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CAS No. : | 22071-15-4 | MDL No. : | MFCD00055790 |
Formula : | C16H14O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DKYWVDODHFEZIM-UHFFFAOYSA-N |
M.W : | 254.28 | Pubchem ID : | 3825 |
Synonyms : |
RP-19583;2-(3-benzoylphenyl)Propionic Acid;(R,S)-Ketoprofen;(±)-Ketoprofen
|
Num. heavy atoms : | 19 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 72.67 |
TPSA : | 54.37 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.64 cm/s |
Log Po/w (iLOGP) : | 1.91 |
Log Po/w (XLOGP3) : | 3.12 |
Log Po/w (WLOGP) : | 3.11 |
Log Po/w (MLOGP) : | 2.69 |
Log Po/w (SILICOS-IT) : | 3.37 |
Consensus Log Po/w : | 2.84 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -3.59 |
Solubility : | 0.066 mg/ml ; 0.00026 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.93 |
Solubility : | 0.0298 mg/ml ; 0.000117 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.68 |
Solubility : | 0.00535 mg/ml ; 0.000021 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.57 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P261-P301+P310-P305+P351+P338 | UN#: | 2811 |
Hazard Statements: | H301-H315-H319-H335 | Packing Group: | Ⅲ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sulfuric acid at 50℃; for 8h; Reflux; | 4.1 4.1. Synthesis of the intermediary methyl 2- (3-benzoylphenyl) propanoate In a 250 mL flask connected to a reflux condenser there were added 0.5 g (1.96 mmol) of ketoprofen, 50 mL of methanol and 2 drops of concentrated sulfuric acid. The reaction is kept under heating at 50° C and stirring for 8 hours until reaching thin layer chromatography indicated the completion of the reaction (Mobile phase: 70% hexane; 30% ethyl acetate). The product was obtained by removing the solvent at reduced pressure at room temperature to provide 0.527 g of a white color solid. (C17H16O3; MW=268,11; yield: 100%). The NMR H1 spectrum (400MHz, DMSOd) was as follows: δ 1.48 (d; 3H); 3.65 (s; 3H); 3.98 (q; 1H); 7.52-7.59 (3H); 7.63-7.71 (3H); 7.76-7.81 (3H) ppm. |
100% | With sulfuric acid at 50℃; for 8h; | 4.1 In a 250 mL flask connected to a reflux condenser there were added 0.5 g (1.96 mmol) of ketoprofen, 50 mL of methanol and 2 drops of concentrated sulfuric acid. The reaction is kept under heating at 50° C. and stirring for 8 hours until reaching thin layer chromatography indicated the completion of the reaction (Mobile phase: 70% hexane; 30% ethyl acetate).The product was obtained by removing the solvent at reduced pressure at room temperature to provide 0.527 g of a white color solid. (C17H16O3; MW=268,11; yield: 100%).The NMR H1 spectrum (400 MHz, DMSOd) was as follows: δ 1.48 (d; 3H); 3.65 (s; 3H); 3.98 (q; 1H); 7.52-7.59 (3H); 7.63-7.71 (3H); 7.76-7.81 (3H) ppm. |
99% | With sulfuric acid In acetonitrile at 80 - 85℃; |
98% | Stage #1: methanol; ketoprofen With dmap In dichloromethane at 0℃; for 0.0833333h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 3.08333h; | |
98.6% | With hydrogenchloride In water at 5 - 20℃; | Ketoprofen (50g) was added to methanol (200mL) at room temperature and stirred until dissolved. The solution was cooled to about 5-10°C. HCl gas was passed through the solution to yield about a 23g increase in reaction mass. The solution was warmed to room temperature while stirring. The solution was then cooled to about 0-5 °C. Chilled water (200mL) was added dropwise while maintaining a reaction temperature of about 0-20 °C. The solution was then stirred at room temperature for about 30 minutes. The solids were filtered and washed with water. The solids were dried under vacuum at about 40°C to yield about 52g of ketoprofen methyl ester (98.6%). |
96% | With sulfuric acid Heating; | |
96% | With sulfuric acid In chloroform Reflux; | |
94.6% | With sulfuric acid for 3h; Heating; | |
91% | With tert.-butylnitrite at 40℃; for 48h; Green chemistry; | |
86% | With tert.-butylnitrite at 40℃; for 48h; | 5 Add drug molecule 1d (Ketoprofen) (0.5 mmol, 127.2mg) and methanol containing 40mol% tert-butyl nitrite to the reaction test tube; then react for 48 hours at 40°C in air; after the reaction, add sulfur Sodium sulphate is stirred and quenched, and then the solvent is removed with a rotary evaporator, silica gel is adsorbed, and finally the product 3d is obtained by column chromatography with a mixed solvent of ethyl acetate and petroleum ether, with a yield of 86%. |
84.66% | With sulfuric acid for 4h; Reflux; | 2.1.1. Synthesis of methyl-2-(3-benzoylphenyl)propionate (1) The methyl ester of ketoprofen was prepared as per modified procedure reported earlier in the literature [29]. A small amount of concentrated sulphuric acid (1 mL) was added to 2-(3-benzoylphenyl)propanoic acid i.e. ketoprofen (1.5 g) in methanol (10 mL) in a round-bottom flask. The reaction mixture was refluxed for 4 h. After that, the methanol was removed and the contents were allowed to cool. The cooled residue was poured into the separating funnel containing water (150mL). Carbon tetrachloride (10 mL) was also added to obtain a sharp separation of ester layer. The mixture in the funnel was shaken vigorously and allowed to stand. Upon standing, heavy layer of ester separated sharply and rapidly at the bottom of the funnel. The lower layer was run off carefully and the upper layer was rejected. Then the ester was returned to the funnel and was shaken with a strong solution of sodium hydrogen carbonate (10 mL) until all free acid was removed and no further evolution of carbon dioxide occur. Then, it was washed with water once and was poured in to dry conical flask containing magnesium sulphate (1g). After shaking for about 5 min, it was allowed to stand for at least half an hour with occasional shaking. After filtration, carbon tetrachloride was removed to collect white crystals of ester. Yield (84.66%), m.p. 54 oC -56 oC (lit, 55oC). FTIR (KBr pellet) cm-1: 2929 (C-H); 2733 (CH3); 1793 (C=O); 1654 (C=O, cyclic ketone); 1H NMR(CDCl3) δ (ppm): 7.815-7.266 (m, 9H, ArH), 3.840 (q, 1H, CH, J=7.2), 1.55 (d, 3H, CHCH3, J= 7.2), 3.68 (s, 3H, OCH3). |
With hydrogenchloride for 1h; Heating; | ||
With sulfuric acid for 6h; Heating; | ||
With sulfuric acid at 20℃; | ||
With thionyl chloride at 0 - 20℃; | ||
0.95 g | With sulfuric acid at 20℃; | |
With sulfuric acid for 6h; Reflux; | ||
With sulfuric acid at 55℃; for 18h; | ||
With sulfuric acid Reflux; | ||
With sulfuric acid for 2h; Reflux; | ||
With sulfuric acid at 20℃; Inert atmosphere; | ||
With sulfuric acid Inert atmosphere; Reflux; | 4 (+-)-Methyl 2-(3-benzoylphenyl)-2-cyclopentylpropanoate [S24]. In a 50 mL recovery flask was charged 3.814 g (15 mmol) ketoprofen, 25 mL MeOH and 1 mL concentrated H2SO4. The reaction was refluxed overnight. After cooled to room temperature, the reaction was poured into 100 mL water and extract with 50 mL DCM 3 times. Combined organic layer was washed with sat. NaHCO3, dried with MgSO4 then purified by a plug of silica. In a 300 mL flamed dried flask, 1.3416 g (5 mmol) of ketoprofen methyl ester was dissolved in 50 mL anhydrous THF, cooled to -78° C. and 5.5 mmol (1.1 equiv.) freshly made LDA solution and 0.87 mL (5.0 mmol, 1.0 equiv.) HMPA was added sequentially. After stirring at -78° C. for 10 minutes, 1.61 mL (2.2355 g, 15 mmol, 3.0 equiv.) of bromocyclopentane was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with 10 mL saturated NH4Cl, extracted with 30 mL ether 3 times and dried over MgSO4. The crude mixture was purified by CombiFlash using a 40 g silica column and eluted with pure hexane→10% ethyl acetate/hexane to give product in 631.9 mg (1.96 mmol, 39% yield). | |
73 % | With sulfuric acid Reflux; | Synthesis of methyl ester derivatives of selected NSAIDs ( 1-10 ) Selected NSAIDs (10 mmol) were dissolved in methanol (40 ml) and added d. H 2 SO 4 (1 ml), dropwise. The mixture was heated un- der reflux for 5 h. Then the solution was cooled and neutralized with 5% NaHCO 3 solution. The crude product was drawn into the organic phase by extraction with diethylether. After drying the or- ganic phase with anhydrous sodium sulphate, ether is evaporated to obtain the crude product [50] . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 1-hydroxy-pyrrolidine-2,5-dione With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1,4-dioxane at 20℃; for 0.166667h; Inert atmosphere; Stage #2: ketoprofen In 1,4-dioxane at 20℃; for 24h; Inert atmosphere; | |
82% | With dicyclohexyl-carbodiimide In 1,4-dioxane for 8h; Ambient temperature; | |
62% | With dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 1h; |
42% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In ethyl acetate at 20℃; for 3h; | Preparation of KP-NHS KP (191 mg, 0.75 mmol) and WSCD (233 mg, 1.5 mmol) were dissolved in 100 ml of ethyl acetate. NHS (173 mg, 1.5 mmol) was added to the solution and stirred for 3 h at room temperature. After the reaction, the mixture was washed with water (100 ml × 4) and saturated NaCl (in water, 30 ml × 1). After evaporation of the organic layer, the residue was purified by silica gel column chromatography (Kieselgel, 20 g) using toluene:ethyl acetate 10:1 (v/v) as the mobile phase. The collected appropriate fractions were evaporated to give KP-NHS (oil, yield 42%). ESI-MS: m/z 352 ([M+H]+). ESI-MS/MS from m/z 352 (system 1, tR 8.29 min, CID, 30 V): m/z 237 ([M-NHS+H]+), 209 ([M-NHS-CO+H]+), and 105 (Ph-C≡O+). The purity was confirmed as >99% using LC system 1-UV (photodiode array detector; detection wavelength 254 nm). |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | ||
With diisopropyl-carbodiimide In chloroform at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride for 2h; Heating; | ||
With sulfuric acid Reflux; | ||
With sulfuric acid at 65℃; | 4.3. Synthesis of ibuprofen, naproxen and ketoprofen ethyl ester General procedure: The reactant (2.5 g of racemic ibuprofen, naproxen or ketoprofen)was mixed with EtOH (100 mL) ethanol and sulfuric acid(1 mL). The mixture was stirred at 65 C overnight. Then calcium carbonate (2.5 g) was then added and the mixture was stirred again for 30 min. The precipitate was removed by filtration and the filtrate was dried under reduced pressure. The reaction was followedby Thin Layer Chromatography analysis (TLC) using hexane/isopropanol (99/1 v/v) as the eluent. 1H NMR spectra were recorded on a Bruker AC-200.1 (200.1 MHz) spectrometer and confirmedthe purity of both esters. |
With sulfuric acid at 60℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium hydroxide; hydrazine hydrate monohydrate; diethylene glycol 1.) reflux, 1.5 h, 2.) 195 deg C, 4 h; | |
83% | With manganese powder; nickel(II) chloride ethylene glycol dimethyl ether complex; 1,1,3,3-Tetramethyldisiloxane; potassium-t-butoxide; N,N′-dicyclohexylimidazolium tetrafluoroborate In toluene at 70℃; for 5h; | |
34% | With anhydrous sodium formate; Cs2CO3; triphenylphosphine; Diphenylphosphine oxide; palladium (II) chloride In (methylsulfinyl)methane at 150℃; for 1h; |
