Lek Pharmaceuticals D.d.

Lek, Tovarna Farmacevtskih

Lek, Tovarna, Farmacevtskih in Kemicnih . . .

Lek, Torvarna Farmacevtskih

Lek, Tovarna Farmecevtskih in Kemicnih Izdelkov

Anton Copar

Ljubomir Antoncic

Zdenko Casar

Gorazd Sorsak

Andrej Premrl

Borut Furlan

Alenka Jeriha

Erwin Schreiner

Barbara Podobnik

Uros Urleb

Jerome Cluzeau

Zoran Ham

Branko Jenko

Samo Pirc

Breda Husu-Kovacevic

Frank Richter

Natasa H Milac

Andreja C Belcic

Alenka Kosak

Brina Ornik

Furlan Borut

Peter Svete

Boris Marolt

Matej Antoncic

Breda Husu-Kovacecic

The present invention relates to a process for the preparation of 3-aroyl-5-aminobenzofuran derivatives useful as antiarrhythmic drugs which avoids the use of nitro intermediates.

Process for the preparation of 3-aroyl-5-aminobenzofuran derivatives

A process for the preparation of amorphous atorvastatin calcium. The process includes providing a reaction mixture having a pH between 6.5 and 8.0 containing a sodium salt of atorvastatin and tetrahydrofuran. A non-cyclic chlorinated organic solvent selected from the group consisting of dichloromethane, trichloroethane, tetrachloroethane and chloroform or addition of cyclic hydrocarbon solvent selected from the group consisting of cyclohexane, cyclopentane and methyl cyclohexane is added to provide a mixture of organic solvents. An equivalent or an excess quantity of a source of calcium ions selected from the group consisting of calcium acetate and calcium chloride is added. Amorphous atorvastatin calcium is isolated from an organic phase comprising the mixture of organic solvents.

Process for the preparation of amorphous calcium salt of atorvastatin

Novel pharmaceutically acceptable salts of desvenlafaxine with physiologically ubiquitous ions selected from sugar acids and vitamins, processes for their preparation, pharmaceutical compositions containing them and uses therefor are described.

Salts of O-desmethyl-venlafaxine

One embodiment disclosed in the invention is the efficient synthesis of halogenated biaryl starting material via Grignard chemistry and the use thereof. Another embodiment of the invention is the reaction of catalyzed carbonylation of the 3'-(2&#x2032;-halo-biphenyl-4-ylmethyl)-1,7&#x2032;-dimethyl-2&#x2032;-propyl-1H,3&#x2032;H-[2,5&#x2032;]bibenzoimidazolyl (TLMH) using either gaseous carbon monoxide in a solvent mixture containing water; or formic acid salts optionally together with acetic acid in anhydrous solvent.

Catalyzed carbonylation in the synthesis of angiotensin II antagonists

A process for obtaining 2'-halo-4-methylbiphenyls is described, which comprises reacting 4 halotoluene with a 1,2-dihalobenzene in the presence of elemental metal such as magnesium, lithium or zinc, wherein 0 to 0.9 molar, particularly 0 to 0.2 molar excess of 4-halotoluene in regard to 1,2-dihalobenzene is used, and arised organometal intermediates are quenched by elemental mental halogen. In addition, the coupling of arised 2&#x2032;-halo-4-methylbiphenyls with 2-(1-propyl)-4-methyl-6-(1&#x2032;-methylbenzimidazole-2-il)benzimidazole to afford 3&#x2032;-(2&#x2032;-halo-biphenyl-4-ylmethyl)-1,7&#x2032;-dimethyl-2&#x2032;-propyl-1H,3&#x2032;H-[2,5&#x2032;]bibenzoimidazolyl, which can be further converted to organometallic compound and said organometallic compound is further reacted with formic acid derivative, such as N,N-dimethylformamide, alkylformiate or carbon dioxide to obtain telmisartan, is also described. Further described is use of in line analytics for monitoring the aforementioned reactions, process for preparing a pharmaceutical composition and/or dosage for, or use in preparing a medicament.

2'-halobiphenyl-4-yl intermediates in the synthesis of angiotensin II antagonists

Present invention refers to the process of preparing amorphous atorvastatin calcium without intermediate isolation of crystal or undefined mixture of crystal and amorphous atorvastatin calcium, respectively. Forming of calcium atorvastatin salt is carried out in a mixture of chlorinated organic solvent or cyclic hydrocarbon solvent, respectively, the non-hydroxylic organic solvent, and water, the source of calcium ions is calcium acetate or calcium chloride, respectively.

4-bromomethyl-2'-formylbiphenyl and 4-bromomethyl-2&#x2032;-hydroxymethylbiphenyl are useful starting material for the preparation various angiotenzin II antagonists, which are prepared from 4-bromomethyl-2&#x2032;-cyanobiphenyl or 4&#x2032;-bromomethylbiphenylcarboxyilic derivatives using selected hydride reagent.

