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CAS No. : | 2516-96-3 | MDL No. : | MFCD00007294 |
Formula : | C7H4ClNO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QUEKGYQTRJVEQC-UHFFFAOYSA-N |
M.W : | 201.56 | Pubchem ID : | 17287 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 47.23 |
TPSA : | 83.12 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.09 cm/s |
Log Po/w (iLOGP) : | 0.73 |
Log Po/w (XLOGP3) : | 2.03 |
Log Po/w (WLOGP) : | 1.95 |
Log Po/w (MLOGP) : | 1.11 |
Log Po/w (SILICOS-IT) : | -0.26 |
Consensus Log Po/w : | 1.11 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.58 |
Solubility : | 0.532 mg/ml ; 0.00264 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.4 |
Solubility : | 0.0796 mg/ml ; 0.000395 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.77 |
Solubility : | 3.4 mg/ml ; 0.0169 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.78 |
Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P301+P312-P302+P352-P304+P340-P305+P351+P338 | UN#: | |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | |
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 |
---|---|---|
95.1% | With iron; ammonium chloride In ethanol; water at 78 - 80℃; for 5 h; | To the reaction flask was added 75 g of 2-chloro-5-nitrobenzoic acid, 59 g of iron powder, 800 ml of ethanol, 150 ml of water, 115 g of ammonium chlorideHeated to 78 ~ 80° C reflux 5h,TLC (PE / EA: 1/3) After the reaction was monitored, the filtrate was filtered while hot, washed with 150 ml of hot ethanol, and the filtrate was reduced to dryness at 60 ° C to obtain a crude product,Add 400ml ethyl acetate heating reflux beating 2h,Naturally dropped to room temperature after the salt bath cooling to 0 ~ 5° C crystallization more than 30min,Centrifuged, washed with 50 ml of ethyl acetate and dried at 50 ° C under reduced pressure to give a yellow solid 60.7 g of 2-chloro-5-aminobenzoic acid, 99.1percent purity and 95.1percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2 h; Stage #2: With triethylamine In dichloromethane at 20℃; for 16 h; |
To a solution of 2-chloro-5-nitrobenzoic acid (0.500 g, 2.48 mmol) in dichloromethane (8.3 mL) was added oxalyl chloride (0.239 mL, 2.73 mmol) slowly, followed by /V,N-dimethylformamide ( 1 drop). The reaction was stirred at room temperature for 2 hours. To the solution was added triethylamine (0.691 mL, 4.96 mmol) followed by pyridin-4-amine (0.467 g, 4.96 mmol) in dichloromethane ( 1 mL). The reaction was allowed to stir at room temperature for 16 hours. Purification by flash column chromatography using 0-100percent ethyl acetate/hexanes as eluent provided the title compound as a tan solid (0.401 g, 58percent) : ' H NMR (400 MHz, DMSO-de) δ 11.10 (s, 1H), 8.64 - 8.45 (m, 3H), 8.37 (dd, J = 8.9, 2.8 Hz, 1 H), 7.92 (d, J = 8.8 Hz, 1H), 7.73 - 7.61 (m, 2H) ; 13C NMR ( 101 MHz, DMSO-de) δ 163.67, 150.56, 146.14, 145.04, 136.95, 131.40, 126.06, 124.00, 113.68 ; ESIMS m/z 278 ( [M + H ]+ ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | 2-Chloro-5-nitro-benzoic acid (3g, 14mmol) was added to a solution of freshly prepared sodium methoxide (from sodium (1.36g, 56mmol) in dry methanol (15ml)) and the reaction was heated to reflux for 12hr. Methanol was evaporated and the reaction mass diluted with water (25ml). Cone hydrochloric acid was added until the pH was ~2. The raction mixture was stirred at room temperature for 30min, then the precipitate was filtered and washed with water. Drying at 60-700C yielded 2-methoxy-5-nitro benzoic acid (2.4g, 81%). | |
25 g | In methanol; for 15h;Reflux; | To a solution of 2-chloro-5-nitrobenzoic acid (3.0 g, 0.14 mol) in methanol (500 mL) was added sodium methoxide (28.1 g, 0.520 mol). The reaction mass was refluxed for 15 h. Excess of solvent was removed under vacuum and the reaction mass was diluted with water and acidified with dilute HC1 to obtain solid which was filtered off to afford 25.0 g of desired product. 1H NMR (300 MHz, DMSO d6): delta 3.96 (s, 3H), 7.36 (d, = 9.3 Hz, 1H), 8.37 (d, J = 9.0 Hz, 1H), 8.45 (s, 1H), 13.32 (br s, 1H) ); MS (m/z): 198.25 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.1% | With iron; ammonium chloride; In ethanol; water; at 78 - 80℃; for 5h; | To the reaction flask was added 75 g of 2-chloro-5-nitrobenzoic acid, 59 g of iron powder, 800 ml of ethanol, 150 ml of water, 115 g of ammonium chlorideHeated to 78 ~ 80° C reflux 5h,TLC (PE / EA: 1/3) After the reaction was monitored, the filtrate was filtered while hot, washed with 150 ml of hot ethanol, and the filtrate was reduced to dryness at 60 ° C to obtain a crude product,Add 400ml ethyl acetate heating reflux beating 2h,Naturally dropped to room temperature after the salt bath cooling to 0 ~ 5° C crystallization more than 30min,Centrifuged, washed with 50 ml of ethyl acetate and dried at 50 ° C under reduced pressure to give a yellow solid 60.7 g of 2-chloro-5-aminobenzoic acid, 99.1percent purity and 95.1percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With pyridine; water; potassium carbonate for 0.25h; sonication; | |
97% | With water; potassium hydroxide for 6h; Heating; Large scale; | 1.1 Preparation of (II) In a 100 L reactor, 14 kg (250 mol) of potassium hydroxide was added, and 50 L of water was added to fully dissolve it.While maintaining the temperature at 20-40°C, slowly add 10 kg (49.6 mol) of 2-chloro-5-nitrobenzoic acid (I).The temperature was raised to 120-140°C, and the reaction was carried out at this temperature for 6 hours. TLC followed the progress of the reaction until the reaction of the raw materials was complete.Cool to room temperature, use 17L hydrochloric acid to adjust the pH of the reaction system between 1-3, continue stirring for 1.5 hours, and filter.The filter cake was washed with 50 L of water, the cake was beaten with 30 L of water at 30 °C, filtered, and the filter cake was washed with 50 L of water.Drying at 65°C for 12 hours yields 8.81 kg of 2-hydroxy-5-nitrobenzoic acid (Intermediate II).Yield: 97%, purity: 99.88%. |
96% | Stage #1: 2-chloro-5-nitrobenzoic acid With potassium hydroxide In water at 25 - 30℃; for 0.333333h; Industrial scale; Stage #2: In water at 125 - 130℃; for 5h; Industrial scale; | 1.1 Step-1; Synthesis of Compound 2 To a stirred solution of potassium hydroxide (70 kg, 1250 mol) and water (250 L) was added 2 (50 kg, 248 mol) over a period of 20 minutes between 25 and 30° C. in an autoclave. The reaction mixture was heated to 125-130° C., stirred at the same temperature for 5 hours under 2.5 kg/cm2. The reaction mass was cooled to 25° C. and acidified to pH 1.0-2.0 using hydrochloric acid (85 L), stirred for 1 hour. The precipitated solid was filtered and washed with water (150 L), and the cake was slurried in water (300 L) at 30° C. for 1 hour, filtered, washed with water (150 L) and dried at 65° C. for 10 hours to afford 3 43.5 kg Yield: 43.5 kg (96%) (Purity: 99.87%). |
96% | With potassium hydroxide In water at 25 - 130℃; for 5.33333h; Autoclave; Large scale; | 1 Step-1: Synthesis of Compound 2: To a stirred solution of potassium hydroxide (70 kg, 1250 mol) and water (250 L) was added 2 (50 kg, 248 mol) over a period of 20 minutes between 25 and 30° C. in an autoclave. The reaction mixture was heated to 125-130° C., stirred at the same temperature for 5 hours under 2.5 kg/cm2. The reaction mass was cooled to 25° C. and acidified to pH 1.0-2.0 using hydrochloric acid (85 L), stirred for 1 hour. The precipitated solid was filtered and washed with water (150 L), and the cake was slurried in water (300 L) at 30° C. for 1 hour, filtered, washed with water (150 L) and dried at 65° C. for 10 hours to afford 3 43.5 kg Yield: 43.5 kg (96%) (Purity: 99.87%). |
96% | With potassium hydroxide In water at 25 - 130℃; for 5.33h; Autoclave; Large scale; | 1.1 Step 1: Synthesis of Composite 2: 2 (50 kg, 248 mol) was added to a stirred solution of potassium hydroxide (70 kg, 1250 mol) and water (250 L) over 20 minutes in an autoclave at a temperature between 25 and 30 ° C. The reaction mixture was heated from 125 to 130 ° C. and stirred at the same temperature for 5 hours until it was less than 2.5 kg / cm 2. The reaction solids were cooled to 25 ° C., acidified to pH 1.0-2.0 using hydrochloric acid (85 L) and stirred for 1 hour. The precipitated solid was filtered, washed with water (150 L) and the cake was slurried in water (300 L) at 30 ° C. for 1 h, filtered, washed with water (150 L), washed with 3 (43.5 kg (96%) (purity: 99.87%) dried at 65 ° C for 10 hours in order to produce the product. |
95% | With pyridine; copper; potassium carbonate In water for 2h; Heating; | |
With potassium hydroxide | ||
With copper(l) iodide; copper; potassium carbonate | ||
Multi-step reaction with 3 steps 1: thionyl chloride 2: water; aqueous ammonia 3: aqueous KOH-solution | ||
Stage #1: 2-chloro-5-nitrobenzoic acid With sodium carbonate In water at 50 - 75℃; Stage #2: With water at 100℃; for 4h; Stage #3: With hydrogenchloride In water at 20℃; | 17 Under nitrogen, 2 mmol of the halogen-substituted benzoic acid indicated in Table 6 was stirred with a solution of 3 mmol Na2CO3 at 50-75° C. until all of the halogen-substituted benzoic acid was dissolved. Subsequently, 0.02 mmol CuSO4 and 0.04 mmol rac-trans-N,N'-dimethylcyclohexane-1,2-diamine (Ligand F) dissolved in 1 mL deionized water were added and the reaction mixture was heated at 80-100° C. for 4 h. After cooling to ambient temperature the reaction mixtures were carefully acidified with 35% aqueous HCl.In isolation method A, the products were extracted from the aqueous layer twice with ethyl acetate, the ethyl acetate fractions were combined and the crude reaction product was isolated by evaporation of ethyl acetate under vacuum. In isolation method B, the products were isolated by filtration, washed with water and dried under vacuum. The crude reaction product was analyzed by 1H NMR (d6-dmso). The results are summarized in Table 6. TABLE 6 Examples 8~23 Starting material Halogenated Benzoic Acid Isolation CONV SEL Example Benzoic Acid Product T (° C.) Method (%) (%) 8 2,5-dibromo- 2-hydroxy-5- 80 B >99 >99 bromo- 9 2-bromo-5-nitro- 2-hydroxy-5- 80 B >99 >99 nitro- 10 2-bromo-5-nitro- 2-hydroxy-5- 100 A >99 >99 nitro- 11 2-bromo-5-methyl- 2-hydroxy-5- 80 B >99 >99 methyl- 12 2-bromo-5-methyl- 2-hydroxy-5- 100 A >99 >99 methyl- 13 4-bromo- 4-hydroxy- 100 A >99 >99 14 4-chloro- 4-hydroxy- 80 B >99 >99 15 2,4-dichloro- 2-hydroxy-4- 100 A 70 >99 chloro- 16 2,5-dichloro- 2,5-dihydroxy- 80 B 93 >99 17 2-chloro-5-nitro- 2-hydroxy-5- 100 A 74 >99 nitro- 18 2-chloro-3,5-dinitro- 2-hydroxy-3,5- 100 A >99 >99 dinitro- 19 2-chloro-3,5-dinitro- 2-hydroxy-3,5- 80 B >99 >99 dinitro- 20 2-chloro-5-methyl- 2-hydroxy-5- 100 A >99 >99 methyl- 21 2-bromo-5- 2-hydroxy-5- 100 A >99 >99 methoxy- methoxy- 22 2-bromo-5- 2-hydroxy-5- 80 B >99 >99 methoxy- methoxy- 23 2-chloro-5-bromo- 2-hydroxy-5- 80 B 73 >99 bromo- | |
With sodium hydroxide at 150℃; for 0.0833333h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride; | EXAMPLE 4 2-(2-Chloro-5-propionamidophenyl)-5-methylbenzooxazole (CT-116563) A mixture of 2-chloro-5-nitrobenzoic acid (7.06 g, 35.0 mmol) and thionyl chloride (35 ml) was heated at reflux for 2 h. Excess thionyl chloride was removed by distillation under reduced pressure to provide 2-chloro-5-nitrobenzoyl chloride (7.7 g, 100% yield). |
95% | In toluene; | Example 1 Production of 2-chloro-5-nitrobenzoyl chloride To a 3 L 3 neck round bottom flask equipped with a mechanical stirrer, nitrogen inlet, reflux condenser, heating mantle, vacuum system, and scrubber system for efficient removal of HCl and SO2 gas which is liberated during the reaction, was charged, under nitrogen, 1.0 L (1.63 Kg, 13.7 moles) of thionyl chloride, and 1.3 Kg (6.4 moles) of 2-chloro-5-nitrobenzoic acid. The stirred mixture was placed under a N2 flow, which was vented to the scrubber system. The stirred mixture was heated to reflux for 12 hours during which time the reaction slowly becomes complete. The clear yellow solution was placed under vacuum and excess thionyl chloride was removed by evaporation under vacuum. The resulting slurry was dissolved in 800 mL of toluene, and concentrated to dryness by evaporation under vacuum. The resulting yellow solid was dried at about 50 C. and about 20 mm Hg for about 4 hours to give 1.35 Kg of 2-chloro-5-nitrobenzoyl chloride as a yellow solid (95% yield). |
