Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1999-10-20
2001-05-29
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S396000, C544S399000
Reexamination Certificate
active
06239277
ABSTRACT:
FIELD OF INVENTION
This invention relates to an improved method for preparing aliphatic esters and carboxylic acids substituted with a substituted piperazine group. More particularly, this invention relates to the preparation of aliphatic carboxylic acids substituted with a 4-aralkylpiperazinyl group.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 4,525,358 discloses the preparation of aliphatic carboxylic acids substituted with 1-alkoxy-4-alkylpiperazines having the formula
where Y is an ester, hydroxy or amino group, X and X′ are independently hydrogen, halo, linear or branched lower alkoxy or trifluoromethyl and m and n are the integers 1 or 2. A number of reaction routes for the preparation of these acetic acid derivatives are shown, e.g., the reaction of 1-(diphenylmethyl)-piperazine with an omega haloacetamide followed by hydrolysis, the reaction of the alkali metal salt of an omega-[4(diphenylmethyl)-1-piperazinyl]alkanol with a 2-haloacetamide followed by hydrolysis, etc.
UK Patent Application 2,225,321, published on May 30, 1990 discloses that 2-[2-[-4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid, i.e., the compound shown above where Y is hydroxy, X is hydrogen, X′ is chloro and m and n are the integer 1, may be prepared by hydrolyzing 2-[2-[-4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetonitrile with base or with acid. The nitrile is prepared by reaction of racemic 1-[(4-chlorophenyl)phenylmethyl]-piperazine with 2-chloroethoxyacetonitrile.
UK Patent Application 2,225,320, published May 30, 1990 discloses the preparation of 2-[2-[-4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid by the reaction of 2-[-4-[(4-chlorophenyl)-phenylmethyl]-piperazinyl]1-ethan-1-ol with an alkali metal haloacetate in the presence of an alkali metal alcoholate followed by removal of the alkali metal salt with acid to form the free acid or its acid salt.
In a reaction that uses one of the same starting materials disclosed in the UK '320 application, Polish patent PL 163415 B1 published on Apr. 21, 1992 discloses preparation of 2-[2-[-4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-acetic acid by the reaction of 2-[4-[(4-chlorophenyl)-phenylmethyl]-piperazinyl] 1-ethan-1-ol with chloroacetic acid, in a two phase system that is an organic phase (the substrate and an inert solvent) and an inorganic phase (the hydroxide of an alkali metal in water). A yield of 67% was reported.
Japanese patent application JP 04112852 A2 , published Apr. 14, 1992 discloses a method for the preparation of haloalkoxy acetic acid derivatives having the formula
X—(CH
2
)
m
—O—CH(R)—CO(O)R′
where X is a halide, m is a number between 2 and 7, R is hydrogen or lower alkyl and R′ is hydrogen or an ester group. This reference further discloses that the above compound is a useful intermediate for the preparation of Cetirizine [(2-(4-(4-chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy acetic acid. Details of such preparation are not, however, shown in this reference.
It would be desirable to have synthetic routes for the preparation of the physiologically active compounds similar to those disclosed in U.S. Pat. No. 4,525,358 that result in higher yields or higher purity products.
SUMMARY
A process is disclosed for the preparation of a piperazine-substituted aliphatic carboxylate having the formula
where n is an integer of from 1 to 6, R and R′ are the same or different and are hydrogen, C
1
to C
6
alkyl or aryl or heteroaryl that is unsubstituted or is substituted with at least one substituent that is halo, C
1
to C
6
alkyl or C
1
to C
6
alkoxy and R″ is C
3
to C
12
branched alkyl or a cation. The process comprises treating a substantially anhydrous mixture comprising a compound of the formula
wherein R and R′ are as defined above and an alkoxy ester of the formula
X—(CH
2
)
n
—O—CH
2
—CO(O)R″
where X is a leaving group and n and R″ are as defined above, in the presence of an effective amount of a base for a time and at a temperature sufficient to form a piperazine-substituted aliphatic carboxylate. Hydrolysis of the carboxylate with acid produces a piperazine-substituted aliphatic carboxylic acid or the acid salt thereof.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the process of the present invention to prepare a piperazine-substituted aliphatic carboxylate the following definitions apply:
The phrase “C
1
to C
6
alkyl” is intended to mean and include linear or branched alkyl groups having from one to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, n-pentyl, 2-methylbutyl, n-hexyl and the like.
The phrase “C
1
to C
6
alkoxy” is intended to mean and include linear or branched alkoxy groups having from one to six carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, secondary butoxy, tertiary butoxy, n-pentoxy, 2-methylbutoxy, n-hexyloxy and the like.
The phrase “aryl or heteroaryl that is unsubstituted or substituted with at least one substituent that is halo, C
1
to C
6
alkyl or C
1
to C
6
alkoxy” is intended to mean and include the unsubstituted aryl groups such as illustrated by phenyl, 1-naphthyl, 2-naphthyl and the like, the unsubstituted heteroaryl groups such as illustrated by furanyl, thiophenyl, pyrrolyl, pyranyl, pyridinyl and the like as well as the illustrated unsubstituted aryl or heteroaryl groups substituted by at least one halo such as chloro, bromo, etc., C
1
to C
6
alkyl or C
1
to C
6
alkoxy such as those shown above.
The phrase “C
3
to C
12
branched alkyl” is intended to mean and include branched alkyl groups having from three to twelve carbon atoms such as isopropyl, 2-methylpropyl, 2-methylbutyl, 2-methylpentyl, 3-methylhexyl, 3-methyloctyl and the like.
The phrase “X is a leaving group” is intended to mean and include leaving groups which are those organic moieties commonly the subject of unimolecular, multistage or bimolecular, concerted elimination reactions and include the moieties illustrated by halo (Cl, Br or I), OSO
2
R, OCOR, OR, NR
3
, PR
3
, SR
2
, SO
2
R, and the like, where R is defined above. Such leaving groups are well known in the prior art.
The word “base” is intended to mean and include an ammonium, alkali metal or alkaline earth metal hydroxide, carbonate or (if appropriate) bicarbonate, hydride or amide such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, lithium hydride, sodamide and the like.
The phrase “cation” is intended to mean and include the cation employed to form the base as defined above and includes such cations as sodium, potassium, lithium, ammonium and the like.
The piperazine-substituted aliphatic carboxylates prepared in accordance with the process of the present invention comprises one or more compounds having the following formula
wherein n is an integer from 1 to 6, R and R′ are the same or different and are C
1
to C
6
alkyl or aryl or heteroaryl that is unsubstituted or is substituted with at least one substituent that is halo, C
1
to C
6
alkyl or C
1
to C
6
alkoxy and R″ is C
3
to C
12
branched alkyl or an cation.
In the above piperazine-substituted aliphatic carboxylate compounds it is preferred that n is an integer that is 1 or 2, R and R″ are different and are aryl either unsubstituted or substituted with at least one substituent that is methyl, ethyl or chloro and R″ is isopropyl, secondary butyl, tertiary butyl or neopentyl. Most preferably, n is 2, R is hydrogen, R′ is chloro and R″ is tertiary butyl.
The process of the present invention requires that an anhydrous mixture be formed comprising a piperazine compound of the formula
where R and R′ are defined above and an ester of the formula
X—(CH
2
)
n
—O—CH
2
—CO(O)R″
where X is a leaving group and n and R″ are as defined abov
Fairfax David John
Hernandez Pedro E.
Michalson Erik T.
Hammond Richard J.
McKenzie Thomas
Salsbury Chemicals, Inc.
Shah Mukund J.
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