Dimethyl Sulfoxide → HCID 54563660, compound

The reaction sequence shown in Reaction Scheme VII was followed to yield the above product. Into a reaction flask was added 25 gm (135 mmol) of bromofluoroethylacetate, 29.2 gm (176 mmol) of triethyl phosphite and the resultant mixture heated to about 150° C. under nitrogen. Ethyl bromide was distilled off and condensed as the reaction proceeded. After 31/2 hours the reaction was cooled and the reaction mixture distilled under high vacuum and the fraction collected boiling at 105°-110° C. There was obtained 26.78 gm of the fluoromethylphosphonate. Into a reaction vessel containing 50 ml of dry THF at -8° C. was added 2.13 gm (21 mmol) of diisopropylamine and a solution of 8 ml (20 mmol) of n-butyllithium in hexane. After 30 minutes, 5.08 gm of the above phosphonate was added dropwise with stirring and the reaction mixture was stirred at room temperature overnight. Distilled acetone (2.94 ml) was added at room temperature to the Witting salt and a rapid temperature rise (from 25°-40° C.) was observed. The mixture was cooled to 3° C. and the remaining acetone added. The reaction mixture was stirred for 2 hours, poured into a cold mixture of dilute sodium chloride and 0.5 N HCl and shaken with ether (100 ml). The organic layer was separated, washed with cold sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. Following filtration, the excess solvent was distilled off yielding 2.02 gm of the ethyl 2-fluoro-3- methyl-but-2-en-oate. The ester (0.438 gm, 3 mmol) was dissolved in THF and cooled to -5 to -10° C. To the mixture was added lithium aluminum hydride (2.25 ml, 2.25 mmol) slowly with stirring. After the addition, the reaction was held at room temperature for about 30 minutes. The reaction mixture was poured into cold saturated ammonium chloride solution and extracted once with diethyl ether and acidified with 2N HCl. The mixture was extracted with diethyl ether and washed with saturated sodium chloride and dried over magnesium sulfate. The solvent was distilled off at atmospheric pressure yielding the 2-fluorobutenol. The butenol was reacted in the same manner as discussed in Example 7 using 4.17 ml of DMSO, 2.5 ml of oxalyl chloride, 16.7 ml of triethylamine, 300 ml of dichloromethane and 10.0 gm of 1-triphenylphosphoranylidene-2-propanone. The reaction yielded 2.73 gm of the 6-methyl-5-fluoro-hept-3,5-diene-2-one having a boiling point of 55°-56° C. The ketone was reacted through a Grignard reaction in the method described in Example 7 using 3.35 gm (23.6 mmol) of the heptadienone, 3.54 gm (29.7 mmol) of propargyl bromide, 0.77 gm (31.9 mmol) of magnesium and 50 ml of THF. The Grignard step was complete after approximately 30 minutes to yield after workup 5.28 gm of a yellow oil which was chromatographed yielding 2.66 gm of the nonyne. The nonyne was reacted in a manner similar to that of Example 7. In a flask was added 1.27 gm of 7-fluoro-4,7-dimethyl-4-hydroxy-non-5,7-diene-1 -yne (7.0 mmol) tributyltin hydride (3.06 gm, 10.5 mmol) and a trace of AIBN. The reagents were stirred under argon. After 4 hours of irradiation with a sunlamp at ambient temperature, the reaction mixture was purified by chromatography yielding 1.8 gm of the vinyl stannane product. The 1.8 gm of the 4-hydroxy-7-fluoro-4,8-dimethyl-1-trans-stannyl-1,5,7-octatriene (3.8 mmol) was protected with a trimethylsilyl group in the manner described in Example 7 using 0.60 ml (52 mg, 4.76 mmol) of trimethylchlorosilane, 0.41 gm imidazole (6 mmol) and 6 ml of DMF yielding 1.87 gm of the protected product. The trimethylsilyl vinyl stannane was reacted with n-butyllithium and pentynyl copper followed by the protected cyclopentenone to provide the protected prostaglandin product using the following quantities of reagents: 0.935 gm (1.7 mmol) of the vinylstannane; 0.68 ml (1.7 mmol) of n-butyllithium; 4 ml of THF; 0.25 gm of pentynyl copper (1.9 mmol); 0.64 gm of HMPT; 10 ml of ether; and 0.352 gm (1.0 mmol) of the triethylsilyl protected cyclopentenone. The resultant reaction workup provided 1.4 gm of a clear oil. Following chromatography, 0.31 gm of the prostaglandin product was obtained and this product was deprotected in a solution of 18 ml of acetone/water (5 to 1) containing approximately 15 mg of pyridine p-toluenesulfonate. The product of the above formula was obtained.

ORD record

ord-6eac2dca77c84b988b893dc4399f2bbb

Source dataset

uspto-grants-1993_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05177251