91.7% | With thionyl chloride; In chloroform; at 0℃; for 4h;Heating / reflux; | a) Preparation of 2-chloro-N-(2,2-dimethoxy-ethyl)-5-nitro-benzamide. Thionyl chloride (14 mL, 192 mmol) was added'dropwise to a solution of 2- chloro-5-nitrobenzoic acid (10 g, 49.6 mmol) in chloroform (150 mL) at 0 0C. The mixture was heated to reflux for 4h then cooled to r.t, concentrated in vacuo and dried under high vacuum to yield 2-chloro-5-nitrobenzoyl chloride (10 g, 91.7%) as a solid. Under nitrogen, triethylamine (19 mL, 136 mmol) was added slowly to a solution of aminoacetaldehyde dimethyl acetal (5.43 mL, 50.0 mmol) in dry DCM (20 mL) at 0 C. 2-Chloro-5-nitrobenzoyl chloride (10 g, 45.5 mmol) was slurried in dry DCM (30 mL) and added over a period of 30 minutes. The mixture was allowed to warm to r.t. and stirred overnight then partitioned between water and~DCM. The organic phase was washed with saturated sodium bicarbonate solution, water and brine then dried over sodium sulfate and concentrated. The crude product was triturated with petroleum ether then diethyl ether and finally purified by column chromatography on silica gel (60-120 mesh) eluting with ethyl acetate/petroleum ether (2% to 40% gradient) to afford 2-chloro-iV- (2,2-dimethoxy-ethyl)-5-nitro benzamide (8.3 g, 63%) as a yellow solid. |
With oxalyl dichloride; at 20℃; | To a suspension of 2-chloro-5-nitro-benzoic acid (10 g, 49.6 mmol), oxalyl chloride was added dropwise (12.6 g, 2.0 equiv.). The resulting yellow solution was stirred at room temperature under argon overnight. The solvent was removed under vacuum to give a yellowish solid (10.8 g). | |
With thionyl chloride; | REFERENCE EXAMPLE 24 2-Chloro-5-nitrobenzoyl chloride As described for Reference Example 21, 5.0 g of 2-chloro-5-nitrobenzoic acid is reacted with 50 ml of thionyl chloride to give 5.6 g of the product as an off-white solid. | |
With thionyl chloride; | REFERENCE EXAMPLE 29 2-Chloro-5-nitrobenzoyl chloride As described for Reference Example 26, 5.0 g of 2-chloro-5-nitrobenzoic acid is reacted with 50 ml of thionyl chloride to give 5.6 g of the product as an off-white solid. | |
With thionyl chloride; | Reference Example 24 2-Chloro-5-nitrobenzoyl chloride As described for Reference Example 21, 5.0 g of 2-chloro-5-nitrobenzoic acid is reacted with 50 ml of thionyl chloride to give 5.6 g of the product as an off-white solid. | |
With thionyl chloride; at 60℃; for 18h; | Intermediate 28: Ethyl (4-[(2-chloro-5- nitrophenyl)carbonyl]amino}phenyl)acetate; 2-Chloro-5-nitrobenzoic acid (1.99g, 9.87mmol) was stirred for 18hrs at 6O0C in thionyl chloride (10ml). The excess thionyl chloride was removed by evaporation and the crude oil dissolved in chloroform (20ml). To this solution was added ethyl (4-aminophenyl)acetate (1.18g, 6.58mmol) and the reaction was stirred at 6O0C for 18hrs. The reaction was diluted with water and the phases separated. The organic layer was dried (Na2SO4), solvent evaporated and the residue <n="52"/>purified by flash chromatography (Biotage SP4, 40+M 0 ? 50% ethylacetate / hexane) to afford the title compound as an off white solid (2.28g, 96%). MS (ES+) m/z 363 [M+H+] (Ci7H1535CIN2O5).1H-NMR (250MHz, CDCI3) delta 1.26 (3H, t, J 7), 3.62 (2H, s), 4.14 (2H, q, J 7), 7.30 (2H, d, J 8.5), 7.63 (3H, m), 7.93 (1 H, br s), 8.24 (1 H, dd, J 9, 3), 8.58 (1 H, d, J 3). | |
With thionyl chloride; for 2h;Reflux; | A mixture of 2-chloro-5-nitrobenzoic acid (35 g), DMF (1 ml) and SOCl2 (430 ml) is heated under reflux for 2 h, concentrated in vacuo and added to the residue of MeOH keeping the temperature at 0 C. After stirring 18 h at AT and evaporation in vacuo, the residue is redissolved in DCM, the organic layer is washed with an aqueous NaOH solution then with an aqueous NaCl solution, and the organic layer is dried over MgSO4, filtered and evaporated to dryness. 37 g of desired product are obtained and used as such. | |
With pyridine; 1,3,5-trichloro-2,4,6-triazine; In dichloromethane; at 50℃; for 0.25h;Microwave irradiation; | General procedure: 2-Chloro-4-nitrobenzoic acid (201 mg, 1.0 mmol) and cyanuric chloride (368 mg, 2 mmol) in 2 mL CH2Cl2 were treated with pyridine (79 mg, 1.0 mmol) and irradiated in the microwave for 15 min at 50 C. Then, the resulting mixture was treated with FeCl3 (324 mg, 2.0 mmol) and irradiated in the microwave for 5 min at 30 C. Finally, 3 mL of toluene was added to the solution and irradiated in the microwave for 15 min at 70 C. Then the reaction mixture was filtered from Celite. The filtrate was washed with sodium thiosulphate followed by brine solution. The separated organic layer was dried on Na2SO4 and concentrated under reduced pressure to give pure product 6a (269.5 mg, 93% yield). Mp 110-112 C (lit. 1 111.2 C). 1H NMR (500 MHz, CDCl3): delta 2.39 (s, 3H), 7.26 (d, J = 7.45 Hz, 2H), 7.54 (d, J = 7.45 Hz, 1H), 7.61 (d, J = 6.85 Hz, 2H), 8.26 (dd, J = 6.85, 2.7 Hz, 1H), 8.30 (d, J = 7.4 Hz, 1H); 13C NMR (500 Hz, CDCl3): delta 21.4 (CH3), 122.0 (CH), 125.1 (CH), 129.6 (CH), 129.7 (CH), 130.15 (CH), 132.2 (C), 144.6 (C), 146.2 (C), 148.9 (C), 193.5 (CO); IR (cm-1): 638.3, 740.8, 801.5, 836.3, 863.0, 1000.7, 1025.9, 1052.5, 1005.1, 1133.9, 1158.3, 1180.7, 1272.5, 1294.3, 1315.8, 1349.1, 1403.2, 1449.5, 1461.2, 1528.8, 1573.3, 1595.7, 1607.9, 1673.9, 3087.5; GC/MS: 275 [M+]; HRMS: calcd for C14H10ClNO3: 275.0349. Found: 275.0467. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; for 3h; | B) Synthesis of Compound 20; 1) Preparation of the Acid Chloride of Formula (III) (FIG. 1a); 2-Chloro-5-nitrobenzoic acid (6.04 g, 0.03 mol) is dissolved in 200 ml of dichloromethane. Oxalyl chloride (3.88 ml, 1.5 eq., 0.045 mol) is then added, followed, dropwise, by dimethylformamide (DMF), and the reaction medium is stirred for 3 hours. The solvent is then evaporated off so as to recover the acid chloride of formula (III). | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 2.33333h;Inert atmosphere; | A catalytic amount of DMF was added to a stirred solution of 2-chloro-5-nitrobenzoic acid (2) (4.00 g, 19.85 mmol) and oxalyl chloride (8.65 mL, 99.19 mmol) in DCM (50 mL) at 0 C under nitrogen atmosphere. After 20 min, the reaction was allowed to warm to room temperature and to proceed for a further 2 h. The reaction mixture was concentrated, re-dissolved in DCM and concentrated again. Triethylamine (13.83 mL, 99.22 mmol) and p-toluidine (2.13 g, 19.85 mmol) were added to the crude product dissolved in DCM (50 mL). The reaction was stirred for 5 h at room temperature under nitrogen atmosphere. After completion, the reaction mixture was diluted with DCM and successively washed with HCl (aq., 1 M), NaHCO3 (aq., sat.), water and brine. The organic phase was dried over MgSO4, filtered, and concentrated to dryness. The crude amide was purified by column chromatography (SiO2, EtOAc/n-heptane, 7:3 / 9:1) to give 3 in 90% yield | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h; | 3.20 g (15.9 mmol) of 2-chloro-5-nitrobenzoic acid are initially charged in 50 ml of dichloromethane p.a., and 0.06 ml of N,N-dimethylformamide p.a. is added. 2.08 ml (23.8 mmol) of oxalyl chloride are then added to the reaction mixture. After 3 h at RT, the reaction mixture is concentrated under reduced pressure on a rotary evaporator. The crude product (2-chloro-5-nitrobenzoyl chloride) is reacted further without further purification. | |
With oxalic acid; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 2.33333h;Inert atmosphere; | Procedure A: Synthesis of an acyl chloride and coupling to an aniline derivative (Exemplified by 3) A catalytic amount of DMF was added to a stirred solution of 2-chloro-5-nitrobenzoic acid (2) (4.00 g, 19.85 mmol) and oxalyl chloride (8.65 mL, 99.19 mmol) in DCM (50 mL) at 0C under nitrogen atmosphere. After 20 min, the reaction was allowed to warm to room temperature and to proceed for a further 2 h. The reaction mixture was concentrated, re-dissolved in DCM and concentrated again. Triethylamine (13.83 mL, 99.22 mmol) and ^-toluidine (2.13 g, 19.85 mmol) were added to the crude product dissolved in DCM (50 mL). The reaction was stirred for 5 h at room temperature under nitrogen atmosphere. After completion, the reaction mixture was diluted with DCM and successively washed with HC1 (aq., 1M), NaHCCb (aq., sat.), water and brine. The organic phase was dried over MgSO/t, filtered, and concentrated to dryness. The crude amide was purified by column chromatography (S1O2, EtOAc/n-heptane, from 7:3 to 9: 1) to give 3 in 90% yield. | |
With pyridine; thionyl chloride; at 50℃; for 3h; | Weigh 2-chloro-5-nitrobenzoic acid (2.06 g, 10 mmol) was dissolved in 5 mL of thionyl chloride, and 3 drops of pyridine was added dropwise,Stirring at 50 C for 3 hours, TLC tracking, raw material reaction is complete, stop the reaction. Remove the thionyl chloride by distillation under reduced pressureProcessed directly into the next reaction. | |
With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; at 20 - 25℃; for 3h;Autoclave; Reflux; | 2.1 kg of 2-chloro-5-nitrobenzoic acid and 10 kg of dichloromethane were charged into a 30 L autoclave at room temperature. After adding 100 ml of anhydrous DMF, 2.4 kg of thionyl chloride was added dropwise, (DCM: MeOH = 10: 1). After the reaction was completed, the reaction was carried out at room temperature to give 2-chloro-5-nitrobenzoyl chloride in methylene chlorid | |
With thionyl chloride; In pyridine; at 50℃; for 3h; | A solution of 9.84 g (48.82 mmol) of 2-chloro-5-nitrobenzoic acid in 30 mL of thionyl chloride was added dropwise and 3 mL of pyridine was added dropwise. The temperature was raised to 50 C for 3 h and concentrated under reduced pressure to remove thionyl chloride. Chloro-5-nitrobenzoyl chloride (without subsequent direct reaction). | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 2h; | General procedure: Analogs 6a-o were synthesized as outlined in Scheme 1: Acid(1.2 eq) was dissolved in anhydrous DCM, oxalyl chloride (1.44eq) was added dropwise at 0C and then one drop DMF was added.The reaction mixture stirred at room temperature for 2 h. The excess oxalyl chloride was removed under reduced pressure, andthe residue dissolved in THF for next transformation.Intermediate 5 (1eq) and triethylamine (1.5 eq) were added sequent to a 25 ml three-neck-bottom flask under a nitrogen atmosphere. Acyl chloride in THF was added dropwise to flask at 0C.The reaction mixture was stirred at 0C. After pale yellow solid appeared, the mixture reacted at room temperature until TLC showed 5 disappeared. Ice water was added to reaction mixtureat 0C, and stirred for another 30 min until no insoluble solid generated.The solid was filtered to get crude product. The crude product further purified by medium pressure column chromatography(C18 padding, ACN: H2O (containing 0.05% TFA) =1:99-99:1) to getproduct as a solid. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; at 35℃; for 4h; | In a 100 mL round bottom flask,2-chloro-5-nitrobenzoic acid 3.18 g (17.6 mmol) was dissolved in 70 mL of anhydrous tetrahydrofuran,Add oxalyl chloride 4.19 g (35.2 mmol),One drop of DMF is added dropwiseStir at 35C for 4 hours.Rotary evaporate to a light yellow 2-methyl-5-nitrobenzoyl chloride solid,Dissolved in anhydrous tetrahydrofuran,stand-by.In another 100 mL round bottom flask,O.Phenylenediamine 1.91g (17.6mmol) dissolved in 40mL anhydrous tetrahydrofuran,Add 2.42 g (23.8 mmol) of triethylamine,A 2-methyl-5-nitrobenzoyl chloride tetrahydrofuran solution was slowly added dropwise on an ice bath.Stir at room temperature overnight,filter,The filtrate was spin-dried,Wash with water,The precipitate is collected by filtrationA dark yellow solid of N-(2-aminophenyl)-2-chloro-5-nitrobenzamide was obtained in a yield of 95%. | |
