 1:1 to obtain 3.6 g of 7-chloro-1-(1,3-dioxolan-2-ylmethyl)-1,8-naphthyridin-2(1H)-one as a yellow solid. 1H-NMR (CDCl3) delta: 3.86-3.96 (2H, m), 4.10-4.20 (2H, m), 4.63 (2H, t, J = 5.4 Hz), 5.60 (1H, t, J = 5.4 Hz), 6.75 (1H, d, J = 9.6 Hz), 7.17 (1H, d, J = 8.0 Hz), 7.62 (1H, d, J = 9.6 Hz), 7.79 (1H, d, J = 8.0 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 1.2 g of <strong>[15936-09-1]1,8-naphthyridin-2(1H)-one</strong> in 18 mL of N,N-dimethylformamide, 0.36 g of 60% sodium hydride was added, and the mixture was stirred at 50 to 60C for 7 minutes. Thereto was added 0.94 mL of 2-bromomethyl-1,3-dioxolan, and the mixture was stirred at 95 to 105C for 3 hours. The reaction mixture was cooled to room temperature, water and ethyl acetate were then added thereto, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate = 1:1 to obtain 1.2 g of 1-(1,3-dioxolan-2-ylmethyl)-<strong>[15936-09-1]1,8-naphthyridin-2(1H)-one</strong> as a white solid. 1H-NMR (CDCl3) δ: 3.83-3.93 (2H, m), 3.95-4.17 (2H, m), 4.72 (1H, d, J = 5.1 Hz), 5.56 (1H, t, J = 5.1 Hz), 6.72 (1H, d, J = 9.5 Hz), 7.17 (1H, dd, J = 7.6, 4.7 Hz), 7.64 (1H, d, J = 9.5 Hz), 7.86 (1H, dd, J = 7.6, 1.8 Hz), 8.57 (1H, dd, J = 4.7, 1.8 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a suspension of 6.0 g of <strong>[54920-82-0]1,7-naphthyridin-2(1H)-one</strong> in 60 mL of N,N-dimethylformamide, 2.5 g of 60percent sodium hydride was added at room temperature, and the mixture was stirred at 50 to 60°C for 1 hour. Thereto was added 6.4 mL of 2-bromomethyl-1,3-dioxolan, the temperature was increased to 90 to 95°C, and the reaction mixture was stirred for 2 hours 30 minutes. The temperature was further increased to 95 to 100°C, and the mixture was stirred for 4 hours. Thereto were added 0.82 g of 60percent sodium hydride and 2.1 mL of 2-bromomethyl-1,3-dioxolan and the mixture was further stirred at the same temperature for 2 hours. Thereto were added 0.49 g of 60percent sodium hydride and 1.3 mL of 2-bromomethyl-1,3-dioxolan and the mixture was stirred at 90 to 100°C for 2 hours. Thereto were further added 0.49 g of 60percent sodium hydride and 1.3 mL of 2-bromomethyl-1,3-dioxolan and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was cooled to 5°C, and ethyl acetate and ice water were then added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate = 100:0 to 0:100 and then, using gradient elution with chloroform:methanol = 100:0 to 90:10 to obtain 3.1 g of 1-(1,3-dioxolan-2-ylmethyl)-<strong>[54920-82-0]1,7-naphthyridin-2(1H)-one</strong> as a brown solid. 1H-NMR (CDCl3) delta: 3.85-3.94 (2H, m), 3.99-4.08 (2H, m), 4.58 (2H, d, J = 4.5 Hz), 5.29 (1H, t, J = 4.5 Hz), 6.91 (1H, d, J = 9.4 Hz), 7.41 (1H, d, J = 5.1 Hz), 7.67 (1H, d, J = 9.4 Hz), 8.45 (1H, d, J = 5.1 Hz), 9.05 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a suspension of 4.0g of 7-bromopyrido(2,3-b)pyrazin-2(1H)-one in 40 mL of N,N-dimethylformamide, 8.2 g of a 28% sodium methoxide/methanol solution and 0.25 g of copper (I) bromide were added at room temperature, and the mixture was stirred at 80 to 90C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to 55C, thereto was added 2.8 mL of 2-bromomethyl-1,3-dioxolan, and the mixture was stirred at 80 to 90C for 1 hour 30 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and then left overnight. The mixture was further stirred at 80 to 90C for 1 hour, and then stirred at 90 to 100C for 1 hour 30 minutes. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added thereto. The insoluble substance was filtered off, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol = 100:0 to 95:5, ethyl acetate was added to the orange oily substance thus obtained, and the solid was filtered off to obtain 0.12 g of 1-(1,3-dioxolan-2-ylmethyl)-7-methoxypyrido(2,3-b)pyrazin-2(1H)-one as an orange solid. 1H-NMR (CDCl3) delta: 3.84-3.93 (2H, m), 3.93-4.02 (2H, m), 3.99 (3H, s), 4.47 (2H, d, J = 3.8 Hz), 5.21 (1H, t, J = 3.8 Hz), 7.39 (1H, d, J = 2.7 Hz), 8.36 (1H, d, J = 2.7 Hz), 8.38 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.15% | With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 135℃; for 10h;Product distribution / selectivity; | EXAMPLE 2 Step a) Preparation of the intermediate (4) of formula 2-[(2-methoxyphenoxv)methyl-1,3-dioxolane (4) in N-methylpyrrolidone The following raw materials were used in the amounts shown in Table 2. Table 2: Substances and amounts used in Example 2 RAW MATERIALS Density g ml moles mole ratio Guaiacol 1.129 99.2 87.9 0.80 1.00 N-methylpyrrolidone 1.028 514.0 500.0 * * Potassium carbonate fine powder 221.14 1.60 2.00 97% <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> 1.628 158.4 97.3 0.92 1.15 Deionized water for quenching 1.00 1400.0 1400.0 Toluene for extraction 0.865 692.0 800.0 Deionized water, 1 st wash 1.00 800.0 800.0 30% NaOH solution 1.335 50.0 37.5 Deionized water, 2nd wash 1.00 800.0 800.0 30% NaOH solution 1.335 50.0 37.5 Deionized water, 3rd wash 1.00 800.0 800.0 30% NaOH solution 1.335 50.0 37.5 Carbon 5.0 Toluene for washing panel 0.865 86.5 100.0 Under nitrogen atmosphere, potassium carbonate fine powder, guaiacol and N-methylpyrrolidone were loaded into a 3 litre flask at ambient temperature. The mixture was subjected to agitation and the temperature brought to 135+/-5C; having reached this temperature, <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> was added drop-wise over a period of at least 2 hours while keeping within the temperature range. At the end of the addition, the reaction was allowed to proceed at a temperature of 135+/-5C for a further 8 hours. (Total <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> addition time and reaction time was about 10 hours). The mixture was then cooled to a temperature of about 25+/-5C and a sample was collected for monitoring the end of the reaction. When the end of the reaction was confirmed, 1400 ml of quenching water and toluene for extraction were then added to the mixture, which was heated to a temperature of 45+/-5C. Agitation was stopped and the phases were allowed to separate for around 1 hour. The lower aqueous phase, black in colour, was discarded and the organic phase was subjected to 3 washes with water/NaOH maintaining the temperature at 45+/-5C, and allowing it to separate for about 30 minutes. The organic extract, pale amber in colour, was cooled to T = 25+/-5C and treated with carbon. The extract was then filtered on a dicalite panel to obtain a perfectly clear yellow ochre filtrate; the panel was washed with toluene so as to combine the wash solution with the main filtrate. The toluenic solution was transferred into a clean 2 litre flask, equipped for distillation. The distillate was concentrated under vacuum with a bath temperature of about 60+/-5C until a residue formed. The obtained intermediate (4) appeared as a dense amber liquid which solidified on cooling. 252.8 g of a dark yellow concentrate were obtained which yielded 153 g of crystalline product at 98% purity. Theoretical yield = 168.18 g. Percentage yield relative to theoretical = 91.15%. |
88.59% | With potassium carbonate; In 2-methoxy-ethanol; at 125 - 126℃; for 17h;Product distribution / selectivity; | EXANIPLES 3-31 Step a) Preparation of the intermediate (4) of formula 2-[(2-methoxyphenoxy)methyl-1,3-dioxolane (4) By following the same procedure as shown in example 1, but using the amounts, reaction solvent, times and temperatures indicated in Table 3, the intermediate (4) was obtained in the yields and purities indicated in Table 4 to follow. Table 3: Reaction conditions for examples 3-31 Guaiacol g (mol)K2CO3 g (mol) 2-BrMe-1,3-dioxolane g (mol) Solvent type (ml)Treaction (C) Time (hours) Ex.3 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (110) 123/124 16 Ex.4 49.6(1) 82.92 (1.5) 79.2 (1.18) 1-methoxy-2-propanol (110) 124/128 18 Ex.5 49.6(1) 110.56(2) 79.2(1.18) 1-methoxy-2-propanol (165) 122/125 17 Ex.6 148.8(1) 331.7(2) 236.5(1.18) 1-methoxy-2-propanol (495) 123/126 20 Ex.7 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/125 20 Ex.8 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/126 20 Ex.9 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/126 20 Ex.10 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (110) 124 20 Ex.11 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (150) 124 20 Ex.12 49.6(1) 66.34(1.2) 79.2(1.18) 1-methoxy-2-propanol (200) 124 20 Ex.13 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 125 20 Ex.14 148.8(1) 331.7(2) 236.5(1.18) 1-methoxy-2-propanol (495) 129 20 Ex.15 99.2(1) 132.68(1.2) 157.7(1.18) 1-methoxy-2-propanol(400) 126/127 20 Ex.16 99.2(1) 221.14(2) 157.7(1.18) 1-methoxy-2-propanol(400) 126/127 20 Ex.17 99.2(1) 132.7(1.2) 158(1.18) 1-methoxy-2-propanol(220) 126 20 Ex.18 99.2(1) 132.7(1.2) 158 (1.18) 1-methoxy-2-propanol(220) 128 20 Ex.19 49.6(1) 66.34(1.2) 79.2 (1.18) Dimethylformamide (110) 127 10 Ex.20 49.6(1) 66.34(1.2) 79.2 (1.18) Dimethylacetamide (110) 128-132 10 Ex.21 49.6(1) 66.34(1.2) 79.2 (1.18) Diglyme(110) 130-138 