* 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.
Reference：
[1] Journal of Agricultural and Food Chemistry, 2013, vol. 61, # 3, p. 517 - 522
[2] Organic and Biomolecular Chemistry, 2014, vol. 12, # 28, p. 5082 - 5088
[3] Patent: WO2014/125410, 2014, A1,
[4] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 9, p. 1615 - 1620
13
[ 109-01-3 ]
[ 62-23-7 ]
[ 21091-98-5 ]
Yield
Reaction Conditions
Operation in experiment
95%
With ethylene dichloride hydrochloride; benzotriazol-1-ol; triethylamine In N,N-dimethyl-formamide at 20℃; for 12 h;
Step 1: (4-Methyl-piperazin-l-yl)-( -nitro-phenyl)-methanoneTo a solution of 4-nitro-benzoic acid (10 g, 0.0598 mol) in DMF (300 mL) 1- methyl-piperazine (7.19 g, 0.0718 mol), HOBt (10.5 g, 0.0777 mol), EDC-HCl (17.12 g, 0.0897 mol) and TEA (12.1 g, 0.1 196 mol) were added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 200 mL). The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford the title compound [14 g, 95percent]; LC-MS (ESI): Calculated mass: 249.1; Observed mass: 250.0 [M+H]+ (RT: 0.10 min).
80%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃;
To a solution of 4-nitrobenzoicacid (1.0 g, 5.98 mmol), 1-methylpiperazine (0.599 g, 5.98 mmol) and DIPEA (2.320 g,17.95 mmol) in DMF (10 mL) was added HATU (4.55 g, 11.97 mmol). The reaction wasstirred overnight at room temperature. The mixture was quenched with water andextracted with a mix solvent of DCM and MeOH (10:1, 20 mL×3). The combinedextracts were dried over Na2SO4, filtered and concentrated. The crude was purified bycolumn chromatography on silica gel (DCM: MeOH= 20:1) to give the title compound 3a(1.2 g, 80 percent yield). LCMS: 250.1 [M+H]+.
59%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃;
Step: 3A-lSynthesis of (4-Methyl-piperazin-l-yl)-(4-nitro-phenyl)-methanone. Procedure:To a solution of 4-Nitro-benzoic acid (500mg, 2.9918mmol) in THF was added EDCI (856mg, 4.4865mmol), followed by HOBt (200mg, 2.9918mmol), DIPEA (1.5ml,8.9754mmol) and 1 -Methyl -piperazine (329mg, 3.291mmol) at 0°C. The resultant was stirred overnight. The reaction was monitored by the TLC (10percent methanol: chloroform).The reaction mixture was extracted with ethyl acetate and washed with water. The organic layer was concentrated and dried over Na2S04 to afford 440mg (59percent yield) of (4- Methy 1-piperazin- 1 -yl)-(4-nitro-phenyl)-methanone.
4-nitro-benzoic acid 1-[2-(2-acetylamino-3-hydroxy-butyrylamino)-3-(4-hydroxy-phenyl)-propionyl]-5-(1,2-dicarbamoyl-ethylcarbamoyl)-pyrrolidin-3-yl ester[ No CAS ]
4-Morpholin-4-ylmethyl-phenylamine is prepared from 4-Nitro-benzoic acid by the following method: A room temperature solution of 2.49 gms. 4-nitro-benzoic acid in tetrahydrofuran (15 mL) is treated with 2.44 gms. 1',1'-carbonyl-diimidizole, and immediately immersed in an ice bath. The reaction mixture is stirred in the ice bath for 30 minutes then it is allowed to warm to room temperature. Once at room temperature the reaction mixture is treated with 1.5 mL piperidine. The reaction mixture is allowed to stir at room temperature overnight. The reaction is then made basic with the addition of saturated aqueous sodium bicarbonate solution, and the resulting mixture is extracted with ethyl acetate. The organics are separated, dried over anhydrous sodium sulfate and subsequently evaporated to dryness in vacuo. The crude product residue is then chromatographed by flash silica gel chromatography using 50% ethyl acetate in hexanes as the eluant.
