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[ CAS No. 90564-26-4 ]

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CAS No. :90564-26-4 MDL No. :MFCD11045625
Formula : C9H9NO5 Boiling Point : -
Linear Structure Formula :- InChI Key :N/A
M.W :211.17 g/mol Pubchem ID :-
Synonyms :

Safety of [ 90564-26-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 90564-26-4 ]

  • Downstream synthetic route of [ 90564-26-4 ]

[ 90564-26-4 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 67-56-1 ]
  • [ 40751-88-0 ]
  • [ 90564-26-4 ]
YieldReaction ConditionsOperation in experiment
With sulfuric acid; at 0℃; for 12h;Reflux; At room temperature, compound 2 (6.36g, 1.0eq) was dissolved in methanol (65mL),Then the temperature was lowered to 0C and concentrated sulfuric acid (3.79g, 1.2eq) was added. Then slowly heat up to reflux,After 12 hours of reaction, TLC monitored the reaction to complete. Cool down to room temperature, then spin off the methanol,Add 50mL of ice water, adjust the pH value to neutral with sodium bicarbonate aqueous solution,Extract with ethyl acetate, wash the organic phase with saturated aqueous sodium chloride solution, dry the organic phase,It was spin-dried to obtain 5.8 g of the crude product of compound 3. Used directly in the next step.
  • 2
  • [ 90564-26-4 ]
  • [ 40751-88-0 ]
YieldReaction ConditionsOperation in experiment
97% With sodium hydroxide; In methanol; at 20℃; for 18h; A mixture of methyl 2-methoxy-3-nitrobenzoate (5.16 g, 24.44 mmol) and NaOH, 1N (51.3 mL,51.3 mmol) in MeOH (200 mL) was stirred at rt for 18 hr. The MeOH was removed on the rotovap and the remaining solution was diluted with 100 ml of water. The pH was adjusted to 1 with 1N HC1 and the resulting suspension was filtered and dried to afford 2-methoxy-3-nitrobenzoic acid (4.65 g, 23.59 mmol, 97 % yield) as a white solid. LCMS m/z 198.0 (M+H)+; HPLC fe 1.01 min (analytical HPLC Method F); NMR (400MHz, chloroform-d) d 8.30 (dd, J=7.9, 1.8 Hz, 1H), 8.04 (dd, J=8.l, 1.8 Hz, 1H), 7.38 (t, J=7.9 Hz, 1H),4.09 (s, 3H) carboxylic acid proton not seen.
94% With sodium hydroxide; In methanol; water; at 75℃; for 0.25h; Step 2[00211j A stirred solution of methyl 2-methoxy-3-nitrobenzoate (0.962 g, 4.56 mmol) in methanol (10 mL) was heated to 75 C. 1.0 N (aq.) sodium hydroxide (9.57 mL, 9.57 mmol) was added dropwise and the reaction mixture heated at 75 C for fifteen minutes. The reaction mixture was cooled to room temperature and concentrated to remove the methanol solvent. The residue was acidified with iN (aq.) HC1 solution to pH 1, stirred and filtered. The solid residue was air-dried to give 0.84 1 g white solid product (94% yield). ‘H NMR (400MHz, DMSO-d6) ö 8.06 (dd, J7.9, 1.5 Hz, 1H), 8.01 (dd, J7.7, 1.5 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 3.89 (s, 3H). LC retention time 1.78 mm [A]
93% With water; sodium hydroxide; In methanol; for 0.25h;Reflux; [00243j Methyl 2-hydroxy-3-nitrobenzoate (2.85 g, 13.50 mmol) was dissolved in hot methanol (10 mL) at 75 C to make clear solution and iN aq. sodium hydroxide (28.3 mL, 28.3 mmol) was added dropwise. The mixture was heated under reflux for 15minutes and then cooled to room temperature, concentrated to remove the methanol and then cooled in an ice bath. The solution was acidified via the dropwise addition of 1M (aq.) HC1 until the pH was 1, resulting in the product precipitating out of solution. The solid was collected by filtration, rinsed with water, and dried on the filter to afford the product 2-methoxy-3-nitrobenzoic acid (2.48 g, 12.58 mmol, 93% yield) as a white solid.HPLC (Method N) RT = 1.57 minutes.
93% With water; sodium hydroxide; In methanol; at 75℃;Reflux; Step 2 Methyl 2-hydroxy-3-nitrobenzoate (2.85 g, 13.50 mmol) was dissolved in hot methanol (10 mL) at 75 C to make clear solution and IN aq. sodium hydroxide (28.3 mL, 28.3 mmol) was added dropwise. The mixture was heated under reflux for 15 min. whereupon HPLC analysis indicated complete conversion to a more polar product. The reaction was cooled to rt, concentrated to remove the methanol and the resulting aqueous solution was cooled in and ice bath and made acidic by a dropwise addition of 1M HC1 (40 mL) until the pH was ~1. The resulting precipitated solid was collected by filtration, rinsed with water, and dried on the filter to afford the product 2-methoxy-3-nitrobenzoic acid (2.48 g, 12.58 mmol, 93% yield) as a white solid. HPLC (method N) RT = 1.57 min,
93% With sodium hydroxide; In methanol; water; at 75℃; for 0.25h; A solution of methyl 2-hydroxy-3-nitrobenzoate (2.85 g, 13.50 mmol) in hot methanol (10 mL) at 75 C was added and a 1 N aqueous solution of sodium hydroxide (28.3 mL, 28.3 Mmol). The mixture was heated at reflux for 15 min, after which the HPLC analysis indicated complete conversion to a more polar product. The reaction was cooled to rt, concentrated to remove methanol and the resulting aqueous solution was cooled in an ice bath and acidified by dropwise addition of IM HCl (40 mL) until the pH was about 1. The resulting precipitated solid was collected by filtration, rinsed with water and dried on a filter to afford product 2-methoxy-3-nitrobenzoic acid (2.48 g, 12.58 mmol, 93% yield) as a white solid.
93% With water; sodium hydroxide; In methanol; at 20℃; for 1h; NaOH (1.1 g, 27.3 mmol, in 6 mL of H2O) was added to a solution of compound 2 (1.1 g, 5.5 mmol) in 10 mL of MeOH. The mixture was stirred at r.t. for 1 h, and then the pH value was adjusted to 5-6 with 1 M HCl (aq.). The mixture was extracted with EtOAc (2×120 mL) and washed with water (80 mL) and brine (60 mL), dried over Na2SO4, and concentrated to give acid 3 (1.0 g, 93%) as a light yellow solid for direct use in the next step.
93% With water; sodium hydroxide; In methanol; at 20℃; for 1h; NaOH (1.1 g, 27.3 mmol, in 6 mL of H2O) was added to a solution of compound 2 (1.1 g, 5.5 mmol) in 10 mL of MeOH. The mixture was stirred at r.t. for 1 h, and then the pH value was adjusted to 5-6 with 1 M HCl (aq.). The mixture was extracted with EtOAc (2×120 mL) and washed with water (80 mL) and brine (60 mL), dried over Na2SO4, and concentrated to give acid 3 (1.0 g, 93%) as a light yellow solid for direct use in the next step.
Reference Example 31 2-methoxy-3-nitrobenzoic acid 1N sodium hydroxide was added to a solution (50 ml) of methyl 2-methoxy-3-nitrobenzoate (4.96 g, 23.5 mmol) in methanol and the mixture was stirred at 50C for 2 hrs.. methanol was evaporated under reduced pressure and water was added.. The aqueous layer was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate.. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.. The obtained residue was recrystallized from hexane-ethyl acetate to give the title compound (4.37 g) as pale-yellow crystals. melting point: 224-226C1H-NMR (CDCl3) δ 4.02 (3H, s), 7.25-7.34 (1H, m), 7.91 (1H, ddd, J = 0.6, 1.8, 8.0 Hz), 8.10 (1H, ddd, J = 0.8, 1.8, 8.4 Hz).
