There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type | HazMat fee for 500 gram (Estimated) |
Excepted Quantity | USD 0.00 |
Limited Quantity | USD 15-60 |
Inaccessible (Haz class 6.1), Domestic | USD 80+ |
Inaccessible (Haz class 6.1), International | USD 150+ |
Accessible (Haz class 3, 4, 5 or 8), Domestic | USD 100+ |
Accessible (Haz class 3, 4, 5 or 8), International | USD 200+ |
Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 70264-94-7 | MDL No. : | MFCD00270115 |
Formula : | C10H11BrO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | UXSNXOMMJXTFEG-UHFFFAOYSA-N |
M.W : | 259.10 | Pubchem ID : | 2759828 |
Synonyms : |
|
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P501-P261-P273-P272-P264-P280-P302+P352-P391-P362+P364-P333+P313-P305+P351+P338+P310 | UN#: | 3261 |
Hazard Statements: | H315-H318-H317-H410 | Packing Group: | Ⅲ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With N-Bromosuccinimide In tetrachloromethane for 16 h; Heating / reflux | STEP 1 : A mixture of methyl 4-methyl-3-(methyloxy)benzoate (1.00 g, 5.55 mmol), N-bromosuccinimide (1.09 g, 6.10 mmol) and a catalytic amount of 2,2'- azobis(isobutyronitrile) (AIBN) was refluxed in carbon tetrachloride (40 ml) for 16h.The reaction mixture was filtered and the solution was washed with brine (25 ml), <n="394"/>dried over sodium sulfate and concentrated to give methyl 4-(bromomethyl)-3- (methyloxy)benzoate (1.4g, 97percent yield). |
94% | With tert.-butylhydroperoxide; cetyltrimethylammonim bromide; potassium bromide In water at 120℃; Microwave irradiation | General procedure: The reaction mixture was treated in a controlled microwavesynthesizer (Biotage Initiator+SP Wave model, 0–200 W at2.45 GHz, capped at 60 W during steady state) for severalminutes (the reaction attained 120 °C at 1 bar pressure). Thefinal products were isolated by column chromatographyusing an EtOAc–hexane gradient |
92% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In ethyl acetateHeating / reflux | Reference Example 49; Methyl 4-(bromomethyl)-3-methoxybenzoate; A mixture of methyl 3-methoxy-4-methylbenzoate (10.0 g, 55.5 mmol), N-bromosuccinimide (10.7 g, 60.9 mmol), 2,2'-azobis(isobutyronitrile)(1.6 mg) and ethyl acetate (200 ml) was heated under reflux overnight. The solvent was evaporated under reduced pressure, and hexane was added to the residue. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (9: 1-7:3, v/v) to give the title compound (12.8 g, 92percent) as a colorless oil. 1H-NMR (CDC13) 8: 3. 92 (3H, s) , 3. 95 (3H, s) , 4. 55 (2H, s), 7.38 (1H, d, J=8.1 Hz) , 7.53 (1H, d, J=1.5 Hz) , 7.60 (1H, dd, J=1.5, 8.1 Hz). |
82% | With N-Bromosuccinimide; azobisisobutyronitrile In tetrachloromethane | Part F. Methyl 4-Bromomethyl-3-methoxybenzoate. Methyl 3-methoxy-4-methylbenzoate (9.95 g; 55.2 mmol) and 10.81 g (60.7 mmol) of NBS were combined in 250 mL of CCl4 and heated to reflux. AIBN (0.75 g; 5.5 mmol) was added and the resultant mixture was heated at reflux for 8 h. The mixture was refrigerated, then filtered and concentrated under reduced pressure. The residue was triturated with hexanes and filtered to give the title compound as white needles (11.7 g; 82percent yield). 1H NMR (CDCl3) δ 7.63 (d, J=7.6 Hz, 1H), 7.58 (s, 1H), 7.41 (d, J=7.9 Hz, 1H), 4.56 (s, 2H), 3.98 (s, 3H), 3.94 (s, 3H); FDMS 528 (M+). |
82% | With N-Bromosuccinimide; azobisisobutyronitrile In tetrachloromethane | A. Methyl 4-Bromomethyl-3-methoxybenzoate. Methyl 3-methoxy-4-methylbenzoate (9.95 g; 55.2 mmol) and 10.81 g (60.7 mmol) of NBS were combined in 250 mL of CCl4 and heated to reflux. AIBN (0.75 g; 5.5 mmol) was added, and the resultant mixture was heated at reflux for 8 h. The mixture was refrigerated, then filtered and concentrated under reduced pressure. The residue was triturated with hexanes and filtered to give the title compound as white needles (11.7 g; 82percent yield). 1H NMR (CDCl3) δ 7.63 (d, J=7.6 Hz, 1H), 7.58 (s, 1H), 7.41 (d, J=7.9 Hz, 1H), 4.56 (s, 2H), 3.98 (s, 3H), 3.94 (s, 3H); FDMS 528 (M+). |
80% | With N-Bromosuccinimide; dibenzoyl peroxide In chloroform for 18 h; Heating / reflux | (4-Bromomethyl)-3-methoxybenzoic acid methyl ester: N-bromosuccinimide (7.2 g, 40 mmol) and benzoyl peroxide (40 mg, 0.16 mmol) were added to a stirred solution of 3-methoxy-4-methylbenzoic acid methyl ester (7.2 g, 40 mmol) in chloroform (300 mL). The mixture was then heated at reflux for about 18 hours. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=30/1, 5/1, v/v, elution) to afford the title product (8.25 g, 80percent). 1H NMR (300 MHz, CDCl3) δ 7.61 (d, 2H, J=7.8 Hz), 7.54 (s, 1H), 7.38 (d, 1H, J=8.1 Hz), 4.55 (s, 2H), 3.95 (s, 3H), 3.88 (s, 3H); LC-MS: m/z=259 (MH)+. |
76.9% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 80℃; for 5 h; | To a solution of methyl 3-methoxy-4-methylbenzoate (10 g, 55.6 mmol) and NBS (1 1.8 g, 66.7 mmol) in CCI4 (200 ml.) was added AIBN (900 mg, 5.56 mmol). The <n="181"/>reaction was stirred for 5 hours at 80 0C. TLC showed the reaction was completed. The mixture was filtered and the solvent was removed under the reduced pressure to give the desired product of Step A (1 1 g, 76.9percent). 1H NMR (CDCI3, 300 MHz) δ 7.63 (dd, J=1.2 and 6.0 Hz, 1 H) ,7.55 (s, 1 H), 7.39 (d, J= 6 Hz, 1 H),4.56 (s ,2 H) ,3.96 (s, 3H) and 3.91 (s, 3H). |
64% | With bromine In tetrachloromethane; water | l. Methyl 4-bromomethyl-3-methoxybenzoate A stirred solution of methyl 3-methoxy-4-methylbenzoate (121.2 g) in carbon tetrachloride (1.4 liter) was heated under gentle reflux with a 350 watt tungsten lamp and subjected to an air purge by means of a T-tube attached to a water aspirator. A solution of bromine (107.2 g) in carbon tetrachloride (500 ml) was added dropwise over 4 h. Evaporation of the solvent gave a light yellow solid which was triturated with 500 ml of 1:9 ether:hexane. The solid was collected by filtration to give methyl 4-bromomethyl-3-methoxybenzoate (111.7 g, 64percent) as a pale yellow solid: mp 87°-90°; NMR (80 MHz, CDCl3): 3.9(2s, 6H, 2 x OCH3), 4.5(s, 2H, BrCH2), 7.4(m, 3H). |
64% | With bromine In tetrachloromethane; water | j. Methyl 4-bromomethyl-3-methoxybenzoate A stirred solution of methyl 3-methoxy -4-methylbenzoate (121.2 g) in carbon tetrachloride (1.4 liter) was heated under gentle reflux with a 350 watt tungsten lamp and subjected to an air purge by means of a T-tube attached to a water aspirator. A solution of bromine (107.2 g) in carbon tetrachloride (500 ml) was added dropwise over 4 hr. Evaporation of the solvent gave a light yellow solid which was triturated with 500 ml of 1:9 ether:hexane. The solid was collected by filtration to give methyl 4-bromomethyl -3-methoxybenzoate (111.7 g, 64percent) as a pale yellow solid: mp 87-90°; NMR (80 MHz, CDCl3): 3.9(2s, 6H, 2 x OCH3), 4.5(s, 2H, BrCH2), 7.4(m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-Bromosuccinimide; azobisisobutyronitrile In tetrachloromethane | D. Methyl 4-Bromomethyl-3-methoxybenzoate Methyl 3-methoxy-4-methylbenzoate (9.95 g; 55.2 mmol) and N-bromosuccinimide (10.81 g; 60.7 mmol) were combined in 250 mL of CCl4 and heated to reflux. AIBN (0.75 g; 5.5 mmol) was added and the resultant mixture was heated at reflux for 8 h. The mixture was refrigerated, then filtered and concentrated under reduced pressure. The residue was triturated with hexanes and filtered to give the bromo ester as white needles (11.7 g; 82percent yield). 1H NMR (CDCl3) δ7.63 (d, J=7.6 Hz, 1H), 7.58 (s, 1H) 7.41 (d, J=7.9 Hz, 1H), 4.56 (s, 2H), 3.98 (s, 3H), 3.94 (s, 3H); FDMS 528 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dichloromethane; ethyl acetate; acetone; | (b) A solution of 6-nitroindole (4.0 g) and <strong>[70264-94-7]methyl 4-bromomethyl-3-methoxybenzoate</strong> (6.71 g) in dry acetone (125 ml) was treated with anhydrous potassium carbonate (4.0 g). The mixture was heated under reflux for 48 hours. The cloudy mixture was evaporated. The residue was suspended in ethyl acetate, and solid removed by filtration. The filtrate was evaporated and the residual oil was purified by flash chromatography on a 6*30 cm column of silica gel using 1:1 (v/v) methylene chloride:hexane as the eluent to give methyl 3-methoxy-4-(6-nitroindol-1-ylmethyl)benzoate as a bright yellow powder (8.0 g); NMR: 3.9(s, 3H, OCH3), 4.0(s, 3H, OCH3), 5.4(s, 2H, NCH2), 6.7(dd, 1H, H3 -indole), 6.8(d, 1H), 7.4(d, 1H, H2 -indole), 7.5-7.7(m, 3H), 8.0(dd, 1H, H5 -indole), 8.3(br s, 1H, H 7 -indole). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tin(IV) chloride; In dichloromethane; | (a) Stannic chloride (0.41 g.) was added to a stirred solution of <strong>[4965-26-8]<strong>[4965-26-8]5-nitrobenzo[b]thiophen</strong>e</strong> (0.28 g.) and methyl 4-bromomethyl-3-methoxybenzoate (B) (0.61 g.) in dichloromethane (5 ml.). The mixture was heated under reflux for 18 hours. The cooled mixture was poured into water (10 ml.) and extracted with dichloromethane (2*20 ml.). The combined extracts were dried (MgSO4) and evaporated. The oil was purified by flash chromatography on silica gel (100 ml.) eluding with 1:9 v/v ethyl acetate:hexane. The solid obtained was crystallized from hexane to give methyl 3-methoxy4-(5-nitrobenzo[b]thien-3-ylmethyl)benzoate (I) as a solid (0.16 g., 30%); NMR: (250 MHz, CDCl3): 3.92(s, 3H, OCH3), 3.98(s,3H, OCH3), 4.28(s,2H, CH2 -Ar), 7.15 (d,1H), 7.22(s,1H), 7.56(m,2H), 7.93(d,1H), 8.19(dd, 1H): 8.73(d,1H). | |
tin(IV) chloride; In dichloromethane; | (a) Stannic chloride (0.41 g.) was added to a stirred solution of <strong>[4965-26-8]<strong>[4965-26-8]5-nitrobenzo[b]thiophen</strong>e</strong> (0.28 g.) and methyl 4-bromomethyl-3-methoxybenzoate (B) (0.61 g.) in dichloromethane (5 ml.). The mixture was heated under reflux for 18 hours. The cooled mixture was poured into water (10 ml.) and extracted with dichloromethane (2x20 ml.). The combined extracts were dried (MgSO4) and evaporated. The oil was purified by flash chromatography on silica gel (100 ml.) eluding with 1:9 v/v ethyl acetate:hexane. The solid obtained was crystallized from hexane to give methyl 3-methoxy-4-(5-nitrobenzo[b]thien-3-ylmethyl)benzoate (I) as a solid (0.16 g., 30%); NMR: (250 MHz, CDCl3): 3.92(s, 3H, OCH3), 3.98(s,3H, OCH3), 4.28(s,2H, C H 2-Ar), 7.15 (d,1H), 7.22(s,1H), 7.56(m,2H), 7.93(d,1H), 8.19(dd, 1H); 8.73(d,1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With N-Bromosuccinimide;2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 16h;Heating / reflux; | STEP 1 : A mixture of methyl 4-methyl-3-(methyloxy)benzoate (1.00 g, 5.55 mmol), N-bromosuccinimide (1.09 g, 6.10 mmol) and a catalytic amount of 2,2'- azobis(isobutyronitrile) (AIBN) was refluxed in carbon tetrachloride (40 ml) for 16h.The reaction mixture was filtered and the solution was washed with brine (25 ml), <n="394"/>dried over sodium sulfate and concentrated to give methyl 4-(bromomethyl)-3- (methyloxy)benzoate (1.4g, 97% yield). |
