Dimethyl (3,3-difluoro-2-oxoheptyl)pho...

Orange Oil

Dimethyl methylphosphonate (215 mL) was diluted in THF (1450 mL) and stirred, and the reaction solution was cooled to -78 ° C. N-BuLi (804 mL) was added dropwise and stirred for 2 hours, and ethyl 2, 2-difluorohexanoate (14) (145 g) was added dropwise. 1After stirring for a time, the temperature was raised to 0 ° C and stirred for 1 hour. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate = 1: 1). After completion of the reaction, pentane (1000 mL) was added and the pH was adjusted to 6 with 2M-sulfuric acid solution. The water layer was separated, re-extracted with pentane, and the organic layers were combined and dried in anhydrous sodium sulfate. After filtration of anhydrous sodium sulfate, the filtrate was concentrated in vacuo to give a mixture which was purified by column chromatography using silica gel (hexane: ethyl acetate = 1: 1) to give pure dimethyl 3, 3-difluoro-2-oxoheptylphosphor Nat 11 (161 g, 78percent) was obtained.Dimethyl-(2-oxo-3, 3-difluoroheptyl)phosphonate 26. A solution of dimethyl methylphosphonoate (6.5 g, 80 mmol, 2.2 equiv) in tetrahydrofuran (100 mL) was cooled to -78° C. and n-butyllithium (2.5 M in hexanes, 14 mL, 36 mmol, 1 equiv) was added dropwise. The solution was stirred at -78° C. for 30 min and ethyl 2, 2-difluorohexanoate (6.5 g, 36 mmol, 1 equiv) was added dropwise. The solution was stirred at -78° C. for 1 h and warmed to 0° C. over 1 h. Pentane (100 mL) was added followed by the dropwise addition of 2M HCompound VIIa (1.7 g, synthesized according to patent US 4187381)Dissolved in 20 mL methyl tert-butyl ether, Under nitrogen protection, lithium hydroxide monohydrate (253 mg) was added and reacted at 20 C for 1 hour.A solution of methyl terbutyl ether (10 mL) of compound VIa (1.7 g) was added followed by 0.9 mL of water, The reaction was allowed to warm to 45 C for 36 hours.20 mL of water was added to the reaction system, stirred and extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 2.04 g of compound Va, which was directly added to the next step. Yield: 86%.(73.63 g) of Preparation of (Z)-7-[(1 R, 2R, 3R)-2-((E)-4, 4-difluoro-3-oxo-1 -octenyl)-3- (phenylmethoxy)-5-oxocyclopentyl]-5-heptenoic acid : ZnCI2 (55.1 g, 136.28 mmoL) was added to water (170 mL), and the solution was cooled to 0C to 10C. Aqueous NaOH (50%, 64.75 g) in 45 mL of water was added and the reaction mass temperature was allowed to raise to room temperature (RT). Dimethyl-(3, 3-difluoro-2, 2-dihydroxyheptyl)phosphonate (I) (77 g, 0.279 mmoL) was added at RT followed by MTBE (260 mL). (5E)-7-[(1 R, 2R, 3R)-3-(Benzyloxy)- 2-formyl-5-oxocyclopentyl]hept-5-enoic acid (43.56 g, 126.48 mmoL) in dichloromethane (260 mL) was added at RT and the reaction mass stirred at for 23 hours. Acetic acid (90 mL) was added to reaction mixture and stirred a further 15 minutes. The two layers separated and the aqueous layer was extracted with MTBE (1X130 mL). The organic layers were combined and washed with brine (1X130 mL), concentrated under vacuum to give 138 g of oil which was purified by column chromatography using 8:2 heptane and ethyl acetate as an eluant to obtain (Z)-7-[(1 R, 2R, 3R)-2-((E)-4, 4-difluoro-3-oxo-1 -octenyl)-3-(phenylmethoxy)- 5-oxocyclopentyl]-5-heptenoic acid (37 g) in the form of an oil.: Preparation of dimethyl-(3, 3-difluoro-2, 2-dihydroxyheptyl)phosphonate (I): Dimethyl-(3, 3-difluoro-2-oxoheptyl)phosphonate (94 g, 364.06 mmoL) was