Reference Example 175 2-Methoxy-3-nitrobenzoic acid [Show Image] A 3N aqueous sodium hydroxide solution (155 mL) was added to a solution of methyl 2-methoxy-3-nitrobenzoate (9.83 g) in a mixture of tetrahydrofuran and methanol (1:1, 400 mL) and stirred for 48 hours. The organic solvent was removed under reduced pressure and water (400 mL) was added to the residue to obtain a solution. This solution was acidified (pH = 1) with 36% hydrochloric acid and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (8.01 g). 1H NMR (400 MHz, CDCl3) δ 8.29 (dd, J = 7.9 and 1.7 Hz, 1H), 8.04 (dd, J = 7.9 and 1.7 Hz, 1H), 7.38 (dd, J = 7.9 and 7.9 Hz, 1H), 4.09 (s, 3H). MS (ESI+) 198 (M+ + 1, 18%), 180 (100%).
With water; sodium hydroxide; In ethanol; at 10 - 35℃; (ii) To a solution of methyl 2-methoxy-3-nitrobenzoate (1.10 g) in ethanol (20.0 mL) was added 1N aqueous sodium hydroxide solution (20.0 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 2-methoxy-3-nitrobenzoic acid (980 mg). The present compound was used for the next reaction without further purification.
2-Methoxy-3-nitrobenzoic acid (3). NaOH (1.1 g, 27.3 mmol, in 6 mL of H2O) was added to a solution of compound 2 (1.1 g, 5.5 mmol) in 10 mL of MeOH. The mixture was stirred at r.t. for 1 h, and then the pH value was adjusted to 5-6 with 1 M HCl (aq.). The mixture was extracted with EtOAc (2*120 mL) and washed with water (80 mL) and brine (60 mL), dried over Na2SO4, and concentrated to give acid 3 (1.0 g, 93%) as a light yellow solid for direct use in the next step.
2-Methoxy-3-nitrobenzoic acid (3). NaOH (1.1 g, 27.3 mmol, in 6 mL of H2O) was added to a solution of compound 2 (1.1 g, 5.5 mmol) in 10 mL of MeOH. The mixture was stirred at r.t. for 1 h, and then the pH value was adjusted to 5-6 with 1 M HCl (aq.). The mixture was extracted with EtOAc (2*120 mL) and washed with water (80 mL) and brine (60 mL), dried over Na2SO4, and concentrated to give acid 3 (1.0 g, 93%) as a light yellow solid for direct use in the next step.

  • 3
  • [ 90564-26-4 ]
  • [ 722538-98-9 ]
YieldReaction ConditionsOperation in experiment
96% With ammonium hydroxide; ammonia In methanol; lithium hydroxide monohydrate at 20℃; for 16h; 1 Synthesis of compound 1.3 To 1.2 (50 g, 236.7 mmol, 1.0 eq) was added aq. H4OH (300mL) followed by methanolic H3 (1600 mL). Reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, reaction mixture was concentrated under reduced pressure and residue was washed with ice cold water. Precipitate was dried to furnish 1.3 (45.0 g, 96.0 %). MS(ES): m/z 197.2 [M+H]+.
94.2% With ammonium hydroxide; ammonia In methanol at 20 - 30℃; Inert atmosphere; 3 Step 3 ;2-methoxy-3-nitrobenzamide I-1-4 The solution of I-1-3 (24.00 g, 113.65 mmol) in NH4OH (50 mL) and 7N NH3 in MeOH (100 mL) was stirred at rt overnight. The mixture was concentrated, the residue was purified by SGC (PE/EA=1) to afford the tittle compound I-1-4 (21 g, 94.20% yield).
94.2% With ammonium hydroxide; ammonia In methanol at 20 - 30℃; Inert atmosphere; 3 Step 3 ;2-methoxy-3-nitrobenzamide I-1-4 The solution of I-1-3 (24.00 g, 113.65 mmol) in NH4OH (50 mL) and 7N NH3 in MeOH (100 mL) was stirred at rt overnight. The mixture was concentrated, the residue was purified by SGC (PE/EA=1) to afford the tittle compound I-1-4 (21 g, 94.20% yield).