94% | With tert.-butylhydroperoxide; cetyltrimethylammonim bromide; potassium bromide; In water; at 120℃; under 750.075 Torr;Microwave irradiation; | General procedure: The reaction mixture was treated in a controlled microwavesynthesizer (Biotage Initiator+SP Wave model, 0-200 W at2.45 GHz, capped at 60 W during steady state) for severalminutes (the reaction attained 120 C at 1 bar pressure). Thefinal products were isolated by column chromatographyusing an EtOAc-hexane gradient |
92% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In ethyl acetate;Heating / reflux; | Reference Example 49; Methyl 4-(bromomethyl)-3-methoxybenzoate; A mixture of methyl 3-methoxy-4-methylbenzoate (10.0 g, 55.5 mmol), N-bromosuccinimide (10.7 g, 60.9 mmol), 2,2'-azobis(isobutyronitrile)(1.6 mg) and ethyl acetate (200 ml) was heated under reflux overnight. The solvent was evaporated under reduced pressure, and hexane was added to the residue. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (9: 1-7:3, v/v) to give the title compound (12.8 g, 92%) as a colorless oil. ¹H-NMR (CDC13) 8: 3. 92 (3H, s) , 3. 95 (3H, s) , 4. 55 (2H, s), 7.38 (1H, d, J=8.1 Hz) , 7.53 (1H, d, J=1.5 Hz) , 7.60 (1H, dd, J=1.5, 8.1 Hz). |
82% | With N-Bromosuccinimide; azobisisobutyronitrile; In tetrachloromethane; | Part F. Methyl 4-Bromomethyl-3-methoxybenzoate. Methyl 3-methoxy-4-methylbenzoate (9.95 g; 55.2 mmol) and 10.81 g (60.7 mmol) of NBS were combined in 250 mL of CCl4 and heated to reflux. AIBN (0.75 g; 5.5 mmol) was added and the resultant mixture was heated at reflux for 8 h. The mixture was refrigerated, then filtered and concentrated under reduced pressure. The residue was triturated with hexanes and filtered to give the title compound as white needles (11.7 g; 82% yield). 1H NMR (CDCl3) delta 7.63 (d, J=7.6 Hz, 1H), 7.58 (s, 1H), 7.41 (d, J=7.9 Hz, 1H), 4.56 (s, 2H), 3.98 (s, 3H), 3.94 (s, 3H); FDMS 528 (M+). |
82% | With N-Bromosuccinimide; azobisisobutyronitrile; In tetrachloromethane; | A. Methyl 4-Bromomethyl-3-methoxybenzoate. Methyl 3-methoxy-4-methylbenzoate (9.95 g; 55.2 mmol) and 10.81 g (60.7 mmol) of NBS were combined in 250 mL of CCl4 and heated to reflux. AIBN (0.75 g; 5.5 mmol) was added, and the resultant mixture was heated at reflux for 8 h. The mixture was refrigerated, then filtered and concentrated under reduced pressure. The residue was triturated with hexanes and filtered to give the title compound as white needles (11.7 g; 82% yield). 1H NMR (CDCl3) delta 7.63 (d, J=7.6 Hz, 1H), 7.58 (s, 1H), 7.41 (d, J=7.9 Hz, 1H), 4.56 (s, 2H), 3.98 (s, 3H), 3.94 (s, 3H); FDMS 528 (M+). |
80% | With N-Bromosuccinimide; dibenzoyl peroxide; In chloroform; for 18h;Heating / reflux; | (4-Bromomethyl)-3-methoxybenzoic acid methyl ester: N-bromosuccinimide (7.2 g, 40 mmol) and benzoyl peroxide (40 mg, 0.16 mmol) were added to a stirred solution of 3-methoxy-4-methylbenzoic acid methyl ester (7.2 g, 40 mmol) in chloroform (300 mL). The mixture was then heated at reflux for about 18 hours. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=30/1, 5/1, v/v, elution) to afford the title product (8.25 g, 80%). 1H NMR (300 MHz, CDCl3) delta 7.61 (d, 2H, J=7.8 Hz), 7.54 (s, 1H), 7.38 (d, 1H, J=8.1 Hz), 4.55 (s, 2H), 3.95 (s, 3H), 3.88 (s, 3H); LC-MS: m/z=259 (MH)+. |
76.9% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 5h; | To a solution of methyl 3-methoxy-4-methylbenzoate (10 g, 55.6 mmol) and NBS (1 1.8 g, 66.7 mmol) in CCI4 (200 ml.) was added AIBN (900 mg, 5.56 mmol). The <n="181"/>reaction was stirred for 5 hours at 80 0C. TLC showed the reaction was completed. The mixture was filtered and the solvent was removed under the reduced pressure to give the desired product of Step A (1 1 g, 76.9%). 1H NMR (CDCI3, 300 MHz) delta 7.63 (dd, J=1.2 and 6.0 Hz, 1 H) ,7.55 (s, 1 H), 7.39 (d, J= 6 Hz, 1 H),4.56 (s ,2 H) ,3.96 (s, 3H) and 3.91 (s, 3H). |
64% | With bromine; In tetrachloromethane; water; | l. Methyl 4-bromomethyl-3-methoxybenzoate A stirred solution of methyl 3-methoxy-4-methylbenzoate (121.2 g) in carbon tetrachloride (1.4 liter) was heated under gentle reflux with a 350 watt tungsten lamp and subjected to an air purge by means of a T-tube attached to a water aspirator. A solution of bromine (107.2 g) in carbon tetrachloride (500 ml) was added dropwise over 4 h. Evaporation of the solvent gave a light yellow solid which was triturated with 500 ml of 1:9 ether:hexane. The solid was collected by filtration to give methyl 4-bromomethyl-3-methoxybenzoate (111.7 g, 64%) as a pale yellow solid: mp 87-90; NMR (80 MHz, CDCl3): 3.9(2s, 6H, 2 x OCH3), 4.5(s, 2H, BrCH2), 7.4(m, 3H). |
64% | With bromine; In tetrachloromethane; water; | j. Methyl 4-bromomethyl-3-methoxybenzoate A stirred solution of methyl 3-methoxy -4-methylbenzoate (121.2 g) in carbon tetrachloride (1.4 liter) was heated under gentle reflux with a 350 watt tungsten lamp and subjected to an air purge by means of a T-tube attached to a water aspirator. A solution of bromine (107.2 g) in carbon tetrachloride (500 ml) was added dropwise over 4 hr. Evaporation of the solvent gave a light yellow solid which was triturated with 500 ml of 1:9 ether:hexane. The solid was collected by filtration to give methyl 4-bromomethyl -3-methoxybenzoate (111.7 g, 64%) as a pale yellow solid: mp 87-90; NMR (80 MHz, CDCl3): 3.9(2s, 6H, 2 x OCH3), 4.5(s, 2H, BrCH2), 7.4(m, 3H). |
With sulfuric acid; hydrogen bromide; dihydrogen peroxide; In chloroform; water; at 55℃; for 2.83333h;Irradiation; | Methyl 3-methoxy-4-methylbenzoate (50 g), chloroform (500 mL), and hydrogen bromide (54.9 g) are charged into a round neck round bottom flask upon which is placed a black cover having an opening in which 200 watt light is arranged for a photochemical reaction. 30% hydrogen peroxide (94.18 g) added drop-wise over about 30 minutes followed by the drop-wise addition of sulphuric acid (81.3 mL) over about 20 minutes. The resultant reaction mass is heated to about 55 C. and stirred for about 2 hours. The reaction mass is cooled to 25 C. and a 40% sodium bicarbonate solution is added slowly by dropper and then stirred for about 15 minutes. The aqueous and organic layers are separated. The aqueous layer is washed with chloroform (2×100 mL). The obtained organic layer is combined and washed with water (2×100 mL) and re-separated. The organic layer is distilled off completely under vacuum to afford the crude. The obtained crude is cooled to 5 C. and cyclohexane is added and stirred for 2 hours for solid separation. The solid is filtered and washed with cyclohexane. The obtained solid is dried under vacuum for about 4 hours at 50 C. to afford the title compound. | |
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione;2,2'-azobis(isobutyronitrile); In cyclohexane; at 25 - 80℃; for 6.5h;Product distribution / selectivity; | Methyl 3-methoxy-4-methylbenzoate (7 kg) and methanol (10.5 L) are charged into a round bottom flask and stirred for about 10 minutes. Thionyl chloride (3.5 L) is added to the solution. The solution is heated to about 65 C., maintained for about 2 hours, and cooled to about 30 C. The resultant reaction solution is charged into water (35 L) at about 10 C. and stirred for solid separation. The solid is separated and washed with a solution of water (14 L) and sodium bicarbonate (14.5 L). The solid is suction dried for 10 minutes. The obtained wet compound (7.3 kg) and cyclohexane (42 L) are charged is a round bottom flask and stirred for about 30 minutes at about 30 C. followed by separation of the organic and aqueous layers. To the obtained organic layer, azo-bis-iso-butyronitrile (AIBN) (0.42 kg) and dibromodimethyl hydantoin (5.6 kg) are charged and stirred for about 30 minutes at 25 C. The resultant reaction solution is heated to about 80 C. and stirred for about 4 hours. The reaction mass is cooled to 50 C. and AIBN (0.014 kg) and dibromodimethyl hydantoin (1.4 kg) are again charged and heated to about 80 C. and stirred for about 2 hours up to completion of the reaction. The reaction mass is cooled to 60 C. and water (28 L) is charged and stirred for about 20 minutes at about 60 C. The organic and aqueous layers are separated. The aqueous layer is washed with cyclohexane (7 L). The organic layer is combined and washed with sodium bicarbonate solution (14 L) and water (14 L). The obtained clear solution is cooled to 10 C. and stirred for about 45 minutes for solid separation. The solid is filtered and washed with cyclohexane (7 L). The solid is suction dried for about 60 min. The obtained wet solid is dried to afford the 6.7 kg of the title compound.HPLC purity: 95.44% | |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform;Reflux; | Stepl : Preparation of methyl 4-(bromomethyl)-3-methoxybenzoateMethyl 3-methoxy-4-methylbenzoate (commercially available, 1 .0 equiv.) was dissolved in chloroform (0.1 M), and was treated with N-bromosuccinimide (1 .1 equiv.) andazobisisobutyronitrile (AIBN, catalytic amount). The reaction mixture was stirred at reflux overnight. After cooling down to room temperature, the reaction mixture was purified by ISCO (silica gel column, EtOAc/hexanes) to afford methyl 4-(bromomethyl)-3-methoxybenzoate as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With silver(l) oxide; In 1,4-dioxane; at 60℃; for 20h; | 3-Methoxy-4-(5-nitro-1H-indol-3-ylmethyl)-benzoic acid methyl ester: Under nitrogen atmosphere, silver oxide (9 g, 38.8 mmol) was added to a stirred solution of 5-nitroindole (6.28 g, 38.8 mmol) and <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (10 g, 38.8 mmol) in dioxane (40 mL). The mixture was heated at about 60° C. for about 20 hours. The solvent was evaporated in vacuo, and ethyl acetate was added. The mixture was filtered, solvent evaporated, and resulting residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=10/1, 3/1, v/v, elution) to afford the title product (6 g, 46percent). 1H NMR (300 MHz, CDCl3) delta 8.59 (s, 1H), 8.39 (br.s, 1H), 8.10 (dd, 1H, J=9.0, 2.1 Hz), 7.56-7.54 (m, 2H), 7.37 (d, 1H, J=9.0 Hz), 7.18-7.11 (m, 2H), 4.20 (s, 2H), 3.97 (s, 3H), 3.84 (s, 3H); LC-MS: m/z=341 (MH)+. |