With 10% palladium on activated charcoal; hydrogen In methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With phosphorus pentachloride In tetrachloromethane at 40℃; for 0.5h; | |
98% | With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 6h; Inert atmosphere; | |
95% | With thionyl chloride In dichloromethane for 3h; | 4.1.5 Synthesis of cis-(±)-4-chloro-6-(naphthalen-1-yl)-tetrahydro-2H-pyran-2-yl)methyl 2-(3-benzoylphenyl)propanoate (7) The reaction was performed by stirring a solution of ketoprofen (2.0g) in SOCl2 (5.0mL) and the mixture was stirred at room temperature at 80°C for 3h. After the end of reaction (verified by chromatography), the resulting mixture on evaporation afforded ketoprofen chloride in 95% yield. 1mmol of ketoprofen chloride and 1mmol of alcohol (±)- 3 were stirred in 10mL of THF and 0.5mL of TEA at 80°C for 7days. After the end of reaction (verified by chromatography using hexane: ethyl acetate (7:3) as solvent), the resulting mixture was extracted with CH2Cl2 (3×20mL). Pure product was obtained from the crude reaction by column chromatography through silica gel, using AcOEt:hexane as solvent at a ratio of 3:7. The solvent mixture was concentrated under reduced pressure to afford 7 in 72% yield; IR (KBr, cm-1): 786 and 721 (C-H aromatics); 1315-1172 (C-O); 1593 and 1450 (C=C aromatics); 1658 (C=O) 1735 (C=O ester); 2958 (C-H sp3). 1H NMR (CDCl3, 400MHz) δ: 2.10 (d, 1H, J=6Hz); 2.48 (m, 1H); 2.73 (m, 3H); 2.91 (m, 2H); 3.11 (m, 1H); 3.39 (m, 1H); 3.74 (m, 1H); 4.66 (m, 1H); 5.01 (m, 2H); 5.31 (m, 1H); 5.47 (m, 2H); 8.73 (m, 16H). 13C NMR (101MHz; CDCl3) δ: 19.74; 27.37; 30.37; 39.75; 44.24; 46.67; 56.41; 65.48; 67.88; 76.32; 124.23; 124.60; 126.93; 127.52; 129.66; 129.81; 130.33; 130.52; 131.43; 132.93; 133.86; 135.08; 137.49; 138.81; 139.19; 142.03; 142.20; 175.27; 197.82. Anal. Calcd for C32H29ClO4: C, 74.92; H, 5.70. Found: C, 74.85; H, 5.62. |
90% | With oxalyl dichloride for 1h; Ambient temperature; | |
With thionyl chloride In chloroform for 3h; Heating; | ||
With thionyl chloride In benzene Heating; | ||
With thionyl chloride In benzene for 2.25h; Heating; | ||
With phosphorus pentachloride In tetrachloromethane at 40℃; for 0.5h; | ||
With thionyl chloride In toluene for 5h; Heating; | ||
With oxalyl dichloride; triethylamine In dichloromethane at 4℃; for 2h; | ||
With oxalyl dichloride at 20℃; for 1h; | ||
With oxalyl dichloride at 40℃; for 12h; | ||
With thionyl chloride In toluene at 80℃; for 2h; | ||
16.a 16a. 16a. 3-benzoyl-α-methylbenzeneacetic acid chloride 3-Benzoyl-α-methylbenzeneacetic acid (3.2 g, 12.6 mmol) was treated in the same manner as set forth in Example 13a. Evaporation of the solvent, afforded the product as a yellow oil in a quantitative yield. 1 H NMR (CDCl3), δ: 1.64 (d, 3H), 4.21 (q, 1H), 7.45-7.51 (m, 4H), 7.62 (d, 1H), 7 72-7.82 (m, 4H). | ||
With thionyl chloride; N,N-dimethyl-formamide In toluene at 20℃; for 0.5h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In benzene at 20℃; for 3h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide for 4h; | ||
With thionyl chloride In chloroform at 60 - 70℃; | ||
With thionyl chloride for 2h; Reflux; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In 1,2-dichloro-ethane for 1h; Reflux; | General procedure forthe synthesis of compounds 18a-b and 18f General procedure: Oxalyl chloride (1.50 mmol) was addedto a solution of Drug-1 (1.00 mmol) in DCE (5 mL), followed by the addition of1-2 drops of DMF. The reaction mixture was refluxed for 1 h and concentrated.The residue was taken up in CH2Cl2 (5 mL), to which wasadded a solution of 11 (2.00 mmol)and Et3N (3.00 mmol) in CH2Cl2 (10 mL) at 0 oC.After stirring for 8 h, the reaction mixture was concentrated. The residue waspartitioned between EtOAc (30 mL) and 0.5 N HCl (10 mL). The organic layer waswashed with brine (10 mL), dried (Na2SO4), concentratedand purified by silica gel column chromatography to afford the title compounds. | |
28 g | With thionyl chloride In benzene for 2.5h; Reflux; | 1a.5 Synthesis of compound 8: A solution of 25.4 g. (0.1 mole) of a-(3-benzoylphenyl)propionic acid 7 in 40 ml. of benzene was added to 19.8 g. (0.166 mole) of thionyl chloride and the solution refluxed for two and a half hours. The solvent was then removed in vacuo, and the resulting oil (28 g.) consisting of a-(3-benzoyiphenyl)propionyl chloride 8 |
With thionyl chloride In benzene for 2.5h; Reflux; | 5 Step-S: Synthesis of Compound 8 [0122] A solution of 2S .4g. (0.1 mole) of a-(3-benzoylphe- nyl)propionic acid 7 in 40 ml. ofbenzene was added to 19.8g. (0.166 mole) of thionyl chloride and the solution refluxed for two and a half hours. The solvent was then removed in vacuo, and the resulting oil (28 g.) consisting of a-(3-benzoylphe- nyl)propionyl chloride 8. | |
With thionyl chloride In benzene Reflux; | General Procedure for the Synthesis of Penicillin Derivatives (4a-h) General procedure: A solution of NSAIDs having carboxylic acid group (1a-h) (1 mmol) in dry benzene (5-8 mL) was refluxed with freshly distilled thionyl chloride (1.2 mmol) for 2-3 h. After the completion of reaction, excess of thionyl chloride was removed under reduce pressure to afford the acid chlorides (2a-h) which were dissolved in anhydrous acetone for further use. The acid chlorides (2a-h) were then treated with a solution of (+)-6-aminopenicillanic acid (6-APA, 1 mmol) in 2% NaHCO3 (40 mL) diluted with acetone (30 mL). The reaction mixture was stirred for 2-4 h at room temperature and then concentrated under reduced pressure and washed with ethyl acetate (25 mL). The aqueous layer was then acidified with HCl (0.1 M), extracted with ethyl acetate and then washed with distilled water dried over anhydrous Na2SO4. The ethyl acetate was rotary evaporated and triturated with n-hexane to afford the title compounds (4a-h). | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h; | 1.8 400 mg of ketoprofen was dissolved in 2 ml of dry DCM, and then the mixture was added with 0.16mg of oxalyl chloride in an ice bath and added with 1 drop of DMF. The system was heated from 00 C. to room temperature and reacted for 2 hrs and then concentrated in vacuum to obtain acyl chloride for standby. | |
With silica chloride In dichloromethane at 20℃; for 1h; | General procedure: For the preparation of modified silica chloride (SiO2-Cl)(Sathe and Kaushik 2006), to a suspension of powderedsilica gel (20 g) in dichloromethane (50 mL), thionylchloride (20 g) in dichloromethane (20 mL) was addeddropwise for 30 min at 0-5 °C. The mixture was furtherstirred for 2 h at room temperature. After evaporation of thevolatile products, a white solid was obtained, which wasused without further purification.To a solution of R1-COOH or R2-COOH (5 mmol) indichloromethane (20 mL), silica chloride (750mg) was suspendedand the mixture was stirred for 1 h at room temperature.To this solution of the acid chloride, a solution of2,6-di-tert-butyl-4-(hydroxymethyl)phenol (5mmol) indichloromethane (5mL) was added and the mixture wasstirred for 3 h. The mixture was filtered, the solvent wasevaporated, the residue was dissolved in ethyl acetate, washedwith 5% ΝaHCO3, saturated NaCl solution and dried overΝa2SO4. The final compounds were purified by columnchromatography with petroleum ether/ethyl acetate as eluents. | |
With thionyl chloride; N,N-dimethyl-formamide In benzene at 0 - 20℃; for 8h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; | ||
With thionyl chloride Reflux; | ||
With thionyl chloride for 2h; Reflux; | Preparation of Compounds 7a,b General procedure: Thionyl chloride (1 gm, 8.41 mmol) was added to 5.9 mmol of ()-ibuprofen/ketoprofenin a dry round-bottom flask. The reaction mixture was refluxed on a steam bath. After for2 h reux, the excess thionyl chloride was removed under reduced pressure. The residue(ibuprofen/ketoprofen acetyl chloride) was dissolved in methylene chloride (30 mL). | |
With phosphorus pentachloride at 50℃; for 0.5h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 4h; Inert atmosphere; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 25℃; | ||
With oxalyl dichloride In dichloromethane at 20℃; | 4.1.2. General procedure for the preparation of the selenoester derivatives NSAID acyl chloride (2 mmol) and THF (5 mL) were added to a watersolution of sodium hydrogen selenide (2 mmol) formed in situ followingthe procedure reported by Sanmartin et al. [62]. The mixture was stirredat room temperature for 15 min and then the corresponding halide (2mmol) was added to the reaction. After 1 h, the reaction mixture wasextracted with methylene chloride (3 x 20 mL) and washed with water(2 x 30 mL). The organic layers were dried with anhydrous sodiumsulfate and concentrated in vacuo. The crude product of the reaction waspurified using silica gel chromatography or by flash chromatographywith a hexane/ethyl acetate gradient. In the case of the NSAIDs Ind (4)and Ket (5), the synthesis of the corresponding acyl chloride reagent wasnecessary prior to the formation of the selenoester derivative. Thesecompounds were obtained by the reaction of the carboxylic acid reagent(2 mmol) with oxalyl chloride (6 mmol) in methylene chloride (25 mL).N,N-dimethylformamide (0.1 mL) was added in the case of Ket (5). Themixture was stirred overnight at room temperature. The resultingproduct was isolated by the rotatory evaporation of the solvent andwashed with methylene chloride (2 x 20 mL). The acyl chlorides wereused without further purification. | |
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0℃; Inert atmosphere; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 25℃; | 4.2.1 General preparation of acyl chloride (a-i) General procedure: The oxalyl chloride (1.5 eq.) was gently added to a mixture of the commercially available non-steroidal anti-inflammatory drugs (1.0 eq.) in DMF and dry dichloromethane at 0 °C. The reaction mixture was stirred at room temperature for 2 h, then the solvent was evaporated to give the corresponding acyl chlorides a-i. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 25℃; | 4.2.1 General preparation of acyl chloride (a-i) General procedure: The oxalyl chloride (1.5 eq.) was gently added to a mixture of the commercially available non-steroidal anti-inflammatory drugs (1.0 eq.) in DMF and dry dichloromethane at 0 °C. The reaction mixture was stirred at room temperature for 2 h, then the solvent was evaporated to give the corresponding acyl chlorides a-i. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 48.2% 2: 25.7% 3: 12.5% | With (5,10,15,20-tetrakis(pentafluorophenyl)porphyrinato)iron(III) chloride; iodosylbenzene In dichloromethane for 20h; Ambient temperature; formation of CO2 confirmed by FT-IR; | |
1: 48.2% 2: 12.5% 3: 25.7% | With (5,10,15,20-tetrakis(pentafluorophenyl)porphyrinato)iron(III) chloride; iodosylbenzene In dichloromethane for 20h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
