Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-09-13
1995-01-10
Ivy, C. Warren
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D21120
Patent
active
053808568
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns a process for preparation of the polymorphic form of terphenadine having a high melting point and enhanced purity, this process consisting of crystallization using a mixture of water and dimethylformamide H--CO--N(CH3)2.
Terphenadine, or .alpha.[4-(1,1-dimethylethyl)phenyl]-4-(hydroxy-diphenylmethyl)-1-piperidi ne butanol, is a non-sedative, antihistaminic substance belonging to the group of histamine 1 antagonists.
One conventional terphenadine-synthesis process is as follows:
A mixture of: ethyl) phenyl-4-chloro-1-butanone (II), potassium bicarbonate, and potassium iodide in toluene
The lukewarm reactive mixture is filtered, and the cooled filtrate is treated with an excess amount of ethereal chlorhydric acid.
The precipitate thus obtained is crystallized twice using a methanol/isopropanol mixture in order to obtain the 1-4-(1,1-dimethyl ethyl)phenyl-4-4-(hydroxidiphenyl methyl)-1-piperidinyl-1-butanone hydrochloride (III).
A solution of (III) is treated in methanol using a solution of potassium hydroxide in methanol, until it becomes basic.
The resulting mixture is cooled, stirred, and treated in parts with potassium borohydride. The cooling bath is removed and the reaction product is stirred and then concentrated on a vapor bath under reduced pressure, so as to obtain a solid residue.
After washing in water and two recrystallization operations utilizing acetone, terphenadine (IV) is obtained. ##STR1##
It appears that terphenadine can take on several polymorphic forms.
Until now, three distinct polymorphic forms and two solvation products have been identified.
These forms were produced from recrystallization of terphenadine in different solvents.
Polymorphic Form I: obtained by recrystallization of a methanol/water mixture (t.sub.f of between 149.degree. C. and 152.degree. C.).
Polymorphic Form II: obtained by recrystallization of methanol (t.sub.f of between 146.degree. C. and 148.degree. C.).
Polymorphic Form III: (metastable): obtained by recrystallization of propylene-glycol (t.sub.f of between 142.degree. C. and 144.degree. C).
These crystallized forms are distinguished by virtue of their physical-chemical properties as regards: diffraction).
As regards the products currently on the market, the polymorphic forms I and II coexist in different proportions. Polymorphic forms II and III could be converted into form I by boiling in water.
The presence of crystallization inhibitors can slow down this transformation.
Furthermore, the vitreous form of terphenadine could be easily obtained by rapid cooling of the melted medicine.
The crystals obtained from the currently-marketed substance are automorphic, since they have circular, laminated crystals, while polymorphic form III exists as a thin-flaked powder.
The chemical literature describes two distinct polymorphic forms of solid terphenadine having melting points of 146.degree. C. and approximately 149.degree.-151.degree. C., respectively, the latter being the form which proves desirable from a commercial perspective. The procedures used to obtain both of these forms in the desired quantities have already been formulated.
In particular, European Patent Application No. EPA-0339118 describes a process for preparation of the polymorphic variety of terphenadine having a high melting point, according to which terphenadine is dissolved in a C.sub.1 -C.sub.6 alkanol mixable in water. The solution thus obtained is heated to around its reflux temperature, and a sufficient quantity of water is slowly added while stirring in order to crystallize the terphenadine. The crystallized product is then cooled and collected.
In addition, European Patent Application No, EPA -0396100 describes a process for preparation of the polymorphic variety of terphenadine having a high melting point, in which terphenadine is dissolved in acetone, the solution is heated to the distillation point so as to remove a portion of the acetone, and the remaining mixture is gradually diluted with water, while stirring.
After crystallization of the terphenadine, the
REFERENCES:
Badwan, Analytical Profiles of Drug Substances, vol. 19 (1990), pp. 628-662.
Deglave Marcel
Mouton Marc-Henri
Wirth Didier G.
Covington Raymond
Isochem
Ivy C. Warren
LandOfFree
Process for preparation of a polymorphic form of terphenadine ha does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for preparation of a polymorphic form of terphenadine ha, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for preparation of a polymorphic form of terphenadine ha will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-851718