In 1,4-dioxane; ethyl acetate; | (a) Silver(I) oxide (7.15 g) was added to a solution of 5-nitroindole (5 g) and <strong>[70264-94-7]methyl 4-bromomethyl-3-methoxybenzoate</strong> (prepared as described in step (a) of Example 1) (7.99 g) in dioxane (30 ml), under a nitrogen atmosphere. The mixture was stirred at 60° C. for 20 hours, dioxane removed by evaporation, and ethyl acetate (50 ml) added to the residue. The resulting suspension was separated by filtration through diatomaceous earth. The filtrate was evaporated to give a dark viscous oil, which was purified by flash chromatography on silica gel (600 ml), eluding with 3:7 v/v ethyl acetate:hexane. The viscous yellow oil obtained was crystallized from a mixture of methylene chloride and hexane to give methyl 3-methoxy-4-(5-nitroindol-3-ylmethyl)benzoate (F) (4.6 g, 45percent) as yellow needles; mp 153°-155° C.; NMR: 3.83(s, 3H, COOCH3), 3.93(s, 3H, OCH3), 4.12(s, 2H, CH2 Ar),7.25(d, 1H), 7.43(d, 1H), 7.49(m, 3H), 7.95(dd, 1H, H6 -indole), 8.47(d, 1H, H4 -indole), 11.65(broad s, 1H, H1 -indole). | |
In 1,4-dioxane; ethyl acetate; | (a) Silver (1) oxide (7.15 g.) was added to a solution of 5-nitroindole (5 g.) and <strong>[70264-94-7]methyl 4-bromomethyl-3-methoxybenzoate</strong> (B) (7.99 g.) in dioxane (30 ml.), under a nitrogen atmosphere. The mixture was stirred at 60° C. for 20 hours, dioxane removed by evaporation and ethyl acetate (50 ml.) added to the residue. The resulting suspension was separated by filtration through diatomaceous earth. The filtrate was evaporated to give a dark viscous oil, which was purified by flash chromatography on silica gel (600 ml.), eluding with 3:7 v/v ethyl acetate:hexane. The viscous yellow oil obtained was crystallized from a mixture of dichloromethane and hexane to give methyl 3-methoxy-4-(5-nitroindol-3-ylmethyl)benzoate (C) (4.6 g., 45percent) as yellow needles, m.p. 153°-155° C. NMR: 3.83(s,3H, COOCH3), 3.93(s,3H, OCH3), 4.12(s,2H, CH2.Ar), 7.25(d,1H), 7.43(d,1H), 7.49(m,3H), 7.95(dd, 1H, H6-indole), 8.47(d,1H, H4-indole), 11.65(broad s,1H, H1 -indole) |
In 1,4-dioxane; ethyl acetate; | (a) Silver (I) oxide (7.15 g.) was added to a solution of 5-nitroindole (5 g.) and methyl 4-bromo-methyl-3-methoxybenzoate (B) (7.99 g.) in dioxane (30 ml.), under a nitrogen atomosphere. The mixture was stirred at 60°C. for 20 hours, dioxane removed by evaporation and ethyl acetate (50 ml.) added to the residue. The resulting suspension was separated by filtration through diatomaceous earth. The filtrate was evaporated to give a dark viscous oil, which was purified by flash chromatography on silica gel (600 ml.), eluding with 3:7 v/v ethyl acetate:hexane. The viscous yellow oil obtained was crystallized from a mixture of dichloromethane and hexane to give methyl 3-methoxy-4-(5-nitroindol-3-ylmethyl)benzoate (C) (4.6 g., 45percent) as yellow needles, m.p. 153-155°C. NMR: 3.83(s,3H, COOCH3), 3.93(s,3H, OCH3), 4.12(s,2H, C H 2.Ar), 7.25(d,1H), 7.43(d,1H) 7.49(m,3H), 7.95(dd, 1H, H6-indole), 8.47(d,1H, H4-indole) 11.65(broad s,1H, H1-indole). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.3% | With water; sodium hydrogencarbonate;tetrabutylammomium bromide; at 20 - 70℃; for 5h; | To a suspension of <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (1 g, 3.9 mmol) in water (35 ml.) was added n-Bu4NBr (0.2 g, 0.624 mmol) and NaHCO3 (3.5 g, 42 mmol) at rt. The reaction mixture was heated to 70 0C and stirred for 5 h. The resulting solution was acidified with aqueous HCI (2 mol/L) and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give the product of Step B (0.4 g, 52.3 percent): 1H NMR (CDCI3, 300 MHz) delta 7.62 (dd, J = 1 1.7 and 12.6 Hz, 1 H), 7.57 (s, 1 H), 7.46 (dd, J= 0.9 and 4.5 Hz, 1 H), 4.66(s, 2 H), and 3.85 (s, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With sodium hydrogencarbonate; In dimethyl sulfoxide; at 50℃; for 3h; | Reference Example 5; Methyl 4-formyl-3-methoxybenzoate; To a solution of methyl 4-(bromomethyl)-3- methoxybenzoate (3.00 g, 11.6 mmol) in dimethyl sulfoxide (16 ml) was added sodium hydrogen carbonate (1.00 g, 13.6 mmol), and the mixture was stirred at 50C for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgS04 and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1: 0-7:3, v/v) to give the title compound (870 mg, 39%) as a colorless oil. ¹H-NMR (CDCl3) No.: 3.96 (3H, s) , 3. 99 (3H, s) , 7. 67 (lH, s) 7,68 (1H, d, J=8.9 Hz), 7.88 (1H, d, J=8.9 Hz), 10.51 (lH, s). |
37% | With sodium hydrogencarbonate; In dimethyl sulfoxide; at 50℃; for 3h; | To a solution of methyl 4-(bromomethyl)-3-methoxybenzoate (1 .93 mmol, 500 mg) in anhydrous DMSO (2.7 ml_) was added NaHC03 (2.32 mmol, 195 mg). The reaction mixture was stirred for 3 h at 505C. Water was added to the reaction mixture, and the mixture was extracted with EtAcO. The organic layer was dried over anhydrous MgS04, the solvent was filtered and evaporated. The crude product was purified by flash chromatography on silica gel using an elution of 8% ethylacetate in hexanes to give methyl 4-formyl-3-methoxybenzoate (140 mg. Yield: 37%). 1 H NMR (400 MHz, CDCI3) delta 10.51 (1 H, s), 7.87 (1 H, d, J=8.Hz), 7.69-7.67 (2H, m), 4.00 (3H, s), 3.95 (3H, s). LC-MS: tR = 2.75 [M+H]+ = 195 (method 3). |
37% | With sodium hydrogencarbonate; dimethyl sulfoxide; at 50℃; for 3h; | full text is not avalable from article |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 45 percent / silver(I) oxide / dioxane / 20 h / 60 °C 2: 1.) NaH / 1.) THF, 10 min, 2.) 30 min 3: 98 percent / H2 / 10percent Pd/C / tetrahydrofuran / 2 h / 2587.7 Torr 4: 74 percent / N-methylmorpholine / CH2Cl2 / 2 h 5: 88 percent / LiOH monohydrate / methanol; tetrahydrofuran; H2O / 20 h 6: 69 percent / 4-(dimethylamino)pyridine, 1-<3-(dimethylamino)propyl>-3-ethylcarbodiimide hydrochloride / CH2Cl2 / 18 h | ||
Multi-step reaction with 7 steps 1: silver carbonate / toluene 2: sodium hydroxide / tetrahydrofuran; water / 20 - 65 °C 3: hydrogenchloride / tetrahydrofuran; water / 35 - 50 °C / pH 1 - 2 4: thionyl chloride / N,N-dimethyl-formamide; dichloromethane / 3.33 h / 41 °C 5: N,N-dimethyl-formamide / 25 °C / Reflux 6: N,N-dimethyl-formamide; dichloromethane / 20 °C / Reflux 7: sodium hydroxide; palladium on activated charcoal; hydrogen |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In tetrahydrofuran; water; ethyl acetate; | Part G. Methyl 3-Methoxy-4-[(1-pyrrolidinyl)methyl]benzoate. Methyl 4-bromomethyl-3-methoxybenzoate (1.0 g; 3.9 mmol) (Part F) was dissolved in THF (10 mL) and pyrrolidine (1.3 mL; 15.4 mmol) was added at room temperature. The mixture was stirred overnight at room temperature, then poured into 50 mL of water. Extraction was carried out with EtOAc (4*25 mL). The combined organics were washed with brine and dried by passage through sodium sulfate. The title compound was isolated (0.92 g; 96percent yield) by flash chromatography on silica gel eluding with EtOAc(100-95percent)/Et3N(0-5percent). 1H NMR (CDCl3) delta 7.62 (d, J=7.8 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J=7.7 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.69 (s, 2H), 2.57 (m, 4H), 1.79 (m, 4H). |
96% | In tetrahydrofuran; water; ethyl acetate; | E. Methyl 3-Methoxy-4-[(1-pyrrolidinyl)methyl]benzoate Methyl 4-bromomethyl-3-methoxybenzoate (1.0 g; 3.9 mmol) (Part D) was dissolved in THF (10 mL) and pyrrolidine (1.3 mL; 15.4 mmol) was added at room temperature. The mixture was stirred overnight at room temperature, then poured into 50 mL of water. Extraction was carried out with EtOAc (4*25 mL). The combined organics were washed with brine and dried by passage through sodium sulfate. The title compound was isolated (0.92 g; 96percent yield) by flash chromatography on silica gel eluding with EtOAc(100-95percent)/Et3N(0-5percent). 1H NMR (CDCl3) delta7.62 (d, J=7.8 Hz, 1H), 7.51 (s, 1H) 7.43 (d, J=7.7 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.69 (s, 2H), 2.57 (m, 4H), 1.79 (m, 4H) |
96% | In tetrahydrofuran; water; ethyl acetate; | B. Methyl 3-Methoxy-4-(1-pyrrolidinylmethyl)benzoate. Methyl 4-bromomethyl-3-methoxybenzoate (1.0 g; 3.9 mmol) (Part A) was dissolved in THF (10 mL) and pyrrolidine (1.3 mL; 15.4 mmol) was added at room temperature. The mixture was stirred overnight at room temperature, then poured into 50 mL of water. Extraction was carried out with EtOAc (4*25 mL). The combined organics were washed with brine and dried by passage through sodium sulfate. The title compound was isolated (0.92 g; 96percent yield) by flash chromatography on silica gel, eluding with EtOAc(100-95percent)/Et3N(0-5percent). 1H NMR (CDCl3) delta 7.62 (d, J=7.8 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J=7.7 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.69 (s, 2H), 2.57 (m, 4H), 1.79 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With dimethyl amine; | Part C. Methyl 4-(Dimethylamino)methyl-3-methoxybenzoate STR309 The title compound was prepared in 77percent yield by essentially following the procedure outlined in Example 37, Part A from <strong>[70264-94-7]methyl 4-bromomethyl-3-methoxybenzoate</strong> (see Example 37, Part A) and dimethylamine. FDMS 223 (M+); Anal. Calcd. for C12 H17 NO3: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.52; H, 7.68; N, 6.43. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | silver carbonate; In ethyl acetate; toluene; | d. Methyl E-3-methoxy-4-[5-[2-(propylcarbamoyl)-1-propenyl]indol-3-ylmethyl]benzoate A mixture of E-alpha-methyl-N-propylindol-5-acrylamide (1.75 g) and silver carbonate (1.99 g) in dry toluene (30 ml) was stirred and heated under reflux for 18 hr, under an atmosphere of nitrogen. The mixture was cooled to 80°, <strong>[70264-94-7]methyl 4-bromomethyl-3-methoxybenzoate</strong> (2.06 g) added, and the mixture stirred at 85° for 15 hours. The mixture was cooled, ethyl acetate (50 ml) added, the salts were removed by filtration through diatomaceous earth, the filter pad was washed with ethyl acetate, and the filtrate evaporated. The product was purified by flash chromatography, eluding with 5:2:3 hexane:methylene chloride:ethyl acetate, to give methyl E-3-methoxy-4-[5-[2-(propylcarbamoyl)-1-propenyl]indol-3-ylmethyl]benzoate (1.62 g, 53percent) as a solid foam; mp 55°-60°; partial NMR (250 MHz, DMSO-d6): 0.87(t, 3H, CH2 CH2 CH3), 1.47(m, 2H, CH2 CH2 CH3), 1.99 (d, J=0.98 Hz, 3H, CCH3), 3.10(m, 2H, CH2 CH2 CH3), 3.82(s, 3H, OCH3), 3.91(s, 3H, OCH3), 4.05(s, 2H, ArCH2 Ar'), 7.93(br t, NHCO), 11.0(br s, 1H, H1 -indole). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In N,N-dimethylformamide (DMF); N,N-dimethyl-formamide; | d. Methyl 3-methoxy-4-(6-formyl-3-propylindol-1-ylmethyl)benzoate. 