To a solution of Compound 10 (0.70 g, 3.48 mmol) and PPh3 (1.37 g, 5.22 mmol) in CH2Cl2 (7 mL) was added DEAD (0.91 mL, 5.22 mmol) at 4 C. [Zhao et al., Eur. J. Med. Chem. 2005, 40, 231]. The resulting mixture was stirred for 10 min and then 4-nitrobenzoic acid (1.62 g, 5.22 mmol) was added. This mixture was allowed to warm up to room temperature and stirred for 16 hours. The reaction mixture was quenched with 2 N NaOH solution and extracted with AcOEt. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography to give Compound 15 (0.885 g, 73%) as a pale yellow solid. Compound 15: 1H NMR (400 MHz, CDCl3): delta 1.38 (d, J=0.4 Hz, 3H), 1.48 (s, 9H), 1.96 (d, J=14.4 Hz, 1H), 2.47 (m, 1H), 3.64-3.83 (m, 2H), 4.11 (m, 1H), 5.55 (m, 1H), 8.21 (d, J=8.0 Hz, 2H), 8.31 (d, J=8.0 Hz, 2H).
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;
(R)-(+)-3-Hydroxy-2-pyrrolidinoneTo a stirring mixture of 4-Nitrobenzoic acid (21.5 g) and (S)-(-)-3-hydroxy-2-pyrrolidinone (11.8 g) (Intermediate 17) in dry THF (360 mL) taken in a round bottomed flask fitted with anhydrous CaCl2 guard tube, triphenyl phosphine (61.2 g) was added.To this reaction mixture, diisopropyl diazodicarboxylate (DIAD) (34 mL) was added drop wise in three portions at room temperature.The reaction was stirred at room temperature.The progress of the reaction was monitored by TLC (developing agents: UV, I2, as well as aqueous acidic KMnO4).After completion, reaction mixture was concentrated under vacuum to obtain residue.Methanol (360 mL) was added to the residue followed by potassium carbonate (10 g) at room temperature.The reaction was stirred at room temperature.The progress of the reaction was monitored by TLC (developing agents: UV, I2, as well as aqueous acidic KMnO4).After completion, reaction mixture was diluted with CHCl3 and filtered through celite.Celite bed was successively washed with 1percent MeOH:CHCl3.The filtrates were combined and concentrated to dryness to remove solvents.The residues were partitioned between EtOAc: dil. HCl (200 mL, 9:1) and stirred for 15 min.Layers were separated, aq.layer was washed with EtOAc thrice until all organic impurities were washed out.The aq.Layer was concentrated to dryness to remove the water and solid residues were obtained.The residues obtained were washed with 1-2percent MeOH: CHCl3 (3*100 mL), dried over sodium sulfate, filtered trough cotton, concentrated to get brown thick liquid product.1H NMR (CDCl3, 400 MHz) delta ppm: 2.03-2.13 (m, 1H), 2.46-2.54 (m, 1H), 3.28-3.35 (m, 1H), 3.38-3.48 (m, 1H), 4.50 (t, J=8.4 Hz, 1H), 4.55 (bs, 1H), 7.02 (bs, 1H); [alpha]D25: +68, c=1, CHCl3
General procedure: At room temperature, organic carbonyl acid 3 (R-COOH, 0.5 mmol) was added into a reaction tube equipped with a small magnet. Then a solution of tertiary amine 1 (R1CH2-NR2R3, 0.5 mmol ) in DCM (2.5 mL) was added dropwise in 2 min. After the mixture was stirred at room temperature for a few minutes, 1 equivalents of dimethyl acetylenedicarboxylate (DMAD, 2) was added. The reaction was stirred overnight at room temperature, and then monitored by TLC with silica gel coated plates. After being stirred for 14 h, the solvent was removed and the residue was purified by a flash column chromatography with silica gel with ethyl acetate/hexane (1:25-30) as eluent to give the desired products 4, 5, and 7. Most of compounds are known and confirmed by NMR, ESI-MS, IR.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 25℃; for 16h;
Step B - Synthesis of Intermediate Compound 6c To a solution of compound 6b (4.1 mg, 19.04 mmol), 4-nitrobenzoic acid (3.82 g, 22.85 mmol), and PPh3 (9.9g, 38.1 mmol) in THF (60 ml) was added DEAD (6.03 mL, 38.1 mmol) at 0C. The reaction mixture was then stirred at 25C for 16 h, quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was washed with water (100 mL x 2), dried over Na2S04, and concentrated in vacuo. The residue was purified using column chromatography (Si02, Petroleum ether: EtOAc = 10: 1 to 5: 1) to provide compound 6c (1.3 g, 81% yield) as a white solid.
