|
|
Part-B): Preparation of Corey aldehyde from Corey lactone.Dimethoxy ethane (60ml) was charged into Corey lactone (10 g) at 25 to 30c in a 250 ml four neck round bottom flask equipped with mechanical stirrer and dropping funnel. The suspension was stirred for 10 minutes, charged dicyclohexyl carbodiimide (23.3) and dimethyl sulfoxide (DMSO) (17.75 g) at 25 to 300C. The reaction mass was cooled to 20 to 220C and phosphoric acid was added (1.65g). The reaction mixture was maintained at 20 to 22 C for about 20 to 30 minutes. The temperature was raised to 25 to 300C. After completion of reaction, the unwanted dicyclohexyl urea was filtered and washed with dimethoxy ethane (20 ml). The filtrate contains Corey aldehyde. |
|
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; potassium acetate; In dichloromethane; at -5 - 17℃; for 1.09167h; |
Step C: Preparation of (3af?,4f?,5f?,6aS)-4-formyl-2-oxohexahvdro-2/-/- cvclopenta[fc>1furan-5-yl biphenyl-4-carboxylate ((-)-Corev aldehyde, PPB-protected) from (3af?,4S,5/:?,6aS)-4-(hvdroxymethyl)-2-oxohexahvdro-2/-/-cvclopenta[irj1furan-5-yl biphenyl-4-carboxylate ((-)-Corev alcohol, PPB-protected). g 4 parts ry ngTo a 20-L jacketed reactor fitted with a mechanical stirrer and a thermocouple was charged the (-)-Corey alcohol, PPB-protected (250 g, 0.71 mol, 1 molar equivalent), trichloroisocyanuric acid (66 g, 0.29 mol, 0.4 molar equivalent), potassium acetate (166.9 g, 1 .74 mol, 2.4 molar equivalents), and dichloromethane (8000 mL). The mixture was stirred and cooled to -5 C with a circulator. Once the mixture was at the desired temperature, a solution consisting of 2,2,6,6-tetramethyl- piperidin-1 -oxyl (TEMPO, 1 .13 g, 7 mmol, 0.01 molar equivalent) dissolved in dichloromethane (3 mL) was added in one portion via pipet. The mixture changed from white to a light orange within 30 seconds. The internal temperature rose to 17 C within 5 minutes. The circulator was adjusted to 3 C and the mixture was stirred for one hour. After about 15 minutes of stirring, the light orange color turned to white and the internal temperature started to gradually cool to 3 C. The resulting white slurry was treated (strongly effervesces.) with aqueous 5% w/w potassium bicarbonate (5000 mL). The resulting white reaction mixture was filtered through a coarse porosity (40-60 muiotaeta) glass fritted funnel. The filtration could be quite slow. The reactor was rinsed with dichloromethane (1000 mL). The rinse was passed through the filter. The layers of the resulting biphasic filtrate were separated and the lower dichloromethane layer was washed with 10% w/w aqueous potassium iodide (2500 mL), 10% w/w aqueous sodium thiosulfate (2500 mL), and 10% w/w potassium dihydrogenphosphate (2500 mL). The lower dichloromethane layer was dried over magnesium sulfate (500 g). The solids were filtered and the title intermediate was carried onto the next step as the filtrate solution. |
|
With phosphoric acid; dimethyl sulfoxide; diisopropyl-carbodiimide; In toluene; at 50℃;Inert atmosphere; Large scale; |
1. Construction of the lower chain (Oxidation and HWE reaction) Preparation of the [l,l'-Biphenyl]-4-carboxylic acid, (3aR,4R,5R,6aS)-hexahydro-2- [( 1 E)-3 -oxo-4-[3 -(trifluoromethyl)phenoxy] - 1 -buten- 1 -yl] -2H-cyclopenta[b] furan-5 -yl /compound of formula (II)/ C2iH2o05 C3iH25F306 Mr: 352.39 Mr: 550.54 1069 g of PPB-Corey-lactone is suspended in an inert atmosphere in 1 1.1 L of water- free toluene. To this suspension are added 1.4 L of diisopropylcarbodiimide and then 0.855 L of dimethyl sulfoxide in phosphoric acid. The reaction mixture is heated to 50C and a further 0.34 L of dimethyl sulfoxide in phosphoric acid is added in portions. After the accomplishment of the oxidation reaction, the mixture is cooled to-10C and while that temperature is maintained, 316 g of potassium hydroxide followed by 1.45 kg of Travoprost phosphonate in toluene solution are added. When the HWE reaction has completed, the reaction mixture is poured onto 1 M hydrochloric acid solution and the mixture is stirred. The precipitated crystals are filtered off and washed. The phases of the filtrate are separated, the organic phase is washed with 1M sodium hydrogen carbonate solution and then with diluted hydrochloric acid solution. The organic phase is evaporated and purified by chromatography on a silica gel column (eluent: toluene - ethyl acetate mixture). The main fraction is evaporated and crystallized from ethyl acetate - hexane mixture. Yield: 915 g, 55 %. Melting point: 112.5-1 14.5C IR spectrum of Travoprost 1. intermediate is shown on Figure 2. Travo rost 1. intermediate , l3C and 19F NMR data: Travoprost 1. intermediate (enone - Formula (II)): 2 118.75 7.20** 1 m (dd) 3 123.95 (q) - - - 'JC-23,F _ 272.5 -61.10 3-F - - - (s, 3) 4 164.94 - - - 5 128.16 - - - 6, 26' 129.95 8.015 2 m J26,27=8.5; 7, 27' 126.87 7.81 2 m 8 144.93 - - -9 138.77 - - -0, 30' 127.01 7.74 2 m (dd) 1, 31 ' 129.10 7 5 1 * * * 2 m (t) 2 128.46 7.43 1 m (tt) ,32~1·6 *, **, ***: Overlapping H NMR signals |
|
With Dess-Martin periodane; In dichloromethane; at 5 - 20℃; |
a) Dess martin (132.36 g, 1.1 eq) was added to a solution of Corey's lactone (100 g, 1 eq) in DCM (1500 ml) at 5-10C. The mixture was stirred for 1-2 hrs at 15-20C. The solution was filtered and washed with DCM. DCM layer was washed with solution of sodium thiosulfate and sodium bicarbonate in DM water followed by washing with 10% NaCl solution. |
|
With Dess-Martin periodane; In dichloromethane; at 22℃; for 0.12h; |
Dess-Martin reagent (86.66 g, 1.2 eq) was added in one portion to a 2L three-necked flask containing DCM (480 mL), mechanical stirring was started, and stirring was performed for 10 minutes to give a white cloudy solution.The ice water bath was allowed to cool for 30 min, and a solution of the compound of formula 1 (60.00 g) in DCM (240 mL) was added dropwise to the three-necked vial in about 30 min at 22C. After the medium-term addition, it is partially dissolved.Late turbidity slowly increased. After dripping, warm up naturally and stir for 12 hours.The ice water bath was cooled to 0-5 C and diluted with 600 mL of DCM. The prepared Na2S2O3 aqueous solution (consisting of Na2S2O3161.5 g, 2.6 eq and water 600 mL) was added dropwise.Keep stirring for 2h until the system is clear. Dispense liquid, combine organic phase, cool to 0-2C,A solution consisting of NaHCO3 (26 g) and water (120 mL) was added dropwise.Adjust pH=8, stir for 15 min, and let stand for 15 min. Phase,The organic phase was stirred with acetic acid (160 mg, 10 drops) and acidified to pH=5-6. The product had an HPLC purity of 86% and the product went directly to the next step. |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