6-Formyl-3-propylindole (1.0 g) in N,N-dimethylformamide (DMF) (10 ml) was added slowly to a stirred suspension of sodium hydride (0.128 g, oil-free) in dry DMF (30 ml) at 0° under an atmosphere of nitrogen. The mixture was stirred at 0° for 60 min and <strong>[70264-94-7]methyl 4-bromomethyl-3-methoxybenzoate</strong> (1.38 g) in dry DMF (10 ml) was added dropwise. The cooling bath was removed, the mixture stirred for 3.5 hr, then poured into 1N hydrochloric acid (75 ml), and extracted with ethyl acetate (15 ml). The organic extract was washed (water (twice), brine), dried (MgSO4) and evaporated to give a dark oil. The product was purified by flash chromatography, eluding with 55:40:5 hexane:methylene chloride:ethyl acetate, to give methyl 3-methoxy-4-(6-formyl-3-propylindol-1-ylmethyl)benzoate (1.9 g, 97percent) as a yellow oil; partial NMR(250 MHz, DMSO-d6): 0.95(t, 3H, CH2 CH3), 1.65(m, 2H, CH2 CH3), 2.70(t, 2H, CH2 CH2 CH3), 3.83(s, 3H, OCH3), 3.95(s, 3H, OCH3), 5.50(s, 2H, NCH2), 9.96(s, 1H, CHO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In N-methyl-acetamide; ethyl acetate; | (d) A mixture of 60percent sodium hydride dispersion (13 mg) was washed with petroleum ether, and dimethylformamide (0.75 ml) was added. This mixture was cooled to 0° and a solution of 3-bromo-6-(N-cyclopentylmethylcarbamoyl)indazole (107 mg) in dimethylformamide (0.75 ml) was added. After stirring for 30 minutes, methyl 4-bromomethyl-3-methoxy benzoate (95 mg) was added. After 15 minutes of stirring at 0°, the mixture was allowed to warm to room temperature. The reaction was stirred for 1.5 hours and ethyl acetate (40 ml) was added. The solution was washed with brine, water and brine; dried (MgSO4) and evaporated. The residue was flash chromatographed over 10 g of silica gel, eluding with 5:95 ethyl acetate:methylene chloride to afford methyl 4-[3-bromo-6-(N-cyclopentylmethylcarbamoyl)indazol-1-ylmethyl]-3-methoxybenzoate as a white solid (136 mg, 82percent), mp 161.0°-162.5°; Analysis calculated for: C24 H27 BrN3 O4: C, 57.49; H, 5.42; N, 8.38. Found: C, 57.53; H, 5.29; N, 8.28. |
82% | In N-methyl-acetamide; ethyl acetate; | (d) A mixture of 60percent sodium hydride dispersion (13 mg) was washed with petroleum ether, and dimethylformamide (0.75 ml) was added. This mixture was cooled to 0° and a solution of 3-bromo-6-(N-cyclopentylmethylcarbamoyl)indazole (107 mg) in dimethylformamide (0.75 ml) was added. After stirring for 30 minutes, methyl 4-bromomethyl-3-methoxy benzoate (95 mg) was added. After 15 minutes of stirring at 0°, the mixture was allowed to warm to room temperature. The reaction was stirred for 1.5 hours and ethyl acetate (40 ml) was added. The solution was washed with brine, water and brine; dried (MgSO4); and evaporated. The residue was flash chromatographed over 10 g of silica gel, eluding with 5:95 ethyl acetate:methylene chloride to afford methyl 4-[3-bromo-6-(N-cyclopentylmethylcarbamoyl)indazol-1-yl-methyl]-3-methoxybenzoate as a white solid (136 mg, 82percent), mp 161.0-162.5°; Analysis calculated for: C24H27BrN3O4: C, 57.49; H, 5.42; N, 8.38 Found: C, 57.53; H, 5.29; N, 8.28 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | In ethyl acetate; toluene; | a. Methyl 4-(5-cyanoindol-3-ylmethyl)-3-methoxybenzoate A mixture of 5-cyanoindole (10 g) and freshly prepared silver carbonate on diatomaceous earth (40.66 g) was stirred and heated under reflux in toluene (100 ml) for 18 hr, under an atmosphere of nitrogen. The mixture was cooled to room temperature, <strong>[70264-94-7]methyl 4-bromomethyl-3-methoxybenzoate</strong> (22.7 g) added, and stirring continued for 4 hr. Ethyl acetate (200 ml) was added, the mixture filtered through diatomaceous earth, the filter pad washed with ethyl acetate and the filtrate evaporated. The dark oil obtained was purified by flash chromatography, eluding with 45:45:10 hexane:methylene chloride:ethyl acetate, to give a foam which was crystallized from toluene to give methyl 4-(5-cyanoindol-3-ylmethyl)-3-methoxybenzoate (11.8 g, 53percent) as white crystals; mp 148°-149°; partial NMR (250 MHz, DMSO-d6): 3.83(s, 3H, OCH3), 3.91(s, 3H, OCH3), 4.08(s, 2H, ArCH2 Ar'), 8.00(s, 1H, H4 -indole), 11.49(br s, 1H, H1 -indole). |
53% | In ethyl acetate; toluene; | a. Methyl 4-(5-cyanoindol-3-ylmethyl)-3-methoxybenzoate A mixture of 5-cyanoindole (10 g) and freshly prepared silver carbonate on diatomaceous earth (40.66 g) was stirred and heated under reflux in toluene (100 ml) for 18 h, under an atmosphere of nitrogen. The mixture was cooled to room temperature, <strong>[70264-94-7]methyl 4-bromomethyl-3-methoxybenzoate</strong> (22.7 g) added, and stirring continued for 4 h. Ethyl acetate (200 ml) was added, the mixture filtered through diatomaceous earth, the filter pad washed with ethyl acetate and the filtrate evaporated. The dark oil obtained was purified by flash chromatography, eluding with 45:45:10 hexane:methylene chloride:ethyl acetate, to give a foam which was crystallized from toluene to give methyl 4-(5-cyanoindol-3-ylmethyl)-3-methoxybenzoate (11.8 g, 53percent) as white crystals; mp 148°-149°; partial NMR (250 MHz, DMSO-d6): 3.83(s, 3H, OCH3), 3.91(s, 3H, OCH3), 4.08(s, 2H, ArCH2 Ar'), 8.00(s, 1H, H4 -indole), 11.49(br s, 1H, H1 -indole). |
53% | In ethyl acetate; toluene; | a. Methyl 4-(5-cyanoindol-3-ylmethyl)-3-methoxybenzoate A mixture of 5-cyanoindole (10 g) and freshly prepared silver carbonate on diatomaceous earth (40.66 g) was stirred and heated under reflux in toluene (100 ml) for 18 h, under an atmosphere of nitrogen. The mixture was cooled to room temperature, <strong>[70264-94-7]methyl 4-bromomethyl-3-methoxybenzoate</strong> (22.7 g) added, and stirring continued for 4 h. Ethyl acetate (200 ml) was added, the mixture filtered through diatomaceous earth, the filter pad washed with ethyl acetate and the filtrate evaporated. The dark oil obtained was purified by flash chromatography, eluding with 45:45:10 hexane:methylene chloride:ethyl acetate, to give a foam which was crystallized from toluene to give methyl 4-(5-cyanoindol-3-ylmethyl)-3-methoxybenzoate (11.8 g, 53percent) as white crystals; mp 148-149°; partial NMR (250 MHz, DMSO-d6): 3.83(s, 3H, OCH3), 3.91(s, 3H, OCH3), 4.08(s, 2H, ArCH2 Ar'), 8.00(s, 1H, H4 -indole), 11.49(br s, 1H, H1 -indole). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With zinc; In tetrahydrofuran; ethyl acetate; | f. Methyl 4-[7-(cyclopentylacetamido)naphth-1-ylmethyl]-3-methoxybenzoate A mixture of activated zinc dust (806 mg), methyl 4-bromomethyl-3-methoxybenzoate (2.14 g) and tetrahydrofuran (15 ml) was stirred for 18 h. To the reaction was added dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (76 mg). After stirring for 15 min, 7-(cyclopentylacetamido)naphth-1-yl triflate (830 mg) in tetrahydrofuran (10 ml) was added and the mixture was stirred for 72 h. The mixture was added to 100 ml of ethyl acetate and the ethyl acetate solution was washed (1N HCl, brine), dried (MgSO4) and evaporated. The residue was flash chromatographed, eluding with ether:petroleum ether (2:8,4:6, and 1:4, successively), to give a white solid. Recrystallization from methylene chloride and petroleum ether gave the title compound as a colorless solid (705 mg, 79percent); mp 172.5°-174.5° C. Analysis for C27 H29 NO4: Calculated: C, 75.15; H, 6.77; N, 3.24. Found: C, 74.82; H, 6.78; N, 2.85. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-Bromosuccinimide; azobisisobutyronitrile; In tetrachloromethane; | D. Methyl 4-Bromomethyl-3-methoxybenzoate Methyl 3-methoxy-4-methylbenzoate (9.95 g; 55.2 mmol) and N-bromosuccinimide (10.81 g; 60.7 mmol) were combined in 250 mL of CCl4 and heated to reflux. AIBN (0.75 g; 5.5 mmol) was added and the resultant mixture was heated at reflux for 8 h. The mixture was refrigerated, then filtered and concentrated under reduced pressure. The residue was triturated with hexanes and filtered to give the bromo ester as white needles (11.7 g; 82percent yield). 1H NMR (CDCl3) delta7.63 (d, J=7.6 Hz, 1H), 7.58 (s, 1H) 7.41 (d, J=7.9 Hz, 1H), 4.56 (s, 2H), 3.98 (s, 3H), 3.94 (s, 3H); FDMS 528 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(I) oxide; In 1,4-dioxane; at 100℃; for 30h; | <strong>[29906-67-0]1-methyl-5-nitro-1H-indole</strong> (2.5 kg), methyl 3-methoxy-4-bromomethylbenzoate (4.78 kg), and 1,4 dioxane (17.5 L) are charged and stirred for about 10 minutes. Cuprous oxide (6.1 kg) is added. The reaction solution is heated to about 100 C. and stirred for about 30 hours under nitrogen atmosphere up to completion of the reaction. The resultant reaction solution is cooled to 30 C. and passed through diatomaceous earth, which is washed with 1,4 dioxane (5 L). The obtained clear solution is distilled off completely under vacuum below 50 C. to afford the crude. To the resultant crude, ethyl acetate (2.5 L) is charged and stirred to about 50 C. for about 20 minutes followed by the addition of methanol (22.5 L). The resultant reaction solution is heated to about 50 C. and stirred for about 4 hours then cooled to about 25 C. and stirred for about 4 hours for solid separation. The solid is filtered, washed with methanol (2.5 L), and suction dried. The solid is dried under vacuum at 50 C. to afford the title compound. | |
With silver(l) oxide; In 1,4-dioxane; at 60℃; for 20h;Inert atmosphere; Microwave irradiation; | General procedure: Silver (I) oxide (1 eq.) was added to a stirred solution of indole (1eq.) and benzyl bromide (1 eq.) in dioxane (1 mL/mmol of indole) ina microwave tube under nitrogen gas. The reaction was sealed andstirred at 60 C for 20 h. EtOAc (2 mL/mmol of indole) was added tothe reaction. The reaction was then filtered through celite and thefiltrate was rotovapped. Product was purified by column chromatographyto give a yellow solid; 25-45%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(i) Methyl 4-(2-(ethoxycarbonyl)-3-oxobutyl)-3-methoxybenzoateSodium hydride (60percent in mineral oil; 1.45g) was added portionwise over lOmin to a solution of ethyl acetoacetate (4.4mL) in THF (6OmL) at O0C. The resulting suspension <n="87"/>was stirred at O0C for lOmin and a solution of <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (7.5g) in THF (4OmL) added portionwise over lOmin. The mixture was warmed to 70°C and stirred for 15h. The mixture was allowed to cool and then poured cautiously into ice/water (30OmL) and stirred for 30min. The aqueous phase was extracted with EtOAc and the combined organic phase was dried filtered and evaporated to afford crude product. The reaction was repeated on an identical scale and the two batches of crude product were combined and purified by chromatography eluting with 20-30percent EtOAc in isohexane to give the subtitle compound as a colorless oil 14.7Og.1H NMR DMSO-J6: delta 7.48 (dd, IH), 7.45 (d, IH), 7.24 (d, IH), 4.05 (q, 2H), 3.95 (dd, IH), 3.86 (s, 3H), 3.84 (s, 3H), 3.10 (dd, IH), 3.00 (dd, IH), 2.17 (s, 3H), 1.09 (t, 3H) | ||
