Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-23
2003-11-11
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S217000
Reexamination Certificate
active
06645986
ABSTRACT:
The present invention is directed to a process for the preparation of the mesylate trihydrate of the compound of formula (I), (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol:
from its D-(−)-tartrate salt.
The compound of formula (I), (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol, exhibits potent activity as an NMDA (N-methyl-D-aspartic acid) receptor antagonist and is useful in the treatment of epilepsy, anxiety, cerebral ischemia, muscular spasms, multi-infarct dementia, traumatic brain injury, pain, AIDS-related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drug and alcohol addiction, drug and alcohol withdrawal symptoms, psychotic conditions, urinary incontinence and degenerative CNS (central nervous system) disorders such as stroke, Alzheimer's disease, Parkinson's disease and Huntington's disease.
The mesylate trihydrate form of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol is superior to the anhydrous mesylate as an active therapeutic agent because of its properties. The mesylate trihydrate has a more stable crystalline form than the anhydrous mesylate salt, and hence, a substantially longer shelf life. The trihydrate is also less subject to breakdown in crystal structure due to the inclusion of water in the crystal. U.S. Pat. No. 6,008,233 describes the mesylate salt trihydrate, the anhydrous mesylate salt and free base of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol, and methods for their preparation.
Further, the free base, the anhydrous mesylate and methods of preparing them are also referred to, generically, in U.S. Pat. No. 5,185,343, which issued on Feb. 9, 1993. Their use in treating certain of the above disorders are referred to, specifically, in U.S. Pat. No. 5,272,160, which issued on Dec. 21, 1993; and International Patent Application PCT/IB 95/00380, which designates the United States, filed on May 18, 1995 and published as WO 96106081. Their use in combination with a compound capable of enhancing and thus restoring the balance of excitatory feedback from the ventral lateral nucleus of the thalamus into the cortex to treat Parkinson's disease is referred to in International Patent Application PCT/IB 95/00398, which designates the United States, filed on May 26, 1995 and published as WO96/37226. The foregoing U.S. patents and patent applications are incorporated herein by reference in their entireties.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of the methanesulfonate trihydrate salt of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol:
comprising the steps of
(i) dissolving the D-(−)-tartrate salt of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol in an aqueous methanesulfonic acid solution; and
(ii) allowing the methanesulfonate trihydrate salt to separate out of solution.
In the foregoing process, the molar ratio of methanesulfonic acid to the D-(−)-tartrate salt of (1S, 2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol is preferably in the range of 1.3 to 1.0. More preferably, the molar ratio of methanesulfonic acid to the D-(−)-tartrate salt of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol is in the range of 1.10 to 1.05; most preferably, it is in the range of 1.10 to 1.08.
In the process of the present invention, the aqueous methanesulfonic acid solution of step (i) is preferably created using pyrogen-free water.
The present invention is also directed to any of the above described processes for the preparation of the methanesulfonate trihydrate salt of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol further comprising the steps of
(i) dissolving a racemic mixture comprising compounds of formulae (I) and (II):
in aqueous methanol in the presence of D-(−)-tartaric acid; and
(ii) allowing the D-(−)-tartrate salt of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol to separate out of solution. In this process, the aqueous methanol preferably has a water content of 5 to 20%. More preferably, embodiment is wherein the aqueous methanol has a water content of 7 to 10%. The present invention is also directed to the process steps of enantiomeric resolution and isolation of the (D)-(−)-tartrate salt of the compound of the formula (I).
The present invention is also directed to the D-(−)-tartrate salt of a compound of formula (I), (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol
wherein the ratio of the (1S,2S)-enantiomer to its (1R,2R)-antipode is greater than 97%. More preferably, the ratio of the (1S,2S)-enantiomer to its (1R,2R)-antipode is greater than 98%.
DETAILED DESCRIPTION OF THE INVENTION
The mesylate salt trihydrate of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol is a white crystalline solid which has a single crystalline form and good solubility in water (25 and 15 mg/mL in pH 3 and 7 aqueous buffered solutions, respectively). The mesylate salt trihydrate is known to form upon allowing the anhydrous mesylate salt to equilibrate in an 81% relative humidity environment. Previous preparations of the mesylate salt trihydrate, e.g., in U.S. Pat. No. 6,008,233, required the use of the free base as the starting material, which required the extra step in the overall synthesis of isolating and drying the free base compound of formula (I) after enantiomeric resolution.
The present invention, however, permits the preparation of the mesylate salt trihydrate directly from the D-(−)-tartrate salt of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1yl)-1-propanol without proceeding via the free base. The D-(−)-tartrate salt used in the foregoing is the product of the enantiomeric resolution of racemic 1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol. According the present invention permits a more efficient synthesis of the mesylate salt with fewer steps.
The process of the present invention further comprises an improvement in the process for resolving the D-(−)-tartrate salt of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1yl)-1-propanol. Previous processes, e.g., in U.S. Pat. No. 6,008,233, for resolving the racemate of 1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol involved selective crystallization with optically active tartrate salts from absolute methanol, and almost always required subsequent reslurries and/or recrystallization to achieve an acceptable enantiomeric purity of (1S,2S) 97% or better. The present invention thus provides a means for eliminating repetitive purification steps and greater efficiency in the overall synthetic pathway.
The following reaction Schemes illustrates the process of the present invention.
Referring to Scheme 1, the racemic benzyl protected ketone compound of formula (III) is subjected to reduction conditions, either to NaBH
4
in ethanol for 6-7 hours at 40 to 50° C. or potassium selectride (CalSelect K) in tetrahydrofuran for 1 to 2 hours at 10 to 20° C., or any other suitable agents and conditions known to those of skill in the art, to produce a mixture of threo and erythro isomers, wherein the threo isomer predominates in a ratio of approximately 80:20 or better in the crude reaction mixture. The ethanol or THF solvents should not contain appreciable amounts of water, i.e., not greater than 0.2 to 0.5% water.
After actual isolation from the solvent, a product of nearly 90% threo orientation, i.e., the threo component being a racemic mixture of compounds of formula (IVA) (i.e., IVA-1 and IVA-2), may be obtained. The starting material of formula (III) is obtained by a procedure disclosed in U.S. Pat. No. 6,008,233, already noted above and incorporated by reference in its entirety.
Referring to Scheme 2, the benzyl group is removed from the racemate of the threo compound of fo
Rainville Joseph Philip
Sinay, Jr. Terry Gene
Walinsky Stanley Walter
Chang Ceila
Pfizer Products Inc.
Scully Scott Murphy & Presser
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