Taiho Pharmaceutical Company Limited

Otsuka Kagaku Kabushiki Kaisha

Akira Nakai

Hideo Tanaka

Motoaki Tanaka

Sigeru Torii

Shozo Yamada

Hisashi Ohbayashi

Michio Sasaoka

Daisuke Suzuki

Masatoshi Taniguchi

Shigeru Torii

Kiyotoshi Matsumura

Ichiro Kawahara

Tomoyasu Ohno

Kenji Kase

Disclosed is a process for preparing 2.beta.-substituted-methylpenicillin derivative of the formula ##STR1## wherein R is H or carboxyl protecting group, R.sub.1 is H or halo, R.sub.2 is H, lower alkyl, lower alkoxy, halogen, azido, lower alkylthio, phthalimide or a group --NHR.sub.3 (wherein R.sub.3 is H or acyl), and --N Y is an optionally substituted monocyclic or bicyclic heterocyclic group having 1 to 4 nitrogen atoms in the ring structure, the process comprising reacting a compound of the formula ##STR2## wherein X is Cl or Br, and R, R.sub.1 and R.sub.2 are as defined above with a heterocyclic compound of the formula ##STR3## wherein --N Y is as defined above.

Process for preparing 2.beta.-substituted-methylpenicillin derivatives

The present invention provides a process for preparing a penicillanic acid derivative of the formula ##STR1## which comprises reacting lead with a halogenated penicillanic acid derivative of the formula ##STR2## wherein X, Y, Z and R.sup.1 are as defined in the specification. The reaction is advantageously conducted in the presence of a metal having higher ionization tendency than lead such as aluminum, iron, magnesium or a mixture thereof.

Process for preparing penicillanic acid derivatives

A process for preparing a 2.beta.-substituted-methylpenicillin compound of the formula ##STR1## wherein --N Y is an optionally substituted heterocyclic group containing 2 to 4 nitrogen atoms as the hetero atom in the ring structure, and R.sub.1 is a penicillin carboxyl protecting group, the process comprising reacting an azetidinonedisulfide compound of the formula ##STR2## wherein R.sub.1 is as defined above and R is a substituted or unsubstituted heterocyclic group with a nitrogen-containing heterocyclic compound of the formula ##STR3## wherein ##STR4## is as defined above in the presence of a metal compound.

2.alpha.-Methyl-2.beta.-(1,2,3-triazol-1-yl)methylpenam-3.alpha.-carboxylic acid derivatives are prepared by reacting a penicillanic acid sulfoxide derivative of the formula ##STR1## wherein R is a penicillin carboxyl protecting group, and R.sub.1 is hydrogen or halogen, R.sub.2 is hydrogen, lower alkyl or the like with a triazole derivative of the formula ##STR2## wherein R.sub.3 and R.sub.4 are hydrogen, trialkylsilyl, lower alkyl, lower alkoxy or the like and R.sub.5 is hydrogen or silyl substituted with 3 groups selected from the class consisting of lower alkyl, benzyl and phenyl in a solvent.

Process for preparing

Disclosed are 2.beta.-substituted-methylpenicillanic acid compounds of the formula ##STR1## wherein n is 0, 1 or 2; and ##STR2## is monocyclic or bicyclic heterocyclic ring group which has 2 to 4 nitrogen atoms as hetero atom in its ring structure and which may be optionally substituted with alkyl, alkoxycarbonyl, phenyl, formyl or benzyloxycarbonyl optionally having alkyl, nitro or a halogen atom on the benzene ring, with the proviso that said heterocyclic ring group is not 1,2,3-triazol-1-yl; or salts or esters thereof. These compounds are useful as .beta.-lactamase inhibitor.

2.beta.-Substituted-methylpenicillanic acid derivatives, and salts and

Disclosed is a penicillin derivative of the formula: ##STR1## wherein n is an integer of 0, 1 or 2; Y is a cyano group, a lower acyl group, a mono- or di-lower alkylthiocarbamoyl group, ##STR2## wherein R.sub.1 is a hydrogen atom, a lower alkyl group, a phenyl group, a group --(CH.sub.2).sub.m --OR.sub.2 or --(CH.sub.2).sub.m COOR.sub.2 (m is an integer of 1 to 6 and R.sub.2 is a hydrogen atom or a penicillin carboxyl ester-forming group which is commonly used for penicillin derivatives) or a phenyl group substituted by at least one member selected from the class consisting of lower alkyl group, halogen atom and lower alkoxy group; and R is a hydrogen atom or a penicillin carboxyl ester-forming group, or a salt thereof. They are useful as .beta.-lactamase inhibitors.

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Okayama, Japan

Akira Nakai