NaH (60percent in mineral oil, 1.45 g) was added portionwise over 10 min to a solution of ethyl acetoacetate (4.4 mL) in THF (60 mL) at O0C and the mixture was stirred for 10 min. A solution of <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (7.5 g) in THF (40 mL) was added and the mixture was warmed to 700C and stirred for 15 h. The reaction was poured into ice/water (300 mL) and stirred for 30 min. The aqueous mixture was extracted with EtOAc, dried and concentrated by evaporation to afford the subtitle compound. The reaction was repeated on an identical scale. The two batches of crude product were combined and purified by FCC eluting with 8:2 to 7:3 isohexane -EtOAc to afford the subtitle compound as a colourless oil (14.7 g); 1H NMR: 7.48 (dd, IH), 7.45 (d, IH), 7.24 (d, IH), 4.05 (q, 2H), 3.95 (dd, IH), 3.86 (s, 3H), 3.84 (s, 3H), 3.10 (dd, IH), 3.00 (dd, IH), 2.17 (s, 3H), 1.09 (t, 3H). | ||
(i) Methyl 4 2-(ethoxycarbonv0-3-oxobutyl1-3-methoxybenzoateNaH (60percent) in mineral oil, 1.45 g) was added portion-wise over 10 mins to a solution of ethyl acetoacetate (4.4 mL) in THF (60 mL) at 0°C. The mixture was then stirred for 10 mins. Then, a solution of <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (7.5 g) in THF (40 mL) was added and the mixture was warmed to 70°C and stirred for 15h. The mixture was then poured into ice/water (300 mL) and stirred for 30 mins. The resulting aqueous mixture was extracted with EtOAc. The organic extracts were combined, dried and concentrated in vacuo to provide crude product. The reaction was repeated on the same scale. The two batches of crude product were combined and purified by FCC, eluting with 20-30percent EtOAc in isohexane, to give the sub-title compound (14.7 g) as a colourless oil; 1H NMR: 7.48 (dd, 1H), 7.45 (d, 1H), 7.24 (d, 1H), 4.05 (q, 2H), 3.95 (dd, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.10 (dd, 1H), 3.00 (dd, 1H), 2.17 (s, 3H), 1.09 (t, 3H). |
15 g | NaH (60percent in mineral oil, 1.5 g) was added portion-wise over 10 mins to a solution of ethyl acetoacetate (4.4 mL) in THF (60 mL) at 0 °C. The mixture was then stirred for 10 mins. Then, a solution of methyl 4- (bromomethyl ) -3-methoxybenzoate (7.5 g) in THF (40 mL) was added and the mixture was warmed to 70°C and stirred for 15 h. The mixture was then poured into ice/water (300 mL) and stirred for 30 mins. The resulting aqueous mixture was extracted with EtOAc. The organic extracts were combined, dried and concentrated in vacuo to provide crude product. The reaction was repeated on the same scale . The two batches of crude product were combined and purified by flash column chromatography on silica gel to give the sub-title compound (15 g) as a colourless oil; XH NMR (300 MHz, CDC13) delta= 7.48 (1H, dd), 7.45 (1H, d) , 7.24 (1H, d) , 4.05 (2H, q) , 3.95 (1H, dd) , 3.86 (3H, s), 3.84 (3H, s), 3.10 (1H, dd) , 3.00 (1H, dd) , 2.17 (3H, s) , 1.09 (3H, t) . | |
Sodium hydride (60percent in mineral oil, 1.25 eq) was added in portions over 10 min to a solution of ethyl 3-oxobutanoate (1.2 eq) in THF (0.8M) at 0° C. The resulting suspension was stirred at 0° C. for 10 min and a solution of <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (1.0 eq) in THF (0.5M) was added dropwise over 10 min. The mixture was warmed to 70° C. and stirred for 3 h. The mixture was allowed to cool and then poured into ice water and stirred for 30 min. The mixture was partitioned between EA/water. The organic layer dried over Na2SO4, filtered, concentrated and purified by flash chromatography on silica (eluent PE/EA=100/1 to 5/1) to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | A solution of methyl 4-bromomethyl-3-methoxy-benzoate (Trans World Chemicals, 5.18 g, 20 mmol) in 50 mL dioxane, 15 mL water and 50 mL 1 N aqueous sodium hydroxide is heated at reflux for 6 h. The reaction mixture is neutralized with 50 mL 1 N hydrochloric acid and extracted several times with ethyl acetate. The organic layer is washed with water, dried over MgSO4 and evaporated under reduced pressure.Yield: 3.40 g (93 percent of theory); ESI Mass spectrum: [M-H]" = 181 Retention time HPLC: 0.81 min (method J). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | To a solution of <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (0.518 g, 2 mmol, Trans World Chemicals) in THF (10 mL) at room temperature was added (4- fluorophenyl)methanamine (1.00 g, 8.00 mmol, Aldrich) and triethylamine (0.56 mL, 4 mmol). The reaction mixture was stirred at rt for 1 h and quenched by the addition of 5 mL of saturated aq. NaHCCb solution . The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic extracts were dried over MgS(^ and concentrated. The residue was purified by flash column chromatography (ISCO system, eluting with with CHzCVEtOAc) to give the desired compound (0.35 g, 57percent) as a white solid 1H NMR (CD3OD) delta 7.64 (d, 1H, J= 6.0 Hz), 7.60 (s, 1H), 7.40 (d, 2H, J= 7.7 Hz), 7.36 (d, 1H, J= 6.0 Hz), 7.08 (t, 2H, J= 7.7 Hz), 3.97 (s, 3H), 3.96 (s, 3H), 3.82 (s, 2H), 3.76 (s, 2H). MS (ESI): 304.1 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetone; at 20℃; | b) Methyl 3-methoxy-4-(p-tolyloxymethyl)benzoatePotassium carbonate (0.693 g, 5.02 mmol) was added to a stirred solution of methyl 4- (bromomethyl)-3-methoxybenzoate (1.0 g, 3.86 mmol) and p-cresol (0.417 g, 3.86 mmol) in anhydrous acetone at room temperature. The reaction mixture was stirred over night, filtered and the filtrate was evaporated. Purification by column chromatography using heptane/ethyl acetate (10:1 and 7:1) as the eluent, gave the crude title compound. GC MS (EI) m/z 286 [M]+*. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of 1 .0 M NaHMDS in THF (75 muIota_, 75 muetaiotaomicronIota) is added dropwise to an ice- cold solution of 4007 (25.0 mg, 77.0 muetatauiotaomicronIota) in THF (0.5 mL). After the addition, the mixture is allowed to warm to RT and DMF (0.1 mL) is added. A solution of <strong>[70264-94-7]methyl (4-bromomethyl)-3-methoxybenzoate</strong> (Aldrich; 26.0 mg, 100 muetatauiotaomicronIota) in THF (0.2 mL) is added and the mixture is stirred at RT for 1 .5 h. An aqueous 1 .0 N LiOH solution (0.25 mL, 0.25 mmol) and MeOH (0.15 mL) are added and the mixture is stirred at RT for 16 h. The mixture is acidified by addition of AcOH and the crude mixture is purified by preparative HPLC to give compound 4029. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With caesium carbonate; In acetone; at 60℃; for 2h; | Example 20AMethyl 4-[3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]methyl}-3-methoxybenzenecarboxylateAn amount of 800 mg (3.39 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one (preparation as per WO 2007/134862 Example 36A) and 1.66 g (5.09 mmol) of caesium carbonate were suspended in 10 ml of acetone and admixed with 1.14 g (4.41 mmol) of methyl-4-(bromomethyl)-3-methoxybenzenecarboxylate.The mixture was stirred at 60° C. for 2 h.The suspension was diluted with water.It was extracted with twice 15 ml of ethyl acetate.The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator.Purification by flash chromatography over silica gel with elution with cyclohexane/ethyl acetate (gradient 4:1?1:1) gave 910 mg (64percent of theory) of the target compound.LC/MS [Method 4] Rf=1.28 min; MS [ESIpos]: m/z=414 (M+H)+1H NMR (400 MHz, CDCl3): delta=0.75-0.83 (m, 2H), 1.00-1.07 (m, 2H), 2.97-3.05 (m, 1H), 3.90 (s, 3H), 3.92 (s, 3H), 5.08 (s, 2H), 7.17 (d, 1H), 7.43 (d, 2H), 7.53 (s, 1H), 7.59 (d, 1H), 7.68 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3.5h; | a)Methyl 4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzoateA suspension of <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (400 mg, 1.544 mmol) and 1H-pyrazole (105 mg, 1.544 mmol) and K2CO3 (533 mg, 3.86 mmol) in DMF (5 ml) was stirred for 3.5 h at rt.A saturated solution of NaHCO3 was added and the mixture was extracted with ethyl acetate.The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude Methyl 4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzoate. MS [M+H]+=247. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h; | The mixture of (5)-4-chloro-N-(l-phenylpropyl)benzenesulfonamide (309 mg, 0.997 mmol) and <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (279 mg, 1.077 mmol) in 3 mL of DMF was added Cs2C03. The reaction mixture was stirred at room temperature for 16 h. Water (12 mL) was then added to the reaction and the reaction mixture was then extracted with ethyl acetate. The organic layer was separated and washed with water, brine and dried over sodium sulfate. Filtration and removal of solvent in vacuo provided 473 mg of white solid which was purified by combiflash chromatography (0-30percent hexane and ethyl acetate). Desired product as a white solid was isolated (415 mg) Mp 108- 110°C; MS mlz 488; Elemental Analysis (C25H26C1N05S) Calcd: C 61.53, H, 5.37, N, 2.87; Found: C, 61.71, H, 5.25, N, 2.62. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With manganese; dichloro(1,2-bis(diphenylphosphino)ethane)cobalt(II); water; In 1,2-dichloro-benzene; at 25℃; for 48h;Inert atmosphere; | General procedure: A suspension of CoCl2dppe (36.7 mg, 0.069 mmol), Mn (114 mg, 2.07 mmol), C60 (500 mg, 0.69 mmol), <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (536 mg, 2.07 mmol), and H2O (124 muL, 6.9 mmol) in ODCB (1,2-dichlorobenzene) (90 mL) was stirred for 48 h under Ar atmosphere at 25 °C. The reaction mixture was monitored by TLC and HPLC analysis (elution with toluene at 0.6 mL/min flow rate, detection at 320 nm). The mixture was filtered through a short florisil pad using ODCB as an eluent. After concentration, the residue was purified through silica gel chromatography using toluene as an eluent. After evaporation of toluene, the residue was washed with acetone and dried under vacuo, affording 2-MeO?4-CO2Me?BnHC in 60percent yield (373 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triethylamine; In tetrahydrofuran; for 4h; | Intermediate X.1 Stage 1: A mixture of the halide <strong>[70264-94-7]methyl-4-(bromomethyl)-3-methoxy-benzoate</strong> (0.50 g; 1.93 is mmol), the amine tert-butyl N-(piperidin-4-yl)carbamate (0.386 g; 1.93 mmol) and triethylamine (0.538 ml; 3.86 mmol) in THF (10 ml) is stirred for 4 h. The solvent is evaporated. The residue is taken up in water and sodium carbonate solution and extracted with DCM. The organic layer is dried with magnesium sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography (gradient: DCM/Methanol 100:0?92:8 to yield Methyl 4-[(4-[(tertbutoxy)carbonyl]amino}piperidin-1-ylmethyl]-3-methoxybenzoate. Yield: 650 mg (89percent of theory) C20H30N2O5 ESI Mass spectrum: m/z=379 [M+H]+; m/z=423 [M+HCOO]- |