20 Ex.22 49.6(1) 66.34(1.2) 79.2(1.18) Ethylcellosolve (110) 132 20 Ex.23 49.6(1) 66.34(1.2) 79.2(1.18) Ethylene glycol (110) 132 20 Ex.24 49.6(1) 66.34(1.2) 79.2 (1.18) Methylcellosolve (110) 125-126 17 Ex.25 99.2(1) 132.7(1.2) 158.4(1.18) 1-methoxy-2-propanol(220) 128 20 Ex.26 99.2(1) 132.7(1.2) 158.4(1.18) 1-methoxy-2-propanol(220) 131 20 Ex.27 148.8(1) 199.02(1.2) 237.68(1.18) 1-methoxy-2-propanol(330) 128/131 24 Ex.28 49.6(1) 82.92 (1.5) 79.2(1.18) 1-methoxy-2-propanol(110) 125/127 16 Ex.29 49.6(1) 82.92 (1.5) 79.2(1.18) 1-methoxy-2-propanol(110) 123/126 20 Ex.30 148.8(1) 199.02 (1.2) 237.6(1.18) 1-methoxy-2-propanol(330) 124/129 24 Ex.31 148.8(1) 248.78(1.5) 237.6 (1.18) 1-methoxy-2-propanol(330) 125/129 24Table 4: Yield and purity of the intermediate (4) obtained from examples 3-31 Yield (g) Theoretical yield (g) % yield/theoretical yield HPLC purity GC purity Ex.3 74.26 84.09 88.31 99.63 99.23 Ex.4 72.62 84.09 86.35 99.61 99.56 Ex.5 73.65 84.09 87.58 99.72 99.25 Ex.6 223.0 251.78 88.56 99.70 99.46 Ex.7 214.2 251.78 85.07 99.48 99.40 Ex.8 207.4 251.78 82.37 99.65 99.28 Ex.9 206.0 251.78 81.81 99.70 99.36 Ex.10 70.34 84.09 83.65 99.89 99.02 Ex.11 71.41 84.09 84.92 99.74 99.68 Ex.12 67.77 84.09 80.59 99.83 99.50 Ex.13 209.1 251.78 83.0 99.73 99.16 Ex.14 206.0 251.78 81.82 99.68 99.14 Ex.15 127.4 168.19 75.75 99.46 - Ex.16 138.8 168.19 82.52 99.71 - Ex.17 129.2 168.19 76.86 99.06 99.89 Ex.18 127.45 168.19 75.78 99.12 99.55 Ex.19 65.5 84.09 77.8 99.31 98.50 Ex.20 67.9 84.09 80.75 95.94 99.34 Ex.21 21.70 84.09 25.8 98.98 99.21 Ex.22 66.6 84.09 79.2 98.60 99.38 Ex.23 67.8 84.09 80.6 97.01 97.81 Ex.24 74.50 84.09 88.59 99.48 99.82 Ex.25 138.36 168.19 82.3 99.39 99.88 Ex.26 136.75 168.19 81.3 98.76 99.88 Ex.27 207 251.78 82.15 99.87 99.87 Ex.28 72 84.09 85.71 99.95 99.78 Ex.29 72.6 84.09 86.43 99.86 99.89 Ex.30 212.3 251.78 84.32 99.76 99.78 Ex.31 217.1 251.78 86.22 99.77 99.77 Therefore, in all the examples the intermediate (4) is obtained in high yields and at purities greater than 99%. According to the present invention, the intermediates of examples 1, 28, 29 and 31 had the best appearance and quality. |
80.6% | With potassium carbonate; In ethylene glycol; at 132℃; for 20h;Product distribution / selectivity; | EXANIPLES 3-31 Step a) Preparation of the intermediate (4) of formula 2-[(2-methoxyphenoxy)methyl-1,3-dioxolane (4) By following the same procedure as shown in example 1, but using the amounts, reaction solvent, times and temperatures indicated in Table 3, the intermediate (4) was obtained in the yields and purities indicated in Table 4 to follow. Table 3: Reaction conditions for examples 3-31 Guaiacol g (mol)K2CO3 g (mol) 2-BrMe-1,3-dioxolane g (mol) Solvent type (ml)Treaction (C) Time (hours) Ex.3 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (110) 123/124 16 Ex.4 49.6(1) 82.92 (1.5) 79.2 (1.18) 1-methoxy-2-propanol (110) 124/128 18 Ex.5 49.6(1) 110.56(2) 79.2(1.18) 1-methoxy-2-propanol (165) 122/125 17 Ex.6 148.8(1) 331.7(2) 236.5(1.18) 1-methoxy-2-propanol (495) 123/126 20 Ex.7 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/125 20 Ex.8 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/126 20 Ex.9 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/126 20 Ex.10 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (110) 124 20 Ex.11 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (150) 124 20 Ex.12 49.6(1) 66.34(1.2) 79.2(1.18) 1-methoxy-2-propanol (200) 124 20 Ex.13 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 125 20 Ex.14 148.8(1) 331.7(2) 236.5(1.18) 1-methoxy-2-propanol (495) 129 20 Ex.15 99.2(1) 132.68(1.2) 157.7(1.18) 1-methoxy-2-propanol(400) 126/127 20 Ex.16 99.2(1) 221.14(2) 157.7(1.18) 1-methoxy-2-propanol(400) 126/127 20 Ex.17 99.2(1) 132.7(1.2) 158(1.18) 1-methoxy-2-propanol(220) 126 20 Ex.18 99.2(1) 132.7(1.2) 158 (1.18) 1-methoxy-2-propanol(220) 128 20 Ex.19 49.6(1) 66.34(1.2) 79.2 (1.18) Dimethylformamide (110) 127 10 Ex.20 49.6(1) 66.34(1.2) 79.2 (1.18) Dimethylacetamide (110) 128-132 10 Ex.21 49.6(1) 66.34(1.2) 79.2 (1.18) Diglyme(110) 130-138 20 Ex.22 49.6(1) 66.34(1.2) 79.2(1.18) Ethylcellosolve (110) 132 20 Ex.23 49.6(1) 66.34(1.2) 79.2(1.18) Ethylene glycol (110) 132 20 Ex.24 49.6(1) 66.34(1.2) 79.2 (1.18) Methylcellosolve (110) 125-126 17 Ex.25 99.2(1) 132.7(1.2) 158.4(1.18) 1-methoxy-2-propanol(220) 128 20 Ex.26 99.2(1) 132.7(1.2) 158.4(1.18) 1-methoxy-2-propanol(220) 131 20 Ex.27 148.8(1) 199.02(1.2) 237.68(1.18) 1-methoxy-2-propanol(330) 128/131 24 Ex.28 49.6(1) 82.92 (1.5) 79.2(1.18) 1-methoxy-2-propanol(110) 125/127 16 Ex.29 49.6(1) 82.92 (1.5) 79.2(1.18) 1-methoxy-2-propanol(110) 123/126 20 Ex.30 148.8(1) 199.02 (1.2) 237.6(1.18) 1-methoxy-2-propanol(330) 124/129 24 Ex.31 148.8(1) 248.78(1.5) 237.6 (1.18) 1-methoxy-2-propanol(330) 125/129 24Table 4: Yield and purity of the intermediate (4) obtained from examples 3-31 Yield (g) Theoretical yield (g) % yield/theoretical yield HPLC purity GC purity Ex.3 74.26 84.09 88.31 99.63 99.23 Ex.4 72.62 84.09 86.35 99.61 99.56 Ex.5 73.65 84.09 87.58 99.72 99.25 Ex.6 223.0 251.78 88.56 99.70 99.46 Ex.7 214.2 251.78 85.07 99.48 99.40 Ex.8 207.4 251.78 82.37 99.65 99.28 Ex.9 206.0 251.78 81.81 99.70 99.36 Ex.10 70.34 84.09 83.65 99.89 99.02 Ex.11 71.41 84.09 84.92 99.74 99.68 Ex.12 67.77 84.09 80.59 99.83 99.50 Ex.13 209.1 251.78 83.0 99.73 99.16 Ex.14 206.0 251.78 81.82 99.68 99.14 Ex.15 127.4 168.19 75.75 99.46 - Ex.16 138.8 168.19 82.52 99.71 - Ex.17 129.2 168.19 76.86 99.06 99.89 Ex.18 127.45 168.19 75.78 99.12 99.55 Ex.19 65.5 84.09 77.8 99.31 98.50 Ex.20 67.9 84.09 80.75 95.94 99.34 Ex.21 21.70 84.09 25.8 98.98 99.21 Ex.22 66.6 84.09 79.2 98.60 99.38 Ex.23 67.8 84.09 80.6 97.01 97.81 Ex.24 74.50 84.09 88.59 99.48 99.82 Ex.25 138.36 168.19 82.3 99.39 99.88 Ex.26 136.75 168.19 81.3 98.76 99.88 Ex.27 207 251.78 82.15 99.87 99.87 Ex.28 72 84.09 85.71 99.95 99.78 Ex.29 72.6 84.09 86.43 99.86 99.89 Ex.30 212.3 251.78 84.32 99.76 99.78 Ex.31 217.1 251.78 86.22 99.77 99.77 Therefore, in all the examples the intermediate (4) is obtained in high yields and at purities greater than 99%. According to the present invention, the intermediates of examples 1, 28, 29 and 31 had the best appearance and quality. |
80.75% | With potassium carbonate; In N,N-dimethyl acetamide; at 128 - 132℃; for 10h;Product distribution / selectivity; | EXANIPLES 3-31 Step a) Preparation of the intermediate (4) of formula 2-[(2-methoxyphenoxy)methyl-1,3-dioxolane (4) By following the same procedure as shown in example 1, but using the amounts, reaction solvent, times and temperatures indicated in Table 3, the intermediate (4) was obtained in the yields and purities indicated in Table 4 to follow. Table 3: Reaction conditions for examples 3-31 Guaiacol g (mol)K2CO3 g (mol) 2-BrMe-1,3-dioxolane g (mol) Solvent type (ml)Treaction (C) Time (hours) Ex.3 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (110) 123/124 16 Ex.4 49.6(1) 82.92 (1.5) 79.2 (1.18) 1-methoxy-2-propanol (110) 124/128 18 Ex.5 49.6(1) 110.56(2) 79.2(1.18) 1-methoxy-2-propanol (165) 122/125 17 Ex.6 148.8(1) 331.7(2) 236.5(1.18) 1-methoxy-2-propanol (495) 123/126 20 Ex.7 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/125 20 Ex.8 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/126 20 Ex.9 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/126 20 Ex.10 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (110) 124 20 Ex.11 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (150) 124 20 Ex.12 49.6(1) 66.34(1.2) 79.2(1.18) 1-methoxy-2-propanol (200) 124 20 Ex.13 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 125 20 Ex.14 148.8(1) 331.7(2) 236.5(1.18) 1-methoxy-2-propanol (495) 129 20 Ex.15 99.2(1) 132.68(1.2) 157.7(1.18) 1-methoxy-2-propanol(400) 126/127 20 Ex.16 99.2(1) 221.14(2) 157.7(1.18) 1-methoxy-2-propanol(400) 126/127 20 Ex.17 99.2(1) 132.7(1.2) 158(1.18) 1-methoxy-2-propanol(220) 126 20 Ex.18 99.2(1) 132.7(1.2) 158 (1.18) 1-methoxy-2-propanol(220) 128 20 Ex.19 49.6(1) 66.34(1.2) 79.2 (1.18) Dimethylformamide (110) 127 10 Ex.20 49.6(1) 66.34(1.2) 79.2 (1.18) Dimethylacetamide (110) 128-132 10 Ex.21 49.6(1) 66.34(1.2) 79.2 (1.18) Diglyme(110) 130-138 20 Ex.22 49.6(1) 66.34(1.2) 79.2(1.18) Ethylcellosolve (110) 132 20 Ex.23 49.6(1) 66.34(1.2) 79.2(1.18) Ethylene glycol (110) 132 20 Ex.24 49.6(1) 66.34(1.2) 79.2 (1.18) Methylcellosolve (110) 125-126 17 Ex.25 99.2(1) 132.7(1.2) 158.4(1.18) 1-methoxy-2-propanol(220) 128 20 Ex.26 99.2(1) 132.7(1.2) 158.4(1.18) 1-methoxy-2-propanol(220) 131 20 Ex.27 148.8(1) 199.02(1.2) 237.68(1.18) 1-methoxy-2-propanol(330) 128/131 24 Ex.28 49.6(1) 82.92 (1.5) 79.2(1.18) 1-methoxy-2-propanol(110) 125/127 16 Ex.29 49.6(1) 82.92 (1.5) 79.2(1.18) 1-methoxy-2-propanol(110) 123/126 20 Ex.30 148.8(1) 199.02 (1.2) 237.6(1.18) 1-methoxy-2-propanol(330) 124/129 24 Ex.31 148.8(1) 248.78(1.5) 237.6 (1.18) 1-methoxy-2-propanol(330) 125/129 24Table 4: Yield and purity of the intermediate (4) obtained from examples 3-31 Yield (g) Theoretical yield (g) % yield/theoretical yield HPLC purity GC purity Ex.3 74.26 84.09 88.31 99.63 99.23 Ex.4 72.62 84.09 86.35 99.61 99.56 Ex.5 73.65 84.09 87.58 99.72 99.25 Ex.6 223.0 251.78 88.56 99.70 99.46 Ex.7 214.2 251.78 85.07 99.48 99.40 Ex.8 207.4 251.78 82.37 99.65 99.28 Ex.9 206.0 251.78 81.81 99.70 99.36 Ex.10 70.34 84.09 83.65 99.89 99.02 Ex.11 71.41 84.09 84.92 99.74 99.68 Ex.12 67.77 84.09 80.59 99.83 99.50 Ex.13 209.1 251.78 83.0 99.73 99.16 Ex.14 206.0 251.78 81.82 99.68 99.14 Ex.15 127.4 168.19 75.75 99.46 - Ex.16 138.8 168.19 82.52 99.71 - Ex.17 129.2 168.19 76.86 99.06 99.89 Ex.18 127.45 168.19 75.78 99.12 99.55 Ex.19 65.5 84.09 77.8 99.31 98.50 Ex.20 67.9 84.09 80.75 95.94 99.34 Ex.21 21.70 84.09 25.8 98.98 99.21 Ex.22 66.6 84.09 79.2 98.60 99.38 Ex.23 67.8 84.09 80.6 97.01 97.81 Ex.24 74.50 84.09 88.59 99.48 99.82 Ex.25 138.36 168.19 82.3 99.39 99.88 Ex.26 136.75 168.19 81.3 98.76 99.88 Ex.27 207 251.78 82.15 99.87 99.87 Ex.28 72 84.09 85.71 99.95 99.78 Ex.29 72.6 84.09 86.43 99.86 99.89 Ex.30 212.3 251.78 84.32 99.76 99.78 Ex.31 217.1 251.78 86.22 99.77 99.77 Therefore, in all the examples the intermediate (4) is obtained in high yields and at purities greater than 99%. According to the present invention, the intermediates of examples 1, 28, 29 and 31 had the best appearance and quality. |
