Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-16
2001-08-07
Huang, Evelyn Mei (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S093000
Reexamination Certificate
active
06271378
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention provides an improved process and novel intermediates for preparing antihistamines. In particular, the process and the intermediates of this invention are useful in the preparation of loratadine, disclosed in U.S. Pat. No. 4,282,233, and descarboethoxyloratadine (8-chloro-6,11 -dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine) (“DCL”), disclosed in U.S. Pat. No. 4,659,716.
U.S. Pat. No. 4,659,716 discloses the following process for preparing loratadine and DCL:
According to this process, the tricyclic ketone (1) is coupled with Grignard reagent derived from 4-chloro-N-methylpiperidine. The alcohol (2) derived from this addition reaction is dehydrated under acidic conditions to produce compound (3). Compound (3) is then subjected to a Von Braun reaction with ethyl chloroformate to produce loratadine. DCL may be prepared by decarbalkoxylating loratadine. This process suffers from a number of serious drawbacks. The halide, 4-chloro-N-methylpiperidine, required for the Grignard reaction with the ketone (1) is accessible only by a 5 step synthesis, and is unstable at temperatures above ambient temperature. The reaction of ketone (1) with N-methylpiperidin-4-yl magnesium chloride to produce the alcohol (2) is not a high yielding reaction (about 60%) due to the ocurrence of conjugate addition (i.e., to the pyridine ring) and reduction. The dehydration of alcohol (2) to produce compound (3) is a sensitive reaction, and isomerization of compound (3) can occur. The Von Braun reaction of compound (3) to produce loratadine produces noxious chloromethane as a gaseous by-product. This noxious by-product must be decomposed chemically before discharge to the atmosphere. These problems are eliminated by the present invention.
SUMMARY OF THE INVENTION
This invention provides a process for preparing a compound having the formula:
wherein R
1
is selected from the group consisting of: alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, and cycloalkylalkyl, R
1
being optionally substituted by substituents selected from halo, —OH, alkyl, alkoxy, or —CF
3
, said process comprising the following steps:
(a) reacting a ketone having the formula
with a carbanion having the formula
wherein R
1
is as defined above, and R
2
and R
3
are independently selected from the group consisting of —OR
A
and —R
A
, wherein R
A
is alkyl, phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl;
(b) treating the reaction mixture from step (a) with a protonating agent to form a &bgr;-hydroxy intermediate having the formula
wherein R
1
, R
2
and R
3
are as defined above; and
(c) thermally decomposing the &bgr;-hydroxy intermediate to form the compound of formula (I).
This invention further provides a process for preparing a compound having the formula:
said process comprising the following steps:
(a) reacting a ketone having the formula
with a carbanion having the formula
wherein R
1
is selected from the group consisting of: alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, and cycloalkylalkyl, R
1
being optionally substituted by substituents selected from halo, —OH, alkyl, alkoxy, or —CF
3
; and R
2
and R
3
are independently selected from the group consisting of —OR
A
and —R
A
, wherein R
A
is alkyl, phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl;
(b) treating the reaction mixture from step (a) with a protonating agent to form a &bgr;-hydroxy intermediate having the formula
wherein R
1
, R
2
and R
3
are as defined above;
(c) thermally decomposing the &bgr;-hydroxy intermediate to form a compound having the formula
wherein R
1
is as defined above; and
(d) converting the compound of formula (I) to the compound of formula (IV).
In a particularly preferred embodiment for preparing compound (IV) (DCL), R
1
in the foregoing process is selected for ease of removal under acidic conditions, and is preferably alkyl, most preferably t-butyl.
This invention firer provides a novel intermediate having the formula
wherein R
1
, R
2
, and R
3
are as defined above.
Also provided is a novel intermediate having the formula
wherein R
1
, R
2
, and R
3
are as defined above.
DETAILED DESCRIPTION
As used herein, the term “alkyl” means straight or branched hydrocarbon chains of 1 to 6 carbon atoms.
“Alkenyl” refers to straight or branched hydrocarbon chains of 1 to 6 carbon atoms having at least one carbon to carbon double bond.
“Alkynyl” refers to straight or branched hydrocarbon chains of 1 to 6 carbon atoms having at least one carbon to carbon triple bond.
“Aryl” refers to a carbocyclic group having at least one aromatic ring (e.g., phenyl or naphthyl).
“Aralkyl” refers to a group having the formula aryl-R—, wherein R is alkyl.
“Cycloalkyl” refers to a non-aromatic carbocyclic ring of from 3 to 6 carbon atoms.
“Cycloalkylalkyl” refers to a group having the formula cycloalkyl-R—, wherein R is alkyl.
“Halo” refers to fluorine, chlorine, bromine or iodine radicals.
“Substituted phenyl” refers to phenyl substituted by substituents selected from halo, —OH, alkyl, alkoxy, or —CF
3
.
“Substituted cycloalkyl” refers to cycloalkyl substituted by substituents selected from halo, —OH, alkyl, alkoxy, or —CF
3
.
“Substituted cycloalkylalkyl” refers to cycloalkylalkyl, wherein the cyloalkyl portion is substituted by substituents selected from halo, —OH, alkyl, alkoxy, or —CF
3
.
The present process is a significant improvement over prior art processes for preparing loratadine and related compounds. One significant advantage is that the starting ketone can be converted to the desired product (e.g., loratadine) as a one pot process (i.e., without isolating the &bgr;-hydroxy intermediate) with high yield and purity. The carbanion used in the present process is derived from the thermally stable compound of formula (III), which is considerably more stable than the thermally labile 4-chloro-N-methyl piperidine disclosed in U.S. Pat. No. 4,659,716. Moreover, the compound of formula (III) can be obtained from pyridine in two steps, in about 70% yield, which is a much simpler preparation than the five steps required to prepare the 4-chloro-N-methyl piperidine used in the prior art process.
R
1
is preferably alkyl, more preferably ethyl or t-butyl, most preferably, ethyl.
R
2
and R
3
are preferably alkyl, more preferably, methyl, ethyl, isopropyl, or t-butyl, and most preferably ethyl.
When R
1
, R
2
, and R
3
are substituted, the number of substituents is preferably 1 to 3.
The carbanion used in step (a) of our process is preferably generated by treating the compound of formula (III), above, with a strong base in a suitable aprotic organic solvent. Preferably, the base is an organolithium base. Examples of suitable bases include, but are not limited to lithium diisopropyl amide (“LDA”); n-butyl lithium; t-butyl lithium; sec-butyl lithium; and lithium diethylamide. LDA is most preferred. Examples of suitable aprotic organic solvents for generating the carbanion, and for carrying out step (a), include, but are not limited to: xylene; tetrahydrofuran (“THF”); diethyl ether; ethylene glycol dimethyl ether; tert-butyl methyl ether; diethylene glycol dimethyl ether; benzene; toluene, and mixtures thereof. Preferably, the solvent employed in step (a) is an ether, most preferably, THF. In a particularly preferred embodiment, step (a) is carried out in a mixture of an ether solvent with a non-ether solvent having a higher boiling point. Step (a) is preferably carried out at a temperature of −150° to +10° C., more preferably, −80° to −10° C., most preferably, −40° to −20° C. Preferably, the compound of formula (III), and the carbanion generated therefrom, are used in amounts ranging from 1 to 3 equivalents, more preferably, 1 to 1.5 equivalents, most preferably, 1.05 to 1.1 equivalents relative to the ketone.
Step (b) of our process is carried out by adding a protonating agent to the reaction mixture fr
Doran Henry J.
O'Neill Pat M.
Huang Evelyn Mei
Lee William
Mann Arthur
Schering Corporation
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