Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2000-11-14
2001-09-25
Geist, Gary (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C558S359000, C514S529000, C514S561000
Reexamination Certificate
active
06294690
ABSTRACT:
BACKGROUND OF THE INVENTION
U.S. Pat. Nos. 4,024,175 and 4,087,544, which are herein incorporated by reference, disclose novel cyclic amino acids of Formula A
wherein R
1
is a hydrogen atom or a lower alkyl radical, and n is 4, 5, or 6 and the pharmacologically compatible salts thereof:
The compounds disclosed in the above United States patents are useful for the therapy of certain cerebral, diseases, for example, they can be used for the treatment of certain forms of epilepsy, faintness attacks, hypokinesia, and cranial traumas. Additionally, they bring about an improvement of cerebral functions, and thus are useful in treating geriatric patients. Particularly valuable is 1-(aminomethyl)cyclohexaneacetic acid (gabapentin).
Gamma-aminobutyric acid (GABA) is an inhibitory amino acid found in the mammalian central nervous system (CNS). It has been reported that dysfunction with GABA neurotransmission in the CNS may contribute or even cause psychiatric and neurological diseases such as epilepsy, schizophrenia, Parkinson's disease, Huntington's Chorea, and dyskinesia (Saletu B., et al.,
International Journal of Clinical Pharmacology, Therapy and Toxicology
, 1986;24:362-373). Gabapentin was designed as a GABA analog that would cross the blood-brain barrier. Gabapentin was found to have anticonvulsant and antispastic activity with extremely low toxicity in man.
U.S. Pat. No 5,084,479 discloses the use of gabapentin in neurodegenerative disorders. U.S. Pat. No. 5,025,035 discloses the use of gabapentin in depression. U.S. Pat. No. 5,510,381 discloses the use of gabapentin in mania and bipolar disorders.
The aforementioned compounds of Formula A including gabapentin have been prepared from a compound of formula
wherein R
2
is an alkyl radical containing up to eight carbon atoms, and n is as defined above by well-known standard reactions such as, for example, the Hofmann, Curtius, or Lossen rearrangements into the amino derivatives of Formula A. Although these reactions provide the target compounds, they require a large number of synthetic steps and in some cases involve potentially explosive intermediates.
U.S. Pat. No. 4,152,326 discloses cyclic sulphonyloxyimides of formula
wherein R
2
is a saturated, straight-chained, branched or cyclic lower aliphatic radical or an unsubstituted or substituted aryl radical, and n is 4, 5, or 6, which can be converted into a compound of Formula A. Again, similar to the previous processes, this process requires a large number of synthetic steps to obtain a compound of Formula A. Finally, all of the previous processes require as the penultimate step conversion of an intermediate salt of the target compound to an amino acid of Formula A.
U.S. Pat. Nos. 5,132,451, 5,319,135, 5,362,883, 5,091,567, 5,068,413, 4,956,473, 4,958,044, 5,130,455, 5,095,148, 5,136,091, and 5,149,870 disclose additional processes and intermediates for preparing gabapentin. These processes require a number of steps and in some cases utilize large quantities of hazardous materials.
The object of the present invention is an improved process for preparing gabapentin employing a novel synthesis.
Further, we have unexpectedly found that gabapentin can be prepared from novel intermediates in fewer steps and higher yields than the previous methods. Moreover, the present method proceeds from inexpensive starting materials and is amenable to large-scale synthesis.
SUMMARY OF THE INVENTION
Accordingly, a first aspect of the present invention is an improved process for the preparation of the compound of Formula I
which comprises:
Step (a) treating the compound of Formula VII
with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI
Step (b) treating the compound of Formula VI with a compound of Formula V
wherein X is halo or sulfonate and R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl in the presence of a solvent to afford a compound of Formula IV
wherein R is as defined above;
Step (c) treating a compound of Formula IVa
wherein R
1a
is alkyl with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula III
wherein R
1a
is as defined above;
Step (d) treating the compound of Formula IIIa
with an acid in a solvent to afford the compound of Formula II
or treating a compound of Formula IIIb
wherein R
1b
is alkyl excluding tertiary butyl with an acid or base in a solvent to afford the compound of Formula II or treating the compound of Formula IVb
with hydrogen in the presence of a catalyst and a solvent to afford the compound of Formula II or treating the compound of Formula IVc
with hydrogen in the presence of a catalyst and a solvent to afford the compound of Formula II;
Step (e) treating the compound of Formula IVa-1
with an acid in a solvent to afford the compound of Formula IVb or treating a compound of Formula IVa-2
wherein R
1a-2
is alkyl excluding tertiary butyl with an acid or base in a solvent to afford the compound of Formula IVb; and
Step (f) treating either the compound of Formula IVb or the compound of Formula IVc or the compound of Formula II with hydrogen in the presence of a catalyst and a solvent to afford the compound of Formula I.
A second aspect of the present invention is an improved process for the preparation of a compound of Formula IV
wherein R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl which comprises:
Step (a) treating the compound of Formula VII
with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI
Step (b) treating the compound of Formula VI with a compound of Formula V
wherein X is halo or sulfonate and R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl in the presence of a solvent to afford a compound of Formula IV.
A third aspect of the present invention is an improved process for the preparation of a compound of Formula III
wherein R
1a
is alkyl which comprises:
Step (a) treating the compound of Formula VII
with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI
Step (b) treating the compound of Formula VI with a compound of Formula V
wherein X is halo or sulfonate and R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl in the presence of a solvent to afford a compound of Formula IV
wherein R is as defined above; and
Step (c) treating a compound of Formula IVa
wherein R
1a
is alkyl with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula III.
A fourth aspect of the present invention is an improved process for the preparation of the compound of Formula II
which comprises:
Step (a) treating the compound of Formula VII
with an alkali metal in ammonia or higher order amine in the presence of a solvent to afford in situ the compound of Formula VI
Step (b) treating the compound of Formula VI with a compound of Formula V
wherein X is halo or sulfonate and R is hydrogen, an alkali metal, an alkaline earth metal, ammonium, an amine cation, alkyl, or benzyl in the presence of a solvent to afford a compound of Formula IV
wherein R is as defined above;
Step (c) treating a compound of Formula IVa
wherein R
1a
is alkyl with hydrogen in the presence of a catalyst and a solvent to afford a compound of Formula III
wherein R
1a
is as defined above; and
Step (d) treating the compound of Formula IIIa
with an acid in a solvent to afford the compound of Formula II or treating a compound of Formula IIIb
wherein R
1b
is alkyl excluding tertiary butyl with an acid or base in a solvent to afford the compound of Formula II or treating the compound of Formula IVb
with hydrogen in the presence of a catalyst and a solvent to afford the compound of Formula II or treating the compound of Formula IVc
with hydrogen in the presence of a catalyst and a solvent
Deering Carl Francis
Mennen Kenneth Earl
Ramage Robert
Geist Gary
Merchant & Gould P.C.
Warner-Lambert & Company
Zucker Paul A.
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