* 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.
3-Nitrophthalic acid (500 g, 2.37 moles) was added to 2500 ml of methanoland 260 ml of thionyl chloride below ambient temperature. The mixture washeated at reflux for about 24 hours and then was concentrated under reducedpressure, followed by expelling the excess thionyl chloride under nitrogen. 1500ml of toluene was mixed with the residue, and then filtered. The obtained solidwas dried at 60-70°C to get 522.0 grams (98percent) of methyl 2-carboxyl-3-nitrobenzoate, which was substantially free from 3-nitrodimethylphthalate; 500 g of 3-Nitrophthalic acid, and methanol (2.5 I) were charged in a roundbottom flask followed by cooling to about 5-10°C. 259.5 ml of thionyl chloride wasadded under stirring for about 60-90 minutes followed by heating to about 60-65°C and was maintained for about 20-25 hours. Solvent was distilled completelyat about 60-65°C; 1500 ml of toluene was added and stirred for about 5-6 hoursunder nitrogen atmosphere. Separated solid was filtered and washed with 500mlof toluene, followed by drying the solid at about 55-65°C for about 5-10 hours toafford 525 grams of 3-nitrophthalic acid-1-methylester compound of Formula (II).
Reference：
[1] Patent: WO2006/15134, 2006, A1, . Location in patent: Page/Page column 13
[2] Journal of Organic Chemistry, 1986, vol. 51, # 17, p. 3308 - 3314
[3] Monatshefte fuer Chemie, 1900, vol. 21, p. 791
[4] Chemische Berichte, 1901, vol. 34, p. 680
[5] Monatshefte fuer Chemie, 1900, vol. 21, p. 791
[6] Patent: WO2008/142454, 2008, A1, . Location in patent: Page/Page column 27
[7] Patent: WO2006/63578, 2006, A2, . Location in patent: Page/Page column 18
[8] Patent: WO2011/145100, 2011, A1, . Location in patent: Page/Page column 4-5
2
[ 603-11-2 ]
[ 149-73-5 ]
[ 21606-04-2 ]
Yield
Reaction Conditions
Operation in experiment
94.7%
With sulfuric acid In methanol at 59 - 65℃; for 15 - 20 h; Heating / reflux; Industry scale
3-Nitrophthalic acid [NPA] (660 kg), trimethyl orthoformate (400 kg), concentrated sulfuric acid (115 kg) and methanol (1180 kg) were mixed, and the mixture was stirred with heating (59 to 65 °C) for about 15 to 20 hours under reflux.. The reaction solution was cooled, and concentrated at 40 °C or lower under reduced pressure.. The residue was cooled to 30 °C or lower, water (900 L) was added, and the mixture was cooled to 5 °C or lower.. The precipitated crystals were separated by a centrifuge, washed with water, and dried at 50 °C for about 50 hours to give methyl 2-carboxy-3-nitrobenzoate [MNA] (666.8 kg, 94.7 percent). mp. 166-168 °C 1H-NMR (200MHz, CDCl3) δ: 4.03 (3H, s), 7.74 (1H, t), 8.39 (1H, dd), 8.42(1H, dd)
Reference：
[1] Patent: EP1420016, 2004, A1, . Location in patent: Page 17
[2] Journal of Medicinal Chemistry, 1993, vol. 36, # 15, p. 2182 - 2195
3
[ 13365-26-9 ]
[ 21606-04-2 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 20℃; for 2 h; Acidic conditions
(1) Put 30 g of 3-nitrophthalic acid into a 500 ml reaction flask and add 300 ml of methanol (1:10, optionally 1:5 to 1:20, preferably 1:10 to 1:15). Sulfuric acid 30g (1:0.5-1:2, preferably 1:1) was warmed at reflux.(2) TLC monitoring, when the formation of the double esterification product exceeds the reduction of the raw material, the refluxing reaction is ended; below 50° C., the methanol is concentrated under reduced pressure to almost no fraction.(3) Add 200ml of water, control the temperature below 25°C, add potassium carbonate to neutralize the pH to 7-8, and add 100ml of ethyl acetate to extract.The extract is concentrated and crystallized to obtain dimethyl 3-nitrophthalate, the aqueous layer is acidified to pH 4-5, stirred at room temperature for 2 hours, and the product is filtered to obtain methyl 3-nitro-2-carboxybenzoate (AM1). , Content more than 98percent, yield more than 90percent,Drying standby.
