Acetic acid, 2-[(methylsulfonyl)oxy]-, (3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyldecahydro-5-hydroxy-4,6,9,10-tetramethyl-1-oxo-3a,9-propano-3aH-cyclopentacycloocten-8-yl ester

Pleuromutilin (222.Og, 0.59mol) was dissolved in dichloromethane (2.25L) under nitrogen and triethylamine (92mL, 66.45g, 0.66mol) was added at ambient temperature over 15min, during which time a slight exotherm (16.5 to 18.5Pleuromutilin (20.1g) and triethylamine (6.86g) in methylisobutyl ketone (0.21 L) were cooled to -10Example 7 Example 6 Sulfamethoxazole (12.6 g, 0.05 mol)Potassium hydroxide (2.8 g, 0.05 mol) in dichloromethane solution of intermediate III, Was loaded into a 150 ml three-neck reaction flask, The reaction was stirred at 40 C for 9 hours, A solution of the sulfonamidomethyl isoxazole truncated dendrites derivatives in dichloromethane.Sulfadiazine was used to shorten the solution of the dorsalin derivative in methylene chloride, Washed with 0.1 M NaOH solution, Collecting organic layer, The organic layer was washed with 0.1 M HCl solution, Collecting water, Adjust the PH value to neutral, The organic layer was extracted with dichloromethane, Vacuum drying of dichloromethane, Sulfamethyl isoxazole Truncated Tyrone Derivatives3.7 g (yield 11.7%).sulfadiazine (12.5 g, 0.05 mol)Sodium hydroxide (2 g, 0.05 mol) in dichloromethane solution of intermediate III, Was loaded into a 150 ml three-neck reaction flask, The reaction was stirred at 40 C for 12 hours, A solution of the sulfadiazine truncated levulide derivative in dichloromethane.Sulfadiazine was used to shorten the solution of the dorsalin derivative in methylene chloride, Washed with 0.1 M NaOH solution, Collecting organic layer, The organic layer was washed with 0.1 M HCl solution, Collecting water, Adjust the PH value to neutral, The organic layer was extracted with dichloromethane, Vacuum drying of dichloromethane, Sulfadiazine truncated pterosin derivatives 2.8 g (yield 8.9%)sulfanilamide (8.6 g, 0.05 mol)Potassium carbonate (6.8 g, 0.05 mol) in dichloromethane solution of intermediate III, Was loaded into a 150 ml three-neck reaction flask, The reaction was stirred at 40 C for 8 hours, A solution of the sulfonamine truncated dengurin derivative in dichloromethane.A solution of the sulfonamide truncated pendant dicarboxylate in methylene chloride, Washed with 0.1 M NaOH solution, Collecting organic layer, The organic layer was washed with 0.1 M HCl solution, Collecting water, Adjust the PH value to neutral, The organic layer was extracted with dichloromethane, Vacuum drying of dichloromethane, Sulfonated truncated pterosin derivatives3.2 g (yield 11.7%).General procedure: The M1 (1.88g, 4.3mmol) was dissolved in THF (40ml) was added 1NNaOH (20ml) andbenzyl tributylammonium chloride (1g), the reaction was cooled to 15 , dropwise asolution of Intermediate 664 608 (0.88 g, 4.3mmol) was added. 20 reaction was stirred1h. After the reaction, the organic phase was separated, dried and concentrated to giveIntermediate 664609 (1.4g, 62%). Referring to the method of Example 1, synthesis route is as follows: Compound 3 was obtained 0.52g, 11.2% yield.Preparation of PLM-SAcInto 3L round bottom flask with mechanical stirrer, PLM-mesylate (20Og), EtOAc (1600ml), Et3N (70ml) and thioacetc acid (33 ml) were charged. The reaction was stirred for 18 h at room temperature as solution. The reaction was washed with water. The solution was dried (Na2SO4) filtrated and evaporated. To the obtained oil Cyclohexane (750ml) was added. After one hour the oil crystallized and stirred as slurry 20hrs. The product was filtered and washed with Cyclohexane. PLM-SAc was obtained 95% yield.Example 7:Preparation of PLM-SAcInto 250 ml round bottom flask with magnetic stirrer, Pleuromutilin-mesylate (7g, 15.3 mmol) and potassium thioacetate (1.82 gr, 1.04 eq) and THF (50ml) were charged. The reaction was stirred for 4 h at room temperature solution (gel). The reaction was evaporated almost to dryness and EtOAc (70 ml) was added and extracted with water. The solution was dried (MgSO4) filtrated and evaporated. PLM-SAc was obtained in quantitative yield.Example 17 Preparation of Retapamulin A 3 neck-flask (100 ml) was charged with tropine thiol (5-10 mmol), a solvent (5 vol) and a base (2.5 eq). The solvents and bases are listed in Table 1 below. Pleuromutilin mesylate (11 mmol) was then added to the flask in portions. The resulting combination was stirred at room temperature to 40 C. for 2-24 hours until full conversion to Retapamulin was achieved. Example 18Preparation of RetapamulinIn a 500 ml round bottom flask, tropine thiol (15 g), methyl isobutyl ketone (8 vol) and triethylamine (2.4 eq.) were charged. The mixture was stirred at 40 C. for 15 minutes. Pleuromutilin mesylate (1 eq.) was added. The mixture was stirred as a slurry at 40 C. for 12 hours. Water (7 vol) was added and the pH was adjusted to 8.5 using 4N HCl. The phases were separated. Water (7 vol) was added to the organic phase, the pH was adjusted to 8.2, and the phases separated again. The organic phase was extracted with water (7 vol) and the pH was adjusted to 1.5. After separation, the pH of the aqueous phase was adjusted to 12.5 with 4N NaOH. The mixture was stirred at room temperature for 20 hours. The product was vacuum filtered and washed with water. The collected crystals were dried in a 55 C. vacuum oven to yield 80% Retapamulin at 99.8% purity as determined by HPLC.A solution of (1R, 3s, 5S) -8-methyl-8-azabicyclo [3.2.1] octane-3-thiol (6) obtained in Example 6 was added with pleuromutil mesylate 2(23.44 g, 51.38 mmol, 1 eq.), The mixture was cooled in an ice-water bath (internal temperature <30 C.) and 2 mol / L H2SO4 (90 ml, 359.66 mmol, 7 eq.) Was added dropwise thereto and reacted at 30 C. for 2 h. After the reaction was completed, the pH was adjusted with 2 mol / L HCl (25 ml, 1 eq.)?8, EtOH (35 ) was evaporated under reduced pressure, water (280ml) and ethyl acetate (200ml) were added, mixed, separated and separated.The aqueous phase is extracted with ethyl acetate (150 ml + 50 ml).The organic phases were combined, washed with water (35ml), added with 4mol / L HCl (100ml) and stirred for 10min, allowed to stand, layered and separated.The organic phase was added 4mol / L HCl (100ml), stirred for 10min, allowed to stand, layered and separated.The organic phase was added with 4mol / L HCl (40ml), stirred for 10min, allowed to stand, layered and separated.Hydrochloric acid layers were combined and adjusted to pH 8 with 6 mol / L NaOH (200 ml) under ice-water bath and extracted with ethyl acetate (200 ml + 100 ml).The ethyl acetate layers were combined, washed with water (40 ml) and dried over anhydrous Na2SO4. The mixture was suction filtered and the ethyl acetate (40 C) was evaporated under reduced pressure to give 21.8 g of an off-white solid.Add EtOH / H2O (1: 1, 110ml) heated to dissolve, the temperature was lowered to 50 C with stirring seed, cooled to room temperature and stirred (14h), precipitated a large amount of solid, suction filtered.The filter cake was washed with EtOH: H2O (1: 1, 15ml) and baked at 60 C for 6h to obtain 18.4g of white solid with a yield of 69.2%Example 17 Preparation of Retapamulin A 3 neck-flask (100 ml) was charged with tropine thiol (5-10 mmol), a solvent (5 vol) and a base (2.5 eq). The solvents and bases are listed in Table 1 below. Pleuromutilin mesylate (11 mmol) was then added to the flask in portions. The resulting combination was stirred at room temperature to 40 C. for 2-24 hours until full conversion to Retapamulin was achieved.Example 17 Preparation of Retapamulin A 3 neck-flask (100 ml) was charged with tropine thiol (5-10 mmol), a