| 95% |
With thionyl chloride In dichloromethane for 3h; |
4.1.6 Synthesis of cis-(±)-4-chloro-6-(naphthalen-1-yl)-tetrahydro-2H-pyran-2-yl)methyl 2-(6-methoxynaphthalen-2-yl)propanoate (8)
The reaction was performed by stirring a solution of naproxen (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 using hexane: ethyl acetate (7:3) as solvent), the resulting mixture on evaporation afforded naproxen chloride in 95% yield. 1mmol of naproxen 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), 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 in a ratio of 3:7. The solvent mixture was concentrated under reduced pressure to afford 8 in 74% yield; IR (KBr, cm-1): 825 and 800 (C-H aromatics); 1327-1178 (C-O); 1600 and 1500 (C=C aromatics); 1730 (C=O ester); 2970 (C-H sp3). 1H NMR (CDCl3, 400MHz) δ: 0.84 (t, 2H); 1.24 (m, 1H); 1.59 (m, 5H); 1.71 (m, 2H); 3.44 (m, 1H); 3.87 (m, 1H); 4.01 (s, 3H); 4.04 (m, 1H); 4.10 (m, 2H); 7.28 (m, 2H); 7.52 (m, 4H); 7.70 (m, 5H); 8.17 (d, 2H). 13C NMR (101MHz; CDCl3) δ: 10.29; 18.32; 18.43; 21.91; 25.93; 28.97; 44.41; 45.30; 56.97; 63.98; 66.44; 113.88; 113.94; 116.73; 123.88; 123.97; 126.12; 126.13; 127.39; 127.49; 127.81; 129.45; 129.50; 130.99; 131.03; 136.41; 136.63; 152.75; 174.50. Anal. Calcd for C32H29ClO4: C, 74.92; H, 5.70. Found: C, 74.85; H, 5.62. |
| 94% |
With phosgene In dichloromethane at 20 - 25℃; for 1.83333h; |
2
Example 2Example 1 was repeated with the differences given in table 2._Example 1 To a suspension of compound of formula (II-down) (30.5 g, 132.4 mmol), DCM as solvent (78 ml) and DMF as catalyst (0.51 g, 7.0 mmol) at 20 to 25°C, phosgene as chlorination agent (25.6 g / 258.8 mmol) was added in 20 min. The mixture was stirred at 20 to 25°C for 1.5 h (conversion 99%). The DCM was distilled off at an inner temperature of 35 to 40°C until having a final volume of ca. 50 mL. The resulting suspension was cooled to 5 to 10°C in ca. 1 h. n-Hexane (252 ml) was added in the process of the cooling. After stirring for another 2 h the solid was filtered off under Nitrogen. The filtrate was washed with n-Hexane (2 times with 32mL each). 29.1 g of compound of formula (I-down) (118 mmol) were obtained based on LOD-method.Yield: 89% yieldPurity: 99.2%.Enantiomeric purity: 0.5 area% (R)-enantiomer (HPLC, method 2) |
| 91% |
With dmap; thionyl chloride In benzene for 3h; Reflux; |
General method for the synthesis of acid chloride
General procedure: To a solution of 1.2 Molar equivalents of NSAID’s in drybenzene, thionyl chloride (1 ml) and dimethyl-amino-pyridine(1 mg) were added. Then, the reaction mixture wasrefluxed for 2-3 h. After completion of refluxing, thionylchloride along with benzene was evaporated. |
| 89% |
With thionyl chloride; N,N-dimethyl-formamide In chloroform 1.) reflux, 2 h, 2.) r.t., 18 h; |
|
| 89% |
With thionyl chloride In cyclohexane at 60℃; for 2h; |
8
Example 8; Preparation of (5) -2- ( 6-Methoxy-2-naphtyl) propionyl chloride (compound Va' ); (S) -Naproxen (compound Ia, 56 kg, 243 mol) and cyclohexane (420 L) and triethylamine (51 g, 0.50 mol) were added to a 800 L reaction vessel and the resulting suspension was stirred under nitrogen and heated to an inner temperature of 600C. After this a parallel addition of thionyl chloride (34.7 kg, 292 mol) and a solution of triethylamine (76 g, 0.75 mol) in cyclohexane (14 L) was started and continued over 1.5 h. The solution of triethylamine was added under the liquid surface of the suspension. After