With oxalyl dichloride; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 4h; | In a 100 mL round bottom flask, 2.01 g (10 mmol) of 2-chloro-5-nitrobenzoic acid was dissolved in 50 mL of anhydrous tetrahydrofuran.Add 5 ml of oxalyl chloride and add 3 drops of DMF.Stir at room temperature for 4 hours. Evaporation to give a pale yellow 2-chloro-5-nitrobenzoyl chloride solid.Dissolve in anhydrous tetrahydrofuran and set aside. In another 100 mL round bottom flask,O-phenylenediamine 2.16 (20 mmol) was dissolved in 40 mL of anhydrous tetrahydrofuran, and 5 ml of triethylamine was added.A solution of 2-chloro-5-nitrobenzoyl chloride in tetrahydrofuran was slowly added dropwise under ice-cooling, and stirred at room temperature overnight.Concentrated, add 100 ml of water, precipitate a solid, suction filtration, wash with water,A dark yellow N-(2-aminophenyl)-2-methyl-5-nitrobenzamide solid was obtained. | |
With thionyl chloride; for 2h;Reflux; | General procedure: Thionyl chloride (5 mL) was slowly added to a roundbottomedflask containing carboxylic acid (3.1 mmol). Themedium was refuxed for 2 h. Only acyl chloride ( 9-19)remained in the fask after the excess thionyl chloride wasremoved by distillation.20 | |
With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; at 35℃; for 4h; | In a 100 mL round bottom flask,3.18 g (17.6 mmol) of 2-chloro-5-nitrobenzoic acid was dissolved in 70 mL of anhydrous tetrahydrofuran.4.19 g (35.2 mmol) of oxalyl chloride was added, and 1 drop of DMF was added dropwise, and the mixture was stirred at 35 C for 4 hours.The mixture was evaporated to give a pale yellow 2-methyl-5-nitrobenzoyl chloride as a solid. In another 100 mL round bottom flask,1.91 g (17.6 mmol) of o-phenylenediamine was dissolved in 40 mL of anhydrous tetrahydrofuran.Add 2.42 g (23.8 mmol) of triethylamine,Slowly add a solution of 2-methyl-5-nitrobenzoyl chloride in tetrahydrofuran under ice bath.Stir at room temperature overnight, filter, spin the filtrate and wash with water.The precipitate was collected by filtration.Obtaining a dark yellow N-(2-aminophenyl)-2-chloro-5-nitrobenzamide solid in a yield of 95%. | |
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 2.25h;Cooling with ice; | Dissolve 2-chloro-5-nitrobenzoic acid (5.04g, 25mmol) in 25ml of anhydrous dichloromethane, add 10 drops of DMF, and slowly add oxalyl chloride (2.25ml, 26.25mmol) under ice bath stirring, stirring After 15min. Remove the ice bath and stir at room temperature for 2h. The solvent and unreacted oxalyl chloride were removed by rotary evaporation to obtain 2-chloro-5-nitrobenzoyl chloride. The crude 2-chloro-5-nitrobenzoyl chloride was dissolved in 60 ml of anhydrous tetrahydrofuran and slowly added to Under an ice bath, 5 ml of triethylamine o-phenylenediamine (2.65 g, 24.5 mmol) in 20 ml of dry THF solution was reacted at room temperature for 12 h. The reaction solution was filtered with suction to remove the triethylamine salt formed and washed with petroleum ether. The filtrate was spin-dried and extracted with ethyl acetate / water. The organic phase was washed sequentially with saturated NaHCO3 and NaCl solutions, dried over anhydrous Na2SO4, concentrated and recrystallized to obtain Target compound, yellow powder, 3.948g, yield 54%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: 2-chloro-5-nitrobenzoic acid With hydrazine In ethanol at 100℃; for 3.5h; Stage #2: With hydrogenchloride; water In ethanol | 19.A Example 19: methyl 3-((R)-l-((R)-2-(3,4-dimethoxyphenyl)-2-(3-oxo-2,3-dihydro- lH-indazol-5-ylamino)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate trifluoroacetate [00279] 2-chloro-5-nitrobenzoic acid (5.000 g, 24.81 mmol) was dissolved in ethanol (10 mL), and hydrazine hydrate (12.08 mL, 248 mmol) was added. The mixture was heated at 100 0C for 3.5 h. The reaction mixture was cooled to rt, diluted with water and acidified to pH -5.0 with HCl (12 N). The resultant bright-yellow solid was filtered, washed with water (2 x), ether and dried to give 19A (3.968 g, 20.13 mmol, 81 % yield) as a bright-yellow solid. LC-MS: (Phenom. Luna C18 30 x 4.6mm 5μ; sol. A 10% MeCN - 90% H2O - 0.1% TFA; sol. B 90% MeCN - 10% H2O - 0.1% TFA; wavelength 220 nm; flow rate 5 mL/min; gradient time 2 min; start % B = 0%, final % B = 100%) 0.503 min, [M+l]+ = 198.0. Purity >95%. 1H-NMR: (400 MHz, DMSO-d6) δ ppm 7.38 (d, J=9.34 Hz, 1 H) 8.18 (dd, J=9.34, 2.75 Hz, 1H) 8.59 (d, J=2.75 Hz, 1 H) 9.53 (s, 1 H). 13C-NMR: (101 MHz, DMSO-d6) δ ppm 107.30, 111.70, 128.63, 129.13, 134.22, 156.51, 168.47. |
With ethanol; hydrazine hydrate | ||
With hydrazine In ethanol Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate In water at 170℃; for 2h; | |
30% | With potassium acetate; copper(II) acetate monohydrate; triethylamine In isopropyl alcohol for 24h; Reflux; | |
30% | With potassium acetate; copper(II) acetate monohydrate; triethylamine In isopropyl alcohol for 24h; Reflux; | 2-(naphthale.n-1 -ylamino)-5-nitrobenzoic acid (82.1). 2-(naphthale.n-1 -ylamino)-5-nitrobenzoic acid (82.1). A round-bottom flask was charged with I -napthylamine (4.999g, 34.91 Immol, I .2eq), 2-chloro-5-nitrobenzoic acid (5.7062g, 28.3 iOmmoi, 1 eq), potassium acetate (10.30g. 104.9mmol. 3 .7eq). copper(Hiacetate manohydrate (322.6mg, 3..2S7mmoi, 0.1 2eq), triethylatnine (1 0mL. 71.697mmo1,2.Seq), and isopropanol (200mLl. The mixture was stirred at reflux for 24h, after which thereaction was filtered hot and washed with isopropanol. The resulting solid was stirred in 2MHCI, filtered, washed with Dl H20, and dried in vacuo to afford an orange solid (2.5944g.30%). 1 H MAR (300 MHz, D.MSO-d6) 3 10.64 (s. IN). 8.76 (d. J 2.8 Hz iN). 8, 13 - 7.99Cm. 2K). 8.01 7.83 (m, 2H). 7.67 7.50 Cm. 514). 6.6 (d, J 9.4 Hz. if). 13C NMR (75 Mflz, DMSO-d6)3 16L8, 153.72, 136.36, 134.24, 133.93, 129.25, 129.03, 128.54, 128.33. 127.07, 127.00. 126.66. 126.04. 123.2), 121.89, 113.40, 110.5. |
With copper; potassium carbonate; glycerol at 140℃; | ||
With copper; potassium carbonate; cyclohexanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | at 120℃; for 0.0833333h; microwave irradiation; | |
31% | Stage #1: 2-chloro-5-nitrobenzoic acid; cyclohexylamine at 120℃; for 0.1h; Microwave heating; Stage #2: With sodium hydroxide In dichloromethane; water Stage #3: With hydrogenchloride In water Acidic aqueous solution; | 3.1 2-Chloro-5-nitrobenzoic acid (1.5 g) was dissolved in cyclohexylamine (4 mL) with stirring and warming. The bright yellow solution was heated in a microwave reactor at 120 0C for 6 minutes. The resulting gel was diluted with CH2Cl2 (-100 mL) and extracted with 0.2M NaOH (4 x -100 mL) . The aqueous extracts were acidified with 5M HCl, causing precipitation of a white solid. The solid was recovered by filtration and dried. The solid was recrystallised from methanol/water to yield light yellow crystals of amine 3-1 (0.6 g, 31%) . |
With water; sodium carbonate at 140℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: 2-chloro-5-nitrobenzoic acid; m-phenylenediamine With copper; potassium carbonate; copper(II) sulfate In water at 20℃; for 6.25h; Heating / reflux; Stage #2: With acetic acid In water at 0℃; | 47 (AR-ACO-06) Example 47 2-(3-Amino-phenylamino)-5-nitrobenzoic acid (AR-ACO-06) A mixture of 2-chloro-5-nitrobenzoic acid 16 (150.0 g, 744 mmol), 1,3-phenylenediamine 17 (150.0 g, 1.387 mol), anhydrous potassium carbonate (309.0 g, 2.236 mol), copper powder (2.0 g, 31.5 mmol), cupric sulfate (10 mg) and water (2.0 L) was heated to reflux with stirring for 6.25 hr under argon. It was then allowed to stand overnight at room temperature. Glacial acetic acid was added to the reaction mixture with stirring until pH 5 and the flask cooled in ice water. The mustard yellow solid was collected, washed with ice-cold water (3*100 mL), and redissolved in hot dilute ammonia (300 mL 0.88 s.g. ammonia and 2.7 L water). Charcoal (2.0 g) was added, the mixture refluxed briefly, and then filtered through a fluted paper. On cooling to room temperature the mixture was acidified to pH 5 by adding glacial acetic acid and the flask cooled in ice-water. The product was collected and washed with ice-cold water (2*100 mL) followed by ice-cold ethanol (2*100 mL), dry ether (2*100 mL) and finally hexane (100 mL). The product was dried over P2O5 under vacuum to yield the product AR-ACO-06 (155.10 g, 76%) as brown solid. Mp 270 ° C. dec. (lit. 250 ° C. dec.; Goldstein and de Simo, 1927). |
61% | With copper; potassium carbonate; copper(II) sulfate In water for 6h; Reflux; Inert atmosphere; | |
With i-Amyl alcohol; copper; potassium carbonate at 150 - 160℃; |
With pentan-1-ol; copper; potassium carbonate at 150℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With copper diacetate; potassium carbonate at 185℃; for 2h; Inert atmosphere; | 5.6.1 Step 1: Synthesis of 4-nitrodiphenylamine-2-carboxylic acid by Ullmann reaction Step 1: Synthesis of 4-nitrodiphenylamine-2-carboxylic acid by Ullmann reaction. Aniline (29mL, 317.5mmol) and 2-chloro-5-nitrobenzoic acid (10g, 49.61mmol) were charged to a 250mL rbf equipped with a reflux condenser and nitrogen bubbler. To the resulting mixture was added copper (II) acetate (450mg) followed by anhydrous potassium carbonate (7.9g, 57.05mmol). The reaction mixture was heated to 185°C for 2 hours, and then cooled to room temperature. The dark green solid was diluted with water and acidified with an aqueous hydrochloric acid solution until pH of 2 was reached. The mixture was triturated and the suspension was allowed to stir until a green powder appeared. The solid was filtered, washed with an excess of water to remove aniline and allowed to suck dry over 1 hour. 4-Nitrodiphenylamine-2-carboxylic acid was obtained as a green powdery solid (12.0g, 93%). Analyses by 1H NMR and LCMS conformed to structure. |
90% | With potassium carbonate In water at 150℃; for 2h; | |
90% | With sodium carbonate In N,N-dimethyl-formamide for 4h; Reflux; | 1 3.2. General Procedure for the Synthesis of Substituted N-phenylanthranilicAcid Derivatives (4-6) General procedure: The mixture of substituted o-halobenzoic acid (1) (0.04 mol) andsubstituted aniline (2) (0.08 mol) were refluxed in DMF in presence of anhydrous sodiumcarbonate (1 mol%) and copper powder (3mol%) for4 h. After completion of the reaction as evident fromthin layer chromatography(TLC), the reaction mixture was cooled to room temperatureand then slowly added with shaking to a HCI and water (1:1) solution(100 mL). The reaction mixture was left to stand overnight. The solidprecipitated out was filtered, washed with boiling water and thencrystallized with appropriate solvent to yield substituted Nphenylanthranilicacid (4-6) Scheme 1.3.2.1. 5-Nitro-(2-Phenyl Amino) Benzoic Acid (4)Crystallized frommethanol-acetone as an orange-yellowcolor solid;Yield: 90%, m.p. > 300 °C. Anal.Calc. for C13H10N2O4; C, 60.47; H, 3.90;N,10.85; O, 24.78; found: C, 60.52; H, 4.72; N, 8.24; O, 24.76. IR (KBr)cm-1: 3067 (N-H), 1590-1433 (C = Caromatic), 1523-1329 (NO2),1618 (C_O, acid carbonyl) 1H NMR (400 MHz, DMSO-d6, δ, ppm):12.58 (s, 1H, NH, D2O-exchangeable), 8.82 (s, 1H, COOH), 8.81 (s,1H, H-1), 8.03 (d, 1H, H-3), 7.40 (dd, 2H, H5-H9), 7.26 (dd, 2H, H6-H8) 7.15 (d, 1H, H-4), 7.11 (m, 1H, H-7). 13C NMR (100 MHz, DMSOd6,δ, ppm): 169.49 (C1), 151.83 (C-13), 139.51 (C-6), 136.14 (C-3),129.54 (C4), 128.58 (C-7, C-9), 126.90 (C-2), 124.08 (C-9), 122.24 (C-7, C-11), 111.32 (C-5, C-12). MS (ESI): (m/z) 334.26 [M + H]+•(C13H15N2NaO7). |
85% | In neat (no solvent) at 80℃; for 3h; Green chemistry; | 2.3 General Procedure for DES Catalyzed N-Arylationof Amines with Aryl Halides General procedure: To a solution of amine (1.2 mmol) dissolved in 20% DES,aryl halide (1 mmol) was added at room temperature andstirred for appropriate time. The progress of the reactionwas monitored by TLC. After completion of the reactioncold water was added to the reaction mixture. The precipitatedsolid was filtered off, and recrystallized using ethanol. |