89% | With triethylamine; In dichloromethane; for 4h; | Stage 1 : A mixture of the halide <strong>[70264-94-7]methyl-4-(bromomethyl)-3-methoxy-benzoate</strong> (0.50 g; 1.93 mmol), the amine tert-butyl N-(piperidin-4-yl)carbamate (0.386 g; 1 .93 mmol) and triethylamine (0.538 ml; 3.86 mmol) in THF (10 ml) is stirred for 4 h. The solvent is evaporated. The residue is taken up in water and sodium carbonate solution and extracted with DCM. The organic layer is dried with Magnesium Sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography (gradient: DCM / Methanol 100:0?92:8 to yield Methyl 4-[(4-[(tert- butoxy)carbonyl]amino}piperidin-1-yl)methyl]-3-methoxybenzoate. Yield: 650 mg (89percent of theory). C20H30N2O5. ESI Mass spectrum: m/z = 379 [M+H]+; m/z = 423 [M+HCOO]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; | [0820] To a suspension of 1, 2, 4-triazole (0.52 g, 7.51 mmol), and 2CO3 (2.57 g, 20.49 mmol) in DMF ( 15 mL) was added 434-2 ( 1.77 g, 6.83 mmol) at 0 °C, and stirred at r.t. overnight. The mixture was poured into water ( 100 mL), and extracted by EA (4 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated at lo pressure. The residue was purified by column chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | [0428] LDA (2M solution in THF. 1 .05 mL. 2.10 mmol) was added to a stirred solution of l -(tert-butoxycarbonyl)-2-pyrrolidinone (276 uL, 1 .62 mmol) in THF ( 1 mL). which had been pre-cooled to -78 °C. After 15 mins. a solution of methyl 4-(bromomethyl)- 3-methoxybenzoate (460 mg, 1.78 mmol) in THF ( 1 mL) was added dropwise to the mixture and stirring at 78 °C was continued for 1 h. The reaction was quenched with water. The aqueous portion was extracted with EtOAc (2x). The combined organic portions were dried with a2SC>4, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc 70:30) afforded 2-18 ( 199 mg, 34percent). UPLC/MS(ES+): m/z 364.20 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | [0443] NaH (153 mg, 3.83 mmol) was added to a solution of imidazolidin-2-one (300 mg. 3.48 mmol) in THF (3 niL), which had been pre-cooled to 0 °C. After 1 h. <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (899 mg, 3.48 mmol) was added. The mixture was stirred at r.t. for 18 h, poured in to water and extracted with EtOAc (3x). The combined organic portions were dried with Na2SC4, filtered and concentrated under reduced pressure. Chromatography of the residue (EtOAcMeOH 100:0 to 80:20) afforded 2-29 as a white solid (40 mg, 4percent). UPLC/MS(ES+): m/z 265.20 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.11 g | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; | General procedure: A solution of the substituted pyridazinone and either a benzylic alcohol or benzylic bromide in dimethylformamide was treated with cesium carbonate then optionally heated to 55-80° C. After cooling to ambient temperature, the crude product was isolated as a solution in ethyl acetate, washed with water and aqueous sodium chloride then dried, filtered and concentrated. Subsequent purification by chromatography on silica afforded the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 4-methylpyrrolidin-2-one (574 mg, 5.79 mmol) in anhydrous DMF (15 mL) was added NaH (255 mg, 6.37 mmol, 60percent in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then a solution of methyl 4-(bromomethyl)-3- methoxybenzoate (1.50 g, 5.79 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 14 h and then quenched with saturated aqueous NH4CI (10 mL). The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with H20 (30 mL x 3) and saturated aqueous sodium chloride (30 mL), dried over Na2S04, and concentrated. The residue was purified by silica gel chromatography (petroleum ether :EtO Ac, 20: 1 to 3: 1) to give the racemic title compound. The racemic title compound was resolved by SFC (Chiralpak AD column, eluting with C02:MeOH ((0.2percent NH4OH), 75:25) to give the title compound as the first eluting isomer. MS (ESI) m/z: 278.1 [M+l]+. 1H NMR (400 MHz, CDCI3): delta 7.61 (dd, J = 1.6, 8.0 Hz, 1H), 7.53 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.51 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.42- 3.38 (m, 1H), 2.86-2.84 (m, 1H), 2.63-2.57 (m, 1H), 2.47-2.38 (m, 1H), 2.10-2.04 (m, 1H), 1.09 (d, J = 6.4 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of pyridin-2(lH)-one (8.81 g, 93 mmol) in DMF (100 mL) was added to a stirring 0 °C slurry of NaH (3.86 g, 60percent dispersion in mineral oil, 23.2 mmol) in DMF (100 mL). The mixture was stirred for 15 min at 0 °C and a solution of methyl 4-(bromomethyl)-3- methoxybenzoate (20.0 g, 77.2 mmol) in DMF (100 mL) was added. The resulting mixture was slowly allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was cooled to 0 °C and saturated aqueous ammonium chloride was added. The organics were extracted using EtOAc (3x). The combined organics were washed with saturated aqueous sodium chloride (3x), dried over MgS04, filtered, and concentrated in vacuo. The concentrate was taken up in DCM (260 mL) and cooled to 0 °C. Boron tribromide (232 mL, 1 M in DCM, 232 mmol) was added very slowly to the stirring 0 °C solution. The mixture was stirred at 0 °C for 1 h and then warmed to ambient temperature over 1 h. The mixture was cooled back to 0 °C and carefully quenched with excess MeOH (until the solution stopped bubbling). The mixture was concentrated in vacuo. The concentrate was taken up in MeOH and concentrated (2x). The concentrate was taken up in DCM and saturated aqueous sodium bicarbonate. The aqueous phase was extracted with DCM. The combined organics were washed with saturated aqueous sodium chloride, dried over MgS04, filtered, and concentrated in vacuo to give the title compound. LC-MS m/z = 260.2 [M+l]+. | ||
A solution of pyridin-2(lH)-one (8.81 g, 93 mmol) in DMF (100 mL) was added to a stirring 0 °C slurry of NaH (3.86 g, 60percent dispersion in mineral oil, 23.2 mmol) in DMF (100 mL). The mixture was stirred for 15 min at 0 °C and a solution of methyl 4-(bromomethyl)-3- methoxybenzoate (20.0 g, 77.2 mmol) in DMF (100 mL) was added. The resulting mixture was slowly allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was cooled to 0 °C and saturated aqueous ammonium chloride was added. The organics were extracted using EtOAc (3x). The combined organics were washed with saturated aqueous sodium chloride (3x), dried over MgS04, filtered, and concentrated in vacuo. The concentrate was taken up in DCM (260 mL) and cooled to 0 °C. Boron tribromide (232 mL, 1 M in DCM, 232 mmol) was added very slowly to the stirring 0 °C solution. The mixture was stirred at 0 °C for 1 h and then warmed to ambient temperature over 1 h. The mixture was cooled back to 0 °C and carefully quenched with excess MeOH (until the solution stopped bubbling). The mixture was concentrated in vacuo. The concentrate was taken up in MeOH and concentrated (2x). The concentrate was taken up in DCM and saturated aqueous sodium bicarbonate. The aqueous phase was extracted with DCM. The combined organics were washed with saturated aqueous sodium chloride, dried over MgS04, filtered, and concentrated in vacuo to give the title compound (18.4 g, LC-MS m/z = 260.2 [M+l]+). | ||
A solution of pyridin-2(lH)-one (8.81 g, 93.0 mmol) in DMF (100 mL) was added to a slurry of NaH (3.86 g, 60percent dispersion in mineral oil, 23.2 mmol) in DMF (100 mL) at 0 °C. The reaction mixture was stirred for 15 min at 0 °C before a solution of methyl 4- (bromomethyl)-3-methoxybenzoate (20 g, 77 mmol) in DMF (100 mL) was added. The resulting mixture was warmed to 23 °C and stirred for 1 h. The mixture was cooled to 0 °C, diluted with saturated aqueous ammonium chloride solution, and extracted with EtOAc (3x). The combined organic layers were washed with saturated aqueous sodium chloride solution (3x), dried over MgS04, filtered, and concentrated. The residue was dissolved in CH2C12 (260 mL), cooled to 0 °C, and then a solution of boron tribromide in CH2CI2 (232 mL, 232 mmol, 1M) was slowly added. The reaction mixture was stirred at 0 °C for 1 h and then warmed to 23 °C over the course of 1 h. The mixture was cooled to 0 °C, diluted with excess MeOH, and then concentrated. The residue was taken up in MeOH and concentrated (2x). The residue was diluted with saturated aqueous sodium bicarbonate and extracted with CH2C12. The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgS04, filtered, and concentrated to give the title compound. LC-MS m/z = 260.2 [M+l]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h; | In like manner to the preparation of 1-(methoxycarbonyl)methyl-6-nitro-indazoline, methyl 3-methoxy-4-[(6-nitroindazol-1-yl)methyl]benzoate was prepared by alkylation of 6-nitroindazoline with <strong>[70264-94-7]methyl (4-bromomethyl)-3-methoxybenzoate</strong> in presence of K2CO3. (0541) The desired product (48percent) with high Rf value on the TLC in 30percent EtOAc:hexanes was collected by silica gel column chromatographic purification. 1H NMR (CDCl3): delta 8.50 (d, 1H, J=1.7 Hz), 8.14 (s, 1H), 8.00 (dd, 1H, J=1.8 and 8.8 Hz), 7.82 (d, 1H, J=8.8 Hz), 7.56 (s, 1H), 7.54 (d, 1H, J=1.8 Hz), 7.07 (d, 1H, J=8.2 Hz), 5.70 (s, 2H), 3.96 (s, 3H), 3.88 (s, 3H). Low Rf: Methyl 3-methoxy-4-[(6-nitroindazol-2-yl)methyl]benzoate: 1H NMR (CDCl3): delta 8.68 (br s, 1H), 8.07 (s, 1H), 7.86 (dd, 1H, J=1.8 and 9.0 Hz), 7.72 (d, 1H, J=9.0 Hz), 7.61 (d, 1H, J=7.7 Hz), 7.58 (s, 1H), 7.19 (d, 1H, J=7.7 Hz), 5.69 (s, 2H), 3.93 (s, 3H), 3.90 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of 2-pyrrolidinone (8.60 g, 101 mmol) in DMF (150 mL) was added to a stirred slurry of NaH (4.60 g, 60percent dispersion in mineral oil, 116 mmol) in DMF (150 mL) at 0 °C. The mixture was stirred for 15 min at 0 °C and a solution of methyl 4-(bromomethyl)-3- methoxybenzoate (25. g, 96 mmol) in DMF (150 mL) was added. The resulting mixture was slowly allowed to warm to ambient temperature and stirred for 1 h. The mixture was cooled to 0 °C and saturated aqueous ammonium chloride was added. The aqueous phase was extracted with EtOAc (3x). The combined organic phases were washed with saturated aqueous sodium chloride (3x), dried over MgS04, filtered, and concentrated. Purification of the residue by silica gel chromatography (75? 100percent Hexanes/EtOAc) gave the title compound. LC-MS m/z = 264.3 [M+l]+. | ||
