Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-23
2003-05-27
Chang, Ceila (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S327000
Reexamination Certificate
active
06570018
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:
The present invention is further directed to a process for the preparation of the (2S)-(+)-enantiomer of formula (II):
wherein R
1
is a protecting group selected from the group consisting of benzyl, (C
1
-C
6
)alkylbenzyl, (C
1
-C
6
)alkoxylbenzyl, tri(C
1
-C
6
)alkylsilyl, acyl (e.g., acetyl) and aroyl (e.g., benzoate). In addition, the present invention relates to intermediates useful in said processes.
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 of formula (I), its 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 96/06081. 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.
Previous methods for the preparation of the (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol proceeded via racemic synthetic pathways with resolution of the active optical isomers in the steps prior to therapeutic salt formation. One of the problems associated with resolution of compounds relatively late in a synthetic scheme is the waste and reduced efficiency involved in disposing of significant amounts of inactive or less active enantiomers and diastereomers. To maximize the efficacy of the synthesis, it is desirable to have a synthesis which introduces centers of optical activity into the target molecule precursors early in the synthesis. Accordingly, a method for transforming a racemic starting material into an optically active building block for the directed chiral synthetic pathway to a compound of formula (I) would be a significant advantage.
Although methods for the asymmetric transformation of racemic materials to chiral ones have been reported, the ability to obtain successfully optically active products has often been strictly limited to the specific circumstances and compounds involved. The preparation of optically active &agr;-aminopropiophenones has been achieved by asymmetric transformation. Takamatsu,
J. Pharm. Soc. Japan,
76(11), 1219-1222 (1956). In addition, the transformation of racemic 3-(RS)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one to its nearly optically pure (S)-enantiomer by crystallization induced asymmetric transformation has been reported. Reider et al.,
J. Org. Chem.,
52, 955-957 (1987).
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) reducing the carbonyl group of a compound of formula (II)
wherein R
1
is a protecting group, selected from the group consisting of benzyl, (C
1
-C
6
)alkylbenzyl, (C
1
-C
6
)alkoxylbenzyl, tri(C
1
-C
6
)alkylsilyl, acyl (e.g., acetyl) and aroyl (e.g., benzoate), via reaction with a alkali metal borohydride; and
(ii) cleaving off the protecting group R
1
of a compound of formula (III)
in the presence of methanesulfonic acid.
A preferred embodiment of the invention is where the protecting group R
1
is benzyl, (C
1
-C
6
)alkylbenzyl or (C
1
-C
6
)alkoxylbenzyl. Another preferred embodiment is wherein the alkali metal borohydride is lithium borohydride or sodium borohydride. A more preferred embodiment of the invention is wherein the R
1
group is benzyl and the alkali metal borohydride is lithium borohydride.
Another preferred embodiment is wherein the protecting group R
1
is benzyl and the cleavage of the protecting group of step (ii) is hydrogenolysis conducted in the presence of hydrogen gas and 5%-20% palladium on carbon. A more preferred embodiment is wherein the R
1
group is benzyl and the hydrogenolysis is conducted in the presence of hydrogen gas and 5% palladium on carbon. A preferred embodiment of the invention is wherein steps (i) and (ii) are conducted in a (C
1
-C
6
) alkanol solvent, optionally admixed with water. A more preferred embodiment of the invention is wherein the solvent used in steps (i) and (ii) is ethanol admixed with water.
The invention is also directed to a process for the preparation a compound of formula (II):
comprising the steps of
(i) placing a compound of formula (IV):
together with a diaroyl D-tartrate;
(ii) treating the D-tartrate salt product of step (i) with a weak base.
A “weak base,” as referred to herein, is a basic compound which is not sufficient in basicity to remove readily the &agr;-proton from a compound of formula (IV). A preferred embodiment of the invention is wherein the diaroyl D-tartrate is dibenzoyl D-tartrate or di-p-toluoyl D-tartrate. A preferred embodiment of the invention is wherein the steps of this process are conducted in a lower alkyl ketonic solvent, more preferably acetone. The more preferred embodiment of the invention is wherein the steps of this process are conducted in acetone at a temperature between 25° C. and the reflux temperature, most preferably between 48 and 52° C.
A preferred embodiment of the invention is wherein the weak base is a tri(C
1
-C
6
)alkylamine or an alkali/alkaline-earth metal carbonate, bicarbonate or alkylcarboxylate, e.g., NaHCO
3
, Na
2
CO
3
, NaOOCCH
3
, etc. A more preferred embodiment of the invention is wherein the weak base is NaHCO
3
in water admixed with an organic solvent, such as ethyl acetate or methylene chloride, more preferably, ethyl acetate.
The present invention is also directed to the (2S)-(+)-enantiomer of formula (II):
or a salt thereof, wherein R
1
is hydrogen or a protecting group selected from the group consisting of benzyl, (C
1
-C
6
)alkylbenzyl, (C
1
-C
6
)alkoxylbenzyl, tri(C
1
-C
6
)alkylsilyl, acyl (e.g., acetyl) and aroyl (e.g., benzoate), and the salt is a diaroyl D-tartrate. A preferred embodiment of the invention is wherein R
1
is benzyl. Another preferred embodiment of the invention is wherein the diaroyl salt is dibenzoyl D-tartrate salt or di-p-toluoyl D-tartrate.
DET
Rainville Joseph Philip
Sinay, Jr. Terry Gene
Walinsky Stanley Walter
Chang Ceila
Donahue E. Victor
Ginsburg Paul H.
Pfizer Inc
Richardson Peter C.
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