94.9% With ammonium hydroxide; ammonia In methanol; lithium hydroxide monohydrate at 20℃; for 16h;
92% With ammonium hydroxide; ammonia In methanol at 20℃; 1.1 At room temperature, methyl 2-methoxy-3-nitrobenzoate (5g, 23.7mmol) was dissolved in ammonia methanol solution (100mL, 7M), ammonia water (28wt%, 50mL) was added, and the mixture was It was stirred at room temperature overnight, diluted with ethyl acetate (300 mL), and the organic phase was washed with saturated aqueous NaHCO 3 (300 mL×2) and saturated brine in this order. The organic phase was separated and dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and the title compound 2-methoxy-3-nitrobenzamide (4.3 g, 92%) was isolated by column chromatography.
91% With ammonium hydroxide; ammonia In methanol at 20℃; Sealed tube; 13.1 First step To a solution of compound 13a (4.60 g, 22.0 mmol) in ammonia methanol (5M, 20 mL) was added 25% aqueous ammonia solution (20 mL).The resulting reaction solution was sealed and reacted overnight at room temperature.After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by column chromatography (ethyl acetate: petroleum ether=0-100%) to obtain compound 13b (3.90 g), yield: 91%.
88% With ammonium hydroxide; ammonia In methanol at 20℃; 69.2 Step 2: Methyl 2-methoxy-3-nitrobenzoate (69-b, 3.7 g, 17.3 mmol) was dissolved in methanolic ammonia solution (7N, 83 mL), then concentrated ammonia water (35 mL) was added, room temperature Stir overnight. The completion of the reaction was monitored by TLC, the reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:5) to obtain 2-methoxy-3-nitrobenzamide (69-c, 3.0 g, 15.3 mmol, 88% yield).
86% With ammonium hydroxide; ammonia In methanol; lithium hydroxide monohydrate at 20 - 25℃; Sealed tube; 18.2 [00224j Methyl 2-methoxy-3-nitrobenzoate (11 g, 52.1 mmol) was dissolved in a cold solution of ammonia in methanol (7N, 250 mL) and concentrated aqueous ammonium hydroxide (100 mL) was added. The flask was sealed and the resulting solution was allowed to gently stir at room temperature overnight. The reaction mixture wasconcentrated on the rotovap to yield an aqueous slurry of the product. This slurry was diluted with additional water (3OO mL) and was sonicated briefly then the solid was collected by vacuum filtration and the resulting yellow solid was rinsed with additional water ( 100 mL). The solid was air dried in the funnel for several hours then under vacuum to afford 7.12 g of a yellow solid as the pure product 2-methoxy-3-nitrobenzamide. A second crop of product was obtained by extracting the filtrate with ethyl acetate (3 x 100 mL) followed by washing the extracts with brine, drying over anhydrous. Sodium sulfate, decanting and concentration under vacuum to afford 1.67 g of additional product as a yellow solid (86% overall combined yield). LCMS observedMH+ 197.
86% With ammonium hydroxide; ammonia In methanol; lithium hydroxide monohydrate at 20 - 25℃; for 17h; Sealed tube; 9.2 [00195j Methyl 2-methoxy-3-nitrobenzoate (11 g, 52.1 mmol) was dissolved in a cold solution of ammonia in methanol (7N, 250 mL) and conc. aqueous ammonium hydroxide (100 mL) was added. The flask was sealed and the resulting solution was allowed to gently stir at room temperature overnight ( 17 h). The reaction mixture was concentratedon the rotovap using a slightly warm water bath to yield an aqueous slurry of the product. This slurry was diluted with additional water (3OO mL) and was sonicated briefly then the solid was collected by vacuum filtration and the resulting yellow solid was rinsed with additional water ( 100 mL). The solid was air dried in the funnel for several hours then under vacuum to afford 7.12 g of a yellow solid as the pure product. A second crop ofproduct was obtained by extracting the filtrate with EtOAc (3 x 100 mL) followed by washing the extracts with brine, drying over anhydrous sodium sulfate, decanting and concentration under vacuum to afford 1.67 g of additional product as a yellow solid (86% overall combined yield). LC retention time 0.58 [J]. MS(E) m/z: 197 (MHj
86% With ammonium hydroxide; ammonia In methanol; lithium hydroxide monohydrate at 20℃; for 17h; 6.1 Preparation 6 Step 1 Preparation 6 Step 1 Methyl 2-methoxy-3-nitrobenzoate (from Step 1 in Preparation 4, 11 g, 52.1 mmol) was dissolved in a cold solution of ammonia in methanol (7N, 250 mL) and cone, aqueous ammonium hydroxide (100 mL) was added. The flask was stoppered and the resulting solution was allowed to gently stir at rt overnight (-17 h). LCMS analysis indicated complete conversion to more polar product consistent with the desired amide product (observed MH+ 197). The reaction mixture was concentrated on the rotovap using a slightly warm water bath to yield an aqueous slurry of the product. This slurry was diluted with additional water (-300 mL) and was sonicated briefly then the solid was collected by vacuum filtration and the resulting yellow solid was rinsed with additional water (-100 mL). The solid was air dried in the funnel for several hours then under vacuum to afford 7.12 g of a yellow solid as the pure product 2-methoxy-3- nitrobenzamide. A second crop of product was obtained by extracting the filtrate with EtOAc (3 x 100 mL) followed by washing the extracts with brine, drying over anhyd. Sodium sulfate, decanting and concentration under vacuum to afford 1.67 g of additional product as a yellow solid (86% overall combined yield). LCMS observed MH+ 197.