A solution of 2-pyrrolidinone (8.60 g, 101 mmol) in DMF (150 mL) was added to a stirred slurry of NaH (4.60 g, 60percent dispersion in mineral oil, 1 16 mmol) in DMF (150 mL) at 0 °C. The mixture was stirred for 15 min at 0 °C and a solution of methyl 4-(bromomethyl)-3- methoxybenzoate (25 g, 96 mmol) in DMF (150 mL) was added. The resulting mixture was slowly allowed to warm to ambient temperature and stirred for 1 h. The mixture was cooled to 0 °C and saturated aqueous ammonium chloride was added. The organic phase was extracted using EtOAc (3x). The combined organic phase was washed with brine (3x), dried over MgS04, filtered, and concentrated. Purification of the residue by silica gel chromatography (75? 100percent Hexanes/EtOAc) gave the title compound. LC-MS m/z = 264.3 [M+l]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred slurry of NaH (0.280 g, 6.95 mmol) in DMF (10 niL) at 0 °C was added (5)-4-phenylpyrrolidin-2-one (0.980 g, 6.08 mmol) in DMF (10 mL). The reaction mixture was stirred for 5 min and then <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (1.50 g, 5.79 mmol) in DMF (10 mL) was added. The resulting mixture was slowly allowed to warm to ambient temperature and allowed to stir for 1 h. The reaction mixture was cooled to 0 °C and was quenched by very slow addition of saturated aqueous ammonium chloride solution. The aqueous phase was extracted with EtOAc (3x). The combined organic phase was washed with saturated aqueous sodium chloride (3x), dried over magnesium sulfate, filtered, and concentrated. Purification of the residue by silica gel chromatography (50-100percent EtOAc / Hexanes) afforded the title compound as a tan solid. MS: m/z = 340.2 [M+l]+. | ||
To a stirred slurry of NaH (0.280 g, 6.95 mmol) in DMF (10 mL) at 0 °C was added (S)-4-phenylpyrrolidin-2-one (0.980 g, 6.08 mmol) in DMF (10 mL). The mixture was stirred for 5 min and then Methyl 4-(bromomethyl)-3-methoxybenzoate (1.50 g, 5.79 mmol) was added in DMF (10 mL). The resulting mixture was slowly allowed to come to ambient temperature and was then stirred for lh. The mixture was cooled to 0 °C and was carefully quenched with saturated aqueous ammonium chloride solution. The organic phase was extracted with EtOAc (3x). The combined organic phase was washed with brine (3x), dried over magnesium sulfate, filtered, and concentrated. Purification of the residue by silica gel chromatography (50-100percent EtOAc / Hexanes) afforded the title compound as a tan solid. MS: m/z = 340.2 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 4-methylpyrrolidin-2-one (574 mg, 5.79 mmol) in anhydrous DMF (15 mL) was added NaH (255 mg, 6.37 mmol, 60percent in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then a solution of methyl 4-(bromomethyl)-3- methoxybenzoate (1.50 g, 5.79 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 14 h and then quenched with saturated aqueous NH4C1 (10 mL). The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with H20 (30 mL x 3) and saturated aqueous sodium chloride (30 mL), dried over Na2S04, and concentrated. The residue was purified by silica gel chromatography (petroleum ether :EtO Ac, 20: 1 to 3: 1) to give the racemic title compound. The racemic title compound was resolved by SFC (Chiralpak AD column, eluting with C02:MeOH (0.2percent> NH4OH), 75:25) to give the title compound as the first eluting isomer. MS (ESI) m/z: 278.1 [M+l]+. 1H NMR (400 MHz CDC13): delta 7.61 (dd, J = 1.6, 8.0 Hz, 1H), 7.53 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.51 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.42- 3.38 (m, 1H), 2.86-2.84 (m, 1H), 2.63-2.57 (m, 1H), 2.47-2.38 (m, 1H), 2.10-2.04 (m, 1H), 1.09 (d, J = 6.4 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of pyrimidin-4(3H)-one (8.9 g, 93 mmol) in DMF (150 mL) was added to a stirring 0 °C slurry of NaH (3.9 g, 60percent dispersion in mineral oil, 96 mmol) in DMF (200 mL). The resulting mixture was stirred at 0 °C for 15 min. A solution of methyl 4- (bromomethyl)-3-methoxybenzoate (20 g, 77 mmol) in DMF (150 mL) was then added. The resulting mixture was allowed to slowly warm to ambient temperature and stirred for 1 h. The mixture was cooled to 0 °C and saturated aqueous ammonium chloride was added. The aqueous phase was extracted with EtOAc (3x). The combined organic phases were washed with saturated aqueous sodium chloride (3x), dried over MgS04, filtered, and concentrated in vacuo. Purification of the concentrate by silica gel chromatography (100? 90percent DCM/ MeOH) gave the title compound. LC-MS m/z found = 275.2 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of <strong>[51173-05-8]5-fluoropyridin-2-ol</strong> (500 mg, 4.42 mmol) in 15 mL of DMF was added NaH (60% dispersion, 195 mg, 4.86 mmol). The reaction mixture was stirred at ambient temperature for 10 min before addition of methyl 4-(bromomethyl)-3-methoxybenzoate (1.38 g, 5.31 mmol) dissolved in 15 mL of DMF via pipet. The reaction was stirred at ambient temperature for 30 min and then quenched with water. The reaction mixture was then diluted with ethyl acetate and the organic phase was washed with water (3x's) and saturated aqueous sodium chloride (lx). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes: ethyl acetate (100:0 to 20:80), to give the title compound. MS: mlz = 292.1 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of pyrazin-2-ol (3.0 g, 31 mmol) in 150 mL of DMSO was added NaH (60percent dispersion, 1.8 g, 47 mmol). The reaction mixture was stirred at ambient temperature for 10 min before addition of <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (12 g, 47 mmol) dissolved in 150 mL of DMSO via addition funnel. The reaction mixture was stirred at ambient temperature for 30 min and then quenched with water. The reaction mixture was then diluted with ethyl acetate and washed with water (3x's) and saturated aqueous sodium chloride (lx). The combined organic layers were then dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc -100:0 to 10:90, to give the title compound. MS: mlz = 275.1 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of 2-piperidinone (2.2 g, 22 mmol) in DMF (30 mL) was added to a stirred slurry of NaH (0.90 g, 60percent dispersion in mineral oil, 23 mmol) in DMF (30 mL) at 0 °C. The mixture was stirred for 15 min at 0 °C and then a solution of methyl 4-(bromomethyl)-3- methoxybenzoate (5.0 g, 19 mmol) in DMF (30 mL) was added. The resulting mixture was stirred at 0 °C for 4 h and was then slowly allowed to warm to ambient temperature. The mixture was stirred for 1 h. The mixture was cooled to 0 °C, and saturated aqueous ammonium chloride solution was added and the mixture was extracted using EtOAc (3x). The combined organic phase was washed with brine (3x), dried over MgS04, filtered, and concentrated. Purification of the concentrate by silica gel chromatography (100? 90percent CH2CI2/ MeOH) gave the title compound. LC-MS m/z = 278.3 [M+l]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of 4-(trifluoromethyl)pyrrolidin-2-one (4.96 g, 32.4 mmol) in DMF (50 mL) was added to a slurry of NaH (1.35 g, 60percent dispersion in mineral oil, 33.8 mmol) in DMF (50 mL) at 0 °C. This mixture was stirred at 0 °C for 5 min before a solution of methyl 4- (bromomethyl)-3-methoxybenzoate (7.0 g, 27 mmol) in DMF (50 mL) was added, and the solution was stirred at 0 °C for 15 min. The mixture was quenched with saturated aqueous ammonium chloride solution and then extracted with EtOAc (3x). The combined organic phase was washed with brine, dried over MgS04, filtered, and concentrated. Purification of the residue by silica gel chromatography (100? 0percent Hexanes/EtOAc) gave the title compound. LC-MS m/z found = 332.2 [M+l]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 4-methylpyrrolidin-2-one (574 mg, 5.79 mmol) in dry DMF (15 mL) was added NaH (255 mg, 6.37 mmol, 60percent in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, and then a solution of methyl 4-(bromomethyl)-3- methoxybenzoate (1.50 g, 5.79 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 14 h and then quenched with saturated aqueous NH4CI (10 mL). The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with H20 (30 mL x 3) and brine (30 mL), dried over Na2S04, and concentrated. The residue was purified by columnchromatography (Si02, petroleum ether: EtOAc = 20: 1 to 3: 1) to give the title compound as a racemate, which was separated by SFC (Chiralpak AD column; eluting with C02/MeOH (0.2percent NH4OH) = 75/25) to give the title compound as the first eluting isomer. MS (ESI) m/z: 278.1 [M + 1]. NMR (400 MHz CDC13): delta 7.61 (dd, J = 1.6, 8.0 Hz, 1H), 7.53 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.51 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.42-3.38 (m, 1H), 2.86-2.84 (m, 1H), 2.63- 2.57 (m, 1H), 2.47-2.38 (m, 1H), 2.10-2.04 (m, 1H), 1.09 (d, J = 6.4 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 5-methylpyridin-2(lH)-one (460 mg, 4.25 mmol) in DMF (10 mL) was added NaH (170 mg, 4.25 mmol, 60% in mineral oil) at 0 C. The reaction mixture was stirred at 0 C for 30 min and then a solution of methyl 4-(bromomethyl)-3- methoxybenzoate (1.00 g, 3.86 mmol) in DMF (10 mL) was added dropwise. The reaction mixture was stirred at 23 C for 16 h and then quenched with saturated aqueous NH4C1 (10 mL). The resulting mixture was diluted with water (30 mL) and extracted EtOAc (30 mL x 3). The combined organic phase was washed brine (50 mL), dried over Na2S04, and concentrated. The residue was purified by column chromatography (Si02>petroleum ethenEtOAc = 5: 1 to 1 :2) to give methyl 3-methoxy-4-((5-methyl-2-oxopyridin-l (2H)-yl)methyl)benzoate as a solid. MS: m/z = 287.9 (M + 1). NMR (400 MHz, CDC13): delta 7.59 (dd, J - 1.6, 8.0 Hz, 1H), 7.55 (d, J = 1.2 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.19 (dd, J = 2.8, 9.2 Hz, 1H), 7.10 (s, 1H), 6.55 (d, J = 9.2 Hz, 1H), 5.14 (s, 2H), 3.91 (d, J = 8.0 Hz, 6H), 2.05 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20℃; for 18h;Inert atmosphere; | 4-Chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (commercially available, 1 equiv.) was dissolved in NMP (0.1 M) and stirred at room temperature under N2. Potassium carbonate (1 equiv.) was added, followed by addition of <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (from the previous step, 1 equiv.) to give a suspension. The reaction was stirred at room temperature for 18 hours and LCMS shows complete conversion into methyl 4-((2-amino-4-chloro-5H- pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-3-methoxybenzoate. N-pentyl amine (2 equiv.) was added, followed by potassium carbonate (1 equiv.). The reaction mixture was stirred at 60 °C overnight. After cooling down to room temperature, the reaction mixture was concentrated en vacuuo, and was purified by ISCO chromatography (0 - 100percent EtOAc in hexanes) to afford the title product as a white solid. 1 H NMR (DMSO-d6): delta 7.53 (d, 1 H), 7.51 (d, 1 H), 7.48 (dd, 1 H), 7.40 (br s, 2H), 7.34 (t, 1 H), 6.45 (d, 1 H), 6.27 (d, 1 H), 5.67 (s, 2H), 3.92 (s, 3H), 3.83 (s, 3H), 3.40 (q, 2H), 1 .41 -1 .32 (m, 2H), 1 .17-1 .07 (m, 2H), 0.97-0.87 (m, 2H), 0.73 (t, 3H). LRMS [M+H] = 398.2. | |