lipase from Candida rugosa; In 2,2,4-trimethylpentane; acetone;Resolution of racemate;Product distribution / selectivity; | Ketoprofen (180 mg) was dissolved in acetone (6 ml) followed by addition of 60 ml isooctane containing the ion-paired lipase from Candida rugosa (0.36 mg/ml). The transparent solution thus formed was allowed to evaporate naturally in a fume cupboard to a final volume of 12.5 ml, leading to a crystallization of 97.0% of ketoprofen. The crystals were filtered off and the R- and S- enantiomers in the filtrate I were analyzed (HPLC) to be 0.139 and 0.286 mg/ml, respectively, corresponding to an e.e. of 34.5%. The filtrate I was further evaporated to 1.8 ml, leading to 38.5% of ketoprofen crystallized from filtrate I. The crystals were removed by filtration and the R- and S-enantiomers in the filtrate II were respectively 0.306 and 1.51 mg/ml, corresponding to an e.e. of 66.7%. The chromatograms of the beginning solution of racemic ketoprofen, filtrate I and filtrate II are show?'ih Figures 2A-C, respectively.[0053] Detailed legend £rhor Figure 2: Chromatograms of ketoprofen in the beginning transparent solution (A), filtrate I (B) and filtrate II (C). Ketoprofen (180 mg) was dissolved in acetone (6 ml) followed by addition of 60 ml isooctane containing the ion-paired Candida rugosa lipase (0.36 mg/ml). The transparent solution thus formed was let evaporate naturally in a fume cupboard to 12.5 ml and the crystals thus formed were filtered off to give the filtrate I, which was further evaporated to 1.8 ml and the crystals thus formed were removed to give filtrate II. The first peak in (A) is acetone. | |
lipase fom Mucor javanicus; In 2,2,4-trimethylpentane; acetone;Resolution of racemate;Product distribution / selectivity; | Ketoprofen (180 mg) was dissolved in acetone (12 ml) followed by addition of 60 ml isooctane containing the ion-paired lipase from Mucor javanicus (0.36 mg/ml). The transparent solution thus formed was let evaporate naturally in a fume cupboard to 15.5 ml, leading to a crystallization of 96.5% of ketoprofen. The crystals were filtered off and the R- and S-enantiomers in the filtrate I were 0.173 and 0.228 mg/ml, respectively, corresponding to an e.e. of 13.7%. The filtrate I was further evaporated to 2.2 ml, leading to a crystallization of 40.6% of ketoprofen from filtrate I. The crystals were removed and the R- and S-enantiomers in the filtrate II were 0.588 and 1.091 mg/ml, respectively, corresponding to an e.e. of 29.9%. | |
lipase fom Rhizopus oryzae; In 2,2,4-trimethylpentane; acetone;Resolution of racemate;Product distribution / selectivity; | Ketoprofen (180 rag) was dissolved in acetone (12 ml) followed by addition of 60 ml isooctane containing the ion-paired lipase from Rhizopus oryzae (0.36 mg/ml). The transparent solution thus formed was let evaporate naturally in a fume cupboard to 12.5 ml, leading to a crystallization of 98.2% of ketoprofen. The crystals were removed and , the R- and S-enantiomers in the filtrate were 0.116 and 0.142 mg/ml, respectively, corresponding to an e.e. of 10.1%. The filtrate was further evaporated to 2.0 ml, leading to 63.2% of ketoprofen crystallized from filtrate I. The crystals were removed and the R- and S-enantiomers in the filtrate II were 0.211 and 0.382 mg/ml, respectively, corresponding to an e.e. of 28.7%.[0056] It should be mentioned that the three lipases showed almost no activity or very low activity and enantioselectivity (E<2) for ketoprofen esterification with ethanol in isooctane, which makes them not feasible to be used as biocatalysts for commercial resolution of ketoprofen through the esterification route, but they worked well in the'^dnzyme-mediated crystallization process, giving a high e.e. of the S- ketoprofen in the remaining filtrate after a two-step crystallization, although further improvement is still possible fey further evaporation of the solvents. The enzymes are expected to be easily recovered and reused by ultrafiltration considering the large weight difference and weak interaction between enzyme and enantiomer molecules. |
alpha-chymotrypsin; In 2,2,4-trimethylpentane; acetone;Resolution of racemate;Product distribution / selectivity; | Ketoprofen (360 mg) was dissolved in acetone (30 ml) followed by addition of 120 ml isooctane containing the ion-paired alpha-chymotrypsin (0.70 mg/ml). The transparent solution thus formed was let evaporate naturally in a fume cupboard to 83 ml, leading to a crystallization of 89.5% of ketoprofen. The crystals were filtered off and the R- and S-enantiomers in the filtrate I were analyzed (HPLC) to be 0.180 and 0.227/ml, respectively, corresponding to an e.e. of 21.2%. The filtrate I was further evaporated to 8.4 ml, leading to 88.4% of ketoprofen crystallized from filtrate I. The crystals were removed by filtration and the R- and S- enantiomers in the filtrate II were respectively 0.085 and 0.440 mg/ml, corresponding to an e.e. of 67.6%. | |
With ammonium acetate; In hexane; isopropyl alcohol;Resolution of racemate;Purification / work up; | Enantiomers of test racemates TR 19-23, of known drugs from the non-steroidal antiinflammatory group, were separated on analytical HPLC columns (250 mm x 4,6 mm), filled with CSP-4 or CSP-3. Since these compounds are structurally free carboxyl acids, it was necessary to use a polar mobile phase containing a certain amount of ammonium acetate. Results obtained by the enantioselective separation of these compounds are shown in Table 5 and the chromatogram achieved for the enantiomers of naproxen is shown in Figure 8. <n="20"/>TABLE 5 Enantiomer separations for test racemate TR 20-23 on the column filled withCSP-3 (250 mm x 4.6 mm ID), with hexane : 2-PrOH = 8:2 + lg/L NH4OAc as the mobile phase, 1 ml/min, 254 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium hydroxide In methanol for 1h; Heating; | |
With potassium hydroxide; water for 2h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 56.9% 2: 29% | With sodium hydroxide; nickel In ethanol for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 6.1% 2: 7.6% 3: 46% 4: 1% | With phosphate-buffered saline for 1h; Irradiation; sunlight; Further byproducts given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 46% 2: 6.1% 3: 3.5% 4: 2.8% 5: 5.6% 6: 7.6% | With phosphate-buffered saline; deuterated methanol In water Irradiation; natural sunlight or pyrex-filtered light of a medium-pressure mercury lamp in oxygen or argon atmosphere at different concentrations; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 6.1% 2: 7.6% 3: 46% 4: 3.5% | With phosphate-buffered saline for 1h; Irradiation; sunlight; Further byproducts given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 6.1% 2: 7.6% 3: 46% 4: 1.2% | With phosphate-buffered saline for 1h; Irradiation; sunlight; Further byproducts given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 3.1% 2: 8.3% 3: 29% 4: 3.2% | With phosphate-buffered saline for 1h; Irradiation; Further byproducts given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 6.1% 2: 7.6% 3: 5.6% 4: 46% | With phosphate-buffered saline for 1h; Irradiation; sunlight; Further byproducts given; | |
1: 46% 2: 7.6% 3: 5.6% 4: 6.1% | With phosphste-buffered saline for 1h; Irradiation; sunlight; Further byproducts given; | |
1: 3.1% 2: 8.3% 3: 29% 4: 6.3% | With phosphate-buffered saline for 1h; Irradiation; Further byproducts given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 4% 2: 83% | With sodium hydroxide In methanol for 1h; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 22℃; laser flash photolysis; | ||
In acetonitrile Irradiation; other solvents methanol, cyclohexane; | ||
With phosphate buffer; sodium chloride Irradiation; |
With sodium hydroxide In methanol UV-irradiation; | ||
With sodium hydroxide at 9.5 - 29℃; Irradiation; | ||
With sodium hydride In tetrahydrofuran Flash photolysis; | ||
In water; acetonitrile Photolysis; | ||
With sulfuric acid In water; acetonitrile UV-irradiation; | ||
With L-histidine In aq. phosphate buffer UV-irradiation; | ||
Multi-step reaction with 2 steps 1: 20 °C 2: methanol / UV-irradiation | ||
Multi-step reaction with 2 steps 1: 20 °C 2: methanol / UV-irradiation | ||
Multi-step reaction with 2 steps 1: 20 °C 2: methanol / UV-irradiation | ||
Multi-step reaction with 2 steps 1: 20 °C 2: methanol / UV-irradiation | ||
Multi-step reaction with 2 steps 1: 20 °C 2: methanol / UV-irradiation | ||
With sodium hydroxide In water; acetonitrile for 0.0833333h; Photolysis; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.5% | With triethylamine; potassium iodide In ethyl acetate Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With hydrido(phosphonite)cobalt(I); 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In 2-methyltetrahydrofuran for 16h; Sealed tube; Irradiation; Schlenk technique; chemoselective reaction; | |
With human liver dihydrodiol dehydrogenase 2; NADPH In phosphate buffer at 25℃; | ||
Multi-step reaction with 3 steps 1: H2SO4 / 20 °C 2: H2; Et3N / Pd/C / ethanol / 4 h 3: 0.78 g / aq. KOH / methanol / 20 °C |
With 10% palladium on carbon; hydrogen In tetrahydrofuran | ||
With Pd/C(en); hydrogen In tetrahydrofuran | ||
With palladium on activated charcoal; hydrogen In tetrahydrofuran | ||
With sodium tetrahydroborate at 40℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With (2,2'-dipyridyl)bis(5-methyl-2-(4-fluoro)phenylpyridine-N,C)iridium(III) hexafluorophosphate; oxygen; anhydrous sodium carbonate; ethyl viologen diperchlorate In dimethyl sulfoxide at 20℃; for 16h; Irradiation; | |
71% | With ferric(III) chloride; oxygen In N,N-dimethyl-formamide at 110℃; | |
52% | With tris(2,2′-bipyridine)ruthenium(II) dichloride hexahydrate; 1-butoxy-1λ3-benzo[d][1,2]iodaoxol-3(1H)-one In 2,2,2-trifluoroethanol at 40℃; for 3h; UV-irradiation; |
50% | With oxygen; anhydrous Sodium acetate; Mn(dtbpy)<SUB>2</SUB>(OTf)<SUB>2</SUB> In acetonitrile at 45℃; for 12h; Irradiation; Schlenk technique; chemoselective reaction; | |
Multi-step reaction with 2 steps 1: 1.) KOH, 85percent N2H4*H2O/diethylene glycol / 1.) reflux, 1.5 h, 2.) 195 deg C, 4 h 2: 28.4 percent / 1N NaOH, KMnO4 / H2O / 6 h / Ambient temperature | ||
Multi-step reaction with 2 steps 1: 1.) KOH, 85percent N2H4*H2O/diethylene glycol / 1.) reflux, 1.5 h, 2.) 195 deg C, 4 h 2: 28.4 percent / 1N NaOH, KMnO4 / H2O / 6 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | 3 2-(3-Benzoyl-phenyl)propionitrile EXAMPLE 3 2-(3-Benzoyl-phenyl)propionitrile A mixture of (3-benzoylphenyl)acetonitrile (1 g), dimethyl carbonate (15 ml) and K2 CO3 (3 g) in the 1:40:5 molar ratio, is reacted in a steel autoclave at the temperature of 140° C. for 10 hours and 30 minutes. After recovering DMC, 0.85 g of the title product are obtained, with a monomethylation selectivity >99% (80% yield), which is hydrolyzed to obtain ketoprofen by known methods. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