86% With ammonium hydroxide; ammonia In methanol; lithium hydroxide monohydrate at 20℃; for 17h; 6.1 Step 1 Methyl 2-methoxy-3-nitrobenzoate (from step 1, 11 g, 52.1 mmol in Preparation 4) was dissolved in a cold solution of ammonia in methanol (7N, 250 mL) and added Concentrated aqueous ammonium hydroxide solution (100 mL). The flask was stoppered and the resulting solution was gently stirred overnight (about 17 h) under rt. The LCMS analysis indicated complete conversion to a more polar product, consistent with the desired amide product (observed MH + 197). The reaction mixture was concentrated on a rotary evaporator using a micro-water bath to obtain an aqueous product slurry. The slurry was diluted with additional water (about 300 mL) and subjected to a brief sonic treatment, and the solid was collected by vacuum filtration and the resulting yellow solid was rinsed with additional water (about 100 mL). The solid is in a funnel and then dried in a vacuum for several hours,Provided 7.12 g of pure product as a white solid, 2-methoxy-3-nitrobenzamide. The extract was extracted with EtOAc (3 x 100 mL), then the extract was washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give the second crop to afford 1.67 g of additional yellow solid Product (86% total yield).
86% With ammonium hydroxide; ammonia In methanol; lithium hydroxide monohydrate at 20℃; for 17h; Inert atmosphere; Sealed tube;
86% With ammonium hydroxide; ammonia In methanol; lithium hydroxide monohydrate at 20℃; Sealed tube; 2 Step 2: synthesis of compound Ac Methyl 2-methoxy-3-nitrobenzoate (11 g, 52.1 mmol) was dissolved in a cold solution of ammonia in methanol (7 N, 250 mL) and cone. aqueous ammonium hydroxide(100 mL) was added. The flask was sealed and the resulting solution was allowed to gently stir at room temperature overnight (~17 h). The reaction mixture was concentrated to afford Ac (1.67 g, 86%) as a yellow solid. LCMS [M+1]+ = 196.1.