79.2% | With potassium carbonate; In 2-ethoxy-ethanol; at 132℃; for 20h;Product distribution / selectivity; | EXANIPLES 3-31 Step a) Preparation of the intermediate (4) of formula 2-[(2-methoxyphenoxy)methyl-1,3-dioxolane (4) By following the same procedure as shown in example 1, but using the amounts, reaction solvent, times and temperatures indicated in Table 3, the intermediate (4) was obtained in the yields and purities indicated in Table 4 to follow. Table 3: Reaction conditions for examples 3-31 Guaiacol g (mol)K2CO3 g (mol) 2-BrMe-1,3-dioxolane g (mol) Solvent type (ml)Treaction (C) Time (hours) Ex.3 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (110) 123/124 16 Ex.4 49.6(1) 82.92 (1.5) 79.2 (1.18) 1-methoxy-2-propanol (110) 124/128 18 Ex.5 49.6(1) 110.56(2) 79.2(1.18) 1-methoxy-2-propanol (165) 122/125 17 Ex.6 148.8(1) 331.7(2) 236.5(1.18) 1-methoxy-2-propanol (495) 123/126 20 Ex.7 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/125 20 Ex.8 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/126 20 Ex.9 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/126 20 Ex.10 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (110) 124 20 Ex.11 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (150) 124 20 Ex.12 49.6(1) 66.34(1.2) 79.2(1.18) 1-methoxy-2-propanol (200) 124 20 Ex.13 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 125 20 Ex.14 148.8(1) 331.7(2) 236.5(1.18) 1-methoxy-2-propanol (495) 129 20 Ex.15 99.2(1) 132.68(1.2) 157.7(1.18) 1-methoxy-2-propanol(400) 126/127 20 Ex.16 99.2(1) 221.14(2) 157.7(1.18) 1-methoxy-2-propanol(400) 126/127 20 Ex.17 99.2(1) 132.7(1.2) 158(1.18) 1-methoxy-2-propanol(220) 126 20 Ex.18 99.2(1) 132.7(1.2) 158 (1.18) 1-methoxy-2-propanol(220) 128 20 Ex.19 49.6(1) 66.34(1.2) 79.2 (1.18) Dimethylformamide (110) 127 10 Ex.20 49.6(1) 66.34(1.2) 79.2 (1.18) Dimethylacetamide (110) 128-132 10 Ex.21 49.6(1) 66.34(1.2) 79.2 (1.18) Diglyme(110) 130-138 20 Ex.22 49.6(1) 66.34(1.2) 79.2(1.18) Ethylcellosolve (110) 132 20 Ex.23 49.6(1) 66.34(1.2) 79.2(1.18) Ethylene glycol (110) 132 20 Ex.24 49.6(1) 66.34(1.2) 79.2 (1.18) Methylcellosolve (110) 125-126 17 Ex.25 99.2(1) 132.7(1.2) 158.4(1.18) 1-methoxy-2-propanol(220) 128 20 Ex.26 99.2(1) 132.7(1.2) 158.4(1.18) 1-methoxy-2-propanol(220) 131 20 Ex.27 148.8(1) 199.02(1.2) 237.68(1.18) 1-methoxy-2-propanol(330) 128/131 24 Ex.28 49.6(1) 82.92 (1.5) 79.2(1.18) 1-methoxy-2-propanol(110) 125/127 16 Ex.29 49.6(1) 82.92 (1.5) 79.2(1.18) 1-methoxy-2-propanol(110) 123/126 20 Ex.30 148.8(1) 199.02 (1.2) 237.6(1.18) 1-methoxy-2-propanol(330) 124/129 24 Ex.31 148.8(1) 248.78(1.5) 237.6 (1.18) 1-methoxy-2-propanol(330) 125/129 24Table 4: Yield and purity of the intermediate (4) obtained from examples 3-31 Yield (g) Theoretical yield (g) % yield/theoretical yield HPLC purity GC purity Ex.3 74.26 84.09 88.31 99.63 99.23 Ex.4 72.62 84.09 86.35 99.61 99.56 Ex.5 73.65 84.09 87.58 99.72 99.25 Ex.6 223.0 251.78 88.56 99.70 99.46 Ex.7 214.2 251.78 85.07 99.48 99.40 Ex.8 207.4 251.78 82.37 99.65 99.28 Ex.9 206.0 251.78 81.81 99.70 99.36 Ex.10 70.34 84.09 83.65 99.89 99.02 Ex.11 71.41 84.09 84.92 99.74 99.68 Ex.12 67.77 84.09 80.59 99.83 99.50 Ex.13 209.1 251.78 83.0 99.73 99.16 Ex.14 206.0 251.78 81.82 99.68 99.14 Ex.15 127.4 168.19 75.75 99.46 - Ex.16 138.8 168.19 82.52 99.71 - Ex.17 129.2 168.19 76.86 99.06 99.89 Ex.18 127.45 168.19 75.78 99.12 99.55 Ex.19 65.5 84.09 77.8 99.31 98.50 Ex.20 67.9 84.09 80.75 95.94 99.34 Ex.21 21.70 84.09 25.8 98.98 99.21 Ex.22 66.6 84.09 79.2 98.60 99.38 Ex.23 67.8 84.09 80.6 97.01 97.81 Ex.24 74.50 84.09 88.59 99.48 99.82 Ex.25 138.36 168.19 82.3 99.39 99.88 Ex.26 136.75 168.19 81.3 98.76 99.88 Ex.27 207 251.78 82.15 99.87 99.87 Ex.28 72 84.09 85.71 99.95 99.78 Ex.29 72.6 84.09 86.43 99.86 99.89 Ex.30 212.3 251.78 84.32 99.76 99.78 Ex.31 217.1 251.78 86.22 99.77 99.77 Therefore, in all the examples the intermediate (4) is obtained in high yields and at purities greater than 99%. According to the present invention, the intermediates of examples 1, 28, 29 and 31 had the best appearance and quality. |
77.8% | With potassium carbonate; In N,N-dimethyl-formamide; at 127℃; for 10h;Product distribution / selectivity; | EXANIPLES 3-31 Step a) Preparation of the intermediate (4) of formula 2-[(2-methoxyphenoxy)methyl-1,3-dioxolane (4) By following the same procedure as shown in example 1, but using the amounts, reaction solvent, times and temperatures indicated in Table 3, the intermediate (4) was obtained in the yields and purities indicated in Table 4 to follow. Table 3: Reaction conditions for examples 3-31 Guaiacol g (mol)K2CO3 g (mol) 2-BrMe-1,3-dioxolane g (mol) Solvent type (ml)Treaction (C) Time (hours) Ex.3 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (110) 123/124 16 Ex.4 49.6(1) 82.92 (1.5) 79.2 (1.18) 1-methoxy-2-propanol (110) 124/128 18 Ex.5 49.6(1) 110.56(2) 79.2(1.18) 1-methoxy-2-propanol (165) 122/125 17 Ex.6 148.8(1) 331.7(2) 236.5(1.18) 1-methoxy-2-propanol (495) 123/126 20 Ex.7 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/125 20 Ex.8 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/126 20 Ex.9 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/126 20 Ex.10 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (110) 124 20 Ex.11 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (150) 124 20 Ex.12 49.6(1) 66.34(1.2) 79.2(1.18) 1-methoxy-2-propanol (200) 124 20 Ex.13 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 125 20 Ex.14 148.8(1) 331.7(2) 236.5(1.18) 1-methoxy-2-propanol (495) 129 20 Ex.15 99.2(1) 132.68(1.2) 157.7(1.18) 1-methoxy-2-propanol(400) 126/127 20 Ex.16 99.2(1) 221.14(2) 157.7(1.18) 1-methoxy-2-propanol(400) 126/127 20 Ex.17 99.2(1) 132.7(1.2) 158(1.18) 1-methoxy-2-propanol(220) 126 20 Ex.18 99.2(1) 132.7(1.2) 158 (1.18) 1-methoxy-2-propanol(220) 128 20 Ex.19 49.6(1) 66.34(1.2) 79.2 (1.18) Dimethylformamide (110) 127 10 Ex.20 49.6(1) 66.34(1.2) 79.2 (1.18) Dimethylacetamide (110) 128-132 10 Ex.21 49.6(1) 66.34(1.2) 79.2 (1.18) Diglyme(110) 130-138 20 Ex.22 49.6(1) 66.34(1.2) 79.2(1.18) Ethylcellosolve (110) 132 20 Ex.23 49.6(1) 66.34(1.2) 79.2(1.18) Ethylene glycol (110) 132 20 Ex.24 49.6(1) 66.34(1.2) 79.2 (1.18) Methylcellosolve (110) 125-126 17 Ex.25 99.2(1) 132.7(1.2) 158.4(1.18) 1-methoxy-2-propanol(220) 128 20 Ex.26 99.2(1) 132.7(1.2) 158.4(1.18) 1-methoxy-2-propanol(220) 131 20 Ex.27 148.8(1) 199.02(1.2) 237.68(1.18) 1-methoxy-2-propanol(330) 128/131 24 Ex.28 49.6(1) 82.92 (1.5) 79.2(1.18) 1-methoxy-2-propanol(110) 125/127 16 Ex.29 49.6(1) 82.92 (1.5) 79.2(1.18) 1-methoxy-2-propanol(110) 123/126 20 Ex.30 148.8(1) 199.02 (1.2) 237.6(1.18) 1-methoxy-2-propanol(330) 124/129 24 Ex.31 148.8(1) 248.78(1.5) 237.6 (1.18) 1-methoxy-2-propanol(330) 125/129 24Table 4: Yield and purity of the intermediate (4) obtained from examples 3-31 Yield (g) Theoretical yield (g) % yield/theoretical yield HPLC purity GC purity Ex.3 74.26 84.09 88.31 99.63 99.23 Ex.4 72.62 84.09 86.35 99.61 99.56 Ex.5 73.65 84.09 87.58 99.72 99.25 Ex.6 223.0 251.78 88.56 99.70 99.46 Ex.7 214.2 251.78 85.07 99.48 99.40 Ex.8 207.4 251.78 82.37 99.65 99.28 Ex.9 206.0 251.78 81.81 99.70 99.36 Ex.10 70.34 84.09 83.65 99.89 99.02 Ex.11 71.41 84.09 84.92 99.74 99.68 Ex.12 67.77 84.09 80.59 99.83 99.50 Ex.13 209.1 251.78 83.0 99.73 99.16 Ex.14 206.0 251.78 81.82 99.68 99.14 Ex.15 127.4 168.19 75.75 99.46 - Ex.16 138.8 168.19 82.52 99.71 - Ex.17 129.2 168.19 76.86 99.06 99.89 Ex.18 127.45 168.19 75.78 99.12 99.55 Ex.19 65.5 84.09 77.8 99.31 98.50 Ex.20 67.9 84.09 80.75 95.94 99.34 Ex.21 21.70 84.09 25.8 98.98 99.21 Ex.22 66.6 84.09 79.2 98.60 99.38 Ex.23 67.8 84.09 80.6 97.01 97.81 Ex.24 74.50 84.09 88.59 99.48 99.82 Ex.25 138.36 168.19 82.3 99.39 99.88 Ex.26 136.75 168.19 81.3 98.76 99.88 Ex.27 207 251.78 82.15 99.87 99.87 Ex.28 72 84.09 85.71 99.95 99.78 Ex.29 72.6 84.09 86.43 99.86 99.89 Ex.30 212.3 251.78 84.32 99.76 99.78 Ex.31 217.1 251.78 86.22 99.77 99.77 Therefore, in all the examples the intermediate (4) is obtained in high yields and at purities greater than 99%. According to the present invention, the intermediates of examples 1, 28, 29 and 31 had the best appearance and quality. |