R.10 REFERENCE EXAMPLE 10 STR56 REFERENCE EXAMPLE 10 STR56 According to substantially the same procedure as that of Reference Example 8, ethyl 2-(3-benzoylphenyl) propionate (quantitative yield) was obtained from 2-(3-benzoylphenyl) propionic acid (30 g, 0.118 mol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; potassium hydroxide In diethyl ether; water; toluene | R.3 REFERENCE EXAMPLE 3 REFERENCE EXAMPLE 3 Nitrogen gas was introduced into a reactor fitted with a stirrer, a thermometer and a condenser without being shielded from light, and reaction was carried out as described below. A mixture of 11.8 g 2-(3-benzoylphenyl)propionitrile and 100 g of 50% aqueous methanol containing 3.4 g potassium hydroxide was placed in the reactor and heated under reflux for 24 hours. The reaction mixture was concentrated under reduced pressure, 100 ml water was added to the concentrate, the mixture was stirred well, and the resulting solution was washed twice with 100 ml diethyl ether. To the aqueous layer was added 1 g activated charcoal, the mixture was stirred at 50° C. for two hours and then allowed to cool to room temperature, and the activated charcoal was filtered off. Ten grams of 35% hydrochloric acid was added to the filtrate, 100 ml diethyl ether was further added, the mixture was stirred well and then allowed to stand, and the aqueous layer separated was removed. After distilling off the diethyl ether, the residue was dissolved in 100 ml toluene, 1 g activated charcoal was added to the solution, and the mixture was stirred at 50° C. for two hours. After cooling to room temperature, the activated charcoal was filtered off, the filtrate was cooled to -15° C. and the crystals which separated out were collected by filtration, washed with diethyl ether and dried, giving 7.0 g of 2-(3-benzoylphenyl)propionic acid as white powder (m.p. 95° C.). When dissolved in methanol, it gave a colorless and transparent solution showing UV transmittance at 430 nm of 95%. The total yield of the product was 55%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.8% | With sulfuric acid for 7h; Reflux; | 6 Example 6: Preparation of a compound of formula VII Add a compound of formula VI (10g, 0.042mol) and an 80% sulfuric acid solution (10.3g, 0.084mol) to a 250ml reaction bottle, and start heating to reflux. After holding the reaction for 7 hours, take a sample and test. After the raw materials disappear, the temperature begins to fall. material. After stirring at 7 ° C for 1 hour, suction filtration, washing with a small amount of water, and drying, 10.6 g of a compound of formula VII was obtained, with an HPLC content of 94.6% and a yield of 92.8%. |
With sulfuric acid In water; toluene | 1 EXAMPLE 1 EXAMPLE 1 A reactor fitted with a stirrer, a thermometer and a condenser was shielded from light, nitrogen gas was introduced therein, and reaction was carried out as described below. Fifty grams of 60% sulfuric acid was placed in the reactor, 11.8 g 2-(3-benzoylphenyl)propionitrile was added dropwise over a period of 30 minutes while maintaining the temperature at120° C. to 130° C., and the reaction was continued at 130° C. for four hours. At the end of reaction, 100 ml toluene and 100 ml water were added to dissolve the reaction product, the mixture was allowed to stand, and the aqueous layer separated was removed. The toluene layer was washed with water, 100 ml water and 7 g sodium bicarbonate were added, the mixture was stirred well and then allowed to stand, and the toluene layer was removed. To the aqueous layer was added 1 g activated charcoal, the mixture was stirred at 50° C. for two hours and then allowed to cool to room temperature, the activated charcoal was filtered off, and this decolorization operation was repeated once again. After adding 10 g of 35% hydrochloric arid to the filtrate, 100 g toluene was further added, the mixture was stirred well and then allowed to stand, and the aqueous layer separated was removed. The toluene layer was washed with water, most of the toluene was distilled off, and the concentrate was allowed to cool. The crystals which separated out were collected by filtration, washed with toluene and dried, giving 9.9 g of 2-(3-benzoylphenyl)propionic acid as white powder (m.p. 95° C.). The methanolic solution of this powder was colorless and transparent, with the UV transmittance at 430 nm being 99%. The total yield of 2(3- benzoylphenyl) propionic acid reached 95%. | |
With sodium hydroxide; sulfuric acid In water; toluene | R.1 REFERENCE EXAMPLE 1 REFERENCE EXAMPLE 1 A reactor fitted with a stirrer, a thermometer and a condenser was shielded from light, nitrogen gas was introduced therein, and reaction was carried out as described below. Fifty grams of 60% sulfuric acid was placed in the reactor, 11.8 g 2-(3-benzoylphenyl)propionitrile was slowly added dropwise while maintaining the temperature at 120° C. to 130° C., and the reaction was continued at 130° C. for four hours. At the end of reaction, 100 ml toluene and 100 ml water were added to dissolve the reaction product, the mixture was stirred well and then allowed to stand, and the aqueous layer separated was removed. The toluene layer was washed with water, 100 g of 3.3% aqueous solution of sodium hydroxide was added, the mixture was stirred well and then allowed to stand, and the toluene layer separated was removed. The aqueous layer was treated in the same way as in Example 1, giving 12.1 g of 2-(3-benzoylphenyl)propionic acid as yellow powder (m.p. 95° C.). When dissolved in methanol, it gave a yellow-colored transparent solution showing UV transmittance at 430 nm of 95%. The total yield of the product was 95%. |
With sulfuric acid In water; toluene | 5 EXAMPLE 5 EXAMPLE 5 A reactor fitted with a stirrer, a thermometer and a condenser was shielded from light, nitrogen gas was introduced therein, and reaction was carried out as described below. Fifty grams of 60% sulfuric acid was placed in the reactor, 11.8 g 2-(3-benzoylphenyl)propionitrile was added dropwise over a period of 30 minutes while maintaining the temperature at 120° to 130° C., and the reaction was continued at 130° C. for four hours. At the end of reaction, 100 ml toluene and 100 ml water were added to dissolve the reaction product, the mixture was stirred well and then allowed to stand, and the aqueous layer separated was removed. The toluene layer was washed with water, 100 ml water and 5 g of 28% ammonia water were added, the mixture was stirred well and then allowed to stand, and the toluene layer separated was removed. The aqueous layer was treated in the same way as in Example 1, giving 11.8 g of 2-(3-benzoylphenyl)propionic acid as white powder (m.p. 95° C.). The methanolic solution of this powder was colorless and transparent, with the UV transmittance at 430 nm being 99%. The total yield of the product was 93%. | |
With sulfuric acid for 7h; Reflux; | 6 Example 6: Preparation of a compound of formula VII A compound of formula VI (10 g, 0.042 mol) and 80% sulfuric acid solution (10.3 g, were added to a 250 ml reaction flask.0.084 mol), heating to reflux, heating reaction for 7 hours, sampling and testing, after the disappearance of the raw materials, began to cool the material. 7°CAfter stirring for 1 hour, suction filtration, a small amount of water washing, and drying to obtain 10.6 g of the compound of the formula VII, HPLC content 94.6%, yield92.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydroxide In water | R.2 REFERNCE EXAMPLE 2 REFERNCE EXAMPLE 2 Nitrogen gas was introduced into a reactor fitted with a stirrer, a thermometer and a condenser without being shielded from light, and reaction was carried out as described below. A mixture of 11.8 g 2-(3-benzoylphenyl)propionitrile and 100 g of 50% aqueous methanol containing 2.5 g sodium hydroxide was placed in the reactor and heated under reflux for 24 hours. The reaction mixture was concentrated at 50° C. under a reduced pressure of 20 mmHg, 100 ml water was added to the concentrate, the mixture was stirred well, and the resulting solution was washed twice with 100 ml diethyl ether. To the aqueous layer was added 10 g of 35% hydrochloric acid, and the crystals which separated out were collected by filtration, washed with water and dried, giving 7.6 g of 2-(3-benzoylphenyl)propionic acid as brown solid (m.p. 93° C.). When dissolved in methanol, it gave a brown-colored transparent solution showing UV transmittance at 430 nm of 90%. The total yied of the product was 60%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; triethylamine; In diethyl ether; | EXAMPLE 2 Following a procedure similar to that described in Example 1, 2,6-dimethyl-1-[alpha-(3-benzoylphenyl)propionyl]piperidine (14.3 g. as an oil) was prepared from 12.7 g. of alpha-(3-benzoylphenyl)propionic acid, 10 g. (0.084 mole) of thionyl chloride, 6.22 g. (0.055 mole) of 2,6-dimethylpiperidine and 6.05 g. (0.06 mole) of triethylamine, and the resulting amide (14.3 g.) reduced with 3.9 g. (0.103 mole) of lithium aluminum hydride in diethyl ether to give 13.2 g. of 2,6-dimethyl-1-{2-[3-(alpha-hydroxybenzyl)phenyl]propyl}piperidine as a yellow oil. Anal. Calcd. for C23 H31 NO: C,82.34; H,8.71; N,4.18. Found: C,82,22, H,8.82; N,4.15. | |
With thionyl chloride; triethylamine; In diethyl ether; | Example 2 Following a procedure similar to that described in Example 1, 2,6-dimethyl-1-[alpha-(3-benzoylphenyl)propionyl]piperidine (14.3 g. as an oil) was prepared from 12.7 g. of alpha-(3-benzoylphenyl)propionic acid, 10 g. (0.084 mole) of thionyl chloride, 6.22 g. (0.055 mole) of 2,6-dimethylpiperidine and 6.05 g. (0.06 mole) of triethylamine, and the resulting amide (14.3 g.) reduced with 3.9 g. (0.103 mole) of lithium aluminum hydride in diethyl ether to give 13.2 g. of 2,6-dimethyl-1-{2-[3-(alpha-hydroxybenzyl)phenyl]propyl}piperidine as a yellow oil. Anal. Calcd. for C23 H31 NO: C,82.34; H,8.71; N,4.18. Found: C,82,22, H,8.82; N,4.15. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride In diethyl ether; benzene | 1 EXAMPLE 1 EXAMPLE 1 A solution of 25.4 g. (0.1 mole) of α-(3-benzoylphenyl)propionic acid in 40 ml. of benzene was added to 19.8 g. (0.166 mole) of thionyl chloride and the solution refluxed for two and a half hours. The solvent was then removed in vacuo, and the resulting oil (28 g.) consisting of α-(3-benzoylphenyl)propionyl chloride was dissolved in 40 ml. of diethyl ether and added with stirring over a thirty minute period to a solution of 2-cyclohexylmethylpiperidine in 80 ml. of diethyl ether. The mixture was stirred for about forty-eight hours at ambient temperature, then filtered, the filter washed with ether, and the combined filtrate washed once with dilute acid, once with brine, once with aqueous potassium bicarbonate and evaporated to dryness to give 48.2 g. of 2-cyclohexylmethyl-1-[α-(3-benzoylphenyl)propionyl]piperidine as a pale amber glass. | |
With thionyl chloride In diethyl ether; benzene | 1 EXAMPLE 1 EXAMPLE 1 A solution of 25.4 g. (0.1 mole) of α-(3-benzoylphenyl)propionic acid in 40 ml. of benzene was added to 19.8 g. (0.166 mole) of thionyl chloride and the solution refluxed for two and a half hours. The solvent was then removed in vacuo, and the resulting oil (28 g.) consisting of α-(3-benzoylphenyl)-propionyl chloride was dissolved in 40 ml. of diethyl ether and added with stirring over a 30 minute period to a solution of 2-cyclohexylmethylpiperidine in 80 ml. of diethyl ether. The mixture was stirred for about forty-eight hours at ambient temperature, then filtered, the filter washed with ether, and the combined filtrate washed once with dilute acid, once with brine, once with aqueous potassium bicarbonate and evaporated to dryness to give 48.2 g. of 2-cyclohexylmethyl-1-[α-(3-benzoylphenyl)propionyl]piperidine. | |