Multi-step reaction with 3 steps 1: sodium carbonate; ethanol 2: thionyl chloride 3: aqueous ammonia
With ammonium hydroxide In methanol at 20℃; for 48h; 1.2 2-Methoxy-3-nitrobenzamide (1c) [0070] To a solution of methyl 2-methoxy-3-nitrobenzoate 1b (10 g, 47 mmol) in methanol (40 mL) at room temperature was added ammonium hydroxide (20 mL). After stirring at room temperature for 48 hours, the solvent was removed under reduced pressure to obtain the target compound 1c (crude, 10 g, solid). The crude product was used in the next step without further purification. [0071] MS m/z (ESI) : 197 [M+1]

Reference: [1]Current Patent Assignee: NIMBUS THERAPEUTICS INC; NIMBUS LAKSHMI INC - WO2018/71794, 2018, A1 Location in patent: Paragraph 00341; 00343
[2]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - US2022/2267, 2022, A1 Location in patent: Paragraph 0196; 0201; 0235; 0239; 0240
[3]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - US2022/2267, 2022, A1 Location in patent: Paragraph 0196; 0201; 0235; 0239; 0240
[4]Current Patent Assignee: CULLGEN SHANGHAI - WO2022/100710, 2022, A1 Location in patent: Page/Page column 82; 83
[5]Current Patent Assignee: HANSOH PHARMACEUTICAL GROUP CO LTD - WO2022/17494, 2022, A1 Location in patent: Page/Page column 38-39
[6]Current Patent Assignee: MINGHUI PHARMACEUTICAL HANGZHOU; MINGHUI PHARMACEUTICAL SHANGHAI - CN111909140, 2020, A Location in patent: Paragraph 0240-0244
[7]Current Patent Assignee: SHENZHEN CHIPSCREEN BIOSCIENCES CO LTD - WO2022/117016, 2022, A1 Location in patent: Page/Page column 114
[8]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2014/74660, 2014, A1 Location in patent: Paragraph 00224
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[10]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2015/69310, 2015, A1 Location in patent: Paragraph 00164
[11]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - TWI582077, 2017, B Location in patent: Page/Page column 75
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  • 4
  • [ 85-38-1 ]
  • [ 74-88-4 ]
  • [ 90564-26-4 ]
YieldReaction ConditionsOperation in experiment
83% With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; Step 1[002 10j A mixture of <strong>[85-38-1]2-hydroxy-3-nitrobenzoic acid</strong> (1.0 g, 5.46 mmol), iodomethane (1.02 mL, 16.4 mmol) and potassium carbonate (3.02 g, 21.8 mmol) in DMF (25 mL)was heated at 50 C overnight. The reaction mixture was cooled to room temperature, then diluted with ice-water [100 mL] with vigorous stirring, then filtered. The solid productwas dried to give 0.962 g white solid product (83% yield). ?H NMR (400MHz, DMSOd 6) oe 8.12 (dd, J8.1, 1.5 Hz, 1H), 8.03 (dd, J=7.8, 1.5 Hz, 1H), 7.44 (t, J7.9 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H). LC retention time 2.22 [A]. MS(Ej m/z: 212 (MHj.
With potassium carbonate; In N,N-dimethyl-formamide; Preparation of N-[3-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-methoxy-phenyl]-methanesulfonamide hydrochloride STR134 A solution of 15 g of <strong>[85-38-1]2-hydroxy-3-nitro-benzoic acid</strong> in 200 ml of N,N-dimethylformamide was treated with 58.1 g of iodomethane and 56.6 g of potassium carbonate, and the resultant heterogeneous mixture was stirred and heated to 45 C. for 20 hr. The mixture was cooled to room temperature, poured into ether, washed with water, washed with saturated sodium carbonate solution, washed with water, dried over magnesium sulfate, evaporated, and 14.2 g of 2-methoxy-3-nitro-benzoic acid methyl ester obtained as an oil which crystallized to a white solid. STR135
With potassium carbonate; In N,N-dimethyl-formamide; N-[3-(4,5-dihydro-1H-imidazol-2ylmethyl)-2-methoxy-phenyl]-methanesulfonamide hydrochloride A solution of 15 g of <strong>[85-38-1]2-hydroxy-3-nitro-benzoic acid</strong> in 200 ml of N,N-dimethylformamide was treated with 58.1 g of iodomethane and 56.6 g of potassium carbonate, and the resultant heterogeneous mixture was stirred and heated to 45 C for 20 hr. The mixture was cooled to room temperature, poured into ether, washed with water, washed with saturated sodium carbonate solution, washed with water, dried over magnesium sulfate, evaporated, and 14.2 g of 2-methoxy-3-nitro-benzoic acid methyl ester obtained as an oil which crystallized to a white solid.
With potassium carbonate; In acetone; at 10 - 35℃;Inert atmosphere; (i) Under an argon atmosphere, to a solution of <strong>[85-38-1]2-hydroxy-3-nitrobenzoic acid</strong> (1.0 g) in acetone (20.0 mL) were added potassium carbonate (3.70 g) and methyl iodide (1.70 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added pure water, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated and dried to give methyl 2-methoxy-3-nitrobenzoate (1.10 g). The present compound was used for the next reaction without further purification.

