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OwnerChristian Mathes, Gottfried Sedelmeier +3inventors
InventorsChristian Mathes, Gottfried Sedelmeier, Fritz Blatter, Sabine Pfeffer, Dominique Grimler
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The invention relates to a novel process for the manufacture of substituted enantiopure 10hydroxy-dihydrodibenz[b,f]azepines (Ia), (Ib) wherein each of R1 and R2, independently, are hydrogen, halogen, amino or nitro; and each of R3 and R4, independently, are hydrogen or C1-C6alkyl; by transfer hydrogenation of 10-oxo-dihydrodibenz[b,f]azepines; and to novel catalysts of formula (III′a) and (III′b) wherein M is Ru, Rh, Ir, Fe, Co or Ni; L1 is hydrogen; L2 represents an aryl or aryl-aliphatic residue; and the further radicals have the meanings as defined herein; and to new crystal forms of both enantiomers of 10,11-dihydro-10 hydroxy-5Hdibenz[b,f]azepine-5-carboxamide, obtainable by the new processes, their usage in the production of pharmaceutical preparations, new pharmaceutical preparations comprising these new crystal forms and/or the use of these new crystal forms in the treatment of disorders such as epilepsy, or in the production of pharmaceutical formulations which are suitable for this treatment.
A process for the production of a compound of formula Ia or Ib
A compound of formula III′a and III′b
A crystal form of (R)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5 carboxamide having the reference modification A, which is characterised by a powder X-ray diffraction diagram with d-spacings at 12.6, 8.8, 7.5, 6.28, 5.24, 4.93, 3.84, 3.74, 3.42 Å.
A crystal form of (R)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5 carboxamide having the reference modification B, which is characterised by a powder X-ray diffraction diagram with d-spacings at 8.9, 7.8, 6.8, 6.3, 5.59, 4.13, 3.90, 3.69, 3.29, 2.60 Å.
A crystal form of (S)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5 carboxamide having the reference modification A, which is characterised by a powder X-ray diffraction diagram with d-spacings at 12.6, 8.8, 7.5, 6.28, 5.24, 4.93, 3.84, 3.74, 3.42 Å.
A crystal form of (S)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5 carboxamide having the reference modification B, which is characterised by a powder X-ray diffraction diagram with d-spacings at 8.9, 7.8, 6.8, 6.3, 5.59, 4.13, 3.90, 3.69, 3.29, 2.60 Å.
An anhydrous crystal form of (R)- or (S)-10,11-dihydro-10-hydroxy-5H dibenz[b,f]azepine-5-carboxamide, which is characterised by a melting enthalpy of between 122 J/g and 136 J/g.
The crystal form of (R)-10,11-dihydro-10-hydroxy-5H dibenz[b,f]azepine-5 carboxamide having the reference modification B, which is characterised by a powder X-ray diffraction diagram with d-spacings at 8.9, 7.8, 6.8, 6.3, 5.59, 4.13, 3.90, 3.69, 3.29, 2.60 Å and comprising less than 5% of reference modification A, which is characterised by a powder X-ray diffraction diagram with d-spacings at 12.6, 8.8, 7.5, 6.28, 5.24, 4.93, 3.84, 3.74, 3.42 Å.
The crystal form of (S)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5 carboxamide having the reference modification B, which Is characterised by a Powder X-ray diffraction diagram with d-spacings at 8.9, 7.8, 6.8, 6.3, 5.59, 4.13, 3.90, 3.69, 3.29, 2.60 Å and comprising less than 5% of reference modification A, which is characterised by a powder X-ray diffraction diagram with d-spacings at 12.6, 8.8, 7.5, 6.28, 5.24, 4.93, 3.84, 3.74, 3.42 Å.
A crystal modification of (S)-10,11-dihydro-10-hydroxy-5H dibenz[b,f]azepine-5-carboxamide having a melting point between 193.0 and 197.0° C.
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A process for the preparation of (R)- or (S)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide having reference modification B which is characterised by a Powder X-ray diffraction diagram with d-spacings at 8.9, 7.8, 6.8, 6.3, 5.59, 4.13, 3.90, 3.69, 3.29, 2.60 Å, wherein (R)- or (S)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide having reference modification A which is characterised by a powder X-ray diffraction diagram with d-spacings at 12.6, 8.8, 7.5, 6.28, 5.24, 4.93, 3.84, 3.74, 3.42 Å or being in an amorphous form, is subjected to phase equilibration in a suitable solvent.
A process for the preparation of (R)- or (S)-10,11-dihydro-10-hydroxy-5H dibenz[b,f]azepine-5-carboxamide having reference modification B which is characterised by a powder X-ray diffraction diagram with d-spacings at 8.9, 7.8, 6.8, 6.3, 5.59, 4.13, 3.90, 3.69, 3.29, 2.60 Å, wherein (R)- or (S)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide having reference modification A which is characterised by a powder X-ray diffraction diagram with d-spacings at 12.6, 8.8, 7.5, 6.28, 5.24, 4.93, 3.84, 3.74, 3.42 Å or being in an amorphous form, is dissolved in a suitable solvent and a crystal of (R)- or (S)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, respectively, having reference modification B is added.
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