15(R)-15-METHYL PROSTAGLANDIN E2 Chemical Properties

Boiling point:

417.24°C (rough estimate)

Density 

1.0525 (rough estimate)

refractive index 

1.6120 (estimate)

solubility 

DMF: >100 mg/ml (from PGE2); DMSO: >100 mg/ml (from PGE2); Ethanol: >100 mg/ml (from PGE2); PBS pH 7.2: >5 mg/ml (from PGE2)

form 

A crystalline solid

pka

4.75±0.10(Predicted)

15(R)-15-METHYL PROSTAGLANDIN E2 Usage And Synthesis

Originator

Arbaprostil,ZYF Pharm Chemical

Uses

Antisecretory (gastric).

Definition

ChEBI: 15-methyl-15R-PGE2 is a prostanoid.

Manufacturing Process

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone is added to a solution of PGF2a [(5Z,11α,13E)-11,15-dihydroxy-9-oxoprosta-5,13-dien-1-oic acid or Prostaglandin E2] in dioxane. The mixture is stirred 24 h at 50°C under nitrogen, and then is cooled to 20°C and filtered. The filtered solids are washed with dichloromethane. Evaporation of the combined filtrate and washings at reduced pressure gives a residue which is chromatographed on silica gel (Silicar CC-4; Malincrodt), eluting with 50% ethyl acetate in Skellysolve B (a mixture of isomeric hexanes). Evaporation of the eluates gives 15-oxo-PGF2a.
A mixture of hexamethyldisilazane and tri-methylchlorosilane is added to a solution of 15-oxo-PGF2a in tetrahydrofuran. This mixture is stirred 16 h at 25°C under nitrogen, and is then filtered. The filtrate is evaporated under reduced pressure. Xylene is added to the residue and the mixture is evaporated at 60°C under reduced pressure. This addition of xylene and evaporation is repeated twice. The resulting residue is the tris-(trimethylsilyl) derivative of 15-oxo-PGF2a.
A 3 M diethyl ether solution of methylmagnesium bromide is added dropwise to a stirred solution of the tris-(trimethylsilyl) derivative of 15-oxo-PGF2a in diethyl ether at 25°C.
The mixture is stirred 30 min at 25°C, after which an additional the methylmagnesium bromide solution is added and stirring is continued an additional 30 min. The resulting reaction mixture is poured into saturated aqueous ammonium chloride solution at 0°C. After stirring several minutes, the mixture is extracted repeatedly with diethyl ether. The combined diethyl ether extracts are washed with saturated aqueous sodium chloride solution and then dried with anhydrous sodium sulfate. Evaporation of the diethyl ether gives a yellow oil which is dissolved in ethanol. That solution is diluted with water, and the mixture is stirred 4 h at 25°C. The ethanol in the resulting solution is evaporated at reduced pressure, and the aqueous residue is saturated with sodium chloride and then extracted with ethyl acetate. Solution, dried with anhydrous sodium sulfate, and evaporated under reduced pressure to give a mixture of 15-methyl-PGF2a and 15-methyl-15(R)-PGF2a.
The 520.0 mg mixture of 15-methyl-PGF2a and 15-methyl-15(R)-PGF2a is dissolved in diethyl ether and cooled to 0°C. Excess diazomethane dissolved in diethyl ether is then added, and the mixture is maintained 5 min at 0°C and then 5 min at 25°C. The solution is evaporated in a stream of nitrogen, and the residue is chromatographed on 500.0 g of neutral silica (Merck), eluting successively with 20%, 40%, and of 50% ethyl acetate in Skellysolve B. The corresponding eluates emerging from the column are discarded. Elution is continued successively with gradients of 4 L of 50% and 4 L of 60% ethyl acetate in Skellysolve B, and 5 L of 60% and 5 L of 75% ethyl acetate in Skellysolve B, and then with 4 L of 75% ethyl acetate in Skellysolve B, collecting the corresponding eluates in 500 ml fractions. Elution is further continued successively with 5 L of 75% ethyl acetate in Skellysolve B and with 6 L of 100% ethyl acetate, collecting the corresponding eluates in 200 ml fractions. Eluate fractions 29-35 are combined and evaporated to give 109.0 mg of 15-methyl-15(R)-PGF2a methyl ester.
Aqueous potassium hydroxide solution is added to a solution of 15-methyl- 15(R)-PGF2a methyl ester in a mixture of methanol and of water under nitrogen. The resulting solution is stirred 2 h at 25°C, and is then poured into several volumes of water. The aqueous mixture is extracted with ethyl acetate, acidified with 3 N hydrochloric acid, saturated with sodium chloride, and then extracted repeatedly with ethyl acetate. The latter ethyl acetate extracts are combined, washed successively with water and saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and evaporated under reduced pressure. The crystalline residue is recrystallized from a mixture of ethyl acetate and Skellysolve B to give 15-methyl-15(R)-PGF2a.

Therapeutic Function

Gastric antisecretory; Antiulcer

Safety Profile

Human reproductive effects byintramuscular route: terminates pregnancy. Otherexperimental reproductive effects.

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