Process for the preparation of pyridine derivatives

Details Process for the preparation of pyridine derivatives Process for the preparation of pyridine derivatives

2000-11-20

2001-10-16

Davis, Zinna Northington (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S316000, C544S124000, C544S360000

Reexamination Certificate

active

06303790

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a method of preparing 4-alkyl- or 4-aryl-pyridine derivatives.
BACKGROUND OF THE INVENTION
It is known that certain 4-phenyl-pyridine derivatives can be prepared by the method disclosed in EP1035115.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing a compound of formula
wherein
R
1
is lower alkyl or aryl, optionally substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl;
R
2
and R
2′
are independently from each other hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano; or
R
2
and R
2′
may together be —CH═CH—CH═CH— and form a fused ring with the carbon atoms to which they are attached, optionally substituted by lower alkyl or lower alkoxy;
R
3
/R
3′
are independently from each other hydrogen, lower alkyl, or taken together with the carbon atom to which they are attached, form a cycloalkyl group;
R
4
is hydrogen, lower alkyl, —N(R
5
)
2
, —N(R
5
)(CH
2
)
n
OH, —N(R
5
)S(O)
2
-phenyl, —N(R
5
)S(O)
2
-lower alkyl, —N═CH—N(R
5
)
2
, —N(R
5
)C(O)R
5
or a cyclic tertiary amine of the group
R
5
is hydrogen, lower alkyl, or benzyl, which is optionally substituted by lower alkyl;
R
6
is hydrogen, hydroxy, lower alkyl, —(CH
2
)
n
COO-lower alkyl, —N(R
5
)CO-lower alkyl, hydroxy-lower alkyl, cyano, —(CH
2
)
n
O(CH
2
)
n
OH, —CHO, or a 5-or 6 membered heterocyclic ring, optionally bonded via an alkylene group,
X is —C(O)N(R
5
)— or —N(R
5
)C(O)—;
n is 0-4; and
pharmaceutically acceptable acid addition salts thereof, which process comprises
a) reacting a compound of formula
wherein A denotes R or R
4
, and R is halogen, and R
5′
has the same meaning as R
5
, wherein R
5
and R
5′
may be independent from each other,
with a compound of formula
R
1
MgHal  V
wherein Hal is a halogen atom,
to a mixture of compounds of formulae
 or
a′) reacting a compound of formula IV-1, wherein A is R, with a compound of formula V and with a compound of formula
HR
4
  VII
 in one reaction step, to a compound of formula
 and
b) oxidizing a compound of formulae X-1, XI-1 or VI with an oxidizing agent, to a compound of formula
 and
c) reacting a compound of formula VIII with a compound of formula
wherein R is halogen, to a compound of formula
wherein X is —CON(R
5
)—, or
c′i) reacting a compound of formula VIII with a compound of formula IX, to a compound of formula
 and
ii) reacting a compound of formula XIII to a compound of formula
 or
 and
iii) transforming a compound of formulae XIV or XV to a compound of formula
wherein R
5
is methyl, and
iv) reacting a compound of formula XVI with a compound of formula
 to a compound of formula
wherein X is —N(R
5
)C(O)—.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of compounds of the general formula
wherein
R
1
is lower alkyl or aryl, optionally substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl;
R
2
and R
2′
are independently from each other hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano; or
R
2
and R
2′
may together be —CH═CH—CH═CH— and form a fused ring with the carbon atoms to which they are attached, optionally substituted by lower alkyl or lower alkoxy;
R
3
/R
3′
are independently from each other hydrogen, lower alkyl, or taken together with the carbon atom to which they are attached, form a cycloalkyl group;
R
4
is hydrogen, lower alkyl, —N(R
5
)
2
, —N(R
5
)(CH
2
)
n
OH, —N(R
5
)S(O)
2
-phenyl, —N(R
5
)S(O)
2
-lower alkyl, —N═CH—N(R
5
)
2
, —N(R
5
)C(O)R
5
or a cyclic tertiary amine of the group
R
5
is hydrogen, lower alkyl, or benzyl, which is optionally substituted by lower alkyl;
R
6
is hydrogen, hydroxy, lower alkyl, —(CH
2
)
n
COO-lower alkyl, —N(R
5
)CO-lower alkyl, hydroxy-lower alkyl, cyano, —(CH
2
)
n
O(CH
2
)
n
OH, —CHO, or a 5- or 6-membered heterocyclic ring, optionally bonded via an alkylene group,
X is —C(O)N(R
5
)— or —N(R
5
)C(O)—;
n is 0 -4;
and to pharmaceutically acceptable acid addition salts thereof.
The compounds of formula I and their salts are characterized by valuable therapeutic properties. It has been found that compounds of formula I are antagonists of the Neurokinin 1 (NK-1, substance P) receptor.
The most preferred indications are those which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders, anxiety or emesis by the administration of NK-1 receptor antagonists.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term “lower alkyl” denotes a straight- or branched-chain alkyl group containing from 1-10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms.
The term “lower alkoxy” denotes a group wherein the alkyl residue is as defined above, and which is attached via an oxygen atom.
The term “halogen” denotes fluorine, chlorine, bromine and iodine.
The term “cycloalkyl” denotes a saturated carbocyclic group (e.g., a nonaromatic ring), containing 3-6 carbon atoms (i.e., C
3
-C
6
cycloalkyl).
A “cyclic tertiary amine” denotes a