80% | at 100℃; for 0.166667h; microwave irradiation; | |
at 140℃; | ||
With copper; potassium carbonate at 180℃; | ||
With potassium carbonate; copper(II) oxide at 120℃; | ||
at 100℃; for 0.166667h; Microwave heating; | 34; 31 To an 80 mL microwave reaction vial equipped with a magnetic stirring bar were added 5-nitro-2-chlorobenzoic acid (2.520 g, 12.5 mmol) and an excess (e.g. 6 eq.) of the appropriate aliphatic or aromatic amine derivative (ca. 75 mmol) to obtain a homogenous mixture. The mixture was irradiated in a microwave oven (80-100 W) for 5-30 min at 80-120 °C. Then the reaction mixture was cooled to rt, and the product was purified using the following procedure. The contents of the vial were dissolved in ca. 500 mL of dichloromethane and the organic solution was extracted with diluted aq. sodium hydroxide solution (ca. 500 mL). The extraction procedure was repeated until the aqueous layer became light yellow (3-4 times). Then the aqueous layer was collected and acidified using concentrated aq. hydrochloric acid (37 %) until pH ≤ 3 and the desired product precipitated in the acidic medium. The precipitated solid was filtered off and washed several times (2-3 times) with 100 mL water each to remove the remaining sodium chloride as well as hydrochloric acid. The product was dried in an oven at 100 °C. The purity of the product was ≥95% as determined by LC-MS; Example 34 5-Nitro-2-phenylaminobenzoic acid. Reaction conditions: according to the general procedure E: 10 min, 100 °C, 80 W; pressure up to 10 bar. Analytical data: yellow solid. 1H-NMR: δ 7.11 (d, 1H), 7.26 (ddd, 1H), 7.35 (dd, 2H), 7.45 (m, 2H), 8.15 (dd, 1H), 8.70 (d, 1H, 10.3 5(br, 1H, NH), 13.7 (br, 1H, COOH). 13C-NMR: δ 111.13, 113.35, 124.17, 125.94, 128.58, 129.45, 129.93, 136.73, 138.32, 152.52, 168.77. LC-MS (m/z): 259 [M]+, 276 [M+NH4+]+, 257 [M]-, 213 [M-COO-]-. Purity by HPLC-UV (254 nm)-ESI-MS: 99%. | |
With copper(II) nitrite; potassium carbonate at 185℃; Inert atmosphere; | 1 2-Nitroacridine-9(10)-one (1-H) The reaction between 2-chloro-5-nitrobenzoic acid and aniline in the presence of K2CO3 and catalytic amounts of Cu(NO2)2 (185 °C, 2-4 h) afforded 4-nitro-N-phenylanthranilic acid according to the procedure described in WO 2007/049057 (03.05.2007) by R. Ramage, B. Maltman, G. Cotton, S. C. M. Couturier, and R. A. S. McMordie; see also: US2012/0015373 (19.01.2012) by J. A. Smith and R. M. West.4-Nitro-N-phenylanthranilic acid was cyclized to 2-nitroacridine-9(10H)-one (1-H) (POCl3, reflux, 3 h). 1H NMR (400 MHz, DMSO-d6) d = 12.4 (s, 1 H, NH), 8.96 (d, J = 2.8, 1 H, H-1), 8.46 (dd, J = 9.2, 2.7 Hz, 1 H, H-3), 8.23 (dd, J = 8.1, 1.6 Hz, 1 H, H-8), 7.81 (ddd, J = 8.5, 7.0 and 1.6 Hz, 1 H, H- 6/7), 7.66 (d, J = 9.1 Hz, 1 H, H-4), 7.58 (dm, 1 H, H-5), 7.37 (ddd, J = 8.1, 7.0 and 1.1 Hz, 1 H, H-7/6)ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.4% | With sulfuric acid; nitric acid at -5 - 20℃; for 2h; Large scale; | 1 19.6 kg of concentrated sulfuric acid at room temperature into the 50L reactor, slowly adding 3.12kg o-chlorobenzoic acid, stirring to dissolve(Concentration 65%), drop the temperature of the process of temperature -5 ~ 5 ° C; drop finished 0 ~ 5 ° C after 2 h incubation, TLC (DCM), the temperature was reduced to -5 ~ 0 ° C, : Μ0Η = 10: 1) After the completion of the monitoring reaction, add 20 kg of ice water to quench the reaction. After stirring at 25 ° C for 30 min, the mixture was centrifuged at 50 ° C and dried at 50 ° C under reduced pressure to give 3.83 kg of 2-chloro-5-nitrobenzoic acid, 98.2% purity and 95.4% yield. |
95.8% | With sulfuric acid; nitric acid at -5 - 5℃; for 2h; | 1 Example 1 196 g of concentrated sulfuric acid at room temperature into the reaction flask, slowly adding 31.2 g o-chlorobenzoic acid, stirring to dissolve; down to -5 ~ 0° C ,21.6 g of nitric acid (65% concentration) was added dropwise, and the temperature was -5 to 5 ° C during the dropwise addition.Drop after 0 ~ 5° C incubation reaction 2h,TLC (DCM: MeOH = 10: 1) After the completion of the reaction, add 200 ml of ice water to quench the reaction, control the temperature below 25 , stirring 30min after centrifugation,500 ml of water, dried at 50 ° C under reduced pressure overnight,To give 38.5 g of 2-chloro-5-nitrobenzoic acid as a white solid, 98.5% pure, and 95.8% yield. |
90.2% | With sulfuric acid; potassium nitrate at 25℃; for 3h; | 2. Procedures for the preparation of 2-chloro-5-nitrobenzoicacid (2) 100 g (0.64 mol) Compound 1 was placed in 400 ml ofconcentrated sulfuric acid , 70 g(0.69 mol) potassium nitrate was added slowlyat 25 , stirred at roomtemperature 3 h, the mixture was poured into 800 ml ice-water mixture, filter theprecipitated solid, filter cake was washed to neutral (approximately 1 L) with water, dried to give a whitesolid 2 116 g, in yield of 90.2%. |
85.5% | With sulfuric acid; nitric acid at 0℃; for 0.0180556h; Green chemistry; | 1 Preparation of 2-chloro-5-nitrobenzoic acid (1) weigh o-chlorobenzoic acid (120 g) was added to 580 ml of concentrated sulfuric acid to dissolve and dissolve it as material 1, weigh 80g of fuming nitric acid as material 2, weigh 450ml of concentrated sulfuric acid as material 3; (2) control the flow rate of material 1 15ml / min; control the flow rate of material 2 3min / min; Control the flow rate of material 3 12min / min; the reaction temperature was 0 °C, the molar ratio of o-chlorobenzoic acid to nitric acid was 1: 1.4; the residence time of the reaction was 65 s; (3) After the reactor reached steady state of various materials, collecting the reaction liquid flowing out of the outlet of the reactor, taking the reaction solution corresponding to the material 1 (i.e., 450 mg of 1,95.0 g of o-chlorobenzoic acid) for 30 min, the collected reaction solution was poured into a 1.35 L ice-water mixture, the mixture was stirred at room temperature for 1 hour, filter, filter cake 500ml water washing, the crude product was added to a 160 ml volume of 1: 1 in methanol-water to recrystallize, filter get wet goods, dried at 50 °C for 12 hours under vacuum, to give 104.6 g of 2-chloro-5-nitrobenzoic acid, the yield was 85.5% and the liquid purity was 99.6%. |
With sulfuric acid; nitric acid | ||
durch Nitrierung; | ||
With sulfuric acid; nitric acid | ||
With sulfuric acid; nitric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethoxyacetylene | ||
With dicyclohexyl-carbodiimide In dichloromethane at 20℃; | General procedure: General procedure for synthesis of anhydride (12a-12p) Mixture of substituted acid derivative (0.02 mol) and dicyclohexylcarbodiimide (0.01 mol) was dissolved in dichloromethane (50 ml) and stirred at room temperature for 3-4 h. After then solvent was separated (12a-12p), the reaction mixture was filtered to remove the precipitated dicyclohexylurea and the filtrate was evaporated to get the oily product (12a-12p). | |
With dicyclohexyl-carbodiimide In dichloromethane at 20℃; | 3.1.2. General Procedure for Synthesis of Anhydride (2a-2o) General procedure: Substituted aromatic acid (0.02 M) and dicyclohexylcarbodiimide (0.01 M) were dissolved in 50 ml methylene chloride. The reaction mixture was stirred at room temperature for 3-4 h. The precipitated dicyclohexylurea was removed by filtration. The solvent was evaporated and the oily product obtained was collected and used without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.9% | for 24h; Heating / reflux; | 1.1 To a solution of 2-chloro-5-nitrobenzoic acid (30 g, 148.8 mmol) in methanol (150 ml) was added conc. sulfuric acid (2 ml), and the mixture was heated under reflux for 24 hr. After allowing to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 2-chloro-5-nitrobenzoate (31.3 g, yield 97.9%) as a crude product. The obtained crude product was used for Step 2 without further purification. |
96% | With sulfuric acid for 24h; Reflux; | Methyl 2-chloro-5-nitrobenzoate 3 To a solution of 2-chloro-5-nitrobenzoic acid 2 (7.50 g, 0.037 mol) in MeOH (30 mL) wasadded concentrated H2SO4 (1.35 mL) slowly. The reaction was thenheated at reflux for 24 h. The reaction was cooled and the solventwas then removed in vacuo and ice-water (30 mL) added to theresidue, followed by diethyl ether (30 mL). The organic layer was separated and the aqueous layer further extracted with diethylether (2 x 30 mL). The combined organic extracts were washedwithwater (25 mL),1MNaOH (2 x 25 mL) andwater (25 mL), dried(MgSO4) and the solvent removed in vacuo to give the title product 3(7.68 g, 96%) as a white solid. m.p.: 69-71 °C (Lit [16]. 68-69 °C). RF:0.87 (9:1 CH2Cl2-MeOH). δH (400 MHz; CDCl3; Me4Si) 4.00 (3H, s,OCH3), 7.66 (1H, d, J 8.0 Hz, H-3), 8.27 (1H, dd, J 2.0, 8.0 Hz, H-4), 8.71 (1H, d, J 2.0 Hz, H-6). δC (100 MHz; CDCl3) 53.1 (OCH3),126.7 (C-6), 126.8 (C-4), 131.0 (C-1), 132.3 (C-3), 140.8 (C-2), 146.1(C-5), 164.0 (C=O). The 1H NMR datawas consistent with literaturevalues [15]. |
96% | With sulfuric acid at 80℃; for 24h; |
95.4% | With sulfuric acid at 80℃; for 3h; | 5 Example 5 2-chloro-5-nitrobenzoic acid methyl esterSynthesis Take a 25ml jar, add 5ml of methanol and 0.5g in order2-Chloro-5-nitrobenzoic acid, stirring, slowly adding 1 ml of concentrated sulfuric acid,The reaction was refluxed at 80 °C for 3 h. After TLC monitored the reaction, the methanol was decontaminated under vacuum.Saturated sodium carbonate solution was added dropwise to adjust the pH to 9 and 5 ml of dichloromethane was added.The liquid was separated, the organic layer was washed 3 times with saturated sodium chloride, and the aqueous layers were combined.Dichloromethane was extracted twice, the organic layers were combined, and the organic phase was dried over anhydrous sodium sulfate for 1 hour. After the silica gel column, petroleum ether is separated 5:1 from ethyl acetate,Thus, an off-white solid of methyl 2-chloro-5-nitrobenzoate (0.52 g) was obtained in a yield of 95.4%. |
94% | With sulfuric acid for 18h; Heating; | |
92.5% | With chloro-trimethyl-silane for 12h; Reflux; | 7-1 (7-1) Preparation of 2-chloro-5-nitrobenzoic acid methylester (7-1) Preparation of 2-chloro-5-nitrobenzoic acid methylester By refluxing 2-chloro-5-nitrobenzoic acid and trimethylsilyl chloride (TMSCI) in a methanol solvent for 12 hours, 2-bromo-nitrobenzoic acid methylester was prepared. Yield: 92.5% White solid 1H-NMR (400 MHz, CDCl3) δ 8.72(d, J=2.6 Hz, 1H), 7.28(dd, J=8.8, 2.7 Hz, 1H), 7.66(d, J=8.8 Hz, 1H) |
88% | With sulfuric acid Reflux; | |
75% | With hydrogenchloride In 1,4-dioxane; water for 3h; | 2-Chloro-5-nitro-benzoic acid methyl ester (15) 2-chloro-5-nitrobenzoic acid 14 (5.0 g, 24.8 mmol) was dissolved in methanol (10 mL) and 4 N HCl in dioxane (12 mL) was added. The mixture was stuffed for 3 hr after which the solvents were evaporated and the residue was neutralized and extracted with EtOAc, washed with NaHCO3, brine, dried over MgSO4 and filtered. The solvent was evaporated to give the desired product 15 (3.9 g, 75%). |
With sulfuric acid In 1,2-dichloro-ethane | ||
With sulfuric acid for 18h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 2-chloro-5-nitrobenzoic acid With potassium carbonate In N,N-dimethyl-formamide at 120 - 125℃; Stage #2: ortho-cresol In N,N-dimethyl-formamide at 80 - 125℃; | |
With copper(l) iodide; copper; potassium carbonate In nitrobenzene at 150 - 160℃; | ||