  • 5
  • [ 22621-41-6 ]
  • [ 74-88-4 ]
  • [ 90564-26-4 ]
YieldReaction ConditionsOperation in experiment
98% With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 1h; [00223j To a solution of <strong>[22621-41-6]methyl 2-hydroxy-3-nitrobenzoate</strong> (10 g, 50.7 mmol) indimethylformamide (100 mL) at room temperature was added potassium carbonate (14.02g, 101 mmol) followed by addition of methyl iodide (6.34 mL, 101 mmol) and the resulting orange mixture was heated to 60 C for 1 h. The reaction was cooled to room temperature and added to crushed ice ( 100 mL) and then further diluted with water to a total volume of400 mL causing a nice yellow solid to crystallize. The solid wascollected by vacuum filtration and the resulting initially yellow solid was rinsed withadditional water ( 100 mL) until all of the yellow color was rinsed into the filtrate givinga near white solid in the funnel. Partially air-dried solid in funnel then transferred to around-bottomed flask and further dried under vacuum overnight to afford 10.5 g (98%) ofa yellow solid as the desired product. LCMS MH+ 212.
98% With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 1h; Step 1[00194j To a solution of <strong>[22621-41-6]methyl 2-hydroxy-3-nitrobenzoate</strong> (10 g, 50.7 mmol) in DMF (100 mL) at room temperature was added potassium carbonate (14.02 g, 101 mmol) followed by addition of methyl iodide (6.34 mL, 101 mmol) and the resulting orange mixture was heated to 60 C for 1 h. The reaction was cooled to room temperature and then crushed ice (100 mL) was added, followed by water to a total volume of 400 mLcausing a yellow solid to crystallize from solution. The slurry was stirred for a few minutes and then collected by vacuum filtration and the resulting initially yellow solid was rinsed with additional water ( 100 mL) until all of the yellow color was rinsed into the filtrate giving a near white solid in the funnel. Partially air-dried solid in funnel then transferred to a flask and further dried under vacuum overnight to afford 10.5 g (98%) ofa yellow solid as the desired product. LC retention time 0.83 [J].
98% With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 1h; Preparation 4 To a solution of <strong>[22621-41-6]methyl 2-hydroxy-3-nitrobenzoate</strong> (10 g, 50.7 mmol) in DMF (100 mL) at rt was added potassium carbonate (14.02 g, 101 mmol) followed by addition of methyl iodide (6.34 mL, 101 mmol) and the resulting orange mixture was heated to 60 C for 1 h. LCMS analysis at this time showed complete and clean conversion to a major product consistent with the expected product (observed MH+ 212). Let cool to rt and added crushed ice (-100 mL) followed by water to a total volume of -400 mL causing a nice yellow solid to crystallize from solution. Stirred for a few minutes to give a nice slurry then collected solid by vacuum filtration and the resulting initially yellow solid was rinsed with additional water (-100 mL) until all of the yellow color was rinsed into the filtrate giving a near white solid in the funnel. Partially air-dried solid in funnel then transferred to a round bottomed flask and further dried under vacuum overnight to afford 10.5 g (98%) of a yellow solid as <strong>[22621-41-6]methyl 2-hydroxy-3-nitrobenzoate</strong>. LCMS MH+ 212.
98% With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 1h; To a solution of <strong>[22621-41-6]methyl 2-hydroxy-3-nitrobenzoate</strong> (10 g, 50.7 mmol) in DMF (100 mL) was added potassium carbonate (14.02 g, 101 mmol) at rt followed by iodomethane 6.34 mL, 101 mmol) and the resulting orange mixture was heated to 60 & lt; 0 & gt; C for 1 h. LCMS analysis showed complete and clean conversion to the main product, consistent with the expected product (observed MH + 212).Cooled to rt and crushed (about 100 mL), after which the water was added to a total volume of about 400 mL to allow the bright yellow solid to crystallize out of the solution. Stir for a few minutes to obtain a suitable slurry and then collect the solids by vacuum filtration and rinse the resulting yellowish solid with additional water (about 100 mL) until all the yellow material was rinsed into the filtrate and near the white solid in the funnel. The partially dried solids in the funnel were then transferred to a round bottom flask and further dried in vacuo overnight to afford 10.5 g (98%)Yellow solid2-hydroxy-3-nitrobenzoate.