Synthesis of 4-bromomethyl-2'-formylbiphenyl and 4-bromomethyl-2&#x2032;-hydroxymethylbiphenyl and its use in preparation of angiotensin II antagonists

The present invention relates to a new process for the preparation of crystalline perindopril. The present invention also relates to new alkyl ammonium salts of perindopril and the processes for the preparation thereof.

Process for the preparation of crystalline perindopril

A novel crystalline form of the substrate known under the chemical name 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfiny]-1H-benzimidazole, and having the generic name omeprazole, hereinafter referred to as omeprozole form C, is disclosed. Further, a process for the preparation of omeprazole form C, a pharmaceutical formulation containing omeprazole form C in admixture with pharmaceutically acceptable excipients and the use of omeprazole form C for treatment of gastrointestinal disorders are disclosed.

Crystalline form of omeprazole

Pharmaceutically suitable crystalline and amorphous alkali and earth-alkali salts of 2-n-butyl-4-chloro-5-hidrox-ymethyl-1-[[2'-(1 H-tetrazole-5-yl)[1.1&#x2032;-biphenyl]-4-yl]-1 Himidazole have been prepared and new manufacturing, purification and isolation procedure for said salts in high purity have been described. Stable pharmaceutical compositions containing new crystalline potassium salts of 2-n-butyl-5-chloro-5hidroxymethyl-1-[[2&#x2032;-(1H-tetrazole-5-yl)[1.1&#x2032;-biphenyl]-44-yl]-1H-imidazole have been prepared.

Preparation of new pharmaceutically suitable salt of losartan and forms thereof with new purification and isolation methods

A process for purification of crude clavulanic acid and its subsequent conversion to its potassium salt. A crude clavulanic acid extract is contacted in an organic solvent with an alkylenediamine of the formula II ##STR1## wherein the substituents R.sub.1, R.sub.2, R.sub.3 and R.sub.4 each individually denote a hydrogen atom, or a straight chain or a branched chain alkyl group having 1 to 8 carbon atoms, R.sub.5 denotes a hydrogen atom, and n denotes an integer 1. The thus obtained alkylenediammonium diclavulanates of the formula I are isolated ##STR2## wherein the substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 and n have the meanings as defined at formula II. Salts of the alkylenediammonium diclavulanate of the formula I are converted with potassium 2-ethyl-hexanoate in isopropanol into potassium salt of clavulanic acid.

Alkylenediammonium diclavulanate derivatives, a process for the

There is disclosed a process for the preparation of 3-ethyl 5-methyl (.+-.) 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyri dine-dicarboxylate monobenzenesulphonate (amlodipine benzenesulphonate) of formula ##STR1## wherein 3-ethyl 5-methyl (.+-.) 2-[2-(N-tritylamino)-ethoxymethyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl -3,5-pyridinecarboxylate is reacted with benzenesulphonic acid in a methanolic or an aqueous methanolic medium at a temperature from 20.degree. C. to the reflux temperature and the title compound is isolated and purified. Amlodipine benzene sulphonate is a valuable anti-ischaemic and anti-hypertensive agent.

Process for the preparation of amlodipine benzenesulphonate

There is disclosed a process for the preparation of 3-ethyl 5-methyl (.+-.) 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyri dine-dicarboxylate monobenzenesulphonate (amlodipine benzenesulphonate) of formula ##STR1## wherein 3-ethyl 5-methyl (.+-.) 2-[2-(N-tritylamino)-ethoxymethyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl -3,5-pyridinedicarboxylate is reacted with benzenesulphonic acid in a methanolic or an aqueous methanolic medium at a temperature from 20.degree. C. to the reflux temperature and the title compound is isolated and purified. Amlodipine benzene sulphonate is a valuable anti-ischaemic and anti-hypertensive agent.

3-ethyl

A novel process for the preparation of calvulanic acid and pharmaceutically acceptable salt thereof, such as potassium clavulanate, is described. According to the novel process, crude clavulanic acid, which is present in the form of an extract in an organic solvent, such as ethyl acetate, the extract having been obtained in known manner upon fermentation with a calvulanic acid producing microorganism, is reacted with substituted alkylenediamines of the formula II ##STR1## wherein the substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 and n have the meanings as defined in claim 1, e.g. with N,N'-diisopropylethylenediamine, to the novel alkylenediammonium diclavulanates of the formula I ##STR2## wherein the substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 and n have the meanings as defined in claim 1, e.g. to N,N'-diisopropylethylenediammonium diclavulanate. The obtained compounds of the formula I are optionally isolated and converted with alkali alkanoates, such as potassium 2-ethylhexanoate in isopropanol, to potassium clavulanate. Because of their high inhibitory action against beta-lactamases and because of a significant synergistic action in combination with the beta-lactam antibiotics from the group of penicillins and cephalosporins, clavulanic acid and pharmaceutically acceptable salts thereof are valuable compounds for the preparation of galenic compositions, which are active in the treatment of infectious diseases induced by numerous grampositive and gram-negative microorganisms.

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Anton Copar