Stage #1: 2-chloro-5-nitrobenzoic acid With copper(l) iodide; potassium carbonate In nitrobenzene at 70 - 80℃; for 0.166667h; Stage #2: ortho-cresol In nitrobenzene at 155℃; | 3 EXAMPLE 3; 5-Iodo-2-(2-dimethylaminomethylphenoxy)Benzyl Alcohol; Methyl, 5-nitro-2-(2-methylphenoxy)benzoic acid (34); To a solution of 2-chloro-5-nitro benzoic acid 31 (4.04 g, 20 mmol) in nitrobenzene (20 mL) was added K2CO3 (4.14 g, 3 eq) followed by Cu (0.2 g) and CuI (0.2 g) at 70-80° C. The mixture was stirred at 80° C. for 10 min. O-Cresol (4.32 g, 2 eq) was added and the mixture was stirred at 155° C. overnight. NaOH solution (1M, 30 mL) was added after the mixture was cooled down and the dark slurry was extracted with ether to remove nitrobenzene. The aqueous phase was filtered and acidified with HCl. The resulting mixture was extracted with mixed solvent (CH2Cl2:MeOH=9:1). The organic phase was dried, filtered and concentrated to give a tar (4.6 g). To the solution of tar obtained above in MeOH (100 mL) was added concentrated H2SO4 (2 mL) dropwise at room temperature and the mixture was stirred under reflux overnight. Solvent was removed and ice water was added. The mixture was made basic with KOH solution and extracted with CH2Cl2. The organic phase was dried, filtered and concentrated to give crude product which was purified by chromatography (Flash 40) (EtOAc:Hex=1:10) to give 720 mg of product and 2.5 g of mixture (product and by product). 1H NMR (CDCl3, δ): 2.19 (s, 3H, ArCH2), 3.96 (s, 3H, COOCH3), 6.73 (d, 1H, J=9.2 Hz, ArH), 7.00 (d,d, 1H, J=7.4, 1.8 Hz, ArH), 7.15-7.34 (m, 3H, ArH), 8.23 (d,d, 1H, J=7.5, 1.8 Hz, ArH), 8.79 (d, 1H, J=2.8 Hz, ArH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium tetrahydroborate; boron trifluoride diethyl etherate In tetrahydrofuran at 0 - 20℃; for 1h; | |
90% | With sodium tetrahydroborate; boron trifluoride diethyl etherate In tetrahydrofuran at 0 - 20℃; | |
71% | With phenylsilane; C34H30CoO6; potassium In tetrahydrofuran at 20℃; for 20h; Inert atmosphere; Schlenk technique; Glovebox; |
With sodium tetrahydroborate; boron trifluoride diethyl etherate In tetrahydrofuran at 0 - 20℃; for 1h; | 2.a To a stirred suspension of sodium borohydride (9.9 mmol) in dry THF (20 ml) at [0XB0;C] was added 2-chloro-5-nitrobenzoic acid (4.96 mmol) dissolved in dry THF (5 ml). Boron trifluoride etherate (13.3 mmol) was added dropwise and the reaction mixture allowed to warm to room temperature over 1 hour. The reaction mixture was quenched with 1N [HC1] and then partitioned between DCM and water. The organic layer was separated, washed with brine solution, dried [(MGSO4),] filtered, evaporated and the residue purified by column chromatography on silica. Elution with mixtures of petroleum ether and ethyl acetate afforded 0.92g of the desired product; MS (ES): m/e 189 (M+H); OH (400 MHz, [CDC13)] 8.5 [(1H,] br s), 8.13 [(1H,] br dd), 7.54 [(1H,] d, [J] 8), 4.89 (2H, [S). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; D-glucose at 60 - 65℃; for 8h; | ||
With D-glucose; sodium hydroxide In water; acetic acid at 50 - 60℃; for 8.5h; | ||
With D-glucose; sodium hydroxide In water at 50℃; for 0.166667h; | 2.1 2.2.1 4,4'-Dichloro-3,3'-azobenzenedicarboxylic acid (3,3'-H2Cl2abdc) A similar synthetic procedure to the literature was applied for the preparation of 3,3'-H2Cl2abdc [3]. A mixture of 2-chloro-5-nitrobenzoic acid (7.5 g, 37 mmol) and NaOH (25 g, 625 mmol) was stirred at 50 °C in water (70 mL) in a beaker (250 mL) to get a clear solution. An aqueous solution of glucose (50 g, 277.5 mmol) was added to the previous solution at 50 °C to obtain a dark brown solution. The resulting solution was stirred at this temperature for 10 min. and then cooled to room temperature. The solution was aerated for one day with vigorous stirring and then filtered. The obtained precipitate was washed with a small amount of cold water and dissolved in water (100 ml) again. The solution was acidified with HCl (37%) (pH 1-2) to precipitate 3,3'-H2Cl2abdc. The orange solid was collected by filtration and dried at room temperature. Decomp. Temp.: 335.72 °C (based on DSC analysis). Anal. Calc. for C14H8Cl2N2O4: C, 49.58; H, 2.38; N, 8.26. Found: C, 49.12; H, 2.61; N, 8.44%. FT-IR (KBr, cm-1): 3076 m, 2968 m, 2818 m, 1701 vs, 1680 s, 1597 m, 1447 m, 1319 m, 1267 s, 1203 m, 1043 m, 926 m, 835 m (Fig. S1). 1H NMR (500 MHz, DMSO-d6) d, ppm:13.78 (s, 2H), 8.27 (d, J = 2.4 Hz, 4H), 8.07 (dd, J = 8.6, 2.4 Hz, 4H),7.80 (d, J = 8.6 Hz, 4H) (Fig. S2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With copper; potassium carbonate In N,N-dimethyl-formamide at 25℃; for 0.416667h; ultrasonic irradiation; | |
77% | In 1-methyl-pyrrolidin-2-one at 110℃; for 6h; | 1.1 1) 5-nitro-2-(propylamino)benzoic acid 1) 5-nitro-2-(propylamino)benzoic acid [0174] 2-Chloro-5-nitrobenzoic acid (20.8 g, 100 mmol) was dissolved in NMP (146 mL) and propylamine was added (25 mL, 300 mmol). The reaction mixture was heated to 110 °C and strirred for 6 h. The reaction mixture was cooled down and poured into a mixture of ice and HCl. The precipitate was filtered and washed with cold water and dry overnight. The solid was then crystallized from a mixture of dichloromethane and methanol. 5-nitro-2- (propylamino)benzoic acid was obtained as a yellow solid (17.2 g, 77%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.94 (d, 1 H), 8.48 (br. s., 1 H), 8.25 (dd, 1 H), 6.72 (d, 1 H), 3.51 (s, 2 H), 3.10 (m, 2 H), 1.78 (3, 2 H), 1.03 (t, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 2-chloro-5-nitrobenzoic acid With oxalyl dichloride; sodium carbonate In dichloromethane at 20℃; Inert atmosphere; Stage #2: 2-amino-phenol With sodium carbonate In tetrahydrofuran; diethyl ether; water for 1h; Cooling with ice; | 1.1 Step 1 : Synthesis of 3 Oxalyl chloride (25.2 g, 198.4 mmol, 2.0 equiv.) was added dropwise to a suspension of compound 1 (22.0 g, 99.2 mmol, 1.0 equiv.) in DCM (250 mL). The resulting yellow solution was stirred under argon at room temperature overnight. The solvent was removed under vacuum to give a yellow solid. The solid was dissolved in 120 mL of diethyl ether and then added to an ice-cooled mixture of o-aminophenol (10.8 g, 99.2 mmol, 1.0 equiv.) and sodium bicarbonate (16.6 g, 198.4 mmol, 2.0 equiv.), water (72 mL) and THF (40 mL) over a period of 1 hour. The mixture was allowed to warm to room temperature and stirred overnight. The precipitate was filtered and washed sequentially with water (3x100 mL), 2N HC1 (3x100 mL) and diethyl ether (3x50 mL) to give compound 3 (27.0 g, yield: 84%) as a yellow solid. |
80% | Stage #1: 2-chloro-5-nitrobenzoic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 0.166667h; Stage #2: 2-amino-phenol In tetrahydrofuran Heating; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 2-chloro-5-nitrobenzoic acid With thionyl chloride; N,N-dimethyl-formamide for 3h; Reflux; Stage #2: With ammonium hydroxide In dichloromethane Cooling with ice; | 44.1 20.157 g 2-Chloro-5-nitrobenzoic acid (100 mmol) was heated at reflux temperature in 100 ml thionyl chloride for 3 hours in the presence of 3 drops of dry N,N-dimethylformamide as catalyst. Reaction mixture was evaporated under reduced pressure and 100 ml dry dichloromethane was added. 100 ml Of 12% NH4OH solution was added dropwise to the ice cold solution and it was stirred for further 2 hours. 400 g ice was then added and it was stirred until the ice melted. Precipitated solid was collected by filtration and washed well with water. The white solid was dried in vacuum desiccator over P2O5. Yield: 17.07 g (85%). Ret. time: 1.93 min., (M+H)+=201, (M+H)-=199; 1HNMR (DMSO-d6, 300 MHz), δ (ppm): 8.24 (bs, 2H), 8.13 (s, 1H), 7.87 (s, 1H), 7.81 (d, J=8.04 Hz, 1H). |
Multi-step reaction with 2 steps 1: SOCl2 / 3 h / Heating 2: NH4OH / acetone / Ambient temperature | ||
Multi-step reaction with 2 steps 1: PCl5 2: diethyl ether; aqueous ammonia |
Multi-step reaction with 2 steps 1: thionyl chloride 2: water; aqueous ammonia | ||
Stage #1: 2-chloro-5-nitrobenzoic acid With thionyl chloride In DMF (N,N-dimethyl-formamide); toluene at 20℃; for 3h; Heating / reflux; Stage #2: With ammonia In DMF (N,N-dimethyl-formamide); water; toluene Ice cooling; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 2-chloro-5-nitrobenzoic acid With potassium <i>tert</i>-butylate In ethanol at 20℃; Inert atmosphere; Reflux; Stage #2: With sodium sulfide; sulfur In ethanol; water for 10h; Inert atmosphere; Reflux; Stage #3: With hydrogenchloride In ethanol; water at 20℃; | |
75.5% | With sodiumsulfide nonahydrate; sulfur In water at 60 - 70℃; for 5h; | 2 Synthesis of 2,2'-dithiobis (5-nitrobenzoic acid) Dissolve 8.0 mmol of Na 2 S · 9H 2 O in 20 mL of water,Add 10mmol sulfur powder, heated to reflux the reaction liquid was reddish brown, hot filtered Na2S2 aqueous solution. Then, the above solution was added dropwise to 15 mL of a basic aqueous solution of pH = 10 dissolved in 10 mmol of 2-chloro-5-nitrobenzoic acid at a controlled temperature of 60 to 70 ° C for 5 hours and then cooled to adjust the pH of the reaction solution About 3, for 2 hours, precipitated dark yellow precipitate, suction filtration, washing, drying yellow powder product. Yield 75.5% |
With hydrogenchloride; sodium sulfide nonahydrate; hydrogen sulfide; potassium <i>tert</i>-butylate In ethanol; water | 38 Preparation of 2,2'-Dithiobis[5-nitrobenzoic acid] EXAMPLE 38 Preparation of 2,2'-Dithiobis[5-nitrobenzoic acid] A mixture of 2-chloro-5-nitrobenzoic acid (100 g, 0.496 mol) in ethanol is treated portionwise with potassium tert-butoxide (55.5 g, 0.495 mol), diluted with additional ethanol, heated to reflux, treated portionwise with a solution prepared from sodium sulfide nonahydrate (60.0 g, 0.249 mol), sulfur (8.80 g, 0.274 mol) and water, refluxed for two hours, cooled to room temperature, and treated with concentrated hydrochloric acid. The resultant acidic mixture is stirred for one hour and filtered to obtain a solid. The solid is washed with water and air-dried to give the title product as a yellow powder which is identified by NMR spectral analysis. |
With hydrogenchloride; sodium sulfide nonahydrate; hydrogen sulfide; potassium <i>tert</i>-butylate In ethanol; water | 29 Preparation of 2,2'-Dithiobis[5-nitrobenzoic acid] STR169 EXAMPLE 29 Preparation of 2,2'-Dithiobis[5-nitrobenzoic acid] STR169 A mixture of 2-chloro-5-nitrobenzoic acid (100 g, 0.496 mol) in ethanol is treated portionwise with potassium tert-butoxide (55.5 g, 0.495 mol), diluted with additional ethanol, heated to reflux, treated portionwise with a solution prepared from sodium sulfide nonahydrate (60.0 g, 0.249 mol), sulfur (8.80 g, 0.274 mol) and water, refluxed for two hours, cooled to room temperature, and treated with concentrated hydrochloric acid. The resultant acidic mixture is stirred for one hour and filtered to obtain a solid. The solid is washed with water and air-dried to give the title product as a yellow powder which is identified by NMR spectral analysis. | |
With hydrogenchloride; sodium sulfide nonahydrate; hydrogen sulfide; potassium <i>tert</i>-butylate In ethanol; water | 57 Preparation of 2,2'-Dithiobis[5-nitrobenzoic acid] EXAMPLE 57 Preparation of 2,2'-Dithiobis[5-nitrobenzoic acid] A mixture of 2-chloro-5-nitrobenzoic acid (100 g, 0.496 mol) in ethanol is treated portionwise with potassium tert-butoxide (55.5 g, 0.495 mol), diluted with additional ethanol, heated to reflux, treated portionwise with a solution prepared from sodium sulfide nonahydrate (60.0 g, 0.249 mol), sulfur (8.80 g, 0.274 mol) and water, refluxed for two hours, cooled to room temperature, and treated with concentrated hydrochloric acid. The resultant acidic mixture is stirred for one hour and filtered to obtain a solid. The solid is washed with water and air-dried to give the title product as a yellow powder which is identified by NMR spectral analysis. | |
With hydrogenchloride; sodium sulfide nonahydrate; hydrogen sulfide; potassium <i>tert</i>-butylate In ethanol; water | 25 Preparation of 2,2'-Dithiobis[5-nitrobenzoic acid] EXAMPLE 25 Preparation of 2,2'-Dithiobis[5-nitrobenzoic acid] A mixture of 2-chloro-5-nitrobenzoic acid (100 g, 0.496 mol) in ethanol is treated portionwise with potassium tert-butoxide (55.5 g, 0.495 mol), diluted with additional ethanol, heated to reflux, treated portionwise with a solution prepared from sodium sulfide nonahydrate (60.0 g, 0.249 mol), sulfur (8.80 g, 0.274 mol) and water, refluxed for two hours, cooled to room temperature, and treated with concentrated hydrochloric acid. The resultant acidic mixture is stirred for one hour and filtered to obtain a solid. The solid is washed with water and air-dried to give the title product as a yellow powder which is identified by NMR spectral analysis. | |
