The Upjohn Co.

Jerry A Walker

Edward J Hessler

Sanjay I Amin

David R White

William G Salmond

Thomas A Hylton

In preparing arylalkanoic acids, e.g. ibuprofen or naproxen, via the conversion of the selected .alpha.-haloketal derivative of a 1-haloethyl aryl ketone to the haloalkyl ester of the arylalkanoic acid using a zinc salt catalyst the improvement comprising reacting a ring-substituted 6-membered ring ketal of the selected 1-haloethyl C.sub.6 -C.sub.12 -aryl ketone with a soluble zinc carboxylate salt to form the corresponding 3-haloalkyl arylalkanoic acid ester. The ester is converted to the alkali metal salt of the acid with base in an aqueous/water insoluble organic liquid mixture and the crude salt is converted to the corresponding acid in an aqueous/water insoluble solvent mixture for the acid, the organic solution of the acid is washed with a pH 7.0 to 8.0 buffer solution, and the arylalkanoic acid product is separated from the mother liquor which mother liquor is recycled to the alkali metal arylalkanoate salt forming step of the process to accumulate and recover the arylalkanoic acid values which remained in the mother liquor.

Arylalkanoic acid process improvement

The process of the present invention transforms 17-keto steroids (I) to the corresponding corticoids (IV) in three steps.

Corticosteroids from 17-keto steroids via 20-cyano-.DELTA..sup.17

.DELTA.16-20-keto steroids (I) are converted to 17.alpha.-hydroxy-20-keto steroids (III) in 2 steps, hydrosilylation followed by peracid oxidation.

.DELTA.16-20-Keto steroid conversion to 17.alpha.-hydroxy-20-keto

Disclosed is a 20,21-dihalo steroid (VII) and a steroidal sulfoxide (VIII) as well as processes to produce them. The 20,21-dihalo steroid (VII) and sulfoxide (VIII) are intermediates useful in the preparation of pharmaceutically useful corticoids.

Preparation of corticoids from 17-keto steroids

The present invention is a process for the transformation of a 17-keto steroid (II) to a corticoid (XI) which has pharmaceutical utility.

A process for the preparation of corticoids (XI) which comprises reacting a protected 17-keto steroid (II) with a metallated 1,2-dihaloethene (III).

Preparation of 21-halo steroids

The invention concerns the novel compounds dialkyl 2-(3-fluoro-4-nitrophenyl)-2-methylmalonate IIIa and dialkyl 2-(3-fluoro-4-aminophenyl)-2-methylmalonate IVa useful as intermediates in an improved process for making 2-(2-fluoro-4-biphenylyl)propionic acid, known as flurbiprofen, having the formula ##STR1## and ester thereof. It has anti-inflammatory activity which is about 240 times that of aspirin and analgesic activity which is about 180 times that of aspirin in standard laboratory tests. However, despite this high activity, the toxicity (LD.sub.50) is only 1.2 to 2.4 times greater than that of aspirin in standard laboratory tests. Also within the invention is a novel method of making the above intermediates and analogs thereof useful to prepare corresponding biaryl compounds which have pharmaceutical uses.

Malonic acids and esters thereof

A process for the preparation of corticoids (IX) which comprises reacting a 17-keto steroid (I) with a metallated halogenated acetylene (II) followed by reaction with a sulfenylating agent (IV) and C.sub.17 side chain rearrangement.

Metallated halogenated acetylene corticoid synthesis

Processes for the preparation of hydratropic acids and esters

Substituted ethanes (I) are reacted with an alkyl metal reagent to form isomeric metalated olefins (IIIA and IIIB) having a trans (IIIB) to cis (IIIA) ratio of greater than 70:30.

Process to prepare metalated olefins

Thallium (l) alkanoate salts are oxidized to thallium (lll) salts in a liquid medium with a peroganic carboxylic acid in the presence of a reactive form of manganese or ruthenium.

Process for oxidizing thallium (I) to thallium (III)

2-Aryl-C.sub.3 to C.sub.6 -alkanoate esters are prepared economically by reacting an enol ether of an aryl alkyl ketone with a trivalent thallium salt in an organic solvent. The trivalent thallium ions can be regenerated by adding a peracid and a reactive form of manganese, ruthenium, cobalt, iridium, hafnium, osmium or neobium to oxidize monovalent thallium ions to the trivalent state, in a sequential, continuous or stoichiometric procedure. A continuous process using a Scheibel column is disclosed. The ester intermediate product is then converted to the corresponding 2-aryl-C.sub.3 - to C.sub.6 -alkanoic acid or salt thereof. The aryl group is selected so the resulting acid product will be a useful compound such as an anti-inflammatory, analgesic and anti-pyretic drug or agriculturally useful product. Examples of drug acids which can be made by this process include ibuprofen, flurbiprofen, fenoprofen and naproxen and the like.

Growing community of inventors

Oshtemo Township, MI, United States of America

Jerry A Walker