Synthesis of compound 221.4. To a solution of p-nitro benzoic acid (0.500g, 3.62mmol, l .Oeq) in DMF (10 mL) was added HATU (2.06g, 5.43 mmol, 1.5eq.). The reaction was allowed to stir at room temperature for 15 minutes. Further <strong>[3970-68-1]4-methylpiperidin-4-ol</strong> (0.500g, 4.34mmol, 1.2eq.) and DIPEA (1.402g, 10.86mmol, 3.0eq.) were added to the reaction mixture at room temperature and the reaction was allowed to stir for 2h. After completion of the reaction, reaction mixture was poured in water and product was extracted with EtOAc. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by flash chromatography to furnish 221.4 (0.270g, 34.15%). MS (ES): m/z 264.28 [M+H]+.
General procedure: To a solution of 2-Methylbenzoic acid (1.36 g, 10 mmol) in DCM (50 mL), Et3N (1.12 g, 11 mmol) and TBTU (3.60 g,11 mmol) were added in turn. After 20 min, compound b (n =4, 1.17 g, 5 mmol) and Et3N (0.50 g, 5 mmol) were added. The reaction solution was stirred at room temperature for 8 h.Then, the solvent was evaporated with the residue being takenup in EtOAc (50 mL). the EtOAc solution was washed with saturated citric acid (3 × 20 mL), NaHCO3 (3 × 20 mL), and brine (3 × 20 mL), dried over MgSO4, and evaporated under vacuum. The desired compound c (1.50 g, 76 percent yield) was derived by crystallization in EtOAc/petroleum ether (1/4) as white powder. ESI-MS: m/z: 397.8 [M+H]+.
dimethyl 3,3'-disulfanediylbis(2-(4-nitrobenzamido)propanoate)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃;
General procedure: A suspension of the benzoic acid (1.17 mmol) and L-cystinedimethyl ester dihydrochloride (341 mg, 0.586 mmol) in anhydrous DCM (5mL) was cooled to 0 C to which was added Et3N (179 mL, 1.28 mmol), HOBt (17 mg, 0.117 mmol), and EDCI( 181 mg, 1.17 mmol). The resulting suspension was warmed to room temperature and stirred overnight, eventually turning into a clear solution. The mixture was diluted with EtOAc (10 mL)and washed successively with HCl (1M, 10 mL), saturated NaHCO3(10 mL), and brine (10 mL). The organic phases were dried over MgSO4, filtered, and concentrated under vacuum to afford the corresponding amide.
To a 100 ml three-mouth bottle added (3R, 3aS, 6aR)-hexahydrofuro [2,3-b] furan-3-ol (2.0g, 15 . 4mmol), pyridine (10 ml), triethylamine (2.2g, 21 . 3mmol), the ice-bath is cooled to 0 C, the 10 ml pyridine and P-nitro benzoic acid (2.7g, 16 . 2mmol) was added to the mixture in three-mouth bottle, maintained the temperature in the course of dropping 0-20C, after adding, TLC detection until the raw material the reaction is complete. After the reaction, filtration, filtrate are respectively with dilute hydrochloric acid (3×20 ml), saturated sodium carbonate (20 ml), saturated salt water (20 ml) washing, the organic phase is dried with anhydrous sodium sulfate, the filtrate concentrated to dry, the white solid obtained 4.1g, column chromatography, to obtain refined product 3.96g, yield 92%.
