Two new stable non stoichiomeric crystalline solvate forms of Eluxadoline with 4-methylpentan-2-one or methyl terf-butylether are described as well as the process for the production of the same. The solvate form with 4-methylpentan-2-one is defined as "Eluxadoline form gamma" whereas the solvate with methyl terfbutylether is defined as "Eluxadoline form delta". Form gamma may be obtained by slurrying Eluxadoline amorphous form in 4-methylpentan-2-one; form delta may be obtained by slurrying Eluxadoline form gamma in methyl terf-butylether.
C07D 233/64 - Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
A61K 31/625 - Salicylic acidDerivatives thereof having heterocyclic substituents, e.g. 4-salicyloylmorpholine
A61P 1/06 - Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
A Rifaximin polymorphic mixture of α/β form in a relative ratio of 85/15 ± 3 and a process for its preparation are herein disclosed. Said polymorphic mixture of Rifaximin is also disclosed for use as a medicament, in particular in the treatment of traveler's diarrhea and hepatic encephalopathy. A pharmaceutical composition comprising said polymorphic mixture of Rifaximin as active ingredient, in particular a solid formulation, more in particular a film coated tablet are disclosed. A polymorphic form of crude wet rifaximin and of purified wet rifaximin and their use as intermediates in a process for the preparation of Rifaximin polymorphic mixture of α/β form in a relative ratio of 85/15 ± 3 are also disclosed.
C07D 498/22 - Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
A61K 31/395 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
A cocrystal of tiotropium bromide and lactose monohydrate is herein disclosed. In the cocrystal the components tiotropium bromide and lactose are preferably present in an almost stoichiometric ratio. Said cocrystal has a single endothermic event at about 191-3°C determined by DSC. A process for the preparation of the cocrystal is also disclosed. Preferably, the cocrystal has a particle size distribution of D90 < 10μ. The cocrystal is also disclosed for use as medicament, in particular for the treatment of a respiratory complaint, such as chronic obstructive pulmonary disease (COPD), bronchitis, emphysema and asthma.A pharmaceutical composition comprising the cocrystal as active ingredient is also disclosed, in particular for administration by inhalation. In the latter case, said cocrystal has a mean particle size of 0.5 to 10 µm, preferably 1 to 6 µm, more preferably 1.5 to 5 µm.
BIOCATALYZED SYNTHESIS OF THE OPTICALLY PURE (R) AND (S) 3-METHYL-1,2,3,4-TETRAHYDROQUINOLINE AND THEIR USE AS CHIRAL SYNTHONS FOR THE PREPARATION OF THE ANTITHROMBOTIC (21R)- AND (21S)-ARGATROBAN
The present invention relates to the biocatalyzed synthesis of enantiomerically pure (3R) and (3S)-methyl-1,2,3,4-tetrahydroquinoline. Said enantiomerically pure compounds are useful as chiral synthons in organic synthesis and, in particular, for the preparation of diastereomerically pure (21 R) and (21 S)-agratroban and its analogues. New compounds used as intermediates in the process of the invention are also disclosed.
The present invention relates to a process for the preparation of aminoaryl- and aminoheteroaryl boronic acids and esters thereof of formula (I) in high yield. The claimed process uses diarylketal formula (V) to generate an arylbromide of formula (III) in which the amino-group is protected as bisarylmethylidenimino-group, which is then transformed into a formula (I) compound.
A process for the preparation of the amorphous form of Regadenoson of formula (I) is disclosed together with new crystalline polymorphic forms E, F and G and methods for their preparation. Regadenoson amorphous form can be prepared in mild reaction conditions with high chemical purity (>99.6%) and high stability to the heating. A particularly thermodynamically stable anhydrous crystalline form of Regadenoson (form G) is also disclosed, provided with high stability not when exposed to 90% RH at 25°C for 96 hour, but also to the heating up to 200°C.
The object of the present invention is a new process for the synthesis of tapentadol, both as free base and in hydrochloride form, which comprises the step of alkylation of the ketone (VII) to yield the compound (VIII), as reported in Diagram 1, with high stereoselectivity due to the presence of the benzyl group as substituent of the amino group. It was surprisingly found that this substitution shifts the keto-enol equilibrium towards the desired enantiomer and amplifies the capacity of the stereocenter present in the compound (VII) to orient the nucleophilic addition of the organometallic compound at the carbonyl towards the desired stereoisomer. This substitution thus allows obtaining a considerable increase of the yields in this step, and consequently allows significantly increasing the overall yield of the entire tapentadol synthesis process. A further object of the present invention is constituted by the tapentadol free base in solid form, obtainable by means of the process of the invention. Still another object of the invention is represented by the crystalline forms I and II of the tapentadol free base. A further object of the present invention is the mixture of the crystalline forms I and II of the tapentadol free base.
C07B 57/00 - Separation of optically-active organic compounds
C07C 215/54 - Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
C07C 217/62 - Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
C07C 219/22 - Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
C07C 225/16 - Compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly-bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
A novel process for the synthesis of Lacosamide using D,L-serine as starting material is described, where the methylation reaction of hydroxyl is carried out using an inexpensive base such as NaOH and an inexpensive alkylating agent, non-toxic and non-carcinogenic, such as methyl p-toluenesulfonate; the R enantiomer is isolated from the racemic mixture of Lacosamide after selective hydrolysis of the acetamide, salification of the racemic mixture with a chiral acid (HX*) in an organic solvent, resolution of the diastereoisomeric mixture, preferably by precipitation of the R enantiomer, and subsequent acetylation of the optically pure intermediate.
C07C 231/12 - Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
C07C 231/20 - Preparation of optical isomers by separation of optical isomers
C07C 237/06 - Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
C07C 237/22 - Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
9.
NEW PROCESS FOR THE PREPARATION OF TAPENTADOL AND INTERMEDIATES THEREOF
The present invention refers to a new process for the synthesis of tapentadol comprising the quantitative resolution of the racemic mixture (V) to obtain the stereoisomer of (S)-3-(dimethylamino)-2-methyl-l-(3-nitrophenyl)-propan-l-one (VII) according to the Scheme 2 below (V, VI, VII) Scheme 2 using the (2R,3R)-O,O'-dibenzoyltartaric chiral acid wherein said resolution is quantitative. The present invention also refers to some intermediate compounds of the new synthesis process of tapentadol.
C07C 215/46 - Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
C07C 215/54 - Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
C07C 213/00 - Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
C07C 211/44 - Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
C07C 209/36 - Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings
10.
A CHEMO-ENZYMATIC APPROACH TO THE SYNTHESIS OF PIMECROLIMUS
Processes for preparing pimecrolimus starting from ascomycin, exploiting the selectivity characteristics of the purified enzymatic systems particularly regarding the selective functionalization of the hydroxyl groups present in position 24 and 33 of ascomycin. Such method represents the first example of chemoenzymatic synthesis for preparing pimecrolimus.
C07H 19/01 - Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radicalNucleosidesMononucleotidesAnhydro derivatives thereof sharing oxygen
11.
17-ALPHA-SUBSTITUTED DERIVATIVES OF ESTRADIOL WITH WOUND-HEALING ACTIVITY
The invention relates to 17&agr;-(5-hydroxy-C5-hydrocarbyl)-l,3,5(10)-estratrien-3,17&bgr;-diol derivatives having cicatrising activity, preferably for topical use on wounds, without significant systemic effects, and to pharmaceutical compositions containing them. In particular, the invention relates to estradiol 17&agr;-(5-hydroxypentyn-l-yl)derivatives and 3-esters, 5'-esters and 3,5'-diesters thereof and to a process for the preparation thereof by reaction of 3-OR-protected estrone with an alkali metal derivative of OR-protected 5-pentynol, followed by 3-, 5-' or 3,5'-esterifÊcation.
C07J 1/00 - Normal steroids containing carbon, hydrogen, halogen, or oxygen, not substituted in position 17 beta by a carbon atom, e.g. oestrane, androstane
A61K 31/567 - Compounds containing cyclopenta[a]hydrophenanthrene ring systemsDerivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. oestrane, oestradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
A61P 17/02 - Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
patents