98.8% With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 45℃; Step B: Methyl 2-methoxy-3-nitrobenzoate; To a solution of <strong>[22621-41-6]methyl 2-hydroxy-3-nitrobenzoate</strong> (26.8 g, 136 mmol) in DMF (200 mL) was added K2CO3 (61 g, 440 mmol). Then iodomethane (62 g, 436 mmol) was added dropwise to the mixture at rt. The mixture was stirred at 45 C. for 5 h. Then the mixture was cooled to rt and water was added. The reaction mixture was extracted with EtOAc (500 mL×2). The combined organic layers were washed with water successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound of Step B (28.4 g, 98.8% yield). 1H NMR (400 MHz, DMSO-d6) delta ppm 8.10 (dd, J=1.8 Hz, 8.4 Hz, 1H), 8.00 (dd, J=1.3 Hz, 8.2 Hz, 1H), 7.40 (dd, J=8.2 Hz, 8.4 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H).
98% With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 1h; To a solution of <strong>[22621-41-6]methyl 2-hydroxy-3-nitrobenzoate</strong> (10 g, 50.7 mmol) in DMF (100 mL) at room temperature was added potassium carbonate (14.02 g, 101 mmol) followed by addition of methyl iodide (6.34 mL, 101 mmol) and the resulting orange mixture was heated to 60 C for 1 h. The reaction was cooled to room temperature and then crushed ice (~100 mL) was added, followed by water to a total volume of ~400 mL 10 causing a yellow solid to crystallize from solution. The slurry was stirred for a few minutes and then collected by vacuum filtration and the resulting initially yellow solid was rinsed with additional water (~100 mL) until all of the yellow color was rinsed into the filtrate giving a near white solid in the funnel. Partially air-dried solid in funnel then transferred to a flask and further dried under vacuum over night to afford Ab (10.5 g, 98%) of a yellow solid as the desired product. LCMS [M+1]+ = 197.1.
93% To a solution of 1.1 (50 g, 253.6 mmol, 1.0 eq) in DMF (500 mL), was added K2C03 (70 g, 507.6 mmol, 2.0 eq) at 0 C and stirred for 15 min. To the suspension was added Mel (72 g, 507.6 mmol, 2.0 eq) dropwise and reaction mixture was stirred at 60 C for 2 h. After completion of the reaction, reaction mixture was transferred into ice-water. Precipitated product was filtered, dried to provide 1.2 (50.0 g, 93.0 %). MS(ES): m/z 212.2 [M+H]+.
80% With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 72h; A mixture of <strong>[22621-41-6]methyl 2-hydroxy-3-nitrobenzoate</strong> (6 g, 30.4 mmol), iodomethane (3.81 mL, 60.9 mmol) and potassium carbonate (10.52 g, 76 mmol) in DMF (100 mL) was stirred at rt for 3 days. Ice water (500 ml) was added and the resulting suspension was stirred for 30 minutes. Filtration and drying afforded methyl 2-methoxy-3-nitrobenzoate (5.17 g, 24.48 mmol, 80 % yield) as a white solid. LCMS m/z 219.1 (M+H)+; HPLC IR 1.46 min (analytical HPLC Method F); NMR (400MHz, chloroform-d) d 8.03 (dd, J=7.9, 1.8 Hz, 1H), 7.91 (dd, J=8.l, 1.8 Hz, 1H), 7.31- 7.24 (m, 1H),4.01 (s, 3H), 3.96 (s, 3H).
5 g With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 4h;Inert atmosphere; Methyl 3-nitrosalicylate (6 g, 30.43 mmol), potassium carbonate (16.82 g, 121.73 mmol) and iodomethane (12.96 g, 91.30 mmol) were added to N,N-dimethylformamide. Under argon protection, the reaction was carried out at 60 C. for 4 h. After completion of the reaction, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (40 mL). The organic phase was separated, extracted twice with water (20 mL), dried, concentrated and subjected to column chromatography to give 5 g of the title compound.

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