With thionyl chloride In diethyl ether; benzene | 1 Example 1 Example 1 A solution of 25.4 g. (0.1 mole) of α-(3-benzoylphenyl)propionic acid in 40 ml. of benzene was added to 19.8 g. (0.166 mole) of thionyl chloride and the solution refluxed for two and a half hours. The solvent was then removed in vacuo, and the resulting oil (28 g.) consisting of α-(3-benzoylphenyl)propionyl chloride was dissolved in 40 ml. of diethyl ether and added with stirring over a thirty minute period to a solution of 2-cyclohexylmethylpiperidine in 80 ml. of diethyl ether. The mixture was stirred for about forty-eight hours at ambient temperature, then filtered, the filter washed with ether, and the combined filtrate washed once with dilute acid, once with brine, once with aqueous potassium bicarbonate and evaporated to dryness to give 48.2 g. of 2-cyclohexylmethyl-1-[α-(3-benzoylphenyl)propionyl]piperidine as a pale amber glass. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide In hydrogenchloride; methanol; CaCl2; water; acetonitrile | 1 Hydrolysis of 2-(3-benzoylphenyl)-propionitrile into 2-(3-benzoylphenyl)-propionic acid Hydrolysis of 2-(3-benzoylphenyl)-propionitrile into 2-(3-benzoylphenyl)-propionic acid 10.2 g. of 2-(3-benzoylphenyl)-propionitrile, recrystallized from diisopropylether, are dissolved in 85 ml. of methanol and water (1:1) and under stirring there are added 2.5 g. of KOH. It is refluxed for 24 hours (T-75° C.), cooled and evaporated to dryness. The oily residue is diluted with 63 ml. of water and extracted with four 27.0 ml.-portions of ether (after evaporation the ethereal layer contains 3.2 g. of the oily residue). The aqueous layer is stirred for 15 minutes with 0.54 g. of active carbon, filtered and the filtrate is cooled; 100 ml. of ether are added and the mixture is precipitated under stirring in the presence of some ice lumps by means of 5% w./w. HCl (49.5 ml.). After the separation of the layers, the ethereal layer is dried over Na2 SO4, the drying agent is separated and the ether is evaporated. The residue consists of 7.2 g. of oil (65.2%), to which there are added 10.8 ml. of acetonitrile (1.5 ml./1 g.) and a spatula tip of active carbon. After 15 minutes of refluxing, it is filtered hot over a heated filter. The product is left to cool down to ambient temperature, whereupon it is kept overnight in a freezer (-15° C.). Then it is filtered over a pre-cooled suction filter, sharply aspirated and washed with three 5 ml.-portions of cool ether. It is dried in vacuo over CaCl2 at 40° C. The yield amounts to 4.2 g. (58.4% theor.) of 2-(3-benzoylphenyl)-propionic acid with a m.p. of 92.5° to 94° C. (Kofler). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate | 3 2-(3-Benzoyl-phenyl)propionitrile Example 3 2-(3-Benzoyl-phenyl)propionitrile A mixture of (3-benzoylphenyl)acetonitrile (1 g), dimethyl carbonate (15 ml) and K2CO3 (3 g) in the 1:40:5 molar ratio, is reacted in a steel autoclave at the temperature of 140°C for 10 hours and 30 minutes. After recovering DMC, 0.85 g of the title product are obtained, with a monomethylation selectivity >99% (80% yield), which is hydrolyzed to obtain ketoprofen by known methods. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzoic acid anhydride; N-ethyl-N,N-diisopropylamine;(R)-(+)-2-phenyl-2,3-dihydrobenzo[d]imidazo[2,1-b]thiazole; In dichloromethane; at 20℃; for 6h;Resolution of racemate;Product distribution / selectivity; | Entry 49To a dichloromethane solution (2.0 mL) containing benzoic anhydride (54.2 mg, 0.240 mmol) and racemic ketoprofen (50.8 mg, 0.200 mmol); diisopropylethylamine (62.7 muL, 0.360 mmol), benzotetramisole (2.5 mg, 0.010 mmol), and 1,1-di(1-naphthyl)methanol (28.4 mg, 0.100 mmol) were added in order at room temperature. After stirring the reaction mixture solution at room temperature for 6 hr, the reaction was stopped with saturated ammonium chloride water. After fractionating the organic layer, the aqueous layer was extracted 4 times with diethylether. After combining the organic layers, they were dried with anhydrous sodium sulfate. After filtering the solution, it was vacuum concentrated, and the obtained mixture was fractionated by thin layer silica gel chromatography to obtain the corresponding optically active ketoprofen ester (56.8 mg, 55%, 80% ee) and the unreacted optically active ketoprofen (13.8 mg, 27%, 50% ee).(R)-ketoprofen di(1-naphthyl)methylesterHPLC (CHIRALPAK AD-H, i-PrOH/hexane=1/4, flow rate=1.0 mL/ml): tR=16.7 min (10.1%), tR=46.3 min (89.9%);IR (neat): 3035, 1735, 1660, 1599, 1511, 780, 680 cm-1;1H NMR (CDCl3): delta8.28 (s, 1H, 1'-H), 7.93-7.85 (m, 1H, Ph), 7.82-7.54 (m, 6H, Ph), 7.52-7.44 (m, 2H, Ph), 7.44-7.06 (m, 13H, Ph), 6.95 (d, J=7.1 Hz, 1H, Ph), 3.81 (q, J=7.1 Hz, 1H, 2-H), 1.46 (d, J=7.1 Hz, 3H, 3-H);13C NMR (CDCl3): delta196.3, 173.0, 140.1, 137.8, 137.3, 134.5, 134.4, 133.8, 133.7, 132.4, 131.6, 131.1, 130.8, 129.9, 129.5, 129.2, 128.93, 128.91, 128.86, 128.7, 128.6, 128.3, 128.2, 126.7, 126.4, 126.1, 125.9, 125.7, 125.4, 125.2, 125.0, 123.2, 71.4, 45.5, 17.9.HR MS: calculated for C37H28O3Na (M+Na+)=543.1931; found 543.1910.(S)-ketoprofenHPLC (CHIRALPAK AD-H, i-PrOH/hexane/TFA=1/10/0.01, flow rate=1.0 mL/min); tR=15.0 min (20.0%), tR=17.7 min (80%);1H NMR (CDCl3): delta10.67 (br s, 1H, COOH), 7.85-7.76 (m, 3H, Ph), 7.69 (dt, J=7.5, 1.5 Hz, 1H, Ph), 7.63-7.54 (m, 2H, Ph), 7.52-7.42 (m, 3H, Ph), 3.83 (q, J=7.0 Hz, 1H, 2-H), 1.56 (d, J=7.0 Hz, 3H, 3-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With p-Methoxybenzoic anhydride; N-ethyl-N,N-diisopropylamine;(R)-(+)-2-phenyl-2,3-dihydrobenzo[d]imidazo[2,1-b]thiazole; In dichloromethane; at 20℃; for 12h;Resolution of racemate;Product distribution / selectivity; | Experimental Example 7Production of Optically Active Ester and Optically Active Carboxylic Acid Using Ketoprofen (Optical Resolution of Ketoprofen) As shown by the above formula, an optically active ester and optically active carboxylic acid are obtained by reacting 1,1-di(1-naphthyl)methanol or 1,1-di(9-phenanthryl)methanol and racemic ketoprofen. The results are shown in Table 7.; Entry 51(R)-ketoprofen di(9-phenanthryl)methylesterHPLC (CHIRALPAK AD-H, i-PrOH/hexane=1/9, flow rate=1.0 mL/ml): tR=34.6 min (86.0%), tR=45.7 min (14.0%);IR (neat): 3060, 1733, 1658, 1159, 754, 721 cm-1;1H NMR (CDCl3): delta8.84-8.60 (m, 4H, Ph), 8.42 (s, 1H, 1'-H), 8.16-8.06 (m, 1H, Ph), 7.82-7.32 (m, 20H, Ph), 7.28-7.32 (m, 2H, Ph), 3.99 (q, J=6.9 Hz, 1H, 2-H), 1.60 (d, J=6.9 Hz, 3H, 3-H);13C NMR (CDCl3): delta196.3, 173.1, 140.2, 138.0, 137.4, 134.6, 134.5, 133.9, 133.7, 132.4, 131.6, 131.2, 131.0, 130.0, 129.6, 129.2, 128.9, 128.7, 128.6, 128.3, 128.2, 126.7, 126.5, 126.1, 125.9, 125.8, 125.4, 125.2, 125.0, 123.3, 71.5, 45.6, 18.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With nitric acid In 1,4-dioxane at 20℃; for 10h; | 6 Preparation of ketoprofen 3-benzoyl-a-methyl ethanol was dissolved in 20 ml of dioxane, 20 ml of 60% nitric acid was added and reacted at room temperature for 10 h. After completion of the reaction, 50 ml of ethyl acetate was added and dried over anhydrous sodium sulfate , Filtered, 50 ml of petroleum ether was added to recrystallize to give 8.3 g of a white solid in 90% yield. The reaction was as follows: |
65.6% | With nitric acid In 1,4-dioxane at 20℃; for 10h; | 5 According to the method provided in the patent document CN 16631772A, the compound (3) 8.80g is taken. Soluble in 20ml of dioxane, Add 60ml of 60% nitric acid, React at room temperature for 10 h, After the reaction, Extracted with 50 ml of ethyl acetate. Dry over anhydrous sodium sulfate, filter, 7.62 g of a white solid recrystallized from 50 ml of petroleum ether. After resolution with octacycline, 2.97 g of a white solid was obtained. No. E. |
40% | With 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium hypochlorite; sodium chlorite In water; acetonitrile at 35℃; for 24h; aq. phosphate buffer; |
13% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; laccase from Trametes versicolor; oxygen In water; acetone at 20℃; for 168h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: ketoprofen; 2-bromo-N,N-diethylethanamine hydrobromide With C11H16NPol In chloroform at 20℃; for 5h; Stage #2: sodium acetate In tetrahydrofuran; chloroform for 2h; | 5 5. Preparation of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH[39] 60 g of Polymer-bound triethylamine (3 mol/g, 100-200 mesh) was suspended in180 ml of chloroform. 25.7 g (0.1 mol) of 2-(3-benzoyphenyl) propionic acid was added into the mixture with stirring. 43 g (0.15mol) of diethylaminoethyl bromide.HBr was added into the mixture and the mixture was stirred for 5 hours at RT. The polymer was removed by filtration and washed with tetrahydrofuran (3 x 50 ml). 8.2 g (0.1 mol) of sodium acetate was added into the reaction mixture with stirring. The mixture was stirred for 2 h. The solid was removed by filtration and washed with chloroform (3 x 50 ml). The solution was concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3 x 100 ml). After drying, it yielded 36 g of the desired product (87%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C H NO ; MW: 413.51. Calculated % C: 69.71; H: 7.56; N: 3.39; O: 19.35; Found % C: 69.69; H: 7.59; N: 3.36; O: 19.36. 