Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-10-11
2003-11-04
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S194000
Reexamination Certificate
active
06642385
ABSTRACT:
FIELD OF THE INVENTION
This application specifically discloses a novel process to synthesize 4-(piperidyl) (2-pyridyl)methanone-(E)-O-methyloxime and its salts in high stereochemical purity. It also generically discloses a process to prepare compounds similar to the above in high stereochemical purity. This application claims priority from U.S. provisional application, Serial No. 60/329,561 filed on Oct. 15, 2001. The invention disclosed herein is related to that disclosed in the provisional patent application, Serial No. 60/329,562 filed on Oct. 15, 2001.
BACKGROUND OF THE INVENTION
4-(Piperidyl) (2-pyridyl)methanone-(E)-O-methyloxime dihydrochloride (Formula I) is an intermediate used in the preparation of compounds that are histamine-H
3
antagonists. An example of such histamine-H
3
antagonists is 1-[[1-[(2-Amino-5-pyrimidinyl)methyl]-4-piperidinyl]carbonyl]-4-[(E)-(methoxyimino)-2-pyridinylmethyl]piperidine shown in Formula II.
The conversion of the compound of Formula I into a compound of Formula II is disclosed in the commonly owned U.S. patent application, Ser. No. 09/978,267 (Attorney Docket No. AL01348K) filed of even date herewith. Antagonists of the H
3
receptor are useful for the treatment of allergy, asthma and other such respiratory disorders.
In view of the importance of the antagonists of histamine-H
3
, new, novel methods of making such antagonists and/or their intermediates are always of interest.
SUMMARY OF THE INVENTION
In an embodiment, the present application teaches a novel, simple process of making a compound of Formula I, its monohydrochloride and its free base itself in high stereochemical purity and, via that process, a method of making a compound of Formula II in high yields and high stereochemical purity. The term “high stereochemical purity” refers to at least about 90% of the desired isomer, which, in the present invention, is the E-isomer of the compound of Formula I, its monohydrochloride and its free base. Indeed, the stereochemical purity of the compound of Formula I, its monohydrochloride and its free base made by the inventive process typically exceeds 95% of the E-isomer. The term “high yields” refers to at least about 60% yield of the desired product.
Thus, the present process comprises synthesizing compounds such as the compound of Formula I, its mono acid salt (for example, its monohydrochloride) and its free base from a compound of Formula III:
where R
1
is defined below and n is a number from 1 to 4, and from a compound of Formula IV:
where R
2
is defined below. The process of making a compound such as the compound of Formula I from a compound of Formula III and a compound of Formula IV comprises:
(a) converting the compound of Formula IV into its Grignard form of Formula IVA:
where R
2
is defined below and X is a halogen;
(b) reacting the compound of Formula III with the compound of Formula IVA to obtain a compound of Formula V:
(c) reacting the compound of Formula V with a suitable alkyl chloroformate of Formula VI:
R
3
—OCOCl VI
where R
3
is defined below, to yield a compound of Formula VII:
(d) forming the free base (Formula VIIA) and then the acid salt (mono acid salt or diacid salt) of the free base (Formula VIII):
(e) reacting the compound of Formula VIII with an alkoxyamine (NH
2
OR
4
) or its hydrochloride (where R
4
is defined below) to form an oxime of Formula IX:
and
(f) isomerizing the compound of Formula IX predominantly to the E isomer by treatment with a strong acid and simultaneously converting to the desired acid salt of a compound such as the compound of Formula I with an enriched E isomer, wherein the E isomer predominates over the Z-isomer by at least a 90:10 ratio. The acid salt, which may be the mono acid salt or the diacid salt, may be optionally converted back to its free base, if so desired.
R
1
, R
2
, R
3
and R
4
may be the same or different and are independently selected from the group consisting of H, halogen, alkyl, aryl, alkoxy, aryloxy, aralkyl (with the alkyl being the linker), alkylaryl (with the aryl being the linker), heteroalkyl, heteroaryl, alkyl-heteroaryl, heteroaralkyl, cycloalkyl and cycloalkylalkyl, wherein said alkyl, aryl, alkoxy, aryloxy, arylalkyl, alkylaryl, heteroalkyl, heteroaryl, alkyl-heteroaryl, heteroaralkyl, cycloalkyl and cycloalkylalkyl may optionally be substituted with one or more chemically-suitable substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic and halogen. R
1
itself may be F, Cl, Br or I. The term “halogen” refers to F, Cl, Br or I. The acid-catalyzed isomerization in step (f) above is believed to be novel and offers the desired salt of the desired compound with the enriched E-isomer as noted above. When R
1
is H, n=1, R
4
=methyl, and the acid used in step (f) for isomerization is HCl in the above sequence, the final product is the compound of Formula I.
The inventive process to make the compound of Formulas IX and I has several advantages: it is economical, can be easily scaled-up and yields the desired E-isomer in high yields and in high stereochemical purity.
DESCRIPTION OF THE INVENTION
In one embodiment, the present invention discloses a novel, easy-to-use process for preparing the compound such as the compound of Formula I in high yields and high stereochemical purity. Additionally, it teaches novel processes to prepare intermediates such as the compounds of Formulas V, VII, VIII and IX in high yields. The inventive process to prepare such compounds is schematically described below in Scheme 1:
where the various terms are defined above.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. Thus, for example, the term alkyl (including the alkyl portions of alkoxy) refers to a monovalent group derived from a straight or branched chain saturated hydrocarbon by the removal of a single atom having from 1 to 8 carbon atoms, preferably from 1 to 6;
aryl—represents a carbocyclic group having from 6 to 14 carbon atoms and having at least one benzenoid ring, with all available substitutable aromatic carbon atoms of the carbocyclic group being intended as possible points of attachment. Preferred aryl groups include phenyl, 1-naphthyl, 2-naphthyl and indanyl, and especially phenyl and substituted phenyl;
aralkyl—represents a moiety containing an aryl group linked vial a lower alkyl;
alkylaryl—represents a moiety containing a lower alkyl linked via an aryl group;
cycloalkyl—represents a saturated carbocyclic ring having from 3 to 8 carbon atoms, preferably 5 or 6, optionally substituted.
halogen—represents fluorine, chlorine, bromine and iodine; preferred halogens are Cl and Br.
heteroaryl—represents a cyclic organic group having at least one O, S and/or N atom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic group having from 2 to 14, preferably 4 or 5 carbon atoms, e.g., 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2- or 4-imidazolyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, or 3- or 4-pyridazinyl, etc. Preferred heteroaryl groups are 2-, 3- and 4-pyridyl; Such heteroaryl groups may also be optionally substituted.
heteroalkyl—represents an alkyl group containing one or more heteroatoms.
The synthesis of the specific compound of Formula I, following the above-noted process, is exemplified in Scheme 2:
The compounds of the Formulas XII, XIII, XIIIA, XIV and XV and their isomers (where applicable) are believed to be novel compounds. As stated above, the inventive novel conversion of the compound of Formula XV to I surprisingly yields predominantly the E-isomer of the compound of Formula I in high stereochemical purity and high yields. Isomerization of a mixture of phenyl compounds by acid catalysis is discussed by T. Zsuzsanna et al,
Hung.Magy.Km
Liao Hongbiao
Tsai David J
Wu Wenxue
Kalyanaraman Palaiyur S.
Morris Patricia L.
Schering Corporation
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