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h; | A round bottom flask was charged with 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (1,commercially available, 1 .0 equiv.), <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (2,commercially available, 1.0 equiv.), caesium carbonate (1.0 equiv.) and DMF (1.0 M). The reaction mixture was stirred at room temperature for 18 hours and the solvent was then removed in vacuo. To the resulting mixture was added EtOAc and the solvent was removed in vaccuo. To this mixture was added DCM and the solvent removed in vacuo. The crudereaction mixture was then purified by ISCO chromatography (0? 10percent MeOH:DCM, gradient) to afford methyl 4-((2-amino-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-3-methoxybenzoate (3) as a solid. | |
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h; | A round bottom flask was charged with 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (1 , commercially available, 1 .0 equiv.), <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (2, commercially available, 1 .0 equiv.), caesium carbonate (1 .0 equiv.) and DMF (1 .0 M). The reaction mixture was stirred at room temperature for 18 hours and the solvent was then removed in vacuo. To the resulting mixture was added EtOAc and the solvent was removed in vaccuo. To this mixture was added DCM and the solvent removed in vacuo. The crude reaction mixture was then purified by ISCO chromatography (0 - 10percent MeOH:DCM, gradient) to afford methyl 4-((2-amino-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-3-methoxybenzoate (3) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 17h; | To a stirred suspension of <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (0.53 g, 2.04 mmol, 1 eq.) and potassium carbonate (0.56 g, 4 mmol, 2 eq.) in N,N-dimethylformamide (5 mL) was added isoindoline (280 mu^, 2.45 mmol, 1.2 eq.). The resulting mixture was then stirred at room temperature for 17 hours. The solvent was removed in vacuo and the crude product was partitioned between water and dichloromethane, the layers were separated and the aqueous phase extracted with dichloromethane. The combined extracts were dried with magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography using a 10 - 100 percent ethyl acetate in wo-hexane gradient to afford methyl 4- (isoindolin-2-ylmethyl)-3-methoxybenzoate as a red liquid (0.417 g, 70 percent yield). NMR (400 MHz, CDC13) 7.66 (1H, d, J=7.8 Hz), 7.55-7.53 (2H, m), 7.18 (4H, s), 4.0-3.98 (6H, m), 3.92-3.91 (6H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.5% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 5h; | A solution of N-(pyridin-3-yl)methanesulfonamide (0.500 g, 2.904 mmol), sodium hydride (60.00 percent, 0.139 g, 3.484 mmol) and <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (0.828 g, 3.194 mmol) in N,N-dimethylformide (10 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous Mg504, filtered, and concentrated in vacuo. The residue was chromatographed (5i02, 12 g cartridge; ethyl acetate / hexane = 0 percent to 30 percent) to give methyl3-methoxy-4-((N-(pyridin-3-yl)methylsulfonamido)methyl)benzoate as yellow solid (0.117 g, 11.5 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | [455] To a stirred solution of N-phenylmorpholine-4-carboxamide (0.500 g, 2.424 mmol) in N,N-dimethylformamide ( 10 mL) was added at 0 °C <strong>[70264-94-7]methyl 4-(bromomethyl)-3-methoxybenzoate</strong> (0.817 g, 3. 152 mmol). The reaction mixture was stirred at the same temperature for 30 min, treated at the room temperature with sodium hydride (60.00 percent, 0. 194 g, 4.849 mmol), and stirred for additional 4 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried (anhydrous MgS04). filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 12 g cartridge; ethyl acetate / hexane = 0 percent to 40 percent) to give the title compound methyl 3-methoxy-4-((N-phenylmorpholine-4-carboxamido)methyl )benzoate as Colorless oil (0.690 g, 74.0 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 85℃; for 1h;Microwave irradiation; | To a solution of compound 15 (300 mg, 0.685 mmol) in 1,4-dioxane/H2O (5:2, 14 mL) was added methyl 4-(bromomethyl)-3-methoxy-benzoate (193 mg, 0.75 mmol), Pd(PPh3)4 (79 mg, 0.07 mmol) and K2CO3 (284 mg, 2.06 mmol) and the mixture was stirred at 85 oC for 1 hour under MW. Then, the mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product which was purified by column chromatography to obtain pure compound 16d (200 mg, 60percent) as a white solid. ESI-MS m/z 491.1 [M+H]+ calc. for C27H30N4O5. This intermediate was used in the next step without further characterization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | NaH (1.08 eq.) was added dropwise to indole (1 eq.) dissolvedin DMF (4 mL/mmol of indole) at 0 C. The solution wasstirred for 30 min at room temperature. The halide (1 eq.) wasadded portionwise at 0 C. The solution was then stirred overnight at room temperature. The reactionwas thenwashed 3 EtOAc. Thecombined organic layer was then washed with brine. Organic layerwas dried with Mg2SO4 and rotovapped. Product was purified bycolumn chromatography. Tan solid; 50%; 1H NMR (DMSO): delta 8.60 (d,J 2.3 Hz, 1H), 8.01 (dd, J 9.1, 2.3 Hz, 1H), 7.74-7.60 (m, 2H),7.56-7.44 (m, 2H), 6.89 (d, J 7.9 Hz, 1H), 6.82 (dd, J 3.2, 0.8 Hz,1H), 5.54 (s, 2H), 3.93 (s, 3H), 3.84 (s, 3H); 13C NMR (DMSO):delta166.30,157.07,141.35,139.34,133.64,131.03,130.95,128.52,127.89,122.08, 118.08, 117.07, 111.42, 111.11, 104.53, 56.72, 52.71, 45.34. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; for 24h;Microwave irradiation; Inert atmosphere; Sealed tube; | Cs2CO3 (2 eq.) was dissolved in H2O (2 mL/mmol halide) anddegassed. Halide (1 eq.), Pd(PPh3)4 (0.2 eq), and boronic acid (1 eq.)was added in that order to DME (4 mL/mmol of halide) in a microwavetube under argon gas. Cs2CO3/H2O was then added to thesolution. The microwave tube was then sealed and stirred at90-100 °C for 24 h. The organic layer was then extracted 3 H2O/DCM. The organic layer was then dried with Mg2SO4 and rotovapped.Product was purified by column chromatography. White solid; 51percent; 1H NMR (DMSO): delta 8.06 (tdd, J 3.6, 2.4, 1.1 Hz, 2H), 7.72-7.47(m, 4H), 7.38 (d, J 7.8 Hz, 1H), 4.12 (s, 2H), 3.85 (d, J 1.9 Hz, 6H);13C NMR (DMSO): delta 166.48, 157.38, 148.77, 142.78, 135.99, 134.08,131.00, 130.30, 130.04, 123.55, 122.20, 121.65, 111.45, 56.11, 52.63,35.11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / dimethyl sulfoxide / 3 h / 50 °C 2: formic acid; hydroxylamine hydrochloride / 25 h / 20 - 50 °C 3: methanol; sodium hydroxide; water / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.7% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 20℃; for 8h; | 3.12 12. Preparation of Intermediate 4l Take 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (200mg, 0.66mmol),Add methyl 3-methoxy-4-(bromomethyl)benzoate (205mg, 0.79mmol), K2CO3 (137mg, 0.99mmol), KI (10mg, 0.06mmol) to the 50ml reaction flask, add 15ml DMF to dissolve and stir At room temperature for 8 hours, the reaction was complete by TLC. The reaction solution was poured into 100 ml of ice water, stirred, and a white solid precipitated. 25 ml of ethyl acetate was added, and the extraction was performed three times with a separatory funnel. The organic phases were combined, washed with saturated brine, and the organic phase was distilled off under reduced pressure. Silica gel column chromatography (dichloromethane Methane: methanol = 200:1) to obtain 190 mg of white solid with a yield of 59.7%. |
Tags: 70264-94-7 synthesis path| 70264-94-7 SDS| 70264-94-7 COA| 70264-94-7 purity| 70264-94-7 application| 70264-94-7 NMR| 70264-94-7 COA| 70264-94-7 structure
[ 142031-88-7 ]
Methyl 3-(bromomethyl)-4-methoxybenzoate
Similarity: 0.98
[ 74733-27-0 ]
Methyl 4-(bromomethyl)-2-methoxybenzoate
Similarity: 0.95
[ 788081-99-2 ]
Methyl 2-(bromomethyl)-5-methoxybenzoate
Similarity: 0.88
[ 15365-25-0 ]
Methyl 2-(bromomethyl)-4-methoxybenzoate
Similarity: 0.88
[ 71887-28-0 ]
Methyl 2-(bromomethyl)-3-methoxybenzoate
Similarity: 0.87
[ 142031-88-7 ]
Methyl 3-(bromomethyl)-4-methoxybenzoate
Similarity: 0.98
[ 74733-27-0 ]
Methyl 4-(bromomethyl)-2-methoxybenzoate
Similarity: 0.95
[ 788081-99-2 ]
Methyl 2-(bromomethyl)-5-methoxybenzoate
Similarity: 0.88
[ 15365-25-0 ]
Methyl 2-(bromomethyl)-4-methoxybenzoate
Similarity: 0.88
[ 71887-28-0 ]
Methyl 2-(bromomethyl)-3-methoxybenzoate
Similarity: 0.87
[ 142031-88-7 ]
Methyl 3-(bromomethyl)-4-methoxybenzoate
Similarity: 0.98
[ 74733-27-0 ]
Methyl 4-(bromomethyl)-2-methoxybenzoate
Similarity: 0.95
[ 788081-99-2 ]
Methyl 2-(bromomethyl)-5-methoxybenzoate
Similarity: 0.88
[ 15365-25-0 ]
Methyl 2-(bromomethyl)-4-methoxybenzoate
Similarity: 0.88
[ 71887-28-0 ]
Methyl 2-(bromomethyl)-3-methoxybenzoate
Similarity: 0.87
[ 142031-88-7 ]
Methyl 3-(bromomethyl)-4-methoxybenzoate
Similarity: 0.98
[ 74733-27-0 ]
Methyl 4-(bromomethyl)-2-methoxybenzoate
Similarity: 0.95
[ 788081-99-2 ]
Methyl 2-(bromomethyl)-5-methoxybenzoate
Similarity: 0.88
[ 15365-25-0 ]
Methyl 2-(bromomethyl)-4-methoxybenzoate
Similarity: 0.88
[ 71887-28-0 ]
Methyl 2-(bromomethyl)-3-methoxybenzoate
Similarity: 0.87
[ 142031-88-7 ]
Methyl 3-(bromomethyl)-4-methoxybenzoate
Similarity: 0.98
[ 74733-27-0 ]
Methyl 4-(bromomethyl)-2-methoxybenzoate
Similarity: 0.95
[ 788081-99-2 ]
Methyl 2-(bromomethyl)-5-methoxybenzoate
Similarity: 0.88
[ 15365-25-0 ]
Methyl 2-(bromomethyl)-4-methoxybenzoate
Similarity: 0.88
[ 71887-28-0 ]
Methyl 2-(bromomethyl)-3-methoxybenzoate
Similarity: 0.87
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 :