Research Institute for Medicine & Chemistry, Inc.

Glaxo Laboratories Limited

Other

Schering Corporation

Quest International B.v.

Olin Corporation

Montedison S.p.a.

Derek H Barton

Robert H Hesse

Brian Edgar Looker

Alan Gibson Long

Edward McKenzie Wilson

Peter George Sammes

William George Underwood

Dennis K Taylor

Chi-Lam Tse

Franco Gozzo

Ezio Rizzardo

Stuart W McCombie

Anantha R Sudhakar

Tiruvettipuram K Thiruvengadam

Ronald C Breslow

Roberto Colle

Timothy L McAllister

Chou-Hong Tann

Cesar Colon

Junning Lee

Ciro Preziuso

Graham Hewitt

Catherine Tachdjian

William G Elphinstone

Antony G Barrett

Ezzio Rizzardo

Shyamal I Parekh

This invention provides an improved process for producing azetidinones. More particularly, this invention provides the steps of producing an trans-azetidinone represented by the formula ##STR1## from a carboxylic acid R.sup.2 --D--CH.sub.2 COOH, an aldehyde R.sup.1 --A--CHO and an amine RNH.sub.2, by the steps of: (a1) converting a carboxylic acid to the corresponding acid chloride; (b1) deprotonating a chiral oxazolidinone and treating the resulting anion with the product of step (a1); (c1) enolizing the product of step (b1) and condensing with the aldehyde; (d1) hydrolyzing the product of step (c1); (e1) condensing the product of step (d1) with the amine; and (f1) cyclizing the product of step (e1). Alternatively, the process comprises (a2) enolizing the product of step (b1) and condensing, in the presence of a Lewis acid, with a Schiff's base prepared from the aldehyde and the amine; and (b2) cyclizing the product of step (a2).

Process for the stereospecific synthesis of azetidinones

Process for the catalytic oxidation of a saturated hydrocarbon to obtain a ketone which involves carrying out the oxidation simultaneously with the oxidation of H.sub.2 S to form elemental sulfur and the ketone.

Co-oxidation of H.sub.2 S and saturated hydrocarbons

The invention provides novel compositions for use in pharmaceutical and veterinary medicine which contain 1.alpha.-hydroxy vitamin D compounds. Particular compositions are described which contain steroids which induce or assist in combatting osteoporosis together with 1.alpha.-hydroxy vitamin D.sub.3 or 1.alpha.,25-dihydroxy vitamin D.sub.3. Methods of treatment of diseases are also provided including many which are resistant to vitamin D.sub.3, in particular bone diseases.

Chemical compounds and process

Preparation of a methyl ketone intermediate useful in the synthesis of (-)-dodecahydro-3a,6,6, 9a-tetramethyl-naphtho(2,1-b) furan by subjecting (-)-sclareol to ozonolysis in the presence of iodine or iodine-containing compound. The intermediate can be converted to (-)-dodecahydro-3a,6,6,9a-tetramethyl-naphtho(2,1-b) furan by Baeyer-Villiger oxidation followed by reduction of the resulting product in the presence of a Lewis acid.

Production of (-)dodecahydro-3a,6,6,9a-tetramethyl-naphtho[2,1-b] furan

Synthesis of (-)-dodecahydro-3a,6,6,9a-tetramethyl-naphtho(2,1-b)furan from sclareol in a three-stage process.

Preparation of ambrox

A compound selected from the group consisting of 3,5-diphenyl- and substituted 3,5-diphenyl-1-hydroxy-1,2-dihydroimidazole-2-thiones, and combinations thereof. Also disclosed is a process for producing the compound and an antimicrobial composition comprising the compound and at least one component selected from the group consisting of soaps, shampoos, skin care medicaments, cosmetics and paints.

3,5-diphenyl or substituted

The invention provides novel 1.alpha.-hydroxy vitamin D compounds and a method for their preparation from 1.alpha.-hydroxy-25-hydrogen cholesta-5,7-dienes by irradiation and isomerization techniques. The invention also includes the said 1.alpha.-hydroxy-25-hydrogen-cholesta-5,7-dienes and the corresponding cholest-5-enes. The new compounds may be obtained in a crystalline form substantially free from isomeric or other impurities arising from manufacture.

1-.alpha.-hydroxy vitamin D compounds and process for preparing same

Thiocarbamoyl-guanidine derivatives having herbicide activity are disclosed. The process for their preparation and their use as herbicides are disclosed too.