With octasulfur; sodium sulphide nonahydrate; potassium <i>tert</i>-butylate In ethanol; water for 2h; Heating / reflux; | 27 REFERENCE EXAMPLE 27; Preparation of 2,2'-Dithiobis[5-nitrobenzoic acid] REFERENCE EXAMPLE 27 Preparation of 2,2'-Dithiobis[5-nitrobenzoic acid] A mixture of 2-chloro-5-nitrobenzoic acid (100 g, 0.496 mol) in ethanol is treated portionwise with potassium tert-butoxide (55.5 g, 0.495 mol), diluted with additional ethanol, heated to reflux, treated portionwise with a solution prepared from sodium sulfide nonahydrate (60.0 g, 0.249 mol), sulfur (8.80 g, 0.274 mol) and water, refluxed for two hours, cooled to room temperature, and treated with concentrated hydrochloric acid.. The resultant acidic mixture is stirred for one hour and filtered to obtain a solid.. The solid is washed with water and air-dried to give the title product as a yellow powder which is identified by NMR spectral analysis. | |
With hydrogenchloride; sodium sulfide nonahydrate; hydrogen sulfide; potassium <i>tert</i>-butylate In ethanol; water | 26 Preparation of 2,2'-Dithiobis[5-nitrobenzoic acid] EXAMPLE 26 Preparation of 2,2'-Dithiobis[5-nitrobenzoic acid] A mixture of 2-chloro-5-nitrobenzoic acid (100 g, 0.496 mol) in ethanol is treated portionwise with potassium tert-butoxide (55.5 g, 0.495 mol), diluted with additional ethanol, heated to reflux, treated portionwise with a solution prepared from sodium sulfide nonahydrate (60.0 g, 0.249 mol), sulfur (8.80 g, 0.274 mol) and water, refluxed for two hours, cooled to room temperature, and treated with concentrated hydrochloric acid. The resultant acidic mixture is stirred for one hour and filtered to obtain a solid. The solid is washed with water and air-dried to give the title product as a yellow powder which is identified by NMR spectral analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 12h; | 165 Reference Example 165; 2-chloro-N, N-dimethyl-5-nitrobenzamide A mixed solution of 2-chloro-5-nitrobenzoic acid (4.03 g), dimethylamine hydrochloride (1.96 g), N, N- diisopropylethylamine (4.25 mL), WSC (5.75 g) and HOBt (3.98 g) in acetonitrile (50 mL) was stirred at room temperature for 12 hrs. The reaction solution was poured into water and stirred for 1 hr. The precipitates were collected by filtration, washed with water and hexane and dried to give the title compound as a pale yellow powder (3.66 g, yield 80%). H NMR (200 MHz, CDC) 8 ppm: 2.93 (s, 3 H), 3. 17 (s, 3 H), 7. 58-7. 63 (m, 1 H), 8. 17-8. 23 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.8 g (68%) | In N,N-dimethyl-formamide; | (a) A mixture of 2-chloro-5-nitrobenzoic acid (4.03 g, 0.02 mol), 5-amino-1-ethylpyrazole (2.22 g, 0.02 mol), DMF (25 ml), K2 CO3 (2.76 g, 0.02 mol) and Cu(OAc)2 H2 O (0.5 g) is refluxed for 24 hours. The reaction mixture is cooled to room temperature, poured into ice waterl and acidified with acetic acid to a pH of 5. A solid forms which is collected by filtration and dried to afford 3.8 g (68%) of N-(1-ethylpyrazol-5-yl)-5-nitroanthranilic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.8 g (68%) | In N,N-dimethyl-formamide; | (a) A mixture of 2-chloro-5-nitrobenzoic acid (4.03 g, 0.02 mol), 5-amino-1-ethylpyrazole (2.22 g, 0.02 mol), DMF (25 ml), K2 CO3 (2.76 g, 0.02 mol) and Cu(OAc)2.H2 O (0.5 g) was refluxed for 24 hours. The reaction mixture was cooled to room temperature, poured into ice-water and acidified with acetic acid to a pH of 5. A solid formed which was collected by filtration and dried to afford 3.8 g (68%) of N-(1-ethylpyrazol-5-yl)-5-nitroanthranilic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In pentan-1-ol; | EXAMPLE 5 5-Nitro-N-(2-methyl-3-trifluoromethylphenyl) anthranilic acid To a solution of 25 g. of 2-chloro-5-nitro-benzoic acid in 125 ml. of n-pentyl alcohol add 4.8 g. of sodium hydroxide pellets, 25 g. of <strong>[54396-44-0]2-methyl-3-trifluoromethylaniline</strong> and 2 g. of copper powder. With constant stirring, reflux the reaction mixture for 18 hours. Concentrate the mixture to one half volume and dilute with water and ether. Acidify the aqueous layer to obtain a crude product which is recrystallized to yield 5-nitro-N-(2-methyl-3-trifluoromethylphenyl) anthranilic acid, m.p. 244°-245° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 2-chloro-5-nitrobenzoic acid With thionyl chloride; N,N-dimethyl-formamide In toluene for 1.5h; Heating / reflux; Stage #2: potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.5h; | A 2-Chloro-5-nitrobenzoic acid (22 g, 109.1 mmol) and DMF (500 μL) are refluxed in toluene (50 mL)/thionyl chloride (8.5 mL) for 1.5 h with stirring. The reaction mixture is evaporated down and the residue is taken up in anhydrous THF (200 mL). Potassium- tert.- butoxide (12.5 g, 111.4 mmol) is added at 0 0C, then the cooling is removed and the mixture is stirred for 30 min The solvent is distilled off and the residue is divided between water and EtOAc. The organic phase is washed with water and 0.1 N NaOH, dried, filtered and evaporated down. Yield: 24 g (85 %) |
85% | Stage #1: 2-chloro-5-nitrobenzoic acid With thionyl chloride; N,N-dimethyl-formamide In toluene for 1.5h; Heating / reflux; Stage #2: potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.5h; | A 2-Chloro-5-nitrobenzoic acid (22 g, 109.1 mmol) and DMF (500 μL) are refluxed in toluene (50 mL)/thionyl chloride (8.5 mL) for 1.5 h with stirring. The reaction mixture is evaporated down and the residue is taken up in anhydrous THF (200 mL). Potassium- tert.- butoxide (12.5 g, 111.4 mmol) is added at 0 0C, then the cooling is removed and the mixture is stirred for 30 min. The solvent is distilled off and the residue is divided between water and EtOAc. The organic phase is washed with water and 0.1 N NaOH, dried, filtered and evaporated down. Yield: 24 g (85 %) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.3 - 87.1% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 12h; | Example 3: Preparation of 17-cyclohexyl-18-[4-[2-(4-methanesulfonylpiperazin-l-yl)- 5-nitrobenzyloxy1phenyl]-l Al l-triazatricyclo[l l52016'19^icosa- 7.13(20U4.16alpha9U7-pentaene-3.12-dione (3)O Step A.3-3A solution of 2-chloro-5-nitrobenzoic acid 3-1 (101 mg, 0.503 mmol), JV-methyl- sulfonylpiperazine 3-2 (110 mg, 0.673 mmol) and cesium carbonate (335 mg, 1.03 mmol) in DMF (5 mL) was heated at 100 0C under nitrogen. After 12h, the reaction mixture was successively cooled down at room temperature and acidified to pH 5 with an aqueous 6 N solution of HCl. The precipitate was collected by filtration to give 75 mg (45.3 %) of the target product 3-3: m/z = 330 (M+H)+. On larger scale (4.53 g of 3 1) the target product 3-3 was obtained with a yield of 87.1 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With silver carbonate In dimethyl sulfoxide; N,N-dimethyl-formamide at 110℃; for 16h; Inert atmosphere; | |
90% | With silver carbonate In dimethyl sulfoxide at 120℃; for 16h; | |
85% | With silver(I) acetate; potassium carbonate In 1-methyl-pyrrolidin-2-one at 120℃; for 16h; Inert atmosphere; |
With silver carbonate In dimethyl sulfoxide; N,N-dimethyl-formamide at 120℃; for 16h; Inert atmosphere; | ||
100 %Spectr. | With silver (II) carbonate In dimethyl sulfoxide at 120℃; for 16h; Inert atmosphere; chemoselective reaction; | |
With silver carbonate In dimethyl sulfoxide at 120℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 2-chloro-5-nitrobenzoic acid With thionyl chloride In N,N-dimethyl-formamide Reflux; Stage #2: 2-Hydroxy-4-methylanilin With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 48h; Cooling; | 88 Example 88 7-Methyl-2-nitro-dibenzo[b,f][1,4]oxazenin-11(10H)one (Compound No: BJ4) A slurry of 2-chloro-5-nitrobenzoic acid (1.00g, 5mmol) and SOCl2 (1.2 ml, 14mmol), containing 1 drop of DMF, was heated under reflux to obtain a yellow-brown solution. Excess SOCl2 was removed by evaporation under reduced pressure, and the residue was dissolved in THF (5ml). The resultant acid chloride solution was added dropwise over 30 min to a solution of 6-amino-m-cresol (0.611g, 5mmol) and (i-Pr)2NEt (1.73ml), 10mmol) in THF (5 ml) under ice bath. The reaction mixture was allowed to react at room tempreture for 48 h, the reaction mixture was extracted with Et2O (20ml), washed successively with 1 N HCl, saturated aqueous NaHCO3, and saturated brine, dried over MgSO4, filtered and evaporated by a rotatory evaporator to obtain a yellow oil (1.30g, 85%). mp 190-193°C. 1NMR (300MHz, d6-DMSO): δ 2.23 (s, 3H), 6.65 (d, 1H, J =8.1Hz), 6.73 (s, 1H), 7.64 (d, 1H, J =8.1Hz), 7.84 (d, 1H, J =9.0Hz), 8.31 (d, d, 1H, J =3.0, 9.0Hz), 8.43 (d, 1H, J =3.0Hz), 9.65 (br s, 1H), 9.89 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With tetrabutylammonium triphenyldifluorosilicate In toluene at 60℃; for 24h; | 4.2.6 Synthesis of 2-nitroxanthone (24) o-(Trimethylsilyl)phenyl triflate (1.5 equiv) was added to a mixture of 2-chloro-5-nitrobenzoic acid (0.25 mmol) and TBAT (2.0 equiv) in 5 mL of toluene, and the reaction mixture was then stirred at 60 °C for 24 h. After allowing the reaction mixture to cool to room temperature, the mixture was extracted with EtOAc (20 mL×2) from the brine solution (40 mL), the organic fractions were combined, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using hexanes/EtOAc as the eluent to afford the desired xanthone 24 as a pale brown solid in an 87% yield: mp 203-205 °C (lit. mp46 202-203 °C); 1H NMR (400 MHz, CDCl3) δ 7.47 (t, J=7.6 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.64 (d, J=9.2 Hz, 1H), 7.81 (ddd, J=8.7, 7.1, 1.7 Hz, 1H), 8.33 (dd, J=7.9, 1.7 Hz, 1H), 8.54 (dd, J=9.2, 2.8 Hz, 1H), 9.19 (d, J=2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 118.2, 119.7, 121.3, 121.6, 123.5, 125.3, 126.9, 129.0, 135.9, 155.8, 159.1, 175.7; HRMS (APCI) calcd for [M+H]+ C13H8NO4 242.0448, found 242.0452. The 1H and 13C NMR spectral data are in good agreement with the literature data.47 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 4-methyl-morpholine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate In dichloromethane at 20℃; | 52a a) 2-Chloro-5-nitro-N'-(pyridin-2-yl)benzohydrazide a) 2-Chloro-5-nitro-N'-(pyridin-2-yl)benzohydrazide: A mixture of2-hydrazinylpyridine (1.0 g,9.1 mmol), 2-chloro-5-nitrobenzoic acid (1.8 g, 9.1 mmol), BOP (11.8 mmol), 4-methylmorpholine (1.8 g, 18.2 mmol) and CH2Ch (30 mL) was stirred at room temperatureovernight. The reaction mixture was filtered to give the title compound (2.1g, 78%). MS:mlz 293.2 [M+Ht |
78% | With 4-methyl-morpholine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate In dichloromethane at 20℃; | 52.a N-(3-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-4-chlorophenyl)-3-methyl-4'-(trifluoromethyl)biphenyl-4-carboxamide a) 2-Chloro-5-nitro-N'-(pyridin-2-yl)benzohydrazide A mixture of 2-hydrazinylpyridine (1.0 g, 9.1 mmol), 2-chloro-5-nitrobenzoic acid (1.8 g, 9.1 mmol), BOP (11.8 mmol), 4-methylmorpholine (1.8 g, 18.2 mmol) and CH2Cl2 (30 mL) was stirred at room temperature overnight. The reaction mixture was filtered to give the title compound (2.1 g, 78%). MS: m/z 293.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.5% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃;Inert atmosphere; | a) N-( 4-aminothiophen-3-yl)-2-chloro-5-nitrobenzamide. A mixture of <strong>[78637-85-1]thiophene-3,4-diamine</strong>(0.90 g, 7.89 mmol), 2-chloro-5-nitrobenzoic acid (1.32 g, 6.57 mmol) and BOP (3.49 g,7.89 mmol) in triethylamine (1.8 mL, 13.1 mmol) and MeCN (40 mL) was stirred at roomtemperature overnight under N2 . The mixture was concentrated. The residue was purifiedby the flash column chromatography (EA/PE) to give the title compound as a yellow solid(1.16 g, 49.5%). MS: mlz 298.0 [M+Ht |
