Dsm IP Assets B.v.

Dsm N.v.

Dsm Sinochem Pharmaceuticals Netherlands B.v.

Enzypep B.v.

Dsm IP Assests B.v.

Chemferm V.o.f.

Centrient Pharmaceuticals Netherlands B.v.

Harold Monro Moody

Theodorus Johannes Godfried Maria Van Dooren

Wilhelmus H Boesten

Quirinus B Broxterman

Thomas Van Der Does

Jan Metske Van Der Laan

Peter Jan Leonard Mario Quaedflieg

Timo Nuijens

Dennis Heemskerk

Wilhelmus H J Boesten

Bernardus Kaptein

Richard Kerkman

Wilhelmus Hubertus Joseph Boesten

Johannes Paulus Gerardus Seerden

Marcelles Van Der Sluis

Eric C Roos

Claudia Cusan

Ben Lange De

Johanna Christina Maria Smeets

Theodorus Johannes Godfried Marie Van Dooren

Carlos Enrique Lenhard

Anja Gerarda Margaretha Hogenboom

Carlos Enrique Lenhardt

Edwin Gerard Ijpeij

Theodorus Johannes Godfried Maria Dooren Van

The present invention relates to a mutant prokaryotic penicillin G acylase derived from a wild-type penicillin G acylase characterized in that the mutant is having an amino acid substitution at one or more amino acid positions selected from the group consisting of amino acid positions A3, A77, A90, A144 A192, B24, B109, B148, B313, B460 and B488 according to the amino acid numbering of thepenicillin G acylase having the amino acid sequence depicted in SEQ ID No: 1.

Mutant penicillin G acylases

The present invention describes a process for the synthesis of a semi-synthetic &#x3b2;-lactam compound from a nucleus and a side chain selected from the group consisting of D-phenylglycine and D-dihydro-phenylglycine in the form of a side chain ester and an enzyme catalyzing the coupling of the side chain ester to the nucleus characterized in that the side chain ester is not isolated as a solid intermediate.

Process for the preparation of beta-lactam compounds

The invention relates to a method for preparing an optionally N-protected amino acid C-terminal ester or an optionally N-protected peptide C-terminal ester, comprising transesterifying the C-terminal t-alkyl ester of the amino acid or the C-terminal t-alkyl ester of the peptide with an alcohol (other than the t-alcohol corresponding to the t-alkyl group of the ester) in the presence of a hydrolytic enzyme (E.C. 3). The invention further relates to a method for preparing a peptide comprising coupling an activated, N-protected, amino acid C-terminal ester or an optionally N-protected peptide C-terminal ester with an optionally C-terminal protected amino acid or an optionally C-terminal protected peptide via a peptide bond, in the presence of an enzyme catalysing peptidic bond formation.

Chemo-enzymatic peptide synthesis via C-terminal ester interconversion

The present invention relates to a process for the preparation of cefadroxil in crystal form, comprising a) adding an aqueous solution of cefadroxil to a crystallization vessel and a titrant to keep a pH in the crystallization vessel of between 7 to 9; and b) lowering the pH in the crystallization vessel to a value of between 5 and 6.5 to obtain a suspension of the &#x3b2;-lactam compound in crystal form. The invention further relates to cefadroxil in crystal form obtainable by the process according to the present invention. The invention also relates to cefadroxil in crystal form with a CIE b value of below 12 when stored at a temperature of 25&#xb0; C. for at least 1 month.

Process for the crystallisation of cefadroxil monohydrate

The present invention relates to a process for the synthesis of cefaclor, which process comprises reacting 7-amino-3-chloro cephalosporanic acid (7-ACCA) with D-phenylglycine in activated form (PGa) in the presence of an enzyme in a reaction mixture to form cefaclor, wherein at least part of 7-ACCA and/or PGa are added to the reaction mixture during the course of the reaction. The invention also relates to an aqueous mixture comprising an amount of cefaclor of &#x3e;10 (w/w) %, an amount of 7-amino-3-chloro cephalosporanic acid of &#x3c;2 (w/w) %, and an amount of D-phenyl glycine of &#x3c;2 (w/w) % and a process for the recovery of cefaclor from this aqueous mixture. The invention also relates to cefaclor in crystal form having an absorbance at 400 nm (A) of less than 0.250.

Process for the synthesis of cefaclor

The present invention describes a process for the synthesis of an amino acid methyl ester comprising the following steps: (a) refluxing a reaction mixture comprising a free amino acid, methanol and a strong acid; (b) concentrating the mixture; (c) adding methanol; (d) repeating steps a-c one or more times.

Process for the preparation of amino acid methyl esters

The present invention describes a process for preparing cephradine, said process comprising reacting 7-aminodesacetoxy cephalosporanic acid (7-ADCA) with D-dihydrophenylglycine in activated form (DHa) in the presence of an enzyme in a reaction mixture to form cephradine, resulting in a conversion of 7-ADCA into cephradine of at least 70%, wherein the concentration D-dihydrophenylglycine (DH) in the reaction mixture is below 2 wt.%, wherein the conversion of 7-ADCA into cephradine & equals; (n/n)*100%, wherein n=quantity of cephradine formed (in mole); and n=total quantity of 7-ADCA added to reaction mixture (in mole). The invention also describes a process for the preparation of cephradine hydrate characterised in that the process comprises: &#x2014;reacting 7-amino acid desacetoxy cephalosporanic acid (7-ADCA) with DHa in the presence of an enzyme in a reaction mixture to form cephradine; &#x2014;preparing an aqueous solution comprising at least part of the cephradine; and crystallising the cephradine from said aqueous solution. The invention further describes cephradine hydrate obtainable by a process according to invention. The invention also describes cephradine hydrate with an absorbance at 450 nm of below 0.050.

Process for the preparation of cephradine

Ampicillin is produced in a batch process by enzymatic acylation of 6-aminopenicillanic acid (6-APA) with the aid of phenylglycine derivative such as D-phenylglycine amide. High conversions of phenylglycine derivative may be achieved by having the total concentration in the reaction mixture of 6-APA and ampicillin greater than 250 mM and the molar ration of total quantity of phenylglycine derivative to total quantity of 6-APA less than 2.5. Higher yields of ampicillin may be achieved when the amount of dissolved 6-APA is kept low, e.g. below 300 mM.

Process for the preparation of ampicillin

Process for the preparation of a diasteromerically enriched phenylglycine amide derivative in which an enantiomerically enriched phenylglycine amide is converted into the corresponding Schiff base with the aid of compound R &mdash;C(O)&mdash;R , and the Schiff base obtained is subsequently converted into the diastereomerically enriched phenyglycine amide derivative with the aid of a cyanide source, a reducing agent or an allyl organometallic compound. The phenylglycine amide derivatives obtained are interesting starting materials for the preparation of for example enantiomerically enriched &agr;- and or &bgr;-amino acids and derivatives thereof, such as amides and esters, and amines.

Method for the preparation of enantiomerically enriched compounds

Process for the preparation of a &bgr;-lactam antibiotic in which a &bgr;-lactam nucleus is subjected to an enzymatic acylation reaction with the aid of an acylation agent at a molar ratio of acylation agent/&bgr;-lactam nucleus of less than 2.5, with the acylation agent and/or the &bgr;-lactam nucleus being supersaturated in the reaction mixture during at least part of the acylation reaction. In the process, a concentrated slurry or solution, for instance, of the &bgr;-lactam nucleus and/or the acylation agent with a different pH or a higher temperature than the pH or temperature at which the acylation reaction is carried out is added to the reaction mixture during the acylation reaction. Both the &bgr;-lactam nucleus and the acylation agent may be supersaturated in the reaction mixture.

Process for the preparation of a&bgr;-lactam antibiotic

Process for the recovery of ampicillin from a mixture containing ampicillin and 6-aminopenicillic acid (6-APA), in which a mixture of ampicillin and 6-APA, with a pH higher than 7, which apart from any solid ampicillin being present is homogeneous at a pH between 7 and 8.5, is subjected to a pH lowering till a pH lower than 8.2 is reached, and the solid substance present is recovered. The process is in particular suitable to be applied to the reaction mixture which is obtained after the enzymatic acylation reaction of 6-APA with a phenylglycidine derivative as acylation agent. Pure ampicillin can thus be recovered in a simple way.

Process for the recovery of ampicillin

The invention relates to a method for the preparation of an .alpha.,.alpha.-disubstituted .alpha.-amino alcohol from the corresponding amide with the aid of sodium in the presence of an alcohol as solvent. The conversion of amino acid amide to amino alcohol proceeds virtually quantitatively. Moreover, the reduction of the amino acid amide to the corresponding amino alcohol proceeds with retention of optical activity.

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Gulpen, Netherlands

Harold Monro Moody