75.75 - 88.56% | With potassium carbonate; In 1-methoxy-2-propanol; at 24 - 131℃; for 16 - 24h;Product distribution / selectivity; | Step a) Preparation of the intermediate (4) of formula 2-[(2-methoxyphenoxy)methyl]-1,3-dioxolane (4) in 1-methoxy-2-propanol The raw materials were used in the amounts shown in the following Table 1. Under nitrogen atmosphere, potassium carbonate fine powder and 1-methoxy-2-propanol were loaded into a perfectly dry 6 litre flask and the mass was placed under agitation. When the guaiacol had been loaded in a fine stream, the temperature rose spontaneously from 24C to 42C due to the exothermic salification and the mixture thickened considerably due to precipitation of the corresponding potassium salt. The mass was then heated to reflux (T = 121-123C) and, having reached this temperature, <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> was added drop-wise over a period of 1 hour and 30 minutes, while maintaining always a good reflux. During the addition the presence of the reagent caused the boiling temperature of the mixture to rise to T = 127-129C. The mixture was maintained at reflux for a total of about 24 hours from the start of bromodioxolane addition by dropping. As the reagent was consumed, it was noted that the boiling temperature tended to drop once more, returning to the initial value of T = 121-123C. The mixture was cooled to T = 20+-5C and a sample was collected for monitoring the end of the reaction. When the end of the reaction was confirmed, a 50% KOH solution was added to the mixture. As the temperature of the mixture rose spontaneously by about 10C, it was cooled to T = 20+-25C and the first portion of deionized water was added. Precipitation of the product was then awaited, possibly aided by seeding. To complete the precipitation, the second portion of deionized water was then added. At the end of the addition, a dark green-grey fluid suspension was obtained which was maintained at T = 20+-5C for at least 2 hours, then filtered and washed thoroughly with deionized water until the pH of the final wash liquid was 7-8. 481.0 g of a wet product of light hazel colour was obtained, equal to 425.0 g of dry product. Theoretical yield = 504.54 g Percentage yield relative to theoretical = 84.23% The intermediate (4) obtained was then analyzed and the following results were obtained: HPLC purity = 99.81 % GC purity = 99.85% The product was also subjected to the following analyses for its characterization. The following results were obtained: Melting point was 48C.Elemental analysis: Found C = 62.83% H = 6.76% Theoretical C = 62.85% H = 6.71%Mass analysis: CI+/MS 211 [MH+], 210 [(MH+)-H]+ NMR Spectroscopy analysis: 13C NMR- APT 56.3 (OMe), 65.5 (CH2), 70.5 (CH2), 102.4 (C8-CH), 112.4 (CH), 121.1 (CH), 122.2 (CH), 148.6 (C), 150.1 (C) 1H-NMR 3.84 (3H, s, OMe), 3.9-4.1 (4H, m, H-9/H-10), 4.07 (2H, d, J = 4 Hz, H-7), 5.33 (1 H, t, J = 4 Hz, H-8), 6.7-7.0 (4H, m). EXANIPLES 3-31 Step a) Preparation of the intermediate (4) of formula 2-[(2-methoxyphenoxy)methyl-1,3-dioxolane (4) By following the same procedure as shown in example 1, but using the amounts, reaction solvent, times and temperatures indicated in Table 3, the intermediate (4) was obtained in the yields and purities indicated in Table 4 to follow. Table 3: Reaction conditions for examples 3-31 Guaiacol g (mol)K2CO3 g (mol) 2-BrMe-1,3-dioxolane g (mol) Solvent type (ml)Treaction (C) Time (hours) Ex.3 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (110) 123/124 16 Ex.4 49.6(1) 82.92 (1.5) 79.2 (1.18) 1-methoxy-2-propanol (110) 124/128 18 Ex.5 49.6(1) 110.56(2) 79.2(1.18) 1-methoxy-2-propanol (165) 122/125 17 Ex.6 148.8(1) 331.7(2) 236.5(1.18) 1-methoxy-2-propanol (495) 123/126 20 Ex.7 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/125 20 Ex.8 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/126 20 Ex.9 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/126 20 Ex.10 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (110) 124 20 Ex.11 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (150) 124 20 Ex.12 49.6(1) 66.34(1.2) 79.2(1.18) 1-methoxy-2-propanol (200) 124 20 Ex.13 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 125 20 Ex.14 148.8(1) 331.7(2) 236.5(1.18) 1-methoxy-2-propanol (495) 129 20 Ex.15 99.2(1) 132.68(1.2) 157.7(1.18) 1-methoxy-2-propanol(400) 126/127 20 Ex.16 99.2(1) 221.14(2) 157.7(1.18) 1-methoxy-2-propanol(400) 126/127 20 Ex.17 99.2(1) 132.7(1.2) 158(1.18) 1-methoxy-2-propanol(220) 126 20 Ex.18 99.2(1) 132.7(1.2) 158 (1.18) 1-methoxy-2-propanol(220) 128 20 Ex.19 49.6(1) 66.34(1.2) 79.2 (1.18) Dimethylformamide (110) 127 10 Ex.20 49.6(1) 66.34(1.2) 79.2 (1.18) Dimethylacetamide (110) 128-132 10 Ex.21 49.6(1) 66.34(1.2) 79.2 (1.18) Diglyme(110) 130-138 20 Ex.22 49.6(1) 66.34(1.2) 79.2(1.18) Ethylcellosolve (110) 132 20 Ex.23 49.6(1) 66.34(1.2) 79.2(1.18) Ethylene glycol (110) 132 20 Ex.24 49.6(1) 66.34(1.2) 79.2 (1.18) Methylcellosolve (110) 125-126 17 Ex.25 99.2(1) 132.7(1.2) 158.4(1.18) 1-methoxy-2-propanol(220) 128 20 Ex.26 99.2(1) 132.7(1.2) 158.4(1.18) 1-methoxy-2-propanol(220) 131 20 ... |
25.8% | With potassium carbonate; In diethylene glycol dimethyl ether; at 130 - 138℃; for 20h;Product distribution / selectivity; | EXANIPLES 3-31 Step a) Preparation of the intermediate (4) of formula 2-[(2-methoxyphenoxy)methyl-1,3-dioxolane (4) By following the same procedure as shown in example 1, but using the amounts, reaction solvent, times and temperatures indicated in Table 3, the intermediate (4) was obtained in the yields and purities indicated in Table 4 to follow. Table 3: Reaction conditions for examples 3-31 Guaiacol g (mol)K2CO3 g (mol) 2-BrMe-1,3-dioxolane g (mol) Solvent type (ml)Treaction (C) Time (hours) Ex.3 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (110) 123/124 16 Ex.4 49.6(1) 82.92 (1.5) 79.2 (1.18) 1-methoxy-2-propanol (110) 124/128 18 Ex.5 49.6(1) 110.56(2) 79.2(1.18) 1-methoxy-2-propanol (165) 122/125 17 Ex.6 148.8(1) 331.7(2) 236.5(1.18) 1-methoxy-2-propanol (495) 123/126 20 Ex.7 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/125 20 Ex.8 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/126 20 Ex.9 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 123/126 20 Ex.10 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (110) 124 20 Ex.11 49.6(1) 66.34(1.2) 79.2 (1.18) 1-methoxy-2-propanol (150) 124 20 Ex.12 49.6(1) 66.34(1.2) 79.2(1.18) 1-methoxy-2-propanol (200) 124 20 Ex.13 148.8(1) 199.02(1.2) 236.5(1.18) 1-methoxy-2-propanol (330) 125 20 Ex.14 148.8(1) 331.7(2) 236.5(1.18) 1-methoxy-2-propanol (495) 129 20 Ex.15 99.2(1) 132.68(1.2) 157.7(1.18) 1-methoxy-2-propanol(400) 126/127 20 Ex.16 99.2(1) 221.14(2) 157.7(1.18) 1-methoxy-2-propanol(400) 126/127 20 Ex.17 99.2(1) 132.7(1.2) 158(1.18) 1-methoxy-2-propanol(220) 126 20 Ex.18 99.2(1) 132.7(1.2) 158 (1.18) 1-methoxy-2-propanol(220) 128 20 Ex.19 49.6(1) 66.34(1.2) 79.2 (1.18) Dimethylformamide (110) 127 10 Ex.20 49.6(1) 66.34(1.2) 79.2 (1.18) Dimethylacetamide (110) 128-132 10 Ex.21 49.6(1) 66.34(1.2) 79.2 (1.18) Diglyme(110) 130-138 20 Ex.22 49.6(1) 66.34(1.2) 79.2(1.18) Ethylcellosolve (110) 132 20 Ex.23 49.6(1) 66.34(1.2) 79.2(1.18) Ethylene glycol (110) 132 20 Ex.24 49.6(1) 66.34(1.2) 79.2 (1.18) Methylcellosolve (110) 125-126 17 Ex.25 99.2(1) 132.7(1.2) 158.4(1.18) 1-methoxy-2-propanol(220) 128 20 Ex.26 99.2(1) 132.7(1.2) 158.4(1.18) 1-methoxy-2-propanol(220) 131 20 Ex.27 148.8(1) 199.02(1.2) 237.68(1.18) 1-methoxy-2-propanol(330) 128/131 24 Ex.28 49.6(1) 82.92 (1.5) 79.2(1.18) 1-methoxy-2-propanol(110) 125/127 16 Ex.29 49.6(1) 82.92 (1.5) 79.2(1.18) 1-methoxy-2-propanol(110) 123/126 20 Ex.30 148.8(1) 199.02 (1.2) 237.6(1.18) 1-methoxy-2-propanol(330) 124/129 24 Ex.31 148.8(1) 248.78(1.5) 237.6 (1.18) 1-methoxy-2-propanol(330) 125/129 24Table 4: Yield and purity of the intermediate (4) obtained from examples 3-31 Yield (g) Theoretical yield (g) % yield/theoretical yield HPLC purity GC purity Ex.3 74.26 84.09 88.31 99.63 99.23 Ex.4 72.62 84.09 86.35 99.61 99.56 Ex.5 73.65 84.09 87.58 99.72 99.25 Ex.6 223.0 251.78 88.56 99.70 99.46 Ex.7 214.2 251.78 85.07 99.48 99.40 Ex.8 207.4 251.78 82.37 99.65 99.28 Ex.9 206.0 251.78 81.81 99.70 99.36 Ex.10 70.34 84.09 83.65 99.89 99.02 Ex.11 71.41 84.09 84.92 99.74 99.68 Ex.12 67.77 84.09 80.59 99.83 99.50 Ex.13 209.1 251.78 83.0 99.73 99.16 Ex.14 206.0 251.78 81.82 99.68 99.14 Ex.15 127.4 168.19 75.75 99.46 - Ex.16 138.8 168.19 82.52 99.71 - Ex.17 129.2 168.19 76.86 99.06 99.89 Ex.18 127.45 168.19 75.78 99.12 99.55 Ex.19 65.5 84.09 77.8 99.31 98.50 Ex.20 67.9 84.09 80.75 95.94 99.34 Ex.21 21.70 84.09 25.8 98.98 99.21 Ex.22 66.6 84.09 79.2 98.60 99.38 Ex.23 67.8 84.09 80.6 97.01 97.81 Ex.24 74.50 84.09 88.59 99.48 99.82 Ex.25 138.36 168.19 82.3 99.39 99.88 Ex.26 136.75 168.19 81.3 98.76 99.88 Ex.27 207 251.78 82.15 99.87 99.87 Ex.28 72 84.09 85.71 99.95 99.78 Ex.29 72.6 84.09 86.43 99.86 99.89 Ex.30 212.3 251.78 84.32 99.76 99.78 Ex.31 217.1 251.78 86.22 99.77 99.77 Therefore, in all the examples the intermediate (4) is obtained in high yields and at purities greater than 99%. According to the present invention, the intermediates of examples 1, 28, 29 and 31 had the best appearance and quality. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | In toluene; for 24h;Heating / reflux; | A solution of 2-bromomethyl-[1,3]dioxolane (60.0 mmol) and triphenylphosphine (60.0 mmol) in toluene (50 mL) was refluxed for 24 hours. A solid thus formed was filtered at room temperature, washed with diethyl ether and dried under reduced pressure to yield the title compound.Yield: 3.5 g (54%)M.P: 194-195 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | A 250 mL round bottom flask was charged with anhydrous DMF (30 mL) and sodium hydride (0.56 g of a 60% dispersion, 14.0 mmol). The suspension was cooled to 0 C. and 1-cyclohexyl-2-(2-pyridyl)ethan-1-one (2.03 g, 10 mmol) in THF (30 mL) was added dropwise to the suspension. After addition was complete, the reaction was stirred for 2.5 hours at room temperature. Then <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (1.55 mL, 15 mmol) was added and the reaction was heated at reflux for 16 hours. The reaction mixture was then quenched with water and extracted with diethyl ether (4×50 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate:hexane, 3:7, silica gel) to provide 1-cyclohexyl-3-(2-(1,2-dioxolane))-2-(2-pyridyl)propan-1-one (1.79 g, 62%) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Scheme III, step B: 1-cycloheptyl-2-(2-pyridyl)ethan-1-one (5.0 g, 23.0 mmol, prepared above in Scheme III, step A) was dissolved in anhydrous THF (50 mL) was added dropwise to a suspension of sodium hydride (1.29 g of a 60% dispersion, 32.2 mmol) in anhydrous DMF cooled to 0 C. The reaction mixture was then warmed to room temperature and stirred for one hour. Then <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (3.58 mL, 34.5 mmol) and potassium iodide (0.5 g, crushed) were added and the reaction mixture was heated at reflux for 16 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography (ethyl acetate/hexane, 3/7, silica gel) to provide 1-cycloheptyl-3-(2-(1,3-dioxolane))-2-(2-pyridyl)propan-1-one (4.52 g, 65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | Step 1: Methyl H-imidazo [1, 2-a] pyridine-6-carboxylate (288) [0443] A solution of 2- (BROMOMETHYL)-1, 3-DIOXOLANE (0.18 mL; 1.67 MMOL) in THF (3 mL) and water (0.2 mL) was treated with concentrated HCI (3 drops) and stirred at 88C for 50 min. The solution was cooled down to 0C and transferred into a vial containing 2-amino-5- METHOXYCARBONYLPYRIDINE (287,204mg ; 1. 34MMOL), BU2SNCI2 (134 mg; 0.40 MMOL) and NAHC03 (410 mg) and stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate (60mL) and washed with saturated aqueous sodium chloride. The organic layer was dried (MGS04), filtered and concentrated. After chromatographic purification of the residue using preparative TLC on silica gel (eluent 50% ethyl acetate in dichloromethane), the title compound 288 was obtained (74 mg, 31% YIELD). H NMR: (500.7 MHz, CDCI3) 6 (PPM) : 9. 00 (S, 1H); 7.80 (m, 4H); 4.00 (s, 3H). MS: CALC : 176.1 ; found: 177.1 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | The 5- (1, 3-dioxolan-2-ylmethoxy)-2-methylpyridine used as starting material was prepared as follows:- To a stirred solution of 2-methyl-5-hydroxypyridine (16.0 g, 0.147 mole) in dry DMF (100 mL) at 25C was added portionwise sodium hydride (60% dispersion in oil, 6.0 g, 0.15 mole) during 10 minutes. To the mixture was added 2-bromomethyl-1, 3-dioxolane (16. 0 mL, 0.154 mole) and the resulting mixture heated at 100C for 12 hours, cooled to 25C and diluted with ice/water (400 g). The product was extracted into diethyl ether (400 mL), dried over anhydrous magnesium sulphate, and the solvent evaporated at reduced pressure to give the title compound as an oil (25 g, 87%) ; NMR Spectrum: (CDCl3) 2.50 (s, 3H), 3.94-4. 04 (m, 6H), 5.27 (t, 1H), 7.05 (d, 1H), 7.15 (dd, 1H), 8.22 (d, 1H) ; Mass Spectrum : M+H+ 196. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Step 1: methyl 2-bromo-3-cyclohexyl-l -( 1.3-dioxolan-2-ylmethyl)-l H-indole-6-carboxylate; NaH (1.5 eq, 60 % dispersion in mineral oil) was added to a solution of methyl 2-bromo-3-cyclohexyl- lH-indole-6-carboxylate (prepared as described in published International Patent application WO 2004/065367, from commercially available methyl indole-6-carboxylate) in DMF (0.1 M) and once effervescence had subsided the solution was stirred at RT for a further 30 min. 2-bromomethyl-l,3- dioxolane (4 eq) and catalytic (0.025 eq) KI were then added and the mixture heated at 50 0C for 36 h. The reaction mixture was then allowed to cool to RT, quenched with aqueous HCl (1 N) and extracted EPO <DP n="26"/>with EtOAc. The organics were washed with aqueous HCl (1 N) (3x), water and brine before being dried over Na2SO4, filtered and the solvent evaporated in vacuo. Purification was by flash chromatography (10 % EtOAc/PE) to give a pale yellow solid that was triturated with Et2O/PE) to afford the title compound as a white solid (69 %); MS (ES+) m/z 422 (M+H)+, m/z 424 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
ExampIe-8 Preparation of 2-[2-(2,2,2-trifluoro ethoxy) phenoxy ethyl]-[1,3] dioxalane (XII) Mixture of <strong>[160968-99-0]2-(2,2,2-trifluoroethoxy)phenol</strong> (XI) (6 g, 0.031 mole), N-methyl-2- pyrrolidone (30 ml), potassium carbonate ( 8.6 g 0.062 mole) and Bromo acetaldehyde ethylene glycol ( 6.26 g, 0.037 mole) was heated to 115-120C and stirred for 5 hours. Water (120 ml) was added to reaction mixture at ambient temperature and pH adjusted to 3-4 with mineral acid. The mixture was extracted using Ethyl acetate (200 ml). Organic layer was washed with aqueous sodium bicarbonate solution followed by water. Organic layer was dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (5/95) as eluent to give 4.0 g of (XII) as colourless solid, melting at 37.6-39.6C.Purity (By GC) = 98 %IR (KBr): 1748.8, 1598.6, 1509, 1451.5, 1261.1, 1163, 1127.2, 1055.9, 1047.1 cm'1 1H NMR (300 MHz, CDC13): 3.93-3.98 (2H, d), 4.05-4.08 (4H,m), 4.36-4.45(2H,q), 5.314-5.338 (lH, t) , 6.90-7.05 (4H, m), ppmI3C NMR (75MHz, CDC13): 65.36(2C), 67.39-68.79(lC), 70.01(1C), 101.89(1C), 114.8, 118.10, 121.87, 124.18 (4C), 149.62 (1C), 147.48(1C), 128.22-129.03(1 C) | ||
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 115 - 120℃; for 5.0h; | Mixture of <strong>[160968-99-0]2-(2,2,2-trifluoroethoxy)phenol</strong> (XI) (6 g, 0.031 mole), N-methyl-2-pyrrolidone (30 ml), potassium carbonate (8.6 g 0.062 mole) and Bromo acetaldehyde ethylene glycol (6.26 g, 0.037 mole) was heated to 115-120 C. and stirred for 5 hours. Water (120 ml) was added to reaction mixture at ambient temperature and pH adjusted to 3-4 with mineral acid. The mixture was extracted using Ethyl acetate (200 ml). Organic layer was washed with aqueous sodium bicarbonate solution followed by water. Organic layer was dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (5/95) as eluent to give 4.0 g of (XII) as colourless solid, melting at 37.6-39.6 C.Purity (By GC)=98%IR (Mk): 1748.8, 1598.6, 1509, 1451.5, 1261.1, 1163, 1127.2, 1055.9, 1047.1 cm-1 1H NMR (300 MHz, CDCl3): 3.93-3.98 (2H, d), 4.05-4.08 (4H, m), 4.36-4.45 (2H, q), 5.314-5.338 (1H, t), 6.90-7.05 (4H, m), ppm13C NMR (75 MHz, CDCl3): 65.36 (2C), 67.39-68.79 (1C), 70.01 (1C), 101.89 (1C), 114.8, 118.10, 121.87, 124.18 (4C), 149.62 (1C), 147.48 (1C), 128.22-129.03 (1C) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; | General procedure: A 10 mL round bottom flask was charged with phenylamidinium hydrochloride (31.7 mg, 0.203 mmol), 3-carbethoxy-4-piperidone hydrochloride (50 mg, 0.184 mmol), powdered K2CO3 (63.7 mg, 0.461 mmol), and a stirbar. The flask was sealed and charged with DMF (1.23 mL) followed by allyl chloride (37.9 muL, 0.461 mmol). With vigorous stirring, the reaction mixture was heated to 70 C for 2 h, and reaction progress was monitored by LCMS. Upon completion of the reaction, the reaction mixture was diluted with EtOAc (10 mL), and washed with sat. aq NaHCO3 (10 mL) and brine (10 mL). The combined aqueous phases were back-extracted with EtOAc (5 mL), and the combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by gradient elution on silica gel (0-25% EtOAc/hexanes) to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 5h; | Example 54N-hydroxy-2-{2-[(4-methoxyphenyl)amino]ethyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxamide; Compound I-97 Step 1: methyl 2-(1,3-dioxolan-2-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylateTo a solution of methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.5 g, 1.72 mmol) in DMF (10 mL) was added potassium carbonate (1.2 g, 8.6 mmol) and 2-(bromomethyl)-1,3-dioxolane (0.62 mL, 6.03 mmol). The reaction mixture was heated at 140 C. and stirred for 5 h. The mixture was cooled to rt, water was added and the mixture was extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 50% EtOAc/hexanes) to afford methyl 2-(1,3-dioxolan-2-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.32 g, 64%). LC-MS: (FA) ES+290. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.2% | Step 5: Benzyl 4-(1-((1,3-dioxolan-2-yl)methyl)-4-(4-fluoro-3-(trifluoromimidazol-2-yl)piperidine- 1 -carboxylateThe solution of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1 H-imidazol-2-yl]-piperidine-1 - carboxylic acid benzyl ester (1 100.00 mg; 2.46 mmol; 1 .00 eq.) in 2.0 ml of THF was cooled to -20<?, NaHMDS (541 .00 mg; 2.95 mmol; 1.20 eq.) was added dropwise and the resulting mixture was stirred at RT for 30mins. 2-Bromomethyl-[1 ,3]dioxolane (0.76 ml; 7.38 mmol; 3.00 eq.) was added and stirred at RT for 5min. DMSO (10 ml) was added and the mixture was placed in microwave at ? ??'? for 2hr. The reaction mixture was cooled and diluted with water and extracted with EA. The organic layer was washed with brine, separated, dired and concentrated. The residue was subjected to snap column(I OOg), eluted with 20% -80% EA in hexane to give the title compound (1000mg, yield 76.2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.1% | With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 25℃; for 3.08333h;Inert atmosphere; | A three-necked reactor equipped with a thermometer was charged with 2.00 g (12.1 mmol) of 2-hydrazinobenzothiazole and 30 ml of DMF under a nitrogen stream to prepare a solution. After the addition of 7.88 g (24.2 mol) of cesium carbonate to the solution, the mixture was cooled to 0 C. After the addition of 2.42 g (14.5 mmol) of <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> to the mixture over 5 minutes, the mixture was stirred at 25 C. for 3 hours. After completion of the reaction, 200 ml of water was added to the reaction mixture, followed by extraction twice with 100 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and sodium sulfate was separated by filtration. The filtrate was concentrated using a rotary evaporator, and the concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=55:45) to obtain 1.31 g of an intermediate E2 as a white solid (yield: 43.1%). [0652] The structure of the target product was identified by 1H-NMR. [0653] 1H-NMR (500 MHz, CDCl3, TMS, delta ppm): 7.60 (dd, 1H, J=1.0 Hz, 7.5 Hz), 7.53 (dd, 1H, J=1.0 Hz, 7.5 Hz), 7.27 (ddd, 1H, J=1.0 Hz, 7.5 Hz, 7.5 Hz), 7.06 (ddd, 1H, J=1.0 Hz, 7.5 Hz, 7.5 Hz), 5.19 (t, 1H, J=4.5 Hz), 4.63 (s, 2H), 3.93-4.05 (m, 4H), 3.86-3.94 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium thiocyanide; caesium carbonate; In acetonitrile; at 60℃; for 1h;Inert atmosphere; | General procedure: An oven-dried 20 mL crimp cap vessel with Teflon-coatedstirrer bar was charged with cesium carbonate (652 mg, 1 mmol) and sodiumthiocyanate (100 mg, 1.20 mmol). After exchanging the atmosphere three times withnitrogen, MeCN (2 mL), TMSCF3 (537 mg, 0.6 ml, 1.2 mmol) and the alkyl halide ormesylate (1.00 mmol) were added via syringe. The suspension was heated understirring until completion of the reaction was determined by GC and GC-MS (followingtemperatures were required depending on the leaving group: primary alkyl bromidesand -iodides 60 C; secondary alkyl bromides and primary -chlorides 90 C and alkylmesylates 110 C). After the reaction time the resulting mixture was diluted with Et2O(20 ml), and washed with water (2 × 10 mL) and brine (10 mL). The organic layer wasdried over MgSO4, filtered and concentrated under reduced pressure (700 mbar,40 C). Most compounds were obtained in pure form, for aromatic substitutedcompounds the residue was purified with column chromatography (SiOH,Et2O/pentane gradient). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium hydride; In N,N-dimethyl-formamide; | full text is not available from article |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 18h; | T h e ( 2-methoxyphenyl)methyl 4-(4-chlorophenyl)-6-methyl-2-oxo-3,4-dihydro-1 H-pyridine-5- carboxylate (1 15 mg, 0.30 mmol) was dissolved in anhydrous DMF (1 ml_). Cesium carbonate (195 mg, 0.60 mmol) and 2-Bromomethyl-1 ,3-dioxolane (62 muIota_, 0.60 mmol) were added. The reaction mixture was stirred at 60 C for 18 h. The DMF was removed under reduced pressure. The residue was diluted in water and extracted by EtOAc. The organic layers were assembled, washed by brine and dried on MgSC>4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography using a mixture of Cyclohexane/EtOAc (8/2) as eluent to give the desired (2-methoxyphenyl)methyl 4-(4-chlorophenyl)-1 -(1 ,3-dioxolan- 2-ylmethyl)-6-methyl-2-oxo-3,4-dihydropyridine-5-carboxylate as a colorless oil (73 mg, 52 %). 1H NMR (300 MHz, CDCI3) delta 2.61 (s, 3H), 2.76 (dd, J = 15.9, 2.2 Hz, 1 H), 2.93 (dd, J = 15.9, 7.4 Hz, 1 H), 3.64 (dd, J = 14.6, 5.4 Hz, 1 H), 3.83 (s, 3H), 3.78-3.94 (m, 4H), 4.23 (dd, J = 7.4, 2.2 Hz, 1 H),4.34 (dd, J = 14.6, 3.1 Hz, 1 H), 4.86 (dd, J = 5.4, 3.1 Hz, 1 H), 5.11 (d, J = 12.9 Hz, 1 H), 5.23 (d, J = 12.9 Hz, 1 H), 6.81-6.87 (m, 2H), 7.01 (dd, J = 7.4, 1.5 Hz, 1 H), 7.13 (d, J = 8.6 Hz, 2H), 7.19 (d, J= 8.6 Hz, 2H), 7.27 (td, J= 7.9, 1.9 Hz, 1H).13C NMR (75 MHz, CDCI3) delta 17.1, 36.6, 38.4, 43.6, 55.1, 61.8, 64.9, 101.3, 110.1, 110.8, 120.2, 124.2, 128.5, 128.5, 129.1, 129.3, 132.4, 139.5, 150.0, 157.2, 167.0, 169.2. MS [M+H]+ 472. HRMS : calcd for CaHz/NOeCI, [M+H]+ 472.1527, found 472.1533. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | General procedure: N-2,3-Dihydro-1,4-benzodioxin-6-yl-4-acetamidobenzenesulfonamide (0.2 g; 0.57 mmol; III) in 10 mL N,N-dimethyl formamide (DMF) was placed into 50 mL round bottomed flask along with lithium hydride (0.004 g) and the reaction mixture was stirred for 30 min at 25C. Then alkyl/aralkyl halides (0.57 mmol; IVa-s) were added in the reaction mixture, which was further stirred for 4-5 h. The reaction was monitored by TLC till single spot. After completion, the reaction mixture was poured onto crushed ice and precipitates of products were filtered out, washed, and air-dried to obtain pure products (Va-s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium carbonate; potassium iodide; In dimethyl sulfoxide; at 100℃; for 12h; | (1) Ethyl 2-oxocyclopentanecarboxylate (940 mg, 6 mmol) and 2-bromoacetaldehyde ethylene acetal(2 g, 12 mmol) were dissolved in 20 ml of dimethylsulfoxide,Potassium carbonate (2.1 g, 12 mmol) and potassium iodide (996 mg, 6 mmol) were added sequentially. The above reaction was stirred at 100 C for 12 hours. The mixture was extracted with ethyl acetate (20 ml) three times. The combined organic layers were washed successively with saturated aqueous sodium hydrogencarbonate solution, water and brine, dried over anhydrous magnesium sulfate,And then dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to remove the solvent. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20: 1 by volume) to obtain 940 mg of a colorless oil. Identified as Compound 2 in 65% yield. The correlation analysis data are as follows: |
64% | With potassium carbonate; potassium iodide; In dimethyl sulfoxide; at 100℃; for 12h;Inert atmosphere; | To a solution of ethyl 2-oxocyclopentanecarboxylate (2.0 g, 12.8 mmol)and 2-(bromomethyl)-1,3-dioxolane (4.2 g, 25.6mmol) in DMSO (40ml) under Ar wasadded K2CO3 (3.5g,25.6 mmol) and KI (2.1 g, 12.8 mmol ),the mixture was stirred at 100 C for 12h. After being poured to cold ether/water, the mixture was thoroughly extracted with EtOAc, washed sequentially with saturated aqueous sodium carbonate solution, water, and brine, and dried over Na2SO4. Filtration and concentration afforded the crude product. Purification by column chromatography using EtOAc/Petroleumether (1:10) gave 5(2.0 g, 64%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | General procedure: To a solution of intermediate7(0.5 mmol)inDMFwere added carbon disulfide (0.30 mL, 5.0 mmol) and finely powdered potassium phosphate (0.21 g, 1.0 mmol). After stirring at rt for 30 min, the appropriate benzyl bromide, cyclohexyl bromide, or chloromethylpyridine hydrochloride(0.5 mmol)was added and stirring was continued for 2 h. The mixture was poured into ice-water (40 mL), and the solution was extracted with dichloromethane(15 mL × 3). The combined extracts were washed with saturated brine and dried overanhydrous sodium sulfate overnight. After evaporation of the solvent, the crude productwas purified by column chromatography using dichloromethane/methanol (95:5, v/v) as eluent to give final compounds 8a-q. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.2% | To a reaction vessel, 10.326kg (166.3mol) of ethylene glycol was added with 3.66 Kg (83.185mol) of freshly distilled acetaldehyde and stirred slowly at room temperature for 30 mins. 14.622 Kg (91.504 mol) of bromine was added dropwise, after the dropwise addition, the reaction was carried out at 0-3C for 3.5h, and the fraction was distilled under reduced pressure. The fractions (3.6 kPa) and 11.002 Kg (65.883 mol) of 80-82 C were collected and identified as bromoacetaldehyde ethylene glycol, the yield is 79.2%, the content is more than 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tetrabutylammomium bromide; sodium hydroxide; In acetone; for 6.3h;Reflux; Large scale; | To the reaction tank, 13 Kg (72.16 mol) of theophylline, 8L of acetone, 5.77 Kg of sodium hydroxide (144.32 mol) and 0.7 Kg of tetrabutylammonium bromide (2.16 mol) were added to the reaction vessel. After stirring for 10 min, 14.47 Kg of bromoacetaldehyde ethylene acetal (86.64mmol) was added. The mixture was refluxed for 6.3h and the end point of the reaction was monitored by thin layer chromatography (acetone: dichloromethane = 3: 1). After the completion of the reaction, the solvent was distilled off under reduced pressure, washed three times with saturated brine, and the residue was recrystallized from absolute ethanol to give 17.28 kg of doxofylline (64.98 mol) in a yield of 90%, the content is above 98.5%. |
