Lonza Inc.

Lonza Ag

Other

Barry Jackson

Thomas Scholl

Christian Noti

Guixian Hu

Peter Fankhauser

Paul Hanselmann

Leander Tenud

Christoph Zinsstag

Uwe Zacher

Raimund Miller

Brigitta Heyl-Frank

Heike Irle

The invention discloses a method for the preparation of tert-butyl 6-chloro-3,5-dioxohexanoate from Meldrum's acid derivative and its use for the preparation of tert-butyl (4R,6S)-(6-hydroxymethyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate (BHA), Rosuvastatin and Atorvastatin.

Preparation of 3,5-dioxo hexanoate ester in two steps

The invention discloses a method for the preparation of tert-butyl 6-chloro-3,5-dioxohexanoate from Meldrum's acid derivative and its use for the preparation of tert-butyl(4R,65)-(6-hydroxymethyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate (BHA), Rosuvastatin and Atorvastatin.

A process for preparing solid formulations of sodium 3-hydroxy-3-methylbutyrate of the formulain which, in a first process step, 4,4-dimethyloxetan-2-one is reacted with aqueous sodium hydroxide to form a solution of sodium 3-hydroxy-3-methylbutyrate, and then, if appropriate after concentration, the solution is applied, in a further process step, to synthetic silica, and in which the resultant product is, if appropriate, dried.

Method for the production of solid formulations of sodium 3-hydroxy-3-methylbutyrate

Geranic acid derivatives

Chroman derivatives of the general formula: ##STR1## in which R.sup.1 is hydrogen or C.sub.1-4 -alkyl; R.sup.2 is C.sub.1-6 -alkyl, C.sub.3-6 -cycloalkyl, optionally substituted aryl or optionally substituted aryl-C.sub.1-6 -alkyl; R.sup.3, R.sup.5 and R.sup.6 independently of one another are hydrogen, halogen, C.sub.1-4 -alkyl or optionally substituted aryl; and R.sup.4 is C.sub.1-6 -alkyl, C.sub.3-6 -cycloalkyl, (C.sub.1-6 -alkoxy)methyl, optionally substituted aryl, optionally substituted aryl-C.sub.1-6 -alkyl, C-alkanoyl or optionally substituted aroyl, are obtained from hydroquinone derivatives and alkenes in the presence of Lewis acids. The chroman derivatives (I) are intermediates in the synthesis of pharmaceutical active ingredients, for example, of hypolipidemics.

Process for the preparation of chroman derivatives

A process for the purification of alkyl alkylacetoacetates of the general formula: ##STR1## in which R.sup.1 is a C.sub.1 -C.sub.10 -alkyl group and R.sup.2 is a C.sub.1 -C.sub.4 -alkyl group. In the process, an alkyl alkylacetoacetate which contains an alkyl alkenylacetoacetate of the general formula: ##STR2## in which R.sup.1 and R.sup.2 have the above-stated meaning, and/or further by-products as an impurity, is converted with an ester of the general formula: ##STR3## in which R.sup.2 has the above-stated meaning, in the presence of a base, into an intermediate which is separated off.

Process for the preparation of pure alkyl alkylacetoacetates

4-Oxoimidazolinium salts of the general formula: ##STR1## wherein R.sup.1 and R.sup.2 independently of one another are C.sub.1-10 -alkyl, C.sub.2-10 -alkenyl, C.sub.3-7 -cycloalkyl or optionally substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R.sup.1 and R.sup.2, together with the carbon atom to which they are bonded, form a three-membered to seven-membered saturated or unsaturated carbocyclic or heterocyclic ring, R.sup.3 is a C.sub.1-10 -alkyl group, C.sub.1-10 -alkenyl group, C.sub.3-7 -cycloalkyl group, aryl group, arylalkyl group or heteroaryl group, and A.sup.-- is an anion of a strong acid, are prepared by the cyclization of an .alpha.-acylaminonitrile in a nonaqueous solvent, in the presence of a lower alcohol and a strong acid. The compounds are intermediates for pharmaceutical active substances, for example, angiotensin II antagonists.

Process for the preparation of 4-oxoimidazolinium salts

Bisketals of 1,3-cyclobutanedione with monovalent and divalent alcohols as well as processes for their production from 1,3-cyclobutanedione or from 3-acetoxy-2-cyclobuten-1-one contained in the distillation residues of the diketene production. The bisketals are suitable intermediate products for the production of squaric acid, for the production and/or purification of 1,3-cyclobutanedione, or as a stable form for storage or substitute for this unstable dione.

1,3-cyclobutanedione-bisketals, process for their production and their

A process for the production of squaric acid by halogenation either of pure 3-acetoxy-2-cyclobuten-1-one or of a distillation residue of diketene production containing 3-acetoxy-2-cyclobuten-1-one to a cyclobutenone of formula: ##STR1## and then hydrolysis of these cyclobutenones to squaric acid. The halogenated cyclobutenones are intermediate products in the process.

Process for the production of squaric acid

3-Hydroxy-2-cyclobuten-1-one salts of the general formula: ##STR1## wherein R is an ammonium group of the general formula: ##STR2## wherein R.sub.1, R.sub.2 and R.sub.3 are the same or different in meaning and each is a hydrogen atom, a lower alkyl group or a cycloalkyl group or R is an alkali metal atom. The salts according for formula I are obtained by the reaction of pure 3-acetoxy-2-cyclobuten-1-one, or 1,3-cyclobutanedione or a distillation residue of the diketene production containing 3-acetoxy-2-cyclobuten-1-one, with a base. The base can be an amine of the general formula: ##STR3## wherein R.sub.1, R.sub.2, and R.sub.3 have the above-mentioned meaning, or an alkali metal alcoholate or an alkali metal hydroxide. The salts according to formula I are suitable for the production of squaric acid, by their being halogenated in a first step and then being hydrolyzed to squaric acid in a second step.

3-hydroxy-2-cyclobuten-1-one salts, their production and use

3-Hydroxy-2-cyclobuten-1-one salts of the general formula: ##STR1## wherein R is an ammonium group of the general formula: ##STR2## wherein R.sub.1, R.sub.2 and R.sub.3 are the same or different in meaning and each is a hydrogen atom, a lower alkyl group or a cycloalkyl group or R is an alkali metal atom. The salts according for formula I are obtained by the reaction of pure 3-acetoxy-2-cyclobuten-1-one, or 1,3-cyclobutanedione or a distillation residue of the diketene production containing 3-acetoxy-2-cyclobuten-1-one, with a base. The base can be an amine of the general formula: ##STR3## wherein R.sub.1, R.sub.2 , and R.sub.3 have the above-mentioned meaning, or an alkali metal alcoholate or an alkali metal hydroxide. The salts according to formula I are suitable for the production of squaric acid, by their being halogenated in a first step and then being hydrolyzed to squaric acid in a second step.

3-Hydroxy-2-cyclobuten-1-one salts

Process for the production of 2-chloroacetoacetic acid amides. Diketene is converted at a temperature of +30.degree. to -40.degree. C. with the help of hydrogen chloride into acetoacetic acid chloride. Chlorine is introduced into the mixture at a temperature of +30.degree. to -40.degree. C., whereby 2-chloroacetoacetic acid chloride is formed. The latter is converted into the corresponding amide at a temperature of +50.degree. to -40.degree. C. by reaction with a N-compound having the formula: ##STR1## wherein (i) R=R'=H, or

Process for the produciton of 2-chloroacetoacetic acid amides

A process for the production of a monohaloacetylhalide characterized in that a ketene is reacted with a halogen in the presence of a diester of phosphonic acid of the formula: ##STR1## wherein R.sub.1, R.sub.2 and R.sub.3 are the same or different alkyl or aryl, or R.sub.1 and R.sub.2 are the same or different alkyl or aryl and R.sub.3 is --COOR or --CH.sub.2 COOR, wherein R is alkyl or aryl. The diester is a solvent which impedes or prevents the formation of polyhaloacylhalides and which keeps the formation of acylhalides to a minimum.

Process for the production of monohaloacetylhalides

A process for the trichloroacetyl of orotic acid which comprises (a) converting trichloroacetyl chloride to .gamma., .gamma., .gamma.-trichloroacetoacetyl chloride with ketene, (b) adding reaction mixture (a) to urea dissolved in a polar organic solvent, e.g., acetic acid, 6-trichloromethyluracil being produced, (c) separating the 6-trichloromethyluracil from reaction mixture (b), and (d) hydrolyzing the 6-trichloromethyluracil to orotic acid.

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Brig-Glis, Switzerland

Barry Jackson