the addition was finished the reaction mixture was agitated for another 30 min at an inner temperature of 600C after which HPLC showed full conversion. The reaction solution was filtered hot and then cooled slowly to 00C. Crystallisation started at around 500C and after reaching 00C the slurry was stirred for another 30 min before the crystals were filtered off using a pressure filter. The crystals were washed with cyclohexane (75 L) and then dried under vacuum at 400C to give 54 kg (89%) of pure Via as white crystals. |
| 88.8% |
With thionyl chloride; N,N-dimethyl-formamide In chloroform for 3h; Heating / reflux; |
30
Compound 2: Compound 2 was prepared from the corresponding carboxylic acid. Thionyl chloride (1.24 g, 10.42 mmoles) was added to a solution of (S)-(+)-2-(6- methoxy-naphthalen-2-yl)-propionic acid (Naproxen, 2 g, 8.69 mmoles) in 8.2 mL chloroform in a round bottom flask equipped with magnetic stirring. A drop of DMF was added and the mixture was refluxed for 3 hours. Chloroform and excess thionyl chloride were distilled from the reaction mixture while methylene chloride was added. Evaporation of residual solvent yielded fSj-2-(6-methoxy-naphthalen-2-yl)-propionyl chloride (1.918 g, 88.8 % yield). Rf = 0.2 (1 :1 hexanesrethyl ether). 1H NMR (400 MHz, CDCl3.) δ 9.98 (br, IH), 7.78 (t, 2H), 7.36 (d, IH), 7.18 (d, IH), 7.14 (m, 2H), 4.25 (q, IH), 3.93 (s, 3H), 1.68 (d, 3H). |
| 75% |
With trichlorophosphate In m-xylene for 3h; Reflux; |
|
| 53% |
With oxalyl dichloride In toluene at 90℃; for 4h; |
|
|
With thionyl chloride In toluene for 1h; Heating; |
|
|
With oxalyl dichloride; N,N-dimethyl-formamide In benzene at 45℃; for 1h; |
|
|
With thionyl chloride In benzene for 1.5h; Heating; |
|
|
With oxallyl chloride; N,N-dimethyl-formamide In dichloromethane |
|
|
With thionyl chloride In chloroform Heating; |
|
|
With oxalyl dichloride In dichloromethane at 0 - 20℃; for 3.5h; |
|
|
With oxalyl dichloride |
|
|
With thionyl chloride In toluene for 3h; Heating; |
|
|
With thionyl chloride In benzene Heating; |
|
|
With thionyl chloride In benzene a) reflux, 30 min, b) 20 deg C, 12 h; |
|
|
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 8h; Ambient temperature; |
|
|
With oxalyl dichloride In N,N-dimethyl-formamide; benzene for 1h; Ambient temperature; |
|
|
With oxalyl dichloride at 20℃; for 1h; |
|
|
With thionyl chloride |
|
|
With thionyl chloride In toluene at 80℃; for 2h; |
|
|
With oxalyl dichloride In chloroform at 0 - 20℃; for 1.5h; |
91
This prodrug was synthesized as shown in Scheme 11, Method E. Thus, to a solution of naproxen (1.698 g, 7.37 mmol) in chloroform (20 mL) at 0-5° C. was added oxalyl chloride (0.8 mL, 8.844 mmol), followed by 2-3 drops of DMF. The mixture was stirred at RT for 90 min and concentrated. This acid chloride (7.37 mmol) was treated with LI-5.TFA (6.7 mmol) in THF (20 mL) and cooled to 0° C. To this was added TEA (5.6 mL, 40 mmol) and stirred at RT for 3 h. The mixture was concentrated and the residue, after usual aqueous work-up and chromatographic purification, afforded 0.409 g (14%) of pure I-C1-NOPD12. 1H-NMR (CDCl3, 300 MHz): δ 1.24 (d, 3H), 2.87 (t, 2H, J=6.5 Hz), 2.93 (t, 2H, J=6.7 Hz), 3.64 (q, 2H, 7.5 Hz), 3.76 (m, 1H), 3.88 (s, 3H), 4.70 (t, 2H, J=6.6 Hz), 4.79 (br s, 1H), 6.97-7.08 (m, 3H), 7.35-7.46 (m, 3H). |
|
With thionyl chloride In dichloromethane for 2h; Heating; |
|
|
With oxalyl dichloride at 20℃; for 1h; |
14
(S)-naproxen (5.5g, 0.024mol) and oxalyl chloride (18ml) were added to a reaction flask and reacted at room temperature for 1 hour. The excessive oxalyl chloride was evaporated under reduced pressure to give (S)-6-methoxy-2-naphthyl isopropionyl chloride. |
|
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; Inert atmosphere; |
|
|
With thionyl chloride at 80℃; for 1h; |
|
|
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 3.16h; Inert atmosphere; |
3.1
DMF (~3-4 drops) followed by oxalyl chloride (11.0 mL, 130.4 mmol) were added drop-wise to a stirred solution of naproxen (DC1, 25.0 g, 108.7 mmol) in 200 mL of DCM at RT under a nitrogen atmosphere over 10 minutes. The mixture was stirred at RT under nitrogen atmosphere for 3 h. The mixture was concentrated in vacuo to afford crude naproxen acid chloride as a yellow solid, which was used as such in the next step. Yield: 27.0 g (quantitative). |
|
With oxalyl dichloride for 0.5h; |
|
|
With thionyl chloride In benzene for 3h; Reflux; |
|
|
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 1.5h; Cooling with ice; |
|
|
With oxalyl dichloride In dichloromethane at 0 - 20℃; |
|
|
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 25℃; for 12h; |
|
|
With oxalyl dichloride In hexane for 2h; Reflux; Inert atmosphere; |
|
|
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. |
|
With oxalyl dichloride |
|
|
With thionyl chloride; triethylamine In toluene at 40℃; for 4h; |
|
|
In dichloromethane; N,N-dimethyl-formamide at 0℃; Reflux; |
|
|
With thionyl chloride In benzene for 2h; Inert atmosphere; Reflux; |
|
|
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0℃; for 3h; |
|
|
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2.5h; Inert atmosphere; |
Steps 1 and 2: Synthesis of (2S)-1-chloroethyl 2-(6-methoxynaphthalen-2-yl)propanoate (D2-2a)
To a stirred solution of naproxen (D2-C(=O)OH, 5.0 g, 21.71 mmol) in dichloromethane (50 mL) at 0°C under nitrogen was added oxalyl chloride (5.51 mL, 65.14 mmol) followed by catalytic amount of dry DMF (2 drops) and the mixture was then stirred at room temperature for 2.5 h and concentrated. Intermediate naproxen acid chloride D2-1 was taken in dichloromethane (30 mL), added zinc chloride (0.06 g, 0.43 mmol) as a solid and stirred vigorously at room temperature for 15 min. Reaction flask was then cooled at -15 °C and a solution of acetaldehyde (Aa, 1.22 mL, 21.71 mmol) in dichloromethane (20 mL) was added drop wise. After 25 min of stirring, cooling bath was removed and continued stirring at room temperature for 12 h. Reaction mixture was diluted with dichloromethane (30 mL) and washed with water (50 mL), saturated NaHCO3 solution (50 mL) and brine (50 mL). Organic layer was dried over MgSO4 and concentrated. Crude compound was purified by silica gel (200-400 mesh) column chromatography using 5 % EtOAc / Pet. ether to give the corresponding chloro intermediate D2-2a (5.10 g, 80.0 %) as yellow oil. |
|
With thionyl chloride at 85℃; for 3h; |
|
|
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere; |
|
|
With thionyl chloride In benzene Reflux; |
|
|
With oxalyl dichloride In hexane for 2h; Reflux; Inert atmosphere; enantioselective reaction; |
|
|
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 2.5h; Inert atmosphere; |
3.7. Synthesis of (S)-Naproxen Acyl Chloride 9
To a solution of (S)-Naproxen (2.5 eq.) in anhydrous CH2Cl2 (15 mL) and N,N-dimethylformamide (one drop), oxalyl chloride (3 eq.) at 0 C was added. The reaction mixture was stirredat room temperature for 2.5 h under a nitrogen atmosphere, and after this time, the solvent andresidual oxalyl chloride were removed under reduced pressure to continue the reaction, obtainingthe (S)-Naproxen acyl chloride 9, which was not isolated and used immediately in the next reaction. |
|
With oxalyl dichloride In dichloromethane at 25℃; |
|
|
With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride In dichloromethane |
|
|
With thionyl chloride In toluene at 110℃; for 5h; |
|
|
With thionyl chloride In dichloromethane Reflux; |
|
|
With thionyl chloride In dichloromethane for 5h; Heating / reflux; |
1
A solution of naproxen (1.38 g, 6 mmol) and thionyl chloride (1.06 g, 9 mmol) in 100 mL of methylene chloride was refluxed for 5 hours, before the removal of the solvent under vacuo.Without further purification, the residue was dissolved in 5 mL of methylene chloride, and this solution was added dropwise to a mixture of imidazole (0.41 g, 6 mmol) and triethylamine (1.7 mL, 12 mmol) in 20 mL of methylene chloride. After the mixture was allowed to stir for additional 4 hours, the solvent was removed, and the crude residue was purified on a silica gel column, eluting with 30% ethyl acetate in hexane. The desired product was obtained 1.5 g (90% yield) as an oil first, which was then triturated with ether/hexane to give a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 1.57 (d, J = 6 Hz, 3H); 3.86 (s, 3H); 4.88 (dd, J = 6 Hz, IH); 7.01 (s, IH); 7.15 (dd, J = 3 Hz, IH); 7.29 (s, IH); 7.48 (dd, J = 3 Hz, IH); 7.75 (t, J = 3 Hz, IH); 7.79 (d, J = 3 Hz5 IH); 7.82 (d, J = 3 Hz, IH); 7.88 (s, IH); 8.54 (s, 1H).8.25 (s, IH); 7.52 (s, IH); 7.14 (s, IH); 5.13 (dd, J=4.0 and 9.2 Hz, IH); 3.77- 3.55 (m, 2H); 2.53-2.34 (m, IH); 2.20-2.01 (m, 3H); 1.92-1.61 (m, 2H), 1.23 (s, 6H), 0.88 (t, J=7.6 Hz, 3H). Anal. Calcd. for C17H16N2O2: C, 72.8; H, 5.8; N, 10.0. Found: C, 72.5; H, 5.8; N5 9.9. TLC: Rf = 0.3 (60% EtOAc/hexane). |
|
With thionyl chloride Heating; |
|
|
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 5h; |
|
|
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h; |
|
|
With oxalyl dichloride In benzene at 20℃; for 6h; |
|
|
With thionyl chloride; N,N-dimethyl-formamide for 3h; Reflux; |
Procedure for synthesis of compound 3af
0.5 mmol of Naproxen was added into a solution of 2 mL of SOCl2 and a drop of DMF, the mixture was refluxed for 3 h with a drying tube. After completion, the excess SOCl2 was removed under vacuum to give compound 4, which can be used directly in the next step. In an undivided three-necked flask (25 mL) equipped with a stir bar, 6-aminouracil (0.5 mmol, 63.6 mg), diphenyldiselenides (0.25 mmol, 78.1 mg), KI (0.125 mmol, 20.1 mg) and DMSO (8 mL) were added. The flask was equipped with platinum electrodes (15 mm x 15 mm x 0.3 mm) as cathode, graphite rod (Φ 6 mm) as the anode. The reaction mixture was stirred and electrolyzed at a constant current of 10 mA under room temperature for 15 h. The compound 4 above and NEt3 (3.0 equiv., 1.5 mmol) were added into the reaction mixture at 0 °C, then stirred at rt for another 8 h. After completion, the reaction mixture was diluted by ice water (10 mL), and the product was extracted with ethyl acetate (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The pure products 3af was obtained by flash chromatography on silica gel (elute: dichloromethane/ethylacetate = 3 : 1) . |
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