1H-NMR (400 MHz, CDCl3): δ: 1.51 (d, 3H), δ: 1.56 (t, 6H), 2.21 (s, 3H), 3.27 (m, 4H), 3.52(m, 2H), 3.78 (m, IH), 4.52 (t, 2H), 7.0 (b, IH), 7.31 (m, 2H), 7.36 (m, 2H), 7.45 (m, IH), 7.51 (m, IH), 7.56 (m, IH), 7.70 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.5% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 30 - 35℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triethylamine / toluene 2: triethylamine / toluene / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; | Synthesis of Diacetone 6'-O-Ketoprofen-D-galactopyranoside (3a) 1 g of ketoprofen 3 (3.9 mmol), 1.014 g of 1,2,3,4-di-I-isopropylidene-D-α-galactopyranose (3.9 mmol), 747 mg of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDC) HCl (3.9 mmol), and 24 mg of 4-(dimethyl amino)pyridine (DMAP) (0.195 mmol) were dissolved in anhydrous dichloromethane (10 mL). The reaction mixture was kept under electromagnetic stirring at room temperature for 12 hours. The organic phase was extracted several times with water and dehydrated with anhydrous sodium sulphate, filtered and dried in vacuo. The reaction crude was purified on a chromatography column with silica gel using CH2Cl2 as eluent, to obtain 990 mg of 3a as a white solid (yield 51%). m/z: 497 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: aluminum (III) chloride / 4 h / 150 °C 2: dichloromethane / 5 h / -10 - 20 °C 3: sodium hydroxide / 10 h / Reflux; Inert atmosphere 4: phosphinic acid; hydrogenchloride; sodium nitrite / water / -7 - 20 °C 5: potassium permanganate; sulfuric acid / water / 6 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dihydrogen peroxide; iron(II); In water; at 20℃;pH 2.0; | General procedure: For the Fenton degradation experiment, 10 mL of a Milli Q water sample acidified at pH 2 with 100 muL H2SO4 0.5 mol/L containing 200 ng of each studied anti-inflammatory drug (diclofenac sodium, ibuprofen and ketoprofen) was placed into a 50 mL brown glass bottle. Immediately, 500 muL of Fe2+solution (1 mg/mL Fe2+) and 200 muL of H2O2 (30%) were added into the brown bottle which was kept under magnetic stirring and room temperature for different time intervals in order to perform the degradation process. Because the catalyst (Fe2+) and the oxidant (H2O2) are consumed very fast, these were refreshed at each 30 minutes in the same amounts as it was described previously. To study the Fenton oxidative process efficiency over the selected drugs, different experiments at 30, 60 and 120 minutes were performed. After each Fenton oxidative experiment, the degradation by-products of NAIDs were extracted with organic solvent and analyzed by GC×GC-qMS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 83 %Spectr. 2: 11 %Spectr. | With sodium hydroxide In water; acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Novozym 435; In water; at 45℃; for 72h;Resolution of racemate; Enzymatic reaction; | General procedure: The esterification of R/S-ketoprofen with methanol, ethanoland 1-propanol as reactants and solvents catalyzed by Novozym435 were carried out at the optimum operative conditions pre-viously determined for the esterification of R/S-ibuprofen withethanol [30]. R/S-ketoprofen (0.5000 g; 1.966 mmol) was dissolvedin 0.70 mL (17.28 mmol) of methanol; 1.00 mL (17.15 mmol) ofethanol; 1.9 mL (24.98 mmol) of 1-propanol with 4.76% of wateradded corresponding to the optimum amount of water for theperformance of the biocatalyst [30]. Those volumes correspond tothe minimum amount required to dissolve the profen. The molarratio of alcohol: R/S-ketoprofen is 9 for methanol and ethanol,and 13 for 1-propanol. The esterification of R/S-ketoprofen wascatalyzed with 160 mg of Novozym435. This commercial bio-catalyst was employed as received and previously pretreated withthe alcohols (according to the methodology described in Section2.3) before the esterification reaction. All the reactions were per-formed in closed 100 mL vials, at a constant temperature of 45C ina shaker bath at 200 rpm for 72 h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Novozym 435; In water; at 45℃; for 72h;Resolution of racemate; Enzymatic reaction; | General procedure: The esterification of R/S-ketoprofen with methanol, ethanoland 1-propanol as reactants and solvents catalyzed by Novozym435 were carried out at the optimum operative conditions pre-viously determined for the esterification of R/S-ibuprofen withethanol [30]. R/S-ketoprofen (0.5000 g; 1.966 mmol) was dissolvedin 0.70 mL (17.28 mmol) of methanol; 1.00 mL (17.15 mmol) ofethanol; 1.9 mL (24.98 mmol) of 1-propanol with 4.76% of wateradded corresponding to the optimum amount of water for theperformance of the biocatalyst [30]. Those volumes correspond tothe minimum amount required to dissolve the profen. The molarratio of alcohol: R/S-ketoprofen is 9 for methanol and ethanol,and 13 for 1-propanol. The esterification of R/S-ketoprofen wascatalyzed with 160 mg of Novozym435. This commercial bio-catalyst was employed as received and previously pretreated withthe alcohols (according to the methodology described in Section2.3) before the esterification reaction. All the reactions were per-formed in closed 100 mL vials, at a constant temperature of 45C ina shaker bath at 200 rpm for 72 h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 8h; Inert atmosphere; | General Procedure for Synthesis of Trisubstituted Conjugates8-13 General procedure: To a solution of resveratrol in dry dichloromethane at room temperature, NSAIDs, EDCI and DMAP were added. After 8 h, aqueous NaHCO3 solution was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With dmap; dicyclohexyl-carbodiimide In chloroform at 0 - 20℃; | 3.2.2. Synthesis of Ester-Type Hybrid Compounds 11-18 General procedure: Oleanolic acid (1) or oleanolic acid methyl ester (2) (1 mmol), DCC (1.03 g, 5 mmol), DMAP (0.37 g,3 mmol) and anti-inflammatory drugs: ibuprofen, aspirin, naproxen, or ketoprofen (4 mmol) weremixed at 0 C and then stirred at room temperature in dry CHCl3 (12 mL) for 2 h. Hexane (8 mL)was added to the reaction mixture and cooled. Next, the resulting precipitate of dicyclohexylureawas filtered. The organic phase was washed with 5% aqueous hydrochloric acid, 5% aqueous sodiumbicarbonate and water and dried over anhydrous sodium sulfate. After removal of the drying agentand solvent evaporation, the crude new esters (11-18) were purified with column chromatography onsilica gel using a hexane-ethyl acetate (4:1, v/v) mixture as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With dicyclohexyl-carbodiimide In chloroform at 0 - 20℃; for 2h; | 3.2.3. Synthesis of Iminoester-Type Hybrid Compounds 19-26 General procedure: Oleanolic acid oxime (5) or its methyl ester (6) (1 mmol), DCC (1.03 g, 5 mmol) andanti-inflammatory drugs: ibuprofen, aspirin, naproxen, or ketoprofen (4 mmol), were mixed at 0 Cand then stirred at room temperature in dry CHCl3 (12 mL) for 2 h. Hexane (8 mL) was added tothe reaction mixture and cooled. Next, the resulting precipitate of dicyclohexylurea was filtered. Theorganic phase was washed with 5% aqueous hydrochloric acid, 5% aqueous sodium bicarbonateand water and dried over anhydrous sodium sulfate. After removal of the drying agent and solventevaporation, the crude new iminoesters 19-26 were purified with column chromatography on silicagel using hexane-ethyl acetate (4:1, v/v) mixture as a eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With dmap; dicyclohexyl-carbodiimide In chloroform at 0 - 20℃; | 3.2.2. Synthesis of Ester-Type Hybrid Compounds 11-18 General procedure: Oleanolic acid (1) or oleanolic acid methyl ester (2) (1 mmol), DCC (1.03 g, 5 mmol), DMAP (0.37 g,3 mmol) and anti-inflammatory drugs: ibuprofen, aspirin, naproxen, or ketoprofen (4 mmol) weremixed at 0 C and then stirred at room temperature in dry CHCl3 (12 mL) for 2 h. Hexane (8 mL)was added to the reaction mixture and cooled. Next, the resulting precipitate of dicyclohexylureawas filtered. The organic phase was washed with 5% aqueous hydrochloric acid, 5% aqueous sodiumbicarbonate and water and dried over anhydrous sodium sulfate. After removal of the drying agentand solvent evaporation, the crude new esters (11-18) were purified with column chromatography onsilica gel using a hexane-ethyl acetate (4:1, v/v) mixture as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Cooling with ice; | 1.1 1) Synthesis of Boc-aminopropanol-ketoprofen In 14 ml of dichloromethane, 2.371 g (13.5 mmol) of Boc-aminopropanol and 3.441 g (13.5 mmol) of ketoprofen(manufactured by Tokyo Kasei Kogyo) were dissolved, and 323 mg (2.6 mmol) of 4-dimethylaminopyridine (DMAP) and2.833 g (14.8 mmol) of water-soluble carbodiimide hydrochloride (WSCI·HCl)/14 ml dichloromethane were added theretoin this order under ice-cooling. After returning to room temperature and stirring overnight, dichloromethane was evaporatedunder reduced pressure, and ethyl acetate was added thereto, followed by separation by washing with 5% citricacid twice, water, 5% sodium hydrogen carbonate twice, water and saturatedbrine consecutively. After dehydrationdrying with sodium sulfate, ethyl acetate was evaporated under reduced pressure to give 5.430 g of the titled compound(yield 98%). The structure was identified by 1H-NMR (CDCl3).1H-NMR (500 MHz, CDCl3) δ (ppm) = 1.43 (9H, s, Boc), 1.54 (3H, d, -OCOCH(CH3)-), 1.77 (2H, quant,-NHCH2CH2CH2O-), 3.09 (2H, m, -NHCH2CH2CH2O-), 3.82 (1H, q, - OCOCH(CH3)-), 4.15 (2H, m, -NHCH2CH2CH2O-),4.69 (1H, br, -NHCH2-), 7.42-7.83 (9H, m, Aromatic H) |
87% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; | 11.2 Condensation Reaction Between the Compound 12 and Ketoprofen 1.07 g (1.0 eq., 6.09 mmol) of the compound 12 was dissolved in 12 mL of DCM, and added with 1.55 g (1.0 eq., 6.09 mmol) of ketoprofen and 74 mg (0.1 eq., 0.61 mmol) of DMAP. Then, under ice cooling, 2.34 g (2.0 eq., 12.2 mmol) of WSC was added followed by stirring overnight at room temperature. After confirming by TLC the disappearance of the reacting materials, liquid fractionation extraction was performed 3 times by using ethyl acetate and water. The collected organic layer was washed in order with 5% aqueous solution of citric acid, 5% aqueous solution of NaHCO3, and a saturated aqueous solution of NaCl. After drying over magnesium sulfate, it was concentrated under reduced pressure by using an evaporator in water bath at 40° C., and the desired compound 13 was obtained in an amount of 2.18 g (yield of 87%). 1H-NMR signal assignment is given in the following. 1H-NMR (500 MHz, CDCl3) δ1.45 (9H, s), 1.54 (3H, d), 1.77 (2H, m), 3.11 (2H, m), 3.80 (1H, q), 4.14 (2H, m), 4.69 (1H, br), 7.42-7.83 (9H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.28% | In methanol; isopropyl alcohol at 60℃; for 4h; Inert atmosphere; | 1 Under nitrogen atmosphere, 25.43 g of ketoprofen (0. lmol) and 17.42 g of arginine were added to 76. 2 ml of methanol / isopropanol solution (volume ratio: 4: 6), followed by stirring and heating to 60 degrees Celsius, 1 hour reaction to clarify the reaction, stop heating, slow down to 24 degrees Celsius, cooling time of 4 hours, stirring crystallization 24 hours, filter cake at 50 degrees Celsius, vacuum 400Pa, vacuum drying 7 hour. Arginine ketoprofen solid 37. 83g, the yield was 88. 28%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With tributylphosphine In tetrahydrofuran at -15℃; for 4h; Inert atmosphere; | 6 Example 6. 2- (3-Benzoylphenyl) -propionic acid phenyl selenide A 50 ml flask was charged with phenylselenium bromide (0.70 g, 2.95 mmol) and anhydrous tetrahydrofuran (30 ml)Ice-salt bath cooling to -15 ° C stirring, Followed by addingTributylphosphine (0.80 g, 3.94 mmol),2- (3-benzoylphenyl) -propionic acid (0.50 g, 1.97 mmol),Access to high purity argon gas protection,The reaction was stirred at -15 ° C for 4.0 hours,TLC monitoring reaction was complete,The solvent was removed by distillation under reduced pressure,Silica gel column chromatography separation,The mobile phase consisted of ethyl acetate (V): petroleum ether (V) = 1: 8,A white solid VI of 0.55 g was obtained in 71% yield. |