solvent (5 vol) and a base (2.5 eq). The solvents and bases are listed in Table 1 below. Pleuromutilin mesylate (11 mmol) was then added to the flask in portions. The resulting combination was stirred at room temperature to 40 C. for 2-24 hours until full conversion to Retapamulin was achieved.Example 17 Preparation of Retapamulin A 3 neck-flask (100 ml) was charged with tropine thiol (5-10 mmol), a solvent (5 vol) and a base (2.5 eq). The solvents and bases are listed in Table 1 below. Pleuromutilin mesylate (11 mmol) was then added to the flask in portions. The resulting combination was stirred at room temperature to 40 C. for 2-24 hours until full conversion to Retapamulin was achieved.Example 17 Preparation of Retapamulin A 3 neck-flask (100 ml) was charged with tropine thiol (5-10 mmol), a solvent (5 vol) and a base (2.5 eq). The solvents and bases are listed in Table 1 below. Pleuromutilin mesylate (11 mmol) was then added to the flask in portions. The resulting combination was stirred at room temperature to 40 C. for 2-24 hours until full conversion to Retapamulin was achieved.Example 17 Preparation of Retapamulin A 3 neck-flask (100 ml) was charged with tropine thiol (5-10 mmol), a solvent (5 vol) and a base (2.5 eq). The solvents and bases are listed in Table 1 below. Pleuromutilin mesylate (11 mmol) was then added to the flask in portions. The resulting combination was stirred at room temperature to 40 C. for 2-24 hours until full conversion to Retapamulin was achieved.Example 17 Preparation of Retapamulin A 3 neck-flask (100 ml) was charged with tropine thiol (5-10 mmol), a solvent (5 vol) and a base (2.5 eq). The solvents and bases are listed in Table 1 below. Pleuromutilin mesylate (11 mmol) was then added to the flask in portions. The resulting combination was stirred at room temperature to 40 C. for 2-24 hours until full conversion to Retapamulin was achieved.Example 17 Preparation of Retapamulin A 3 neck-flask (100 ml) was charged with tropine thiol (5-10 mmol), a solvent (5 vol) and a base (2.5 eq). The solvents and bases are listed in Table 1 below. Pleuromutilin mesylate (11 mmol) was then added to the flask in portions. The resulting combination was stirred at room temperature to 40 C. for 2-24 hours until full conversion to Retapamulin was achieved.Example 17 Preparation of Retapamulin A 3 neck-flask (100 ml) was charged with tropine thiol (5-10 mmol), a solvent (5 vol) and a base (2.5 eq). The solvents and bases are listed in Table 1 below. Pleuromutilin mesylate (11 mmol) was then added to the flask in portions. The resulting combination was stirred at room temperature to 40 C. for 2-24 hours until full conversion to Retapamulin was achieved.Example 17 Preparation of Retapamulin A 3 neck-flask (100 ml) was charged with tropine thiol (5-10 mmol), a solvent (5 vol) and a base (2.5 eq). The solvents and bases are listed in Table 1 below. Pleuromutilin mesylate (11 mmol) was then added to the flask in portions. The resulting combination was stirred at room temperature to 40 C. for 2-24 hours until full conversion to Retapamulin was achieved.Example 17 Preparation of Retapamulin A 3 neck-flask (100 ml) was charged with tropine thiol (5-10 mmol), a solvent (5 vol) and a base (2.5 eq). The solvents and bases are listed in Table 1 below. Pleuromutilin mesylate (11 mmol) was then added to the flask in portions. The resulting combination was stirred at room temperature to 40 C. for 2-24 hours until full conversion to Retapamulin was achieved.Example 17 Preparation of Retapamulin A 3 neck-flask (100 ml) was charged with tropine thiol (5-10 mmol), a solvent (5 vol) and a base (2.5 eq). The solvents and bases are listed in Table 1 below. Pleuromutilin mesylate (11 mmol) was then added to the flask in portions. The resulting combination was stirred at room temperature to 40 C. for 2-24 hours until full conversion to Retapamulin was achieved.Example 17 Preparation of Retapamulin A 3 neck-flask (100 ml) was charged with tropine thiol (5-10 mmol), a solvent (5 vol) and a base (2.5 eq). The solvents and bases are listed in Table 1 below. Pleuromutilin mesylate (11 mmol) was then added to the flask in portions. The resulting combination was stirred at room temperature to 40 C. for 2-24 hours until full conversion to Retapamulin was achieved.Example 17 Preparation of Retapamulin A 3 neck-flask (100 ml) was charged with tropine thiol (5-10 mmol), a solvent (5 vol) and a base (2.5 eq). The solvents and bases are listed in Table 1 below. Pleuromutilin mesylate (11 mmol) was then added to the flask in portions. The resulting combination was stirred at room temperature to 40 C. for 2-24 hours until full conversion to Retapamulin was achieved.Example 17 Preparation of Retapamulin A 3 neck-flask (100 ml) was charged with tropine thiol (5-10 mmol), a solvent (5 vol) and a base (2.5 eq). The solvents and bases are listed in Table 1 below. Pleuromutilin mesylate (11 mmol) was then added to the flask in portions. The resulting combination was stirred at room temperature to 40 C. for 2-24 hours until full conversion to Retapamulin was achieved.Example 17 Preparation of Retapamulin A 3 neck-flask (100 ml) was charged with tropine thiol (5-10 mmol), a solvent (5 vol) and a base (2.5 eq). The solvents and bases are listed in Table 1 below. Pleuromutilin mesylate (11 mmol) was then added to the flask in portions. The resulting combination was stirred at room temperature to 40 C. for 2-24 hours until full conversion to Retapamulin was achieved.Example 17 Preparation of Retapamulin A 3 neck-flask (100 ml) was charged with tropine thiol (5-10 mmol), a solvent (5 vol) and a base (2.5 eq). The solvents and bases are listed in Table 1 below. Pleuromutilin mesylate (11 mmol) was then added to the flask in portions. The resulting combination was stirred at room temperature to 40 C. for 2-24 hours until full conversion to Retapamulin was achieved.Example 17 Preparation of Retapamulin A 3 neck-flask (100 ml) was charged with tropine thiol (5-10 mmol), a solvent (5 vol) and a base (2.5 eq). The solvents and bases are listed in Table 1 below. Pleuromutilin mesylate (11 mmol) was then added to the flask in portions. The resulting combination was stirred at room temperature to 40 C. for 2-24 hours until full conversion to Retapamulin was achieved.Pleuromutilin-22-mesylate (11g, 24.09 mMol) and n-Bu4NHSO4 (360.3mg, 1.3 mMol) in MIBK (13OmL) and tropine-3-thiol in HCI (6.3% w/w, 73.9g, ~4.65g tropine-3- thiol, 29.58 mMol) were mixed at 20-220C under nitrogen. The pH (-1) of the stirred mixture was adjusted to 12.8 by the addition of 2M NaOH solution (37mL) over approximately 20min. The pH was re-adjusted 1 h later from 12.4 to 12.8 by the addition of2M NaOH (1mL) the reaction was followed by chromatography until complete. The aqueous phase was separated and discarded. Water (6OmL) was added and the pH adjusted to 7.3 to 7.5 (from 11.4) by the addition of 2M HCI (9.5mL). The aqueous phase was separated and discarded. Water (6OmL) was added and the pH adjusted to 1.25 by the addition of 2M HCI (13mL). After separation, the pH of the lower aqueous phase was adjusted to 7.25 using 12mL of 2M NaOH, at which point the mixture became cloudy and on seeding crystallization occured. After 20min stirring, further 2M NaOH was added to adjust the pH to 9.5 to 10 to precipitate the remaining product. After 30min stirring the EPO

Molecular Weight:456.6
XLogP3:3.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:6
Exact Mass:456.21817466
Monoisotopic Mass:456.21817466
Topological Polar Surface Area:115
Heavy Atom Count:31
Complexity:862
Defined Atom Stereocenter Count:8
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes