Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-04-11
2001-03-06
Chang, Ceila (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C558S406000
Reexamination Certificate
active
06197960
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for producing piperidinecarbinols useful as intermediates for synthesizing medicines, particularly to a process for producing trans-4-(p-fluorophenyl)-1-methyl-3-piperidinecarbinol, which is an important intermediate in synthesis of paroxetine, which is useful as an antidepressant or a therapeutic agent for Parkinson's disease. The present invention also relates to intermediates useful for producing the piperidinecarbinols and a process for producing the intermediates.
2. Discussion of Background
Conventionally known processes for producing 4-aryl-3-piperidinecarbinols useful for synthesizing medicines are the following four processes (a) to (d).
(a) A process which comprises reducing an 4-aryl-3-piperidinecarboxylic acid ester represented by the following general formula (4) with lithium aluminum hydride (U.S. Pat. No. 3,912,743):
wherein R
11
is a lower alkyl group or an aryl group, R
12
is a lower alkyl group, and Y is a hydrogen atom, a halogen atom, a methoxy group or a mercapto group.
A compound represented by the general formula (4) is synthesized by a process which comprises reacting an aryl Grignard reagent with arecoline (J. Org. Chem., 1957, 22, 201) or by a process which comprises a series of steps including reaction of an aryl Grignard reagent with a nicotinic acid ester and reductive hydrogenation of an 4-aryl-1-methyl-3-alkoxycarbonylpyridinium salt with a platinum catalyst (U.S. Pat. No. 4,861,893).
However, the former process has a problem of using expensive and irritating arecoline as a starting material. In addition, since the conjugate addition of a Grignard reagent to arecoline competes with the 1,2-addition, a mixture of the products of these two reactions is produced in the process, and therefore the desired product is very hard to isolate and generally obtainable in a low yield. The latter process is not practical in respect of the production cost and efficiency because it requires many steps.
(b) A process which comprises reducing an 4-aryl-2,6-dioxo-3-piperidinecarboxylic acid ester represented by the general formula (5) with lithium aluminum hydride (Japanese Examined Patent Publication JP-B-6-96551):
wherein R
11
is a hydrogen atom, a lower alkyl group or an aralkyl group, R
12
is a lower alkyl group, and Y is a hydrogen atom, a halogen atom, a lower alkyl group, an aralkyloxy group, a trifluoroalkyl group, a hydroxyl group, a methoxy group or a mercapto group.
A compound represented by the general formula (5) is synthesized by a process which comprises conjugate addition of a N-substituted amidomalonic acid ester to a cinnamic acid derivative, a process which comprises conjugate addition of an amidomalonic acid ester to a cinnamic acid derivative and subsequent N-alkylation (Japanese Examined Patent Publication JP-B-6-96551) or a process which comprises conjugate addition of a malonic acid ester to cinnamamide (EP 0374675).
However, the first two processes have problems that an amidomalonic acid ester as the starting material tends to undergo disproportionation and thus is difficult to produce, and is generally so expensive as to be hardly available, and that a compound represented by the formula (5) is not reactive enough to be readily reduced. The last process uses a free amine as the starting material for synthesis of cinnamamide, and prevention of the bad smell of the amine from leaking out inevitably adds to manufacturing costs.
(c) A process which comprises reducing an 4-aryl-3-hydroxymethyl-1-alkylpyridinium salt represented by the general formula (6) directly or stepwise (U.S. Pat. No. 4,861,893):
wherein R
11
is a hydrogen atom or a lower alkyl group, and Y is a hydrogen atom, a halogen atom, a lower alkyl group, an aralkyloxy group, a trifluoroalkyl group, a hydroxyl group, a methoxy group or a mercapto group.
A compound represented by the general formula (6) is synthesized by a process which comprises a series of conversions such as reduction of an 4-arylnicotinic aldehyde prepared by the method of Jutz et al. (Chem. Ber., 1966, 99, 2479) into a hydroxylmethylpyridine derivative and subsequent N-alkylation. However, the process (c) which involves the series of conversions requires so many steps that it is problematic in the production efficiency and practicability.
(d) A process which comprises reducing an 4-aryl-3-hydroxymethyl-1,2,3,6-tetrahydropyridine represented by the general formula (7) (Tetrahedron Lett., 1983, 24, 5151):
wherein R
11
is a lower alkyl group, and Y is a hydrogen atom or a halogen atom.
A compound represented by the general formula (7) is synthesized by a process which comprises ene reaction of an 4-aryl-1-alkyl-1,4,5,6-tetrahydropyridine and formaldehyde (U.S. Pat. No. 4,007,196), or by a process which comprises reacting a 2-propenylaryl derivative with methylamine and formaldehyde (U.S. Pat. No. 4,593,036). However, because in this process, a highly neurotoxic 4-aryl-1-alkyl-1,4,5,6-tetrahydropyridine is unavoidable, this process is actually impractical in respect of industrial safety.
On the other hand, as processes for producing 4-aryl-6-oxo-3-piperidinecarboxylic acid derivatives, which will be described later, the following two processes (e) and (f) which comprise reduction of the cyano group of a 2-cyano-3-arylglutaric acid derivative to an amino group and subsequent cyclization have been known.
(e) A process reported by Koelsch which comprises hydrogenating diethyl 2-cyano-3-phenylglutarate with a Raney nickel catalyst (J. Am. Chem. Soc., 1943, 2459).
(f) A process reported by Rapoport et al. which comprises hydrogenating diethyl 2-cyano-3-(m-methoxyphenyl)glutarate with a platinum oxide catalyst (J. Org. Chem., 1977, 1485).
The process (e) uses a very high hydrogen pressure around 140 atm and therefore is industrially far from practicable. Besides, the process (e) is not suitable for production of an 4-aryl-6-oxo-3-piperidinecarboxylic acid having a halogen atom on the aryl group, because under such a high pressure, the halogen atom on a benzene ring is also reduced. The process (f) is not advantageous in respect of production costs and efficiency because the reduction of the cyano group and cyclization are conducted in two steps.
SUMMARY OF THE INVENTION
To solve the above-mentioned problems with the conventional processes, the present inventors have found a novel process for producing a piperidinecarbinol represented by the following general formula (2) which uses an 4-aryl-6-oxo-3-piperidinecarboxylic acid represented by the general formula (1) as an important intermediate. The present invention provides the said production process, a novel 4-aryl-6-oxo-3-piperidinecarboxylic acid derivative and a process for producing the derivative. Namely, the present invention provides;
a process for producing a piperidinecarbinol represented by the general formula (2), which comprises reducing the trans isomer of a compound represented by the general formula (1):
wherein R
1
is a hydrogen atom, a lower alkyl group or an aralkyl group, R2 is a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group, and X is a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an aralkyl group, an alkoxy group, a dialkylamino group, an alkylthio group, an arylthio group or C
m
F
2m+1
— wherein m is an integer of from 1 to 20;
a compound represented by the general formula (1′):
wherein R
1
is a hydrogen atom, a lower alkyl group or an aralkyl group, R
2
is a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group, and Z is a halogen atom;
a process for producing a compound represented by the general formula (1′) wherein R
1
is a hydrogen atom, which comprises reducing of the cyano group of a cyanoglutaric acid derivative represented by the general formula (3) and simultaneous intramolecular cyclization of the cyanoglutaric acid derivative:
wherein each of R
2
and R
3
is a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group,
Matsumura Yasushi
Mori Nobuaki
Nishino Jiro
Okazoe Takashi
Ookura Kazuhiro
Asahi Glass Company Ltd.
Chang Ceila
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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