Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Reexamination Certificate
2002-08-29
2003-08-19
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
C544S395000
Reexamination Certificate
active
06608195
ABSTRACT:
The present invention relates to a novel process for the preparation of compounds of formula I:
wherein R
1
is defined herein. The present invention also relates to the preparation of compounds of formula II:
wherein R
1
and R
2
are as defined herein.
Other processes for making compounds of formula I have previously been described in International Patent Publication No. WO 98/14433, published Apr. 9, 1998, which is hereby incorporated by reference in its entirety. Previous methods employed in the art for making compounds of formula I are aryl-piperazine condensations described in Watthey et al.,
J. Med. Chem.,
1983, 26: 1116-1122 and Reinhoudt et al.,
Synthesis,
1987, 641-645. These aryl-piperazine condensations employ polar aprotic solvents, such as dimethyl sulfoxide or N,N-dimethylformamide, to obtain products of formula I in about 40 to 70% yield.
The method of the present invention represents a significant advance over these previously employed methods via the use of water as a solvent. The water solvent-based reaction affords not only higher yielding reactions, but also yields higher purity product and allows for easier product isolation. Water, of course, is a much more convenient solvent from a waste management and environmental viewpoint. Compounds of formula I are intermediates in the process for making compounds of formula II.
The compounds of formula II and pharmaceutically acceptable salts thereof, also described in International Patent Publication No. WO 98/14433, produced by the use of the processes of the present invention, are useful as selective agonists and antagonists of serotonin 1 (5-HT
1
) receptors, specifically, of one or both of the 5-HT
1A
and 5-HT
1D
receptors. These compounds are useful in treating hypertension, all forms of depression (e.g., depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depressive disorder, single episode depression, recurrent depression, child abuse induced depression, post partum depression, dysthymia; mild, moderate, or severe depressions with or without atypical features, melancholic features, psychotic features, catatonic features; seasonal affective disorder, geriatric depression, chronic depression; adjustment disorder with depressed mood or with anxiety and depressed mood; mixed anxiety and depression; substance induced mood disorder; and mood disorder secondary to a general medical condition), bipolar disorder (including in the depressed phase), generalized anxiety disorder, social anxiety, separation anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders (e.g., binge eating disorder, anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, cocaine, heroin, phenobarbital, marijuana, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder; panic disorder with and without agoraphobia; memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson's diseases (e.g., dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette's syndrome, trichotillomania, kleptomania, male impotence, cancer (e.g. small cell lung carcinoma), chronic paroxysmal hemicrania, headache (associated with vascular disorders) autism, pervasive developmental disorder NOS, Asperger's disorder, selective mutism, chronic motor or vocal tic disorder, somatization disorder, insomnia, intermittent explosive disorder, pyromania, pathological gambling, impulse-control disorder, premenstrual dysphoric disorder, and attention-deficit/hyperactivity disorder (ADHD), and other disorders for which a 5-HT
1
agonist or antagonist is indicated.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of a compound of formula I:
wherein R
1
is (C
1
-C
6
) alkyl; comprising the step of allowing a compound of formula III:
to react with a compound of formula IV:
in the presence of water and a metal carbonate.
In a preferred embodiment of the invention, the molar ratio of the compound of formula IV to compound of formula III in the reaction is in the range of 1.0 to 2.0. In a more preferred embodiment, the ratio of the compound of formula IV to compound of formula III is approximately 1.8. The metal carbonate in the process of the invention is preferably an alkali metal carbonate, more preferably potassium or sodium carbonate, most preferably potassium carbonate. Preferably, the molar ratio of metal carbonate to compound of formula III is in the range of 2.0 to 1.2; more preferably, the molar ratio of the molar ratio of metal carbonate to compound of formula III is approximately 1.5. Preferably, the water volume present in the reaction is 4 ml to 30 ml per gram of 2-fluorobenzaldehyde of formula III; more preferably, 6 ml to 30 ml per gram of compound of formula III; most preferably, 8.0 ml per gram of compound of formula III.
In a preferred embodiment, the present invention relates to the process for the preparation of compounds of formula I wherein R
1
is methyl, ethyl or propyl.
In a more preferred embodiment, the present invention relates to the process for the preparation of compounds of formula I wherein R
1
is methyl.
The present invention further relates to a process for the preparation of the hydrochloride salt of the compound of formula I comprising reacting a compound formula I with an acyl chloride in aqueous alkanol or gaseous HCl dissolved in aqueous alkanol. Preferably, the acyl chloride is acetyl chloride and the alkanol is isopropanol.
The present invention also relates to a process for the preparation of compounds of formula II:
wherein R
1
is as defined above and R
2
is —(CH
2
)
m
B, wherein m is zero, one, two or three and B is phenyl or naphthyl, wherein each of the foregoing phenyl and naphthyl groups may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
) alkoxy-(C
1
-C
6
)alkyl-, trifluoromethyl, trifluoromethoxy, and cyano; comprising the step of
allowing the hydrochloride salt of the compound of formula I to react in the presence of a base in a suitable solvent with a compound of formula V:
wherein R
2
is as defined above.
Preferably, the base used in the process for making the compound of formula II is an alkali metal hydroxide, an alkali metal hydride, alkali metal carbonate or an alkali metal alkylamine, or alkali metal amine; more preferably, the base is sodium hydride, lithium hydride, lithium hydroxide, sodium methoxide, lithium isopropoxide, potassium t-butoxide, lithium diisopropylamide; most preferably, the base is lithium hydroxide or sodium hydride, and even further preferred, the base is the monohydrate or anhydrous lithium hydroxide. Preferably, the suitable solvent for this step is isopropanol or toluene, more preferably, toluene.
In a preferred embodiment, the present invention relates to the process for the preparation of compounds of formula II wherein R
2
is phenyl optionally substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
) alkoxy-(C
1
-C
6
)alkyl-, trifluoromethyl, trifluoromethoxy, and cyano.
In a more preferred embodiment, the present invention relates to the process for the preparation of compounds of formula II wherein R
2
is phenyl optionally substituted with one or mor
Rainville Joseph P.
Sinay Terry G.
Walinsky Stanley W.
Ford John M.
Ginsburg P. H.
Joran A. D.
Pfizer Inc.
Richardson P. C.
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