7 g | With sodium carbonate; In N,N-dimethyl-formamide; at 120℃; | take 10g of theophylline, 12g bromoacetaldehyde ethylene glycol, 7.5g anhydrous sodium carbonate, added to 80ml dimethylformamide, the oil bath heated to 120 , until the basic reaction of raw materials, stop heating, The filtrate was evaporated under reduced pressure and recrystallized from ethyl acetate to give the product Doxofylline.The quality of the product Doxofylline was 7 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.4% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; | A mixture of compound 15G (800 mg, 1.55 mmol, 1 .0 eq), 2- (bromomethyl)-l ,3-dioxolane (780mg, 4.65 mmol, 3.0 eq) and CS2CO3 (2.5 g, 7.75 mmol, 5.0 eq) in anhydrous DMF (40 mL) was stirred at room temperature overnight. The mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=10: 1) to give compound 26A (140 mg, 16.4%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.2% | With potassium carbonate; sodium iodide; at 80 - 100℃; for 24h; | 29.24 g (258.5 mmol) of ethyl cyanoacetate, 0.52 g (3.46 mmol) of NaI, 7.41 g (53.6 mmol) of K2CO3, And 9.185 g (55 mmol) of <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> was slowly added dropwise.After completion of the dropwise addition of <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong>, the temperature was slowly raised to 80 C and the reaction was stirred for 4 hours while raising the temperature. Then, the temperature was gradually raised to 100 C and stirring was continued for 20 hours.Then, 50 mL of water was added to dissolve the reaction system, followed by methyl tert-butyl ether extraction (100 ml * 2), organic phase drying, filtration, water pump vacuum distillation and the like, the residue was pumped under reduced pressure, -122 C (2 mm Hg) to give the product as a colorless liquid, 7.8 g (theoretical yield 10.96 g) in 71.2% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 100℃; for 0.5h;Microwave irradiation; | The alkylation process was optimized by irradiation of the microwave in THF at 100 degree C for 30 min. 1.2 equivalents of 2- (bromomethyl) -1,3-dioxolane were used with NEt3 to give a single-alkylated product in a 4: 1 ratio. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 5000 ml dry three-mouth flask was added magnesium chips (14.4g, 0.60 mol) and dry tetrahydrofuran (1L). Drop 1ml 1,2-dibromoethane and initiate the reaction. Then slowly add dropwise bromoacetaldehyde ethylene acetal (100g, 0.60 mol) in tetrahydrofuran solution (500 ml). After adding dropwise, stir for two hours until magnesium chips disappear. Then <strong>[714273-83-3]5-tert-butyl-1H-imidazole-4-carbaldehyde</strong> (30g, 0.20 mol) in tetrahydrofuran solution (500 ml) was slowly added dropwise to the above solution. Stir overnight. Then use concentrated hydrochloric acid to adjust to acidic (pH=1), and heated to 60 C and stir for 30 minutes. Steaming and remove the tetrahydrofuran, adding the ethyl acetate extraction. The organic phase and water washing twice, a saturated salt water washing, final drying with anhydrous sodium sulfate, concentrated. The crude product is purified by column chromatography (petroleum ether/ethyl acetate of the volume ratio: 2/1) to obtain a yellow solid (17.8g, yield: 50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With N,N,N,N,-tetramethylethylenediamine; sulfur; In acetonitrile; at 100℃; for 24h; | specifically includes the following steps: the molar ratio of the compound of the above formula (1a) and sulfur powder and the formula (2r) is 1:2 : 3 The reaction is carried out under the conditions of the base TMEDA and the solvent CH3CN. The molar equivalent of the base TMEDA is 1 eq of the compound of the formula (1a), wherein the amount of the compound of the formula (1a) is 0.2 mmoL, and the solvent CH3CN is 2 mL, which is added to 10 mL in order. The reaction tube was stirred at 100 C. for 24 hours; after the reaction was completed, the mixture was cooled, the mixture was diluted with AcOEt, and the mixture was washed with water. The resulting organic phase was extracted and dried over anhydrous sodium sulfate. The filtrate was filtered off with suction and the solvent was removed by rotary evaporation. The residue was chromatographed on silica gel, eluted with petroleum ether/ethyl acetate, and checked by TLC. The effluent containing the product was combined. The solvent was distilled off on a rotary evaporator and dried in vacuo to give a brown liquid, which was a compound of formula (25). 43%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.6% | In toluene; at 110℃; for 4h; | O,O-dipropylmethylphosphonite (Compound VII) (82.0 g, 0.5 mol) was added to a 500 mL round bottom flask.Bromoacetaldehyde Ethylene Glycol (100.2g, 0.6mol)And toluene (200ml).Heat, reflux at 110C for 4h (GC monitoring reaction),After cooling to room temperature, the reaction solution was distilled under reduced pressure.At a pressure of 15 mmHg, 72.5 g of a 122 C. fraction (Compound V) was collected with a yield of 71.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.8% | In toluene; at 110℃; for 5h;Inert atmosphere; | 136 g (1 mol) of diethyl methylphosphinate was added to a 1 L four-necked flask.Bromoacetaldehyde ethylene glycol 167g (1mol) and toluene 400ml, heated under nitrogen protection,The reaction was refluxed at 110 C for 5 h (GC detection reaction endpoint),After cooling to room temperature, the reaction liquid was distilled under reduced pressure.The 120 C fraction was collected under 10 mmHg to obtain 2-(o-ethylmethylphosphono)acetaldehyde acetal182 g, yield 93.8%, |
82.6% | at 120℃; for 2h; | Methyl-phosphonous acid diethyl ester (Compound VII) (68.0 g, 0.5 mol) was added to a 500 mL round bottom flask. Bromoacetaldehyde ethylene acetal (100.2 g, 0.6 mol).Heat, reflux at 120C for 2h (GC monitoring reaction),After cooling to room temperature, the reaction solution was distilled under reduced pressure.80.1 g of a 120 C. fraction (compound V) was collected under a pressure of 15 mmHg, with a yield of 82.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
870 mg | Ethyl 3-oxo-4-phenylbutyrate (1.03 g, according to the European Journal of Medicinal The method described in Chemistry, 2014, Vol 84, 312-334] is dissolved in anhydrous tetrahydrofuran (20 ml), cooled in an ice-water bath, and slowly added in small portions with 60% purity of mineral oil and sodium hydride under nitrogen flow The solid was mixed (200 mg) and stirred for 0.5 h; then hexamethylphosphoramide (2.7 g) and a 1.6 M solution of n-butyllithium in hexane (3.13 ml) were added sequentially;2-Bromomethyl-1,3-dioxolane (840 mg) was then added. The reaction was stirred at room temperature overnight. The reaction solution was carefully poured into saturated aqueous ammonium chloride, and then extracted with ethyl acetate; the ethyl acetate layer was separated, and then washed twice with dilute aqueous sodium chloride solution; the ethyl acetate phase was dried over anhydrous sodium sulfate; The desiccant was removed by filtration and the filtrate was spin-dried on a rotary evaporator; the residue was purified by column chromatography to give the product 1b (870 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 20℃; for 72h; | The synthesis of compound (21 8) was carried out according to procedure reported in the literature with minor modification [33]. A mixture of 18 benzimidazole (0.11g, 1.0mmol), 17 <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (0.17g, 1.0mmol) and 19 potassium carbonate (0.21g, 1.5mmol) in 20 acetonitrile was stirred in room temperature for 72h. Then the reaction mixture was washed with fresh acetonitrile (3×10mL) and dried under vacuum to access pure (8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | General procedure: To a suspension of NaH (720 mg, 30 mmol, 3.0 equiv) in DMF(35 mL), was added a solution of mercaptobenzothiazole (1.7 g,10 mmol, 1.0 equiv) in DMF (5 mL). The mixture was stirred atroom temperature for 30 min. Alkyl halide (11 mmol, 1.1 equiv)diluted in DMF (2 mL) was then introduced to the yellow solution.The reaction was stirred at 70 C for 3 h, quenched withwater, and extracted with Et2O. The organic layer was washedfive times with brine, dried over MgSO4, filtered, and concentratedunder reduced pressure. The yellow residue was thenpurified by column chromatography on silica gel to afford theexpected compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With bismuth(III) chloride In acetonitrile at 80℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.3% | 167 g of 1 mol of <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong> (compound of formula III) was added to 500 ml of ethyl acetate to give an organic mixture of <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong>. Solution; under the temperature control of 10 C or less, add 100 ml of concentrated hydrochloric acid (1.2 moL) with a concentration of 12 mol/L to the organic mixed solution of <strong>[4360-63-8]2-bromomethyl-1,3-dioxolane</strong>. Stir for 20 minutes, separate the liquid, and add 174 g of 1.5 mol of methyl 3-amino-3-iminopropanoate (compound of formula II) to the organic phase in 4 portions, reflux at 100 C until the reaction is complete, filter, and concentrate the filtrate. 125 g of 2-amino-3-carboxypyrrole methyl ester was obtained in a yield of 89.3%.The next step reaction is carried out without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.6% | 167 g, i.e., 1 mol of 2-bromomethyl-1,3-dioxolane (i.e., a compound of formula III) was added to 500 ml of 2-methyltetrahydrofuran to give 2-bromomethyl-1,3-dioxolane. The organic mixed solution is controlled to a temperature below 10 C; and then 100 ml of sulfuric acid (0.18 moL) with a mass fraction of 10% is added dropwise to the organic mixed solution of 2-bromomethyl-1,3-dioxolane. After stirring for 20 minutes, the liquid was separated, and 174 g of 1.33 mol of ethyl 3-amino-3-iminopropanoate (the compound of formula II) was added portionwise in the organic phase, and the mixture was heated to reflux at 100 C until the reaction was completed, and the filtrate was filtered. Concentration gave 144 g of 2-amino-3-carboxypyrroleethyl ester in a yield of 93.6%.The next step reaction is carried out without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | General procedure: To a cooled solution of compound 6 (361.0 mg, 1 mmol) in DMF (10 mL) was added NaH (60% in oil, 48.0 mg, 1.2 mmol) carefully. The mixture was stirred at 0 C for 1h. A solution of R1X (X=Cl, Br; 1.2 mmol) in DMF (5 mL) was then added dropwise in the mixture. The mixture was heated to 40 C and stirred for 8-16 h. The reaction mixture was cooled and quenched at 0 C with a saturated NH4Cl aqueous solution. Then mixture was concentrated under vacuum to remove most of the DMF and re-dissolved with CH2Cl2. After filtering, the filtrate was washed with saturated NaCl aqueous solution, dried with MgSO4 and concentrated under vacuum. The crude material was purified by column chromatography (PE/EA) on silica gel to afford compound 6a-6r. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.4% | In ethyl acetate; at 55 - 82℃; under 337.534 - 375.038 Torr; for 4h;Inert atmosphere; | The synthesis reaction equation of bromoacetaldehyde ethylene glycol triphenylphosphine salt is shown in Figure 2,167g bromoacetaldehyde ethylene glycol,393.g Triphenylphosphine and 400g ethyl acetate input1L stainless steel reactor,Close to ensure that the reactor is closed.After evacuating, nitrogen gas is introduced to a pressure of 0.045-0.05MPa,Turn on the stirring and heat up to 55-82,After stirring for 4h,Cool down to 25,Filter after pressure relief,Get 425g of crude product,The product purity measured by gas chromatography is not less than 97%.Put 425g of crude product into a 1000mL flask,Then add ethyl acetate twice the weight of the product,Heat up to boiling state,Reflux for 1h, cool to 25C, filter,Obtained purified bromoacetaldehyde ethylene glycol triphenylphosphine salt product,The color is pure white,The weight is 411g,The purity of the product measured by gas chromatography is not less than 99%.In this embodiment, the molar ratio of bromoacetaldehyde ethylene glycol to triphenylphosphine is 1:1.5,The theoretical output of the product is 429.3g,The actual output of the produced product is 401g,Through the theoretical output of the productThe actual yield of the product is calculated and the total yield of the product is 93.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.6% | Under the protection of nitrogen, add 100 g of tetrahydrofuran, 6.7 g (0.28 mol) of magnesium powder, 1.8 g of bromoacetaldehyde ethylene glycol (II1), 0.02 g of iodine to a 500 ml four-necked flask equipped with a stirring and thermometer, and the reaction is initiated After that, a solution of 40.0 g (total 0.25 mol) of bromoacetaldehyde ethylene glycol (II1) in 120 g of tetrahydrofuran was added dropwise at 30-35C, and the solution was dropped in 1 hour. Afterwards, the reaction was stirred at 35-40C for 2 hours . Cool to 20-25C and transfer to a constant pressure dropping funnel for use. In another 500 ml four-necked flask equipped with a stirring and thermometer, 50 g of tetrahydrofuran and 23.5 g (0.25 mol) of (R,S)-epichlorohydrin were added. The temperature was controlled at 0-5C, the obtained Grignard reagent was added dropwise, the addition was completed after 2 hours, and the reaction was stirred at 10-15C for 2 hours. The resulting reaction mixture was added to a mixture of 60 g of water and 100 g of dichloromethane, stirred for 15 minutes, and allowed to stand for liquid separation. The aqueous phase was extracted twice with dichloromethane, 50 g each time. After the organic phases were combined, they were washed once with 30 g of saturated aqueous sodium chloride solution. After the organic phase was distilled under reduced pressure to remove the solvent, reduced pressure distillation (85-95C/2-3mmHg) gave 32.6 g (4R, 4S)-4,5-epoxy n-pentyl glycol acetal (III1), gas phase The purity is 98.6% and the yield is 90.6%. The above product (4R,4S)-4,5-epoxy n-pentyl glycol acetal is also called (2R,2S)-(3,4-epoxy)butyl-1,3-dioxolane . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With trimethylsilyl trifluoromethanesulfonate In acetonitrile at 20℃; for 0.25h; regioselective reaction; | General synthetic procedure B. General procedure: The 6-Chloropurine (1a, 310 mg, 2.0 mmol), 2-bromomethyl-1,3-dioxolane (2a, 334 mg, 0.21 mL, 2.0 mmol) and corresponding acid anhydride or acyl chloride,e.g., acetic anhydride (3a, 204 mg, 0.2 mL, 2.0 mmol), were dissolved in dry acetonitrile (10 mL).Corresponding Lewis acid (3.0 mmol), e.g., TMSOTf (667 mg, 0.54 mL, 3.0 mmol), was added in oneportion at room temperature and the reaction mixture was stirred for 15 min at room temperature.Reaction work up as in General procedure A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With potassium carbonate In N,N-dimethyl-formamide at 80 - 120℃; for 24h; | |
30% | With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 8h; | 12 Preparation of compound 8-methoxy-3-(2-(methylthio)ethoxy)-6H-benzo[c]benzopyran-6-one (formula 2h): General procedure: Anhydrous DMF (30mL) was added to a 250mL round bottom flask, intermediate V (9.4mmol, 2.28g), anhydrous K2CO3(12.2mmol, 1.7g) and 2-bromoethyl methyl sulfide ( 12.2mmol), and the temperature was controlled at 120°C, and the reaction was stirred for 22h.The reaction was monitored by TLC (petroleum ether: ethyl acetate = 3:1).After the completion of the reaction, the reaction solution was added to the ice-water mixture to obtain a brown solid.After suction filtration and drying, the brown solid was purified by silica gel (200-300 mesh) column chromatography to obtain compound 2h with a yield of 40%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Stage #1: 2,7-dichloro-9H-fluorene With n-butyllithium In tetrahydrofuran; cyclohexane at -78 - 20℃; for 0.5h; Inert atmosphere; Stage #2: 2-bromomethyl-1,3-dioxolane In tetrahydrofuran; cyclohexane at -78 - 20℃; Inert atmosphere; |
[ 3400-55-3 ]
2-Bromopriopionaldehydediethylacetal
Similarity: 0.74
[ 18742-02-4 ]
2-(2-Bromoethyl)-1,3-dioxolane
Similarity: 0.70
[ 36236-76-7 ]
4-(Bromomethyl)-2,2-dimethyl-1,3-dioxolane
Similarity: 0.68
[ 18742-02-4 ]
2-(2-Bromoethyl)-1,3-dioxolane
Similarity: 0.70
[ 17739-45-6 ]
2-(2-Bromoethoxy)tetrahydro-2H-pyran
Similarity: 0.66
[ 14347-78-5 ]
(R)-(2,2-Dimethyl-1,3-dioxolan-4-yl)methanol
Similarity: 0.55
[ 18742-02-4 ]
2-(2-Bromoethyl)-1,3-dioxolane
Similarity: 0.70
[ 36236-76-7 ]
4-(Bromomethyl)-2,2-dimethyl-1,3-dioxolane
Similarity: 0.68
[ 14347-78-5 ]
(R)-(2,2-Dimethyl-1,3-dioxolan-4-yl)methanol
Similarity: 0.55
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 :