Reference：
[1] Chemische Berichte, 1902, vol. 35, p. 3877,3879
[2] Journal of the Chemical Society, 1901, vol. 79, p. 1137
[3] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1980, vol. 19, # 6, p. 473 - 486
6
[ 7719-09-7 ]
[ 6744-85-0 ]
[ 21606-04-2 ]
Reference：
[1] Journal of the Chemical Society, 1952, p. 553,566
7
[ 641-70-3 ]
[ 124-41-4 ]
[ 6744-85-0 ]
[ 21606-04-2 ]
Reference：
[1] Chemische Berichte, 1902, vol. 35, p. 3877,3879
8
[ 21606-04-2 ]
[ 57113-91-4 ]
Reference：
[1] Patent: CN104876877, 2018, B,
9
[ 21606-04-2 ]
[ 121-44-8 ]
[ 75-65-0 ]
[ 57113-90-3 ]
Yield
Reaction Conditions
Operation in experiment
86.7%
Stage #1: With diphenyl phosphoryl azide In DMF (N,N-dimethyl-formamide) at 20 - 35℃; for 3 h; Industry scale Stage #2: at 85 - 90℃; for 4 - 7 h; Heating / reflux
methyl 2-carboxy-3-nitrobenzoate [MNA] obtained in Reference Example 2 (164 kg) was dissolved in dimethylformamide [DMF] (242 kg), diphenylphosphoryl azide [DPPA] (204 kg) was added thereto at room temperature, and triethylamine (87 kg) was added dropwise while maintaining at 20 to 35 °C. After stirring at 20 to 30 °C for about 3 hours, t-butyl alcohol (930 kg) was added to the reaction solution.. The temperature was risen to 85 to 90 °C over 3 to 5 hours, and the solution was stirred for 1 to 2 hours under reflux (85 to 90 °C).. The reaction solution was cooled, concentrated, and the residue was dissolved in ethyl acetate (1400 L).. The solution was washed successively with a mixture of 15 percent hydrochloric acid (160 L) and water (1890 L), water (660 L), 5 percent aqueous sodium bicarbonate solution (1100 kg) and water (660 L), and the organic layer was concentrated under reduced pressure.. methanol (300 kg) was added thereto, and concentrated under reduced pressure.. A seed crystal (15 kg) and methanol (450 kg) were added to the residue, and the mixture was heated to 50 to 60 °C to dissolve it.. After cooled to 5 °C, crystals were separated, washed with cold methanol (100 L), and dried to give methyl 2-t-butoxycarbonylamino-3-nitrobenzoate [BAN] (187.0 kg, 86.7 percent).. The mother liquor and the washing were concentrated under reduced pressure, and cooled.. The precipitated crystals were centrifuged, washed with cold methanol, and dried to give second crystal of BAN. 1H-NMR (200MHz, CDCl3) δ: 1.50(9H, s), 3,96(3H, s), 7.23(1H, t), 8.10(1H, dd), 8.17(1H, dd) IR(KBr) cm-1:3360, 1730, 1705, 1580, 1520, 1490, 1440, 1365, 1355, 1310, 1270, 1240, 1150, 870, 835, 770, 725, 705
Stage #1: With diphenyl phosphoryl azide; triethylamine In N,N-dimethyl-formamide at 20 - 31℃; Inert atmosphere Stage #2: at 85 - 87℃; for 9 h; Stage #3: at 50 - 55℃; for 3 h;
Step 1 To a solution of 2-methoxycarbonyl-6-nitrobenzoic acid (18.3 g, 81.3 mmol) in N,N-dimethylformamide (24.1 mL) was added dropwise diphenyl azidophosphonate (22.8 g, 83.0 mmol) at room temperature, and the dropping funnel was washed with N,N-dimethylformamide (1.8 mL). Then, triethylamine (9.75 g, 96.4 mmol) was added dropwise thereto at 22-31° C., and the dropping funnel was washed with N,N-dimethylformamide (1.6 ml). The reaction mixture was stirred at 28-23° C. for 5 hr under a nitrogen atmosphere. The reaction was monitored by HPLC. To the reaction mixture was added dropwise tert-butyl alcohol (104 g) at room temperature, and the reaction mixture was heated to about 85° C. over 5 hr, and stirred at 85-87° C. for 4 hr. The reaction was monitored by HPLC. The reaction mixture was concentrated under reduced pressure at 50° C. or lower, and ethyl acetate (156 mL) and 1.3percent hydrochloric acid (229 ml) were added thereto. The organic layer was separated, and washed successively with water (74 mL), 5percent aqueous sodium hydrogen carbonate solution (117 ml) and water (74 mL), and concentrated under reduced pressure at 40° C. or lower (solidification). The solid was dissolved in methanol (42.3 ml) at about 55° C. Methanol (63.5 mL) was added to the solution, and the solution was cooled from 50° C. to about 5° C. over 3 hr. During cooling, seed crystals were added thereto at 36° C., and the mixture was stirred at about 5° C. for 2 hr. The crystals were collected by filtration, washed with cold methanol (18 mL), and dried under reduced pressure at 50° C. or lower to give methyl 2-(tert-butoxycarbonylamino)-3-nitrobenzoate (compound 19a, 17.5 g, 72.5percent) as pale-yellow crystals. melting point: 92-94° C. IR (KBr): 3368, 1735, 1608, 1540, 1508 cm-1 1H-NMR (CDCl3): δ=9.61 (br s, 1H), 8.16 (dd, J=8.1, 1.5 Hz, 1H), 8.10 (dd, J=8.1, 1.5 Hz, 1H), 7.23 (t, J=8.1 Hz, 1H), to 3.95 (s, 3H), 1.50 (s, 9H) MS: m/z=314 (MNH4+)
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