Herbicides

Saturated organic compounds containing a hydrogen atom bound to a tertiary carbon atom may be electrophilically fluorinated by reaction with an electrophilic fluorinating agent such as molecular fluorine or trifluoromethyl hypofluorite under conditions whereby the formation of free fluorine radicals is suppressed, e.g. by the presence of a free radical inhibitor such as oxygen or nitrobenzene, the reactants being substantially homogeneously dispersed in a liquid medium, e.g. a solvent medium such as fluorotrichloromethane or chloroform/fluorotrichloromethane, so that the said hydrogen atom is electrophilically replaced by a fluorine atom. The fluorination is highly selective and, in the case of complex substrates such as saturated steroids which contain a number of tertiary C--H bonds, may be substantially completely confined to replacement of the hydrogen atom at the tertiary carbon atom which has the highest electron density about the C--H bond. The electron density and thus the direction of the fluorination may be controlled by appropriate selection of substituent groupings in the substrate molecule. Novel 14.alpha.-fluorosteroids are also disclosed, including compounds having valuable androgenic or progestational activity and useful synthetic intermediates.

Chemical process for fluorinating a tertiary carbon atom in the steroid

N,N-difluoroamines are prepared by fluorination of compounds containing a &gt;C.dbd.N-- bond using molecular fluorine or a hypofluorite in which the fluoroxy group is bonded to an inert electron attracting group, such hypofluorites including fluoroalkyl hypofluorites such as trifluoromethyl hypofluorite. The fluorination is advantageously conducted in the presence of an alkanol or other nucleophilic compound. Suitable starting materials include imino ethers and esters and aliphatic and aromatic Schiff's bases, use of the latter being particularly convenient.

Preparation of N,N-difluoroamines

Novel semisynthetic .beta.-lactam intermediates of use in the production of cephalosporins, penicillins and related .beta.-lactam antibiotic compounds are provided. The novel compounds are prepared from .beta.-lactams obtained by cleavage of the 1,2-sulphur-carbon bond of a penicillin 1-oxide (with subsequent internal or external trapping of the sulphur atom to leave a residual substituent as the .beta.-lactam nitrogen) by removal of the said residual substituent by an oxidative cleavage reaction.

Chemical compounds

Novel compounds of general formula ##STR1## (where R.sup.1 and R.sup.2, which may be the same or different, are hydrogen atoms or alkyl groups; and R.sup.3 and R.sup.4, which may be the same or different, represent alkyl groups which may carry substituents, R.sup.4 alternatively representing a hydrogen atom; or R.sup.3 and R.sup.4 together with the intervening N represent a heterocyclic group or an acid-addition salt thereof) are provided, together with a process for their preparation. The new compounds are useful as antidepressants.

5(3-Substituted aminopropyl)-10-trifluoromethoxy-5H-dibenz[b,f]azepines

Novel semisynthetic 4-thio-azetidin-2-one derivatives of use in the production of cephalosporins, penicillins and related .beta.-lactam antibiotic compounds are provided by cleavage reactions involving the corresponding 4-dithio-azetidin-2-one derivative or a suitable thiazoline derivative, which starting materials may be obtained from penicillins without changing the configuration of the .beta.-lactam structure desired in the final product.

Alkylative cleavage of azetidinone disulfides

A process for the preparation of 5,6-cis- and 5,6-trans-10,19-dihydro-vitamin D derivatives which comprises hydrogenating a corresponding vitamin D compound in the presence of a ligand-coordinated homogeneous transition metal catalyst whereby the C-19 methylene group of the vitamin D compound is converted into a methyl group.

Hydrogenation process for the preparation of 5,6 cis- and

The process for removing a secondary hydroxyl group from an organic compound having at least one secondary hydroxyl group and having any amino groups protected, comprises the reaction of a reactive ester of said secondary hydroxyl group selected from the group consisting of an O-alkylthioester and an O-alkylselenoester with at least one mole of an organotin hydride, preferably tri-n-butylstannane, in an inert, aprotic solvent at a temperature of at least about 100.degree. C and under an inert atmosphere. The process is particularly useful in removing secondary alcohols in aminoglycoside antibiotics to produce deoxy derivatives thereof having antibacterial activity. Also described are novel O-sec.-alkylthiobenzoate, O-sec.-alkyl-S-methylxanthate, N-(sec.-alkoxythiocarbonyl)-imidazole esters, and di-O-alkylthiocarbonates having at least one secondary O-alkyl group, useful intermediates of the claimed process.

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London, United Kingdom

Derek H Barton