71% | With tributylphosphine In tetrahydrofuran at -15℃; for 4h; Inert atmosphere; | 6 Example 6. Benzene selenate of 2- (3-benzoylphenyl) -propionic acid In 50mlIn the flaskplusBenzene selenium bromide(0.70 g, 2.95 mmol)And anhydrous tetrahydrofuran (30 ml)Ice-salt bath cooled to -15 ° C,Join in sequenceTributyl phosphorus(0.80 g, 3.94 mmol),2- (3-benzoylphenyl) -propionic acid (0.50 g, 1.97 Mmol),Access to high purity argon protection,The reaction was stirred at -15 ° C for 4.0 hours. The reaction was completely monitored by TLC and distilled under reduced pressure Solvent, silica gel column chromatography, using ethyl acetate (V): petroleum ether (V) = 1: 8 as the mobile phase,A white solid VI of 0.55 g was obtained in 71% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: ketoprofen With dicyclohexyl-carbodiimide In tetrahydrofuran for 1h; Stage #2: 2-Methoxy-4-methylphenol With dmap In tetrahydrofuran for 24h; | General procedure for the preparation of the esters of 2-(hydroxymethyl)phenol and 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one (5, 6, 7) General procedure: To a solution of R1-COOH or R2-COOH (1 mmol) in tetrahydrofuran(5 mL), Ν,Ν′-dicyclohexylcarbodiimide (DCC,1.2 mmol) in tetrahydrofuran (5 mL) was added and, 1 hlater, 2-(hydroxymethyl)phenol or 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one (quercetin), (1.1 mmol)were added together with 4-dimethylaminopyridine(DMAP, 0.2 mol). The mixture was stirred for 24 h, filteredand the filtrate was washed with 1% aqueousCH3COOH solution, water, dried over Νa2SO4 and purifiedby column chromatography, using petroleum ether/ethylacetate as eluents. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.2% | General procedure: To the solution of (naproxen, 230mg 1.0mmol) in 8mL of acetonitrile, DMAP (18mg, 0.15mmol) and EDCI (190mg, 1.0mmol) were added with stirring at room temperature for 0.5h. To the reaction mixture <strong>[25984-63-8]4-hydroxythiobenzamide</strong> (153mg, 1.0mmol) was added and stirred for 4hat room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in trichloromethane; the organic layer was washed with brine, with NaCl 5%, and then dried on anhydrous Na2SO4, filtered and the solvent evaporated. The crude product was chromatographed on a silica gel (CHCl3/CH3OH 30:1), and 148.8mg pale yellow solid was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: chloroacetic acid ethyl ester; (3-acetylphenyl)(phenyl)methanone With sodium ethanolate In ethanol Reflux; Stage #2: With sodium hydroxide In ethanol for 2h; Further stages; | 5 Example 5. Ketoprofen (5) 3-acetylbenzophenone, 24 g of ethyl chloroacetate, dissolved in 100 ml of ethanol, and stirred with sodium ethoxide Ethanol solution (100 ml, sodium ethoxide 15 g) was added dropwise, refluxed for 2-3 h, cooled to room temperature, stirred with 30% sodium hydroxide solution (100 ml) for 2 h, adjusted to pH 2 with hydrochloric acid, To 80 ml of ethyl acetate, washed with water until neutral. Ethyl acetate was recovered under reduced pressure, 10 ml of glacial acetic acid was added, 2 g of Amberlyst 15, 40 ml of hydrogen peroxide and 90 ° for 0 h. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was adjusted to pH 9-10 with 20% sodium hydroxide, 20 ml of ethyl acetate Extraction, aqueous phase, 6mol hydrochloric acid adjusted to pH2, 50ml ethyl acetate extraction, washed to neutral, anhydrous sodium sulfate dried Filter, the filtrate by adding 10 ml of petroleum ether recrystallization, filtration, filter cake was white crystalline powder 41g, yield 83%. |
60.1% | Stage #1: chloroacetic acid ethyl ester; (3-acetylphenyl)(phenyl)methanone With sodium ethanolate In ethanol for 3h; Reflux; Stage #2: With dihydrogen peroxide; acetic acid at 90℃; for 10h; | 4 According to the method provided by the patent document CN 101928214 B, Take compound (1) 22.00g, Ethyl chloroacetate 12.03g, Soluble in 50ml ethanol, Ethanol sodium ethanol solution (ethanol 50 ml, sodium ethoxide 7.51 g) was added dropwise with stirring. After the addition, the reflux was completed for 3 hours. Cooled to 25 ° C, Add 50ml of 30% sodium hydroxide solution, After stirring for 2 h, the pH was adjusted to 2 with hydrochloric acid and refluxed to 25 ° C for 2 h. Add 40 ml of ethyl acetate for extraction. Washed to neutrality, ethyl acetate under reduced pressure, adding 5 ml of glacial acetic acid, 1.02 g of Amberlyst 15 and 20 ml of hydrogen peroxide, reacted at 90 ° C for 10 h, cooled to room temperature after completion of the reaction, filtered, and the filtrate was adjusted to pH 9 with 20% sodium hydroxide. ~10, 20ml ethyl acetate extraction, The aqueous phase was adjusted to pH 1-2 with 6 mol of hydrochloric acid, and extracted with 25 ml of ethyl acetate. Washed to neutral, dried over anhydrous sodium sulfate, Filtration, the filtrate was recrystallized by adding 5 ml of petroleum ether, and filtered. The filter cake was dried to obtain 18.01 g of a white crystalline powder. After resolution with octylamine, 6.84 g of a white solid was obtained. No. D. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Ketoprofen (1.11 mmol) (manufactured by Tokyo Kasei Kogyo) was dissolved in dichloromethane (3 ml), andtriethylamine (1.11 mmol) and dichloromethane solution (2 ml) of dimethylphosphinothioyl chloride (Mpt-Cl) (1.11 mmol)were added thereto in this order, followed by stirring for 25 minutes. Triethylamine (0.36 mmol) was further added thereto,followed by stirring for 20 minutes. The reaction solution was ice-cooled, and triethylamine (1.11 mmol), DMAP (0.19mmol) and the Boc-serinol obtained in Reference Example 2 (0.50 mmol) were added thereto in this order, followed bystirring overnight by returning to room temperature. The reaction solution was again ice-cooled, and 25% aqueousammonia (2 ml) and dioxane (10 ml) were added thereto in this order, followed by stirring for 20 minutes. The reactionsolution was concentrated to 5 ml, and ethyl acetate was added thereto. Separation by washing with water, 5% aqueouscitric acid solution, 5% aqueous sodium hydrogen carbonate solution and saturated brine consecutively was carried out,and after dehydration drying with sodium sulfate the solvent was evaporated under reduced pressure. The precipitatewas purified by silica gel column chromatography (hexane:ethyl acetate = 2:1, 0.5% triethylamine) to give the titledcompound (287.3 mg, yield 87%). The structure was identified by 1H-NMR (CDCl3). 1H-NMR (500 MHz, CDCl3) delta (ppm)= 1.38-1.40 (9H, m, Boc), 1.51-1.53 (6H, m, - OCOCH(CH3)-), 3.76-3.81 (2H, m, -OCOCH(CH3)-), 3.96-4.11 (4H, m, -CH2CH(NHBoc)CH2-), 4.61 (1H, btd, -CH2CH(NHBoc)CH2-), 7.40-7.80 (18H, m, Aromatic) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: ketoprofen With triethylamine; dimethylphosphinothioic chloride In dichloromethane for 0.166667h; Cooling with ice; Stage #2: N-(tert-butyloxycarbonyl)-2-amino-2-(hydroxymethyl)propane-1,3-diol With dmap; ammonia; triethylamine In 1,4-dioxane; dichloromethane; water at 20℃; for 0.666667h; | 31.1 1) Synthesis of Boc-tris(hydroxymethyl)aminomethane-ketoprofen In 3 ml of dichloromethane, 419 mg (1.65 mmol) of ketoprofen (manufactured by Tokyo Kasei Kogyo) was dissolved, and 230 µl (1.65 mmol) of triethylamine and Mpt-Cl 213 mg (1.65 mmol)/2 ml dichloromethane were added thereto in this order under ice-cooling, followed by stirring for 10 minutes. Next, 230 µl (1.65 mmol) of triethylamine, 33 mg (0.27 mmol) of DMAP and 110 mg (0.5 mmol) of the Boc-tris(hydroxymethyl)aminomethane (Boc-NHC(CH2OH)3) obtained in Reference Example 3 were added thereto in this order, followed by stirring overnight after returning to room temperature. After adding 2 ml of aqueous ammonia, dioxane was added thereto until dichloromethane and aqueous ammonia became uniform, and the mixture was stirred for 40 minutes. Dichloromethane was evaporated under reduced pressure, and ethyl acetate was added to the residue, followed by separation by washing twice with 5% citric acid, with water, twice with 5% sodium hydrogen carbonate, with water and with saturated brine consecutively. After dehydration drying with sodium sulfate, ethyl acetate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 → 75:1). The titled compound was quantitatively obtained at a yield of 467 mg. The structure was identified by 1H-NMR (CDCl3) to confirm that 3 molecules of ketoprofen were introduced into 1 molecule of Boc-tris(hydroxymethyl)aminomethane. 1H-NMR (500 MHz, CDCl3) δ (ppm) = 1.29 (9H, s, Boc), 1.44-1.54 (3H×3, m, - OCOCH(CH3)-), 3.76 (1H×3, q, -OCOCH(CH3)-), 4.04-4.27 (6H, m, -NHC(CH2O-KP)3), 4.81 (1H, br, -NH-), 7.37-7.85 (9H×3, m, Aromatic H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20 - 35℃; for 3h;Cooling with ice; | Boc-amino-1,2-propanediol (Boc-NHCH2CH(OH)CH2OH, manufactured by Aldrich Chem. Co.) (2.05 mmol) was dissolved in 6 dichloromethane (2 ml), and a dichloromethane solution (4 ml) of 125 ketoprofen (4.11 mmol) (manufactured by Tokyo Kasei Kogyo) and a dichloromethane solution (1 ml) of 54 DMAP (0.803 mmol) were added thereto in this order, followed by stirring. The reaction solution was ice-cooled, and a dichloromethane solution (5 ml) of 50 WSCI·HCl (4.94 mmol) was added thereto, followed by stirring overnight while gradually returning to room temperature. The reaction solution was ice-cooled, and a dichloromethane solution (1 ml) of WSCI·HCl (1.24 mmol) was added thereto, followed by stirring at room temperature for 1 hour and then at 35C for 2 hours. 14 Ethyl acetate was added thereto, followed by washing with 5% aqueous citric acid solution, 5% aqueous sodium hydrogen carbonate solution and saturated brine consecutively. Dehydration drying with sodium. sulfate was carried out, and then the solvent was evaporated under reduced pressure. The thus obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1, 0.5% triethylamine) to give the titled 142 compound (1.175 g, yield 87%). The structure was identified by 1H-NMR (CDCl3). 1H-NMR (500 MHz, CDCl3) delta (ppm) = 1.36-1.40 (9H, m, Boc), 1.42-1.53 (6H, m, - OCOCH(CH3)-), 3.10-3.30 (2H, m, BocNHCH2-), 3.65-3.82 (2H, m, -OCOCH(CH3)-), 3.99-4.36 (2H, m, BocNHCH2(CHO-)CH2O-), 4.49-4.76 (1H, m, BocNH-), 5.04-5.09 (1H, m, BocNHCH2(CHO-)CH2O-), 7.38-7.80 (18H, m, Aromatic) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1, materialValine (V) protected with fluorenylmethoxycarbonyl (Fmoc),Using methoxycarbonyl (Fmoc) and tert-butyl (But) glutamic acid (E),N,N'-diisopropylcarbodiimide (DIC, 99%), 1-hydroxybenzotriazole (HOBT, 99%),2-(1H-benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 99%),N,N-dimethylaminopyridine (DMAP, 99%), 9-fluorenylmethoxycarbonyl (Fmoc, 99%),N,N-diisopropylethylamine (DIEA, 99%),N,N-dimethylformamide (DMF, 99%), pyridine, piperidine, acetic anhydride, ninhydrin, king resin,Acetonitrile, trifluoroacetic acid (TFA), methanol, 1% aqueous ammonia solution2, preparation methodThe synthesis of the oligomeric polypeptide is carried out using conventional solid phase synthesis methods followed by coupling of the drug. details as follows:(1) first connect glutamic acid (E) to the Wang resin,The reaction DIC was carried out as a condensation reagent with HOBT+E+DMAP. Reaction for 4 hours,After the reaction, the reaction was carried out with an equal amount of pyridine and acetic anhydride.Used to block excess reactive groups on the resin. After half an hour of reaction.The reaction was removed by adding 20% piperidine and deprotected by FMOC and detected with ninhydrin.(2) Adding HBTU+V with DIEA as a condensation reagent for 35 minutes,The reaction time was washed with DMF, and 20% piperidine was added to carry out the reaction to remove FMOC protection.Detection with ninhydrin, detection with ninhydrin,No color indicates complete reaction, if there is color, it means that no reaction completely needs to be re-reacted.(3) After confirming that the valine (V) is connected, the method of removing the protective connection E is the same as that of the E, and then the V is connected.(4) Ketoprofen and the product of the previous step, reacted with HOBT to react with DIC as a condensation reagent,The reaction was carried out for 1 hour. Testing with ninhydrin, no color to prove complete reaction,If there is color, it means that no reaction is completely necessary to re-react.(5) The product of (3) was added to 95% TFA, 2% 1,2-ethanedithiol, 2% isopropanol and water for 2 hours, and then centrifuged with diethyl ether and separated by suction filtration. That is, the crude peptide is obtained, purified by high performance liquid chromatography (HPLC), and freeze-dried to obtain the ketoprofen polypeptide drug conjugate (keto-APD) of the present invention.The amino acid sequence is as described in SEQ ID NO. 1 of the Sequence Listing.The amino acid sequence of keto-VEVE is the first one of SEQ ID NO. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
300 g | With toluene-4-sulfonic acid In toluene at 120℃; for 3h; | 3 Example 3 In a 2 L flask, 1000 g of toluene, ketoprofen (300g, 1.18 mol), tetrakis(2-hydroxypropyl)ethylenediamine (108 g, 0.37 mol) and paratoluenesulfonic acid (5.0 g) were added in this order, followed by stirring at 120 ° C for 3 hours. 1000 g of water was added to the mixture, and the mixture was poured into a reactor, cooled to room temperature and stirred.After 1 hour, the para-toluenesulfonic acid was removed by removing the water layer, and the toluene and remaining moisture were removed at high temperature / high pressure to obtain 300 g of the compound of formula (5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
300 g | With toluene-4-sulfonic acid In toluene at 120℃; for 3h; | 2 Example 2 In a 2 L flask, 1000 g of toluene, ketoprofen (300g, 1.18 mol), 4,4',4"-trihydroxytriphenylmethane(108 g, 0.37 mol) and para-toluenesulfonic acid (5.0 g) were added in this order, followed by stirring at 120 ° C for 3 hours. 1000 g of water was added to the mixture, and the mixture was poured into a reactor, cooled to room temperature, and stirred. After 1 hour, the para-toluene sulfonic acid was removed by removing the water layer, and the toluene and remaining moisture were removed at high temperature / high pressure to obtain 300 g of the compound of formula (4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.6% | Stage #1: 2-isopropyl-5-methylcyclohexyl chloroethanoate With triethylamine; sodium iodide In N,N-dimethyl-formamide at 0 - 20℃; Stage #2: ketoprofen In N,N-dimethyl-formamide at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; | General Method for the Synthesis of Compounds 1-9 General procedure: A) In a solution of the corresponding acid (1mmol) in dichloromethane (CH2Cl2) lorazepam is suspended (1.05 mmol) and N,N'-dicyclohexylcarbodiimide (DCC, 1.3mmol) was added. The reaction mixture was stirred for 4-12h. After filtration, the final compounds were isolated with flash chromatography using petroleum ether and ethyl acetate as eluents. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 4h; | 4.2.3. General Method for the Synthesis of Compounds 7-12 General procedure: The acid (1 mmol) was dissolved in CH2Cl2 (20 mL), the corresponding serinederivative (1.05 mmol), N,N'-dicyclohexylcarbodiimide (DCC, 1.3 mmol) and 4-(dimethylamino)pyridine (DMAP, 0.1 mmol), in the same solvent, were added and the mixture wasleft for 4 h with stirring at room temperature. Then, the resulting mixture was filtered, andthe final compounds were isolated with flash chromatography using petroleum ether andethyl acetate as eluents. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 4h; | 4.2.3. General Method for the Synthesis of Compounds 7-12 General procedure: The acid (1 mmol) was dissolved in CH2Cl2 (20 mL), the corresponding serinederivative (1.05 mmol), N,N'-dicyclohexylcarbodiimide (DCC, 1.3 mmol) and 4-(dimethylamino)pyridine (DMAP, 0.1 mmol), in the same solvent, were added and the mixture wasleft for 4 h with stirring at room temperature. Then, the resulting mixture was filtered, andthe final compounds were isolated with flash chromatography using petroleum ether andethyl acetate as eluents. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine; dicyclohexyl-carbodiimide In chloroform at 20℃; | General procedure: The amino acid methyl ester hydrochloride (1 mol) was dissolved or suspended indry chloroform and Et3N (1.1 mol) was added. Then, the corresponding acid (1.1 mol) andDCC (1.1 mol) were added slowly. The reaction mixture was stirred at room temperatureovernight, filtered and washed with a 10% aqueous potassium carbonate solution. Theorganic layer was dried over sodium sulfate and concentrated. The residue was purified byash chromatography, eluting with petroleum ether-ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39 g | In tetrahydrofuran at 25℃; for 1.5h; | BS-8 <Synthesis example BS-8 to BS-9: Synthesis of BS-8 to BS-9> In a flask equipped with a stirrer and a condenser, 12.7 g (50 mmol) of 2- (3-benzoylphenyl) propionic acid (manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in 130 mL of tetrahydrofuran (manufactured by Tokyo Chemical Industry Co., Ltd.). , Stirred at 25 ° C. Next, 17.2 g of bis [3- (trimethoxysilyl) propyl] amine (manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in 60 mL of tetrahydrofuran, this was added dropwise over 1 hour, and the mixture was stirred at 25 ° C. for 30 minutes. .. This reaction solution was transferred to a one-necked flask while being filtered through a filter paper, and the solvent was removed by an evaporator to obtain 39 g of BS-8. The structure of BS-8 is presumed to be the following structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 2-(m-benzoylphenyl)propionic acid With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In dichloromethane; N,N-dimethyl-formamide at 25℃; for 0.5h; Inert atmosphere; Stage #2: N-(4-(aminomethyl)phenyl)formamide In dichloromethane; N,N-dimethyl-formamide at 25℃; for 16h; Inert atmosphere; | 4.2.2. General Procedure for the Synthesis of Compounds 4a-4h General procedure: 1-ethyl-3(3-dimethylpropylamine) carbodiimide (EDCI, 1.2 eq.), 1-hydroxybenzotriazole (HOBT, 1.2 eq.) and TEA (3.0 eq.) was added to a solution of patent NSAIDS (1.o eq.) in DCM (5 mL) and DMF (5 mL). The mixture was stirred at 25 C for 30 min under nitrogen atmosphere. Then, N-(4-(aminomethyl)phenyl)formamide (compound 3, 1.2 eq.) was added to the mixture. The mixture was stirred at 25 C for 16 h under inert atmosphere. TLC showed the reaction was complete. The mixture was diluted with H2O (20 mL); the aqueous layer was extracted with DCM (15 mL 2); the combined organic layer was washed with brine (20 mL 3), dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethane/methanol solution to obtain the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.9 % | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 19 Synthesis of 2-(3-(4-(7-(2-(3-benzoylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethanesulfonyl)azetidin-3-yl)acetonitrile 2-[1-(ethanesulfonyl)-3-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-1-yl)azetidin-3-yl]acetonitrile(baricitinib, 371 mg, 1 mmol), 4-dimethylaminopyridine (DMAP, 244 mg, 2 mmol), 2-(3-benzoylphenyl)propionic acid (ketoprofen, 280 mg, 1.1 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( EDCI, 288 mg, 1.5 mmol) dissolved in dichloromethane (15 mL) with 3 h of agitation at room temperature. After the reaction, the reaction solution is diluted with dichloromethane and washed with water and saturated saline solution. The organic layer is dried with anhydrous sodium sulfate, and after filtration, the solvent is evaporated under reduced pressure to obtain a crude product. Then separated by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:2), the target compound, white solid, 0.2 g, yield 32.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.4 % | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 32 (3R)-3-(4-(7-(2-(3-benzoylphenyl)propionyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile Incorporate (R)-3-(4-(7H-pyrrole[2,3-d]pyridine-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropane (ruxotinib, 153 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP, 6 mg, 0.05 mmol), 2-(3-benzoylphenyl)propionic acid (ketoprofen, 152 mg, 0.6 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 144 mg, 0.75 mmol) dissolved in dichloromethane (10 mL) and stirred for 16 hours at room temperature. After the reaction, the reaction solution is diluted with dichloromethane and washed with water and saturated saline solution. The organic layer is dried with anhydrous sodium sulfate, and after filtration, the solvent is evaporated under reduced pressure to obtain a crude product. Then separated by silica gel column chromatography (petroleum ether/ethyl acetate = 101 to 11), the target compound, white solid, 0.18 g, yield 66.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.4 % | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 126 Synthesis of (3R,4S)-3-(3-(2-(3-benzoylphenyl)propionyl)-3H-imidazolo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-ethyl-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide Incorporate (3S,4R)-3-ethyl-4-(3H-imidazolo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidin-1-carboxamide (upatinib, 100 mg, 0.25 mmol), 4-dimethylaminopyridine (DMAP, 3 mg, 0.025 mmol), 2-(3-benzoylphenyl)propionic acid (ketoprofen, 67 mg, 0.264 mmol) and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride salt (EDCI, 73mg, 0.377mmol) was dissolved in dichloromethane (4 mL) and stirred for 16 hours at room temperature. After the reaction, the reaction solution is diluted with dichloromethane and washed with water and saturated saline solution. The organic layer is dried with anhydrous sodium sulfate, and after filtration, the solvent is evaporated under reduced pressure to obtain a crude product. Then separated by silica gel column chromatography (dichloromethane/methanol = 50:1 to 25:1), the target compound was obtained, white solid, 0.13 g, yield 84.4%. |
Tags: 22071-15-4 synthesis path| 22071-15-4 SDS| 22071-15-4 COA| 22071-15-4 purity| 22071-15-4 application| 22071-15-4 NMR| 22071-15-4 COA| 22071-15-4 structure
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H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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