Dsm N.v.

Janssen Pharmaceutica Nv

Dsm IP Assets B.v.

Bayer Cropscience Ag

Bernardus Kaptein

Quirinus B Broxterman

Albert Schnatterer

Andras Horvath

Frank Volz

Harold Monro Moody

Anna Maria Cornelia Francisca Castelijns

Wilhelmus Hubertus Joseph Boesten

Johannes Paulus Gerardus Seerden

Marcelles Van Der Sluis

Jinxiong Su

Philip James Pye

Yuanyuan Yuan

Gerardus Karel Maria Verzijl

Bernardus Henricus Nicolaas Dassen

Ben Lange De

Gerardus K Verzijl

Laurent Lefort

Disclosed is a process for the preparation of certain intermediates, e.g. process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, in an enantioenriched form, which intermediate and processes are useful in the preparation of a BTK inhibitor, such as ibrutinib.

Processes and intermediates for preparing a Btk inhibitor

The present invention relates to a novel process for the preparation of cis-1-ammonium-4-alkoxycyclohexanecarbonitrile salts and to novel intermediates or starting compounds which are passed through or used in the process according to the invention.

Process for the preparation of cis-1-ammonium-4-alkoxycyclohexanecarbonitrile salts

Process for the preparation of enantiomerically enriched amino aldehydes and amino alcohols, wherein a corresponding enantiomerically enriched amino nitrile is subjected to hydrogenation in the presence of hydrogen, a hydrogenation catalyst, preferably a Pd-catalyst and a mineral acid. For the preparation of an amino aldehyde hydrogen preferably is present at a hydrogen-pressure between 0.1 and 2 MPa, in particular between 0.5 and 1 MPa. The amino aldehyde preferably is isolated in the form of a chemically and configurationally stable derivative. For the preparation of an amino alcohol, preferably at least during part of the hydrogenation hydrogen is present at a hydrogen-pressure between 2 and 10 MPa, in particular between 4 and 6 MPa. In a preferred embodiment the hydrogen-pressure initially is between 0.5 and 2 MPa and subsequently, after most of the nitrile starting material is converted, the hydrogen pressure is increased to a value between 2 and 10 MPa. The enantiomerically enriched nitrile starting material may a.o. be prepared by enzymatic resolution, classical resolution, resolution via preferential crystallization, diastereomeric synthesis, catalytic asymmetric synthesis or dehydratation of amino acid amides.

Process for the preparation of enantiomerically enriched compounds

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

The invention relates to a process for preparing an optically active trans-compound having formula (1), in which R represents a phenyl group, whether or not substituted, preferably p-methoxyphenyl, and A is derived from an optically active compound, in which an aldehyde having formula (2), in which R is as defined above, is, in the presence of a base, brought into contact with an optically active acetyl compound having formula (3), in which X represents a leaving group and in which A is derived from an amino alcohol, preferably a .beta.-amino alcohol having a rigid structure. Particularly good results were obtained when use was made of a compound having formula (3), in which A is derived from an amino indanol compound having formula (4), in which R.sub.1 and R.sub.2 represent a (hetero)alkyl or (hetero)aryl group, whether or not substituted, having 1-10 C atoms, or R.sub.1 and R.sub.2 constitute an aromatic or aliphatic ring together with the N atom to which they are bound, in particular in which R.sub.1 and R.sub.2 each independently of one another represent methyl, ethyl, isopropyl, n-propyl, n-butyl, allyl, benzyl or tosyl.

Process for preparing an optically active phenylglycidyl acid derivative

Process for the preparation of a threo-phenylserine amide of the general formula 2 in which glycine amide is contacted with the corresponding substituted benzaldehyde of formula 3 in an excess relative to the amount of glycine amide, this taking place at a pH between 9 and 14 in the presence of a suitable solvent. The resulting phenylserine amide can subsequently be hydrolyzed to a phenylserine amide of the general formula 1, which is subsequently hydrolyzed to a phenylserine amide of the general formula 1, which is subsequently subjected to a stereoselective enzymatic hydrolysis yielding a (2S,3R) phenylserine. The non-hydrolyzed (2R,3S) phenylserine amide can be isolated as a Schiff base and be recirculated and simply racemized. The (2S,3R) phenylserine obtained can be used in the preparation of thiamphenicol or florfenicol. The threo-phenylserine amides of the general formula 1 or 2 are new intermediates in this commercially attractive process for the preparation of thiamphenicol and florfenicol.

Phenylserine amides and the preparation of phenylserines/phenylserine

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Sittard, Netherlands

Bernardus Kaptein