Schering Corporation

Schering-plough Corporation

Donald Hou

Janet L Mas

Shen-Chun Kuo

Richard W Draper

Gary M Lee

Martin Steinman

Dinesh Gala

Yee-Shing Wong

George G Wu

Frank Xing Chen

Agnes S Kim-Meade

Ingrid Mergelsberg

Charles F Bernard

Zheng-Yun Zhan

This invention relates to a novel process for the synthesis of Temozolomide, an antitumor compound, and analogs, and to intermediates useful in this novel process.

Synthesis of temozolomide and analogs

Disclosed is a process for preparing a compound of the formula:

Enantioselective alkylation of tricyclic compounds

Disclosed are a process and intermediates of the formulae ##STR1## wherein X.sup.- is halide, BF.sub.4.sup.-, R.sup.3 SO.sub.3.sup.-, wherein R.sup.3 is C.sub.1 -C.sub.6 alkyl, CF.sub.3, C.sub.1 -C.sub.6 alkylphenyl or phenyl, and Q is a group of the formula ##STR2## wherein R is C.sub.1 -C.sub.6 alkyl; useful for preparing benzazepine intermediates of the formula ##STR3## These benzazepine intermediates are useful for preparing benzazepines having activity as selective D1 receptor antagonists.

Process for preparing intermediates for the synthesis of D1 antagonists

Disclosed are a process and intermediates of the formula ##STR1## wherein R is --CH.sub.3 or --C(O)--OR.sup.1, and R.sup.1 is C.sub.1 -C.sub.6 alkyl or --CH.sub.2 C.sub.6 H.sub.5 ; or the formula ##STR2## wherein: R.sup.2 is H or OH, R is --C(O)OR.sup.1 and R.sup.1 is C.sub.1 -C.sub.6 alkyl or --CH.sub.2 C.sub.6 H.sub.5, or where R.sup.2 is H, R can also be CH.sub.3 ; for preparing benzazepine intermediates of the formula ##STR3## The benzazepine intermediates are useful for preparing benzazepines having activity as selective D1 receptor antagonists.

Process for preparing benzazepine intermediates for the synthesis of D1

Disclosed is a process for preparing allylic halides of the formula I ##STR1## wherein X is Cl, Br or I, for use as intermediates in the synthesis of substituted tetrahydrofuran azole anti-fungal agents.

Process for preparing intermediates for the synthesis of antifungal

There is disclosed a compound represented by the formula ##STR1## where P is a hydroxy protecting group.

Anhydro penicillin derivatives

A method for producing a compound of the formula ##STR1## wherein: R.sup.1, R.sup.11 and R.sup.12 may be the same or different and each is hydrogen or alkyl;

Preparation of alpha-(3,4-disubstituted aryl) cyclic ketones

There is disclosed a compound represented by the formula ##STR1## wherein each P is hydrogen or a hydroxy protecting group and R and R' are each the same and are hydrogen, ##STR2## wherein R' is lower alkyl and R'' is a carboxy protecting group. The compounds are useful as intermediates for preparing penems.

Synthesis of azetidinones

A multi-step stereospecific process for preparing (3S,4R,5R)-1-(allyloxycarbonyl)-methyl-3-(1-hydroxyethyl)-4-beta-naphthoxy thi ocarbonylthio-2-azetidinone, stereoisomers thereof or hydroxy protected analogs thereof from anhydropenicillin. The azetidinones are intermediates useful for producing penems which are a known group or antibacterial compounds. The process involves protecting the hydroxy group of anhydropenicillin with a readily removable hydroxy protecting group, then reacting the resulting compound by treatment with oxygen and cuprous chloride in methanol, followed by reaction with ozone to produce a hydroxy protected dithiobis azetidinone and convert the methylidene groups originally in the 2-position of anhydropenicillin and in the bis-compound, to a (methoxycarbonyl)-carbonyl group. The resulting compound is converted to the unprotected dithiobis compound by reaction with ammonium hydroxide, then allyliodoacetate followed by an acid. Reaction of the resulting compound with zinc and a mineral acid followed by reaction with 0-2-naphthalenylcarbonochloridothioate converts the unprotected dithiobis compound to 1-(allyloxycarbonyl)methyl-3-(1-hydroxyethyl)-4-beta-naphthoxy (thiocarbonyl)thio-2-azetidinone.

Synthesis of azetidinones using CuCl

A multi-step stereospecific process for preparing (3S,4R,5R)-1-(allyloxycarbonyl)-methyl-3-(1-hydroxyethyl)-4-beta-naphthoxy thiocarbonylthio-2-azetidinones, stereoisomers thereof or hydroxy protected analogs thereof from anhydropenicillin. The azetidinones are intermediates useful for producing penems which are a known group of antibacterial compounds. The process involves protecting the hydroxy group of anhydropenicillin with a readily removable hydroxy protecting group, then converting the resulting compound by ozonolysis followed by reaction with a trialklyl phosphite, then hydrolysis to remove the methylidene group at the 2-position of anhydropenicillin. The resulting compound is converted to the unprotected 4-beta-naphthoxy thiocarbonylthio derivative by reaction with allyl alcohol and HCl followed by reaction with O-2-napththalenylcarbonochloridothioate, or to the protected compound by reaction with silver imidazolate and allyl alcohol followed by reaction with O-2-naphthalenylcarbonochloridothioate.

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Verona, NJ, United States of America

Donald Hou