3α-(p-nitrophenylcarbonyloxy)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18.1%
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 4 - 22℃; for 12h;
To a two neck flask was added glaterone (1, 2 g, 5.15 mmol), 0.95 g (5.66 mmol) of pnitrobenzoicacid, 1.5 g (5.66 mmol) of PPh3 and 30 mL anhydrous THF. The mixture was stirred until all solids dissolved and then cooled to 4°C in an ice-water bath. A solution of 40percent> DEAD 2.46 rnL (5.66 mmol) in anhydrous toluene was added drop wise, allowed to attain room temperature, stirred for 12 hours. The reaction mixture concentrated in vacuo and the resulting sticky residue was suspended in 5 rnL of ethyl acetate, stirred, cooled and filtered. Mother liquor collected, stirred vigorously and 30 mL of petroleum ether added slowly. Resulting sticky suspension filtered, washed with 10percent ethyl acetate in petroleum ether (25 rnL) and dried under vacuo. The sticky solid made slurry on Buckner funnel with ether (7.5 mL x 2), filtered and dried under vacuo. Free solids (0.8 g) obtained was a mixture of product 11, traces of tripheylphosphinoxide and diethyl 1,2-hydrazinedicarboxylate. The crude product dissolved in hot IPA, allowed to cool to room temperature, resulting precipitate filtered and dried under vacuo to obtain a white solid (0.5 g, 18.1percent) of pure 11, mp 193- 194°C; Rf= 0.4 (3percent acetone in DCM); FontWeight="Bold" FontSize="10" H NMR (400 MHz, CDC13) delta 1.05 (s, 3 H, 18-CH3),
(4-(methylsulfonyl)piperazin-1-yl)(4-nitrophenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50.2%
With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 48h;
To a solution of 4-nitrobenzoic acid (0.43 g, 2.56 mmol) in DMF (10 mL), methanesulfonylpiperazine (0.42 g, 2.56 mmol) was added followed by HATU (0.97 g, 2.56 mmol) , And stirred at room temperature for 48 h.The organic layer was separated and the aqueous layer was extracted with ethyl acetate (30 mL x 2). The organic layers were combined, washed with water (30 mL x 3), and then washed with saturated NaCl (50 mL), washed with water (50 mL) ) Once, anhydrous Na2SO4dry.The solvent was distilled off under reduced pressure, and the residue was subjected to direct column chromatography, eluting with EA / PE = 1/1 - 3/1 to give 0.40 g of the desired product in a yield of 50.20%.
The <strong>[202409-33-4]etoricoxib</strong> 359mg was put into a 50ml methanol,2ml purified water in a single-mouth flaskPlaced in a 50C oil bathThen add 217mg of p-nitrobenzoic acid,Stir and dissolve,Pour the reaction solution into a small high pressure reactor.Then place it in an oven at 130 degrees Celsius.Stay for 2 hours,So <strong>[202409-33-4]etoricoxib</strong> and after sufficient reaction of p-nitrobenzoic acid,Let cool at room temperature.Pour the reaction solution into a 100ml single-mouth bottle.Under ice bath conditions,Vacuum evaporation (vacuum -0.03MPa),After 4h,A lot of transparent crystals,Precipitation,filter,The filter cake is washed with cold methanol.The resulting crystals are the target salt crystals.
trans-p-nitrobenzoic acid (3-methoxycarbonylcyclobutyl) ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at -10 - 20℃; for 16h;Large scale;
<strong>[63485-50-7]cis-3-hydroxycyclobutylcarboxylic acid methyl ester</strong> (2730 g, 21.0 mol, 1.0 eq) prepared in Example 1 was dissolved in tetrahydrofuran (30 L) and cooled to -10 C.p-Nitrobenzoic acid (4178 g, 25.0 mol, 1.2 eq.), diethyl azodicarboxylate (4354 g, 25.0 mol, 1.2 eq.), triphenylphosphine (6557 g, 25.0 mol, 1.2 eq.).It was then stirred at room temperature for 16 h under nitrogen.The reaction was complete by TLC, the tetrahydrofuran was removed, and methyl t-butyl ether (20 L) was added and stirred for 0.5-1 h.Filter and filter cake was washed twice with methyl tert-butyl ether.All filtrates were collected and the filtrate was washed with saturated aqueous sodium bicarbonate.Dispense, dry and concentrate.The crude product was then beaten with a mixed solvent of ethyl acetate/petroleum ether, filtered and concentrated to give a pale yellow powder.Trans-III compound trans-p-nitrobenzoic acid (3-methoxycarbonylcyclobutyl) ester (4468 g, 16.0 mol), yield 76%, purity 95%.
cis-4-[(benzyloxy)carbonyl]amino}cyclohexyl 4-nitrobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
161 mg
With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 60℃; for 2h;
(1) Triphenylphosphine (421 mg) and di-tert-butyl azodicarboxylate (370 mg) were added to a solution of the compound (200 mg) obtained in Reference Example 19-7 and 4-nitrobenzoic acid (268 mg) in tetrahydrofuran (3 mL), and the mixture was stirred at 60C for 2 hours. To the above mixture, 6 mol/L hydrochloric acid was added, and the resultant mixture was stirred for 2 hours and then was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium hydrogen carbonate and brine, and then was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane only, to n-hexane/ethyl acetate=1:1) to give cis-4-[(benzyloxy)carbonyl]amino}cyclohexyl 4-nitrobenzoate (161 mg) as a colorless solid.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; for 8h;
Tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (248mg, 1mmol), 4-nitrobenzoic acid (167mg, 1mmol), EDCI (212mg, 1.1mmol), and catalytic quantity of 4-DAMP are added into DCM (10mL) and the mixture were stirred for 8h. The reaction mixture was diluted with DCM and filtered using Celite, then evaporated. Starting with the residue which was not purified, Tert-butyl 6-(4-(vinylsulfonamido)benzamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate (DC-TEADin07-1) was obtained as a white solid by using general synthesis procedure 1b and 2b (yield 45%). 1H NMR (400MHz, Methanol-d4) delta 7.87 (d, J=8.9Hz, 2H), 7.55-7.41 (m, 2H), 7.28 (d, J=8.9Hz, 2H), 7.11 (d, J=8.5Hz, 1H), 6.71 (dd, J=16.5, 10.0Hz, 1H), 6.24 (d, J=16.5Hz, 1H), 6.01 (d, J=9.9Hz, 1H), 5.48 (s, 2H), 4.53 (s, 2H), 3.63 (t, J=5.9Hz, 2H), 2.83 (t, J=5.9Hz, 2H), 1.49 (s, 9H).
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;
General procedure: A mixture of 2 or 3 (0.50 mmol), the corresponding acids RCOOH (0.60 mmol),DCC (0.60 mmol), DMAP (0.1 mmol) in dry dichloromethane (15 mL) was stirred atroom temperature. When the reaction was completed, and checked by TLC, the mixturewas filtered to remove urea from the reaction, and the filtrate was diluted bydichloromethane (45 mL). Subsequently, the diluted organic phase was washed bysaturated aqueous NaHCO3 (30 mL), and brine (30 mL), dried over anhydrousNa2SO4, concentrated in vacuo, and purified by CC to give the pure 9R/S-acyloxyderivatives of cinchonidine and cinchonine 5a-j,l-o and 6a,c,e-o [17-19]. The dataof target compounds are shown as follows.
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