49.5% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃;Inert atmosphere; | a) N-(4-aminothiophen-3-yl)-2-chloro-5-nitrobenzamide. A mixture of <strong>[78637-85-1]thiophene-3,4-diamine</strong> (0.90 g, 7.89 mmol), 2-chloro-5-nitrobenzoic acid (1.32 g, 6.57 mmol) and BOP (3.49 g, 7.89 mmol) in triethylamine (1.8 mL, 13.1 mmol) and MeCN (40 mL) was stirred at room temperature overnight under N2. The mixture was concentrated. The residue was purified by the flash column chromatography (EA/PE) to give the title compound as a yellow solid (1.16 g, 49.5%). MS: m/z 298.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With polyphosphoric acid; at 150℃; for 3h; | Step A Into a 1000-mL round-bottom flask, was placed <strong>[39903-01-0]2-amino-5-bromopyridin-3-ol</strong> (20 g, 105.81 mmol, 1.00 equiv), 2-chloro-5-nitrobenzoic acid (21.4 g, 106.17 mmol, 1.00 equiv), PPA (300 mL). The resulting solution was stirred for 3 h at 150° C. in an oil bath. The reaction was then quenched by the addition of 1 L of water/ice. The reaction mixture was cooled with a water/ice bath. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 28 g (75percent) of 6-bromo-2-(2-chloro-5-nitrophenyl)-[1,3]oxazolo[4,5-b]pyridine I-21a as a gray solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: triethylamine With iodine; triphenylphosphine In dichloromethane at 0℃; for 0.166667h; Stage #2: 2-chloro-5-nitrobenzoic acid In dichloromethane at 25℃; | |
75% | With iodine; triphenylphosphine In dichloromethane at 0 - 20℃; | General procedure for the synthesis of anhydride via Ph3P-I2 system Unexpected tertiary amide bond formation from nitro-substituted aryl carboxylic acid General procedure: To a solution of iodine (0.1573 g, 0.62 mmol) in CH2Cl2 (2 mL) was added with triphenylphosphine (0.1626 g, 0.62 mmol) in one portion at 0 oC. Carboxylic acid (0.41 mmol)was subsequently added into the mixture, followed by addition of triethylamine (0.17 mL, 1.23mmol) at 0 oC. The reaction mixture was allowed to warm up to room temperature and stirred until completion of the reaction (typically within 10 min). The crude mixture was concentrated under reduced pressure and then purified by column chromatography (CC) using 5-10% ethylacetate in hexane to give the desired anhydride product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: tribenzylamine With iodine; triphenylphosphine In dichloromethane at 0℃; for 0.166667h; Stage #2: 2-chloro-5-nitrobenzoic acid In dichloromethane at 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: thionyl chloride; N,N-dimethyl-formamide / ethyl acetate / 6 h / 60 - 65 °C / Inert atmosphere; Large scale 2: magnesium chloride; triethylamine / ethyl acetate / 45 - 70 °C / Inert atmosphere; Large scale 3: hydrogenchloride; water / ethyl acetate / 70 °C / Inert atmosphere; Large scale 4: sulfuric acid; acetic acid / water / 3 h / 95 - 105 °C / Inert atmosphere; Large scale 5: acetic acid; ammonium acetate / 6 h / 110 - 115 °C / Inert atmosphere; Large scale 6: acetic acid; hydrogen; 1 % platinum and 2% vanadium on carbon / water; methanol / 3 h / 50 - 55 °C / 3750.38 Torr / Large scale |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V); triethylamine In N,N-dimethyl-formamide at 20℃; | 2-Chloro-N′-(p-tolyl)benzohydrazide (1b); Typical Procedure General procedure: To a solution of p-tolylhydrazine hydrochloride (0.79 g, 5 mmol), 2-chlorobenzoic acid (0.78 g, 5 mmol), and HCTU (2.28 g, 5.5 mmol) in DMF (10.0 mL), Et3N (2.08 mL, 15 mmol) was added. The mixture was stirred at r.t. overnight. Then the mixture was washed with sat. aq NH4Cl, aq NaHCO3, and brine. The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc,5:1) to give 1b (0.78 g, 60%) as a white solid; mp 161.3-162.4 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With trichlorophosphate at 120℃; for 1h; Sealed tube; | 29 Example 202,6-dimethoxy-benzoic acid was synthesized and DMF N, N- dimethyl-2,6-dimethoxy-benzamide: Equipped with magnetic sub 20mL reaction flask was added 2,6-dimethoxy-benzoic acid (0.055 g, 0.3 mmol), of POCl3(lequiv), of DMF (2mL), tighten the cap, an external temperature of 120 sealed reactor IH; complete reaction was monitored by gas chromatography; after the reaction solutionwas cooled, to which was added 10mL of saturated of Na2CO.3aqueous solution, extracted with ethyl acetate (3 × 10mL), the combined organic phase was dried over anhydrousmagnesium sulfate, and solvent was removed by rotary evaporation , by column chromatography: after separation (ethyl acetate n-hexane = 1/1) to give a pale yellow solid,yield 79% |
88% | With trichlorophosphate at 120℃; for 1h; | General procedure General procedure: Carboxylic acids (0.3 mmol), POCl3(1equiv.) and N-substituted formamides (2 mL) were mixed in a 20 mL tube. Tighten the cap and the mixture was stirred at 120 °C for 1h. The mixture was cooled to room temperature, and Na2CO3 saturated solution (10 mL) was added. Then the solution was extracted with ethyl acetate (3×10 mL), combined the organic layers and dried with anhydrous MgSO4 over night. The solution was evaporated under reduced pressure and the crude product was purified by column chromatography (silica gel, n-hexane-EtOAc, 1:1). |
35% | With dipotassium peroxodisulfate; (p-cymene)ruthenium(II) chloride; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene at 160℃; for 24h; | 13 General procedure for the synthesis of 3 and 4 General procedure: Carboxylic acids (0.3 mmol), catalyst (5 mol %), Xantphos (10 mol %), K2S2O8 (2 equiv) and N-substituted formamides (2 mL) were mixed in a 20 mL tube. Tighten the cap and the mixture was stirred at 160°C for 12 h or more until the reaction was finished. The mixture was filtered and the solution was evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, n-hexane-EtOAc,1:1). |
35% | With potassium thiosulfate; [RhCl2(p-cymene)]2; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene at 160℃; for 24h; Inert atmosphere; Sealed tube; | 13 Example 13 2-chloro-5-nitrobenzamide (3m) was synthesized from 2-chloro-5-nitrobenzoic acid (1m) and DMF (2a): In a 20 mL reaction flask equipped with a magnet, 2-chloro-5-nitrobenzoic acid (0.06 g, 0.3 mmol), Xantphos (0.017 g, 0.03 mmol), K2S2O8 (0.162 g, 0.6 mmol), Ru(p-cymene)Cl2 (0.0092 g, 0.015 mmol) and DMF (2 mL) were added and charged with argon, tightened caps and sealed at ambient temperature of 160 °C for 24 h; The reaction was complete and the reaction was filtered. The solvent was removed by rotary evaporation and separated by column chromatography (ethyl acetate: n-hexane = 1: 1) to give 3m as a white solid in 35% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In tetrahydrofuran at 20℃; for 5h; Inert atmosphere; | 1.1 pear shaped flask in 50mL 2.98mmol compound -i-12.98mmol o-phenylenediamine (compound -1), 3.28mmol HBTU, under 5.96mmol triethylamine and 20mLTHF, nitrogen at room temperature for 5h, The reaction solution was added 40mL of water, CH 2 Cl 2 and extracted three times with 30mL, and the combined organic phases, 30 mL water Washing, 30 mL brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to give the crude product, the crude product was purified on silica gel column, The mobile phase petroleum ether: ethyl acetate: triethylamine = 1: 1: 0.005, to give the product 714 mg, 82% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 18h; | 85 Example 85: Preparation of tert-butyl-N-((tert-butoxyl)carbonyl)-N-(5-(5-amino-2-chlorobenzamido)-2,4-difluorophenyl)carbamate (C361 ) To a vial containing ieri-butyl-N-((ieri-butoxy)carbonyl)-N-(5-amino-2,4-difluorophenyl)carbamate (C398) (0.4 g, 1.16 mmol) were added 2-chloro-5-nitrobenzoic acid (0.23 g, 1.16 mmol), 4-dimethylaminopyridine (0.15 g, 1.28 mmol), 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.33 g, 1.74 mmol), and dichloromethane (6 mL) . The reaction mixture was stirred at room temperature for 18 h then was directly loaded onto a prepacked C elite* cartridge and flushed through a silica gel column with ethyl acetate/hexanes. The resulting yellow foam was dissolved in ethyl acetate (2 mL) and 10% palladium on carbon ( 10 mg, 0.009 mmol) was added. The slurry was stirred under an atmosphere of hydrogen gas (balloon) for 7 hours. The slurry was filtered through a pad of Celite8 with ethyl acetate and concentrated . Purification by flash column chromatography gave the title compound as a white foam (0.1479 g, 25%) : NM R (400 MHz, DMSO-de) δ 10.27 (s, 1H), 7.67 (t, J = 8.1 Hz, 1 H), 7.50 (t, J = 10.1 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.73 (d, J = 2.7 Hz, 1H), 6.65 (dd, J = 8.6, 2.7 Hz, 1 H), 5.48 (s, 2H ), 1.40 (s, 18H); I9F NM R (376 MHz, DMSO-de) δ - 117.30 (d, J = 6.4 Hz), - 122.18 (d, J = 6.4 Hz) ; ESIMS m/z 495.6 [(M-H)"]. |
25% | Stage #1: 2-chloro-5-nitrobenzoic acid; tert-butyl N-((tert-butoxy)carbonyl)-N-(5-amino-2,4-difluorophenyl)carbamate With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In dichloromethane at 20 - 24℃; for 18h; Stage #2: With palladium on activated charcoal; hydrogen In ethyl acetate for 7h; | 59 Preparation of tert-butyl-N-((tert-butoxyl)carbonyl)-N-(5-(5-amino-2-chlorobenzamido)-2,4-difluorophenyl)carbamate (C137) Example 59 Preparation of tert-butyl-N-((tert-butoxyl)carbonyl)-N-(5-(5-amino-2-chlorobenzamido)-2,4-difluorophenyl)carbamate (C137) To a vial containing tert-butyl-N-((tert-butoxy)carbonyl)-N-(5-amino-2,4-difluorophenyl)carbamate (C183) (0.4 g, 1.16 mmol) were added 2-chloro-5-nitrobenzoic acid (0.23 g, 1.16 mmol), 4-dimethylaminopyridine (0.15 g, 1.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.33 g, 1.74 mmol), and dichloromethane (6 mL). The reaction mixture was stirred at room temperature for 18 h then was directly loaded onto a prepacked Celite cartridge and flushed through a silica gel column with ethyl acetate/hexanes. The resulting yellow foam was dissolved in ethyl acetate (2 mL) and 10% palladium on carbon (10 mg, 0.009 mmol) was added. The slurry was stirred under an atmosphere of hydrogen gas (balloon) for 7 hours. The slurry was filtered through a pad of Celite with ethyl acetate and concentrated. Purification by flash column chromatography gave the title compound as a white foam (0.1479 g, 25%): 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.67 (t, J=8.1 Hz, 1H), 7.50 (t, J=10.1 Hz, 1H), 7.12 (d, J=8.6 Hz, 1H), 6.73 (d, J=2.7 Hz, 1H), 6.65 (dd, J=8.6, 2.7 Hz, 1H), 5.48 (s, 2H), 1.40 (s, 18H); 19F NMR (376 MHz, DMSO-d6) δ -117.30 (d, J=6.4 Hz), -122.18 (d, J=6.4 Hz); ESIMS m/z 495.6 [(M-H]-). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1,2-dichloro-ethane at 20℃; for 20h; | 28 Example 28: Preparation of 2-chloro-N-(4-fluorophenyl)-5-nitrobenzamide (C143) XI 2-chloro-5-nitrobenzoic acid (0.250 g, 1.24 mmol) and 4-dimethylaminopyridine (0.197 g, 1.61 mmol) were sequentially added to a stirred mixture of 4-fluoroaniline (0.141 ml, 1.49 mmol) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.357 g, 1.86 mmol) in 1,2-dichloroethane (12.4 mL) at room temperature. The reaction was stirred at room temperature for 20 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate followed by hydrochloric acid (1 N) to provide the title compound as a light brown solid (0.188 g, 49%): H NMR (400 MHz, CDCb) δ 8.59 (d, J = 2.7 Hz, 1H), 8.26 (dd, J = 8.8, 2.8 Hz, 1H), 7.90 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.15 - 7.05 (m, 2H); 19F NMR (376 MHz, CDCb) δ -116.03; ESIMS m/z 295 ([M + H]+). |
49% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1,2-dichloro-ethane at 20 - 24℃; for 20h; | 64 Preparation of 2-chloro-N-(4-fluorophenyl)-5-nitrobenzamide (C150) Example 64 Preparation of 2-chloro-N-(4-fluorophenyl)-5-nitrobenzamide (C150) 2-Chloro-5-nitrobenzoic acid (0.250 g, 1.24 mmol) and 4-dimethylaminopyridine (0.197 g, 1.61 mmol) were sequentially added to a stirred mixture of 4-fluoroaniline (0.141 mL, 1.49 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.357 g, 1.86 mmol) in 1,2-dichloroethane (12.4 mL) at room temperature. The reaction was stirred at room temperature for 20 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate followed by hydrochloric acid (1 N) to provide the title compound as a light brown solid (0.188 g, 49%): 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=2.7 Hz, 1H), 8.26 (dd, J=8.8, 2.8 Hz, 1H), 7.90 (s, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.64-7.57 (m, 2H), 7.15-7.05 (m, 2H); 19F NMR (376 MHz, CDCl3) δ -116.03; ESIMS m/z 295 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: 2-chloro-5-nitrobenzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; Stage #2: 4-aminopyridine With triethylamine In dichloromethane at 20℃; for 16h; | 30 Example 30: Preparation of 2-chloro-5-nitro-N-(pyridin-4-yl)benzamide (C185) To a solution of 2-chloro-5-nitrobenzoic acid (0.500 g, 2.48 mmol) in dichloromethane (8.3 mL) was added oxalyl chloride (0.239 mL, 2.73 mmol) slowly, followed by /V,N-dimethylformamide ( 1 drop). The reaction was stirred at room temperature for 2 hours. To the solution was added triethylamine (0.691 mL, 4.96 mmol) followed by pyridin-4-amine (0.467 g, 4.96 mmol) in dichloromethane ( 1 mL). The reaction was allowed to stir at room temperature for 16 hours. Purification by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent provided the title compound as a tan solid (0.401 g, 58%) : ' H NMR (400 MHz, DMSO-de) δ 11.10 (s, 1H), 8.64 - 8.45 (m, 3H), 8.37 (dd, J = 8.9, 2.8 Hz, 1 H), 7.92 (d, J = 8.8 Hz, 1H), 7.73 - 7.61 (m, 2H) ; 13C NMR ( 101 MHz, DMSO-de) δ 163.67, 150.56, 146.14, 145.04, 136.95, 131.40, 126.06, 124.00, 113.68 ; ESIMS m/z 278 ( [M + H ]+ ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In ethyl acetate at 20℃; for 16h; | 81 Example 81: Preparation of 2-chloro-N-(3,5-difluoropyridin-2-yl)-5-nitrobenzamide (C350) To a solution of 2-chloro-5-nitrobenzoic acid (2.00 g, 9.92 mmol) and 3,5-difluoropyridin-2-amine ( 1.29 g, 9.92 mmol) in ethyl acetate (50 ml_) were added sequentially pyridine ( 1.6 mL, 19.9 mmol) and 2,4,6-tripropyl-l,3, 5,2,4,6- trioxatriphosphina ne 2,4,6-trioxide (T3P,R ) as a 50% solution in ethyl acetate (9.47 g, 14.88 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was the washed with aqueous hydrochloric acid ( 1 N ), saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in ethyl acetate, and Celite" was added to the solution. The solvent was removed under vacuum. Purification by flash column chromatography using 0-30% ethyl acetate/hexanes as eluent afforded the title compound as a white solid ( 1.97 g, 63%) : NM R (400 MHz, DMSO-c/e) δ 11.20 (s, 1H), 8.51 - 8.28 (m, 3H), 8. 12 (ddd, J = 10.7, 8.6, 2.6 Hz, 1H), 7.90 (d, J = 8.7 Hz, 1 H) ; 19F NM R (376 MHz, DMSO-de) δ - 117.71, - 126.11 ; ESIMS m/z 314 ( [M + H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With tin(II) chloride dihdyrate In water at 55℃; for 2.5h; Green chemistry; | General procedure for tin(II) chloride-mediated reductive cyclization General procedure: To a mixture of the methyl o-nitrobenzoate (0.53 g, 2.00 mmol) and 2,5-dimethoxytetrahydrofuran (0.39 mL, 3.0 mmol) in H2O (5 mL) was added tin(II) chloride dihydrate (1.35 g, 6.0 mmol). The reaction mixture was heated to 55°C for 2.5 h. Upon cooling, the reaction mixture was dissolved in EtOAc and quenched with saturated aq.NaHCO3. The resulting emulsion was filtered through a pad of Celite, and rinsed well with EtOAc. The remaining aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhyd. Na2SO4 and concentrated. The residue was purified by silica-gel column chromatography (10-25% EtOAc/hexane) to affort a white solid (0.5 g, 88%). |
82% | With tin(II) chloride dihdyrate In water at 55℃; for 0.5h; | 1-(2,4-Dichlorophenyl)-1H-pyrrole (2a): General procedure: To a mixtureof 2,4-dichloro nitrobenzene (1 g, 5.20 mmol) in H 2 O (10 mL)was added SnCl 2 ·2H 2 O (3.51 g, 15.62 mmol) at room tempe-rature and heated to 55 C for 30 min. After completion of thereaction (monitored by TLC), basified the reaction mixtureslowly with saturated aqueous NaHCO 3 at 0 °C and compoundwas extracted with ethyl acetate (2 × 30 mL). The combinedorganic phase was washed with brine (1 × 15 mL), dried overanhydrous Na 2 SO 4 , removed solvent in vacuo and the cruderesidue was purified by column chromatography on silica gel(ethylacetate:hexane, 2:8) to afford compound 2a (0.93 g, 85% yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With di-tert-butyl peroxide; copper(I) bromide; In ethyl acetate; at 120℃; | General procedure: Benzoic acid (1.0 mml), tetramethylthiuram disulfide (TMTD) (1.1 mmol), CuBr (10% mmol), DTBP (di-tert-butyl peroxide, 2.0 equiv) were added in dried seal tube equipped with a septum and magnetic stirrer bar, EtOAc (ethyl acetate, 2 mL) was then added. The mixture was stirred at 120 oC and checked by TLC until the starting material was finished (about 10-12 h). The reaction was cooled down to room temperature, quenched with sat. NH4Cl solution (5 mL) and then extracted with ethyl acetate (10 mml). The crude solution was dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by flash column chromatography to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sulfuric acid In water at 65 - 95℃; for 3h; | 1 Take the mass fraction of 96% concentrated sulfuric acid, add water to adjust the acid concentration to 85wt%. The temperature of the acid was adjusted to about 65 °C and the purified 2-chloro-5-nitrobenzotrichloride started to be added portionwise. The temperature was then adjusted to 95 °C, noting the gradual formation of solid product dispersed in the mixture. The temperature is maintained for about 3 hours and then the reaction mixture is cooled to about 50 °C and diluted with additional water. The product is extracted with ethyl acetate at room temperature. The phases are separated and the organic phase is washed with water. Finally, the solvent was evaporated to give 2-chloro-5-nitrobenzoic acid (HPLC titer = 98.7%, molar yield 95%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20 - 24℃; for 16h; | 102 Preparation of 2-chloro-N-(2,2-difluoropropyl)-5-nitrobenzamide (C386) Example 102 Preparation of 2-chloro-N-(2,2-difluoropropyl)-5-nitrobenzamide (C386) To a solution of 2-chloro-5-nitrobenzoic acid (0.7 g, 3.5 mmol) in dichloromethane (10 mL) were added sequentially 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU; 4.0 g, 10.4 mmol), diisopropylethylamine (3 mL, 17.36 mmol) and 2,2-difluoropropan-1-amine (0.5 g, 3.8 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and was extracted with dichloromethane (2*20 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (silica gel 100-200 mesh) eluting with 40-50% ethyl acetate in petroleum ether afforded the title compound as an off-white solid (0.9 g, 93%): 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J=2.4 Hz, 1H), 8.24 (dd, J=2.4, 8.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 6.46-6.41 (m, 1H), 3.94-3.86 (m, 2H), 1.73 (t, J=18.8 Hz, 3H); ESIMS m/z 279.12 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 2h; | 16.1 Step-1 : Preparation of methy -chloro-5-nitrobenzoate To a solution of 2-chloro-5-nitrobenzoic acid ( 10 g, 49.6 mmol) in N,N-dimethylformamide ( 100 mL), potassium carbonate ( 1 3.7 g, 99 mmol) was added at room temperature. The suspension was cooled to 0 °C and methyl iodide ( 14 g, 99 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was di luted with cold water and extracted witli ethyl acetate (3X300 mL). The combined organic layers were washed with water (2X 100 mL), brine solution ( 100 mL), dried over anhydrous sodium sulphate. The organic solvent was removed under reduced pressure to afford methyl 2-chloro-5-nitrobenzoate (8.5 g, 79 %) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 1H-imidazole; copper ammonium sulphate hexahydrate; lithium tert-butoxide In N,N-dimethyl-formamide; isopropyl alcohol for 72h; Irradiation; | 5.1; 5.2; 5.3 Example 5 Hydrodechlorination of 2-chloro-5-nitrobenzoic acid Step 1: Weigh out 101 mg (0.5 mmol) of 2-chloro-5-nitrobenzoic acid, respectively.Imidazole 34 mg (0.5 mmol), copper ammonium sulphate (hexahydrate) 24 mg (12 mmol%),Rose red 11mg (2mmol%),Lithium tert-butoxide lithium t-BuOli 72 mg (0.9 mmol) was placed in a quartz reaction tube.1.5 ml of each of isopropyl alcohol and DMF was added as a solvent.Step 2: The quartz reaction tube was exposed to ultraviolet light at 254 nm under air for 72 hours. The reaction formula is as follows:Step 3: The product was isolated by column chromatography after completion of the reaction, yield 89%. The resulting product was 5-nitrobenzoic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: 2-chloro-5-nitrobenzoic acid With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 0℃; for 0.25h; Stage #2: N,O-dimethylhydroxylamine*hydrochloride With triethylamine In dichloromethane at 20℃; for 1h; chemoselective reaction; | General procedure for the synthesis of Weinreb amides General procedure: A. To a mixture of benzoic acid (50 mg, 0.41 mmol, 1 equiv), PPh3 (160 mg, 0.61 mmol, 1.5 equiv) and NBS (108.5 mg, 0.61 mmol, 1.5 equiv), CH2Cl2 (2 ml) was added and the reaction was stirred at 0 °C for 15 min. The reaction was brought to room temperature and N,O-dimethylhydroxylamine hydrochloride (59.5 mg, 0.61 mmol, 1.5 equiv) and Et3N (45.5 mg, 63 µl, 0.45 mmol, 1.1 equiv) were added and reaction was stirred for 1 h at room temperature. The reaction mixture was quenched with aqueous sodium bicarbonate solution and diluted with CH2Cl2. The bicarbonate washings were again extracted with CH2Cl2 and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Column chromatography was performed using EtOAc/Petroleum ether (1:5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46.3% | Stage #1: 2-chloro-5-nitrobenzoic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.5h; Stage #2: 2-ethyl-8-(hydroxymethyl)-7-methoxy-4H-chromen-4-one In dichloromethane at 20℃; | 4.9. General procedure for the synthesis of compounds 6a-w, 7a-fand 8a-e General procedure: The corresponding aromatic acids (1.2 eq) and EDCI (1.2 eq)were dissolved and stirred in CH2Cl2 (10 mL) in an ice bath for30 min, and then the corresponding alcohol 5a-c (1.0 eq)was addedto the reaction solution. The reaction mixturewas removed to roomtemperature and monitored by TLC. After reaction completion,15 mL of water were added to the mixture solution. The organiclayers were washed with saturated sodium chloride solution(2 15 mL) and dried over anhydrous sodium sulfate. Then, thesolvent was removed under reduced pressure, and the residue waspurified by column chromatography to yield 6a-w, 7a-f and 8a-e. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.5% | With sodium hydroxide In methanol at 25℃; for 0.5h; | 2.3.2. Synthesis of copper II complex [Cu(ambt)2(cnbz)2] The 2-amino-6-methoxybenzothiazole (ambt, 0.30 mmol) and 2-chloro-5-nitrobenzoic acid (cnbz, 0.90 mmol) were dissolved in 5.0mL of absolute methanol and a solution of cupric nitrate trihydrate(0.18 mmol) in absolute methanol (10.0 mL) was added dropwise to themixture. Sodium hydroxide (NaOH) solution (1.0 M 1) was used tostandardize the pH to 6 and stirred at 25 for 30 min. After 20 days,well-formed brown crystals suitable for single-crystal XRD werecollected. The final yield was 68.5%. The calculated values forC30H22Cl2CuN6O10S2 (MW = 825.11) were 43.67% C; 2.69% H, and10.19 % N, while the measured values for C30H22Cl2CuN6O10S2 were43.15% C, 2.59% H, and 10.51 % N. The IR (cm 1) data are v(=CH)3,409, v(=NH) 2,918 and 2,849, v(C = C) 1,612 and 1,546, v(N = O)1,473, v(C-N) 1,343 and 1,280, and v(C-N-C) 1,061 and 719. |
Tags: 2516-96-3 synthesis path| 2516-96-3 SDS| 2516-96-3 COA| 2516-96-3 purity| 2516-96-3 application| 2516-96-3 NMR| 2516-96-3 COA| 2516-96-3 structure
[ 55775-97-8 ]
2,6-Dichloro-3-nitrobenzoic acid
Similarity: 0.87
[ 55775-97-8 ]
2,6-Dichloro-3-nitrobenzoic acid
Similarity: 0.87
[ 55775-97-8 ]
2,6-Dichloro-3-nitrobenzoic acid
Similarity: 0.87
[ 55775-97-8 ]
2,6-Dichloro-3-nitrobenzoic acid
Similarity: 0.87
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