Merck + Co., Inc.

Norman L Wendler

David Taub

Zbigniew S Zelawski

Harry L Slates

Chan-Hwa Kuo

Narindar N Girotra

Zbigniew S Zelawski, Deceased

A method for the total chemical synthesis of flavipucine employs the condensation of 4-hydroxy-6-methyl-2-pyridone with isobutylglyoxal in alkali alkoxide. The resulting alkali salt is acylated in both the 1' and 4 positions. Treatment of the 1',4-diacyloxy derivative with excess alkaline peroxide yields flavipucine.

Chemical synthesis of flavipucine

Racemic or optically-active prostaglandin E.sub.1 is synthesized from racemic or optically-active precursors in good yield at the various steps from 3.alpha.,6,7,7.alpha.-tetrahydro-4-methyl-2-oxo-1.beta.-indaneheptanoic acid methyl ester proceeding through 2.alpha.-(2-carboxyethyl)-3.beta.-hydroxy-5-oxo-1.beta.-cyclopentaneheptan oic acid methyl ester, .delta.-lactone, 5-cyclic ethylene acetal, 2.alpha.-(2-carboxy-2-formylethyl)-3.beta.-hydroxy-5-oxo-1.beta.-cyclopent aneheptanoic acid methyl ester, .delta.-lactone, 5-cyclic ethylene acetal, 2.alpha.-(2-carboxy-2-oxoetyl)-3.beta.-hydroxy-5-oxo-1.beta.-cyclopentaneh eptanoic acid methyl ester, .delta.-lactone, 5-cyclic ethylene acetal, and 3.beta.-hydroxy-2.alpha.-(3-oxo-1-octenyl)-5-oxo-1.beta.-cyclopentanehepta noic acid methyl ester, 5-cyclic ethylene acetal.

3.beta.-[(Methoxalyl)oxy]-2.alpha.-(3-oxo-1-octeny

Racemic or optically-active prostaglandin E.sub.1 is synthesized from racemic or optically-active precursors in good yield at the various steps from 3.alpha.,6,7,7.alpha.-tetrahydro-4-methyl-2-oxo-1.beta.-indaneheptanoic acid methyl ester proceeding through 2.alpha.-(2-carboxyethyl)-3.beta.-hydroxy-5-oxo-1.beta.-cyclopentaneheptan oic acid methyl ester, .delta.-lactone, 5-cyclic ethylene acetal, 2.alpha.-(2-carboxy-2-formylethyl)-3.beta.-hydroxy-5-oxo-1.beta.-cyclopent aneheptanoic acid methyl ester, .delta.-lactone, 5-cyclic ethylene acetal, 2.alpha.-(2-carboxy-2-oxoethyl)-3.beta.-hydroxy-5-oxo-1.beta.-cyclopentane heptanoic acid methyl ester, .delta.-lactone, 5-cyclic ethylene acetal, and 3.beta.-hydroxy-2.alpha.-(3-oxo-1-octenyl)-5-oxo-1.beta.-cyclopentanehepta noic acid methyl ester, 5-cyclic ethylene acetal.

2.alpha.-(2-Carboxy-2-formylethyl

Racemic or optically-active prostaglandin E.sub.1 is synthesized from racemic or optically-active precursors in good yield at the various steps from 3.alpha., 6,7,7.alpha.-tetrahydro-4-methyl-2-oxo-1.beta.-indaneheptanoic acid methyl ester proceeding through 2.alpha.-(2-carboxyethyl)-3.beta.-hydroxy-5-oxo-1.beta.-cyclopentaneheptan oic acid methyl ester, .delta.-lactone, 5-cyclic ethylene acetal, 2.alpha.-(2-carboxy-2-formylethyl)-3.beta.-hydroxy-5-oxo-1.beta.-cyclopent aneheptanoic acid methyl ester, .delta.-lactone, 5-cyclic ethylene acetal, 2.alpha.-(2-carboxy-2-oxoethyl)-3.beta.-hydroxy-5-oxo-1.beta.-cyclopentane heptanoic acid methyl ester, .delta.-lactone, 5-cyclic ethylene acetal, and 3.beta.-hydroxy-2.alpha.-(3-oxo-1-octenyl)-5-oxo-1.beta.-cyclopentanehepta noic acid methyl ester, 5-cyclic ethylene acetal.

2.alpha.-(2-Carboxy-2-oxoethyl)-3.beta.-hydroxy-5-oxo-1.beta.-c

2.alpha.-Formyl-3.beta.-[(methoxalyl)oxy]-5-oxo-1.beta.-cyclopentanehepta

The invention relates to a new and novel synthesis of prostaglandin E.sub.2, and it particularly relates to a novel process starting with relatively inexpensive starting materials. The invention further relates to a synthesis which is readily adaptable for large scale processing because of the high yields in the individual reaction steps. The invention further relates to novel compounds formed as intermediates in the synthesis of prostaglandin E.sub.2. The invention still further relates to synthetic analogs and known metabolites of prostaglandin E.sub.2 and prostaglandin E.sub.1, useful as standards in certain biological assays for determining prostaglandin-like activity.

Intermediates in the synthesis of prostaglandins

2.alpha.-(2-Loweralkanoyloxy-2-carboxyvinyl)-3.beta.-hydroxy-5-oxo-1.beta.-

(.+-.)-Prostaglandin E.sub.1 is totally synthesized with a high degree of stereoselectivity and in good yield at the various steps from 6-methoxy-3-indanol by a sequence of reactions proceeding through 6-methoxy-3-indeneheptanoic acid ester, 2,6-dioxo-4,5,6,7-tetrahydro-7-methyl-3-indanheptanoic acid ester 2-cyclic ethylene acetal, cis-3,4,5,7a-tetrahydro-7-methyl-2-oxoindanheptanoic acid ester, trans-trans 3-acetyl-2-(2-carboxy-ethyl)-5-oxocyclopentane heptanoic acid ester 5-cyclic-ethylene acetal, 3-acetoxy-2-formyl-5-oxocyclopentaneheptanoic acid ester 5-cyclic ethylene acetal, and 15-dehydro (.+-.)-prostaglandin E.sub.1. The end compound has the biological activity of naturally occurring prostaglandin E.sub.1.

Prostaglandin intermediate

The disclosure relates to novel precursors for the synthesis of prostaglandin E.sub.1 and the production of said precursors.

Precursors for prostaglandin E.sub.1

Disclosed is a novel stereospecific synthesis of Prostaglandin E.sub.1.

Prostaglandin E.sub.1 intermediate

Prostaglandins and methods of making same

6 .alpha.-Carboxy-5.alpha. (1-hydroxyethyl)-2-cyclohexene-1-heptanoic acid, .gamma. - lactone, and lower alkyl and aralkyl esters thereof, are useful intermediates for the production of Prostaglandin E.sub.1.

This case relates to the synthesis of novel precursors of prostaglandin E.sub.1, particularly the intermediate 4-hydroxy-3 .alpha.-methyl-1.alpha., 2.alpha.-dilower-alkanoyloxymethylcyclohexene.

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Summit, NJ, United States of America

Norman L Wendler