added to a mixture of heptanes (450 mL) and water (45 mL) at room temperature. The reaction mixture was stirred at room temperature for 4.5 hours. The thick white suspension was filtered through a Buchner funnel and the solid washed with heptanes, suction dried and then dried in an oven under vacuum at room temperature overnight to furnish dimethyl-(3, 3-difluoro- 2, 2- dihydroxyheptyl)phosphonate (I) (84.35 g, 83.89%) as a crystalline white solid. The PXRD diffractogram is depicted in Figure 1 , the FTIR spectrum in Figure 2 and the DSC thermogram in Figure 3. 1H NMR (CDCI3): delta 1H-NMR (DMSO-d6): 6.45 (s, 2H), 3.68 (d, 6H, J = 11.3 Hz), 2.23 (d, 2H, J = 18.8 Hz), 2.06-1.89 (m, 2H), 1.48-1.38 (m, 2H), 1.36- 1.26 (m, 2H), 0.89 (t, 3H, J = 7.2 Hz).To a solution of 3, 3-difluoro-2-oxo-hexyl- dimethylphosphonate (0.192moldry THF (100 ml) at 0C under argon atmosphere was added potassium tert-butoxide ( 1.0M in THF ) . The reaction. mixture was stirred and warmed to room temperature for '30 min anhydrous zinc chloride(0.192mol) was added to the reaction ' mixture and stirred at room temperature for 3h. The reactions were then mixed with a solution of the aldehyde above in dry THF (100 -ml), and were stirred at 45C for 18 h. The mixture was poured into aqNH4Cl (400 ml) and extracted with ethyl acetate three times. The combined organic layer was washed with 1N-HC1, aqNaHC03 and brine then dried over MgS04, filtered and concentrated. The' crude residue was purified by flash chromatography (Fuji Silysia silicagel BW-300SP, 30:70 to 60:40 EtOAc/Hexanes ) to give compound [3] in' 76.3 % yield.1H-NMR (400MHz, CDC13) delta 6.98 ( 1H, m, ), 6.60 ( 1H, m, ), 5.03( 1H, . m, ), 4.65 ( 1H, m, ) , 4.25 - 4.05 ( 1H, m, ), 3.78 ( 1H, m, ) , 3.50 ( 1H, m, ), 2.92 - 1.35 ( 18H, m, ), 0.92 ( 3H, t, J = 7.2 Hz, ) .Under nitrogen protection, 45 g of compound 6 is dissolved in 100 ml MTBEAdd 6.9g of lithium hydroxide monohydrate, The reaction was performed at room temperature for 1 hour.A mixed solution of 30 g of compound 7 and 200 ml of dichloromethane was added, Then add 8ml H2O, The reaction system was warmed to 45C and reacted for 24 hours.Add 480ml of water to the system, stir for 20 minutes, extract three times with ethyl acetate, combine the organic phases, and dry over anhydrous sodium sulfate.Filtration, concentration and chromatography with ethyl acetate/petroleum ether gave compound 8 as 28 g of an oily product.To a mixture of dimethyl(3, 3-difluoro-2-oxoheptyl)phosphonate (210 g, 0.81 mol) in methyl i-butyl ether/water (300/10 mL) was added Zn(OH)2 (100 g, 0.81 mol) and the mixture was stirred under nitrogen for 1 hour. A solution of compound 6 (200 g, 0.77 mol) in dichloromethane (300 mL) was added and the mixture was stirred for 24 hours. After completion of the reaction, the reaction was then quenched with cold 1 hydrochloric acid (120 mL). The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to dryness under vacuum. The crude material was further purified by column chromatography (25% ethyl acetate in heptanes) to yield compound 7[(3aR, 4R, 5R, 6aS)-4-((E)-4, 4-difluoro-3-oxo-1-octenyl)-2-oxo-5-(phenylmethox y)hexahydro-2H-cyclopenta[ib]furan] in 85% yield.

Molecular Weight:258.20
XLogP3:1.7
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:8
Exact Mass:258.08325234
Monoisotopic Mass:258.08325234
Topological Polar Surface Area:52.6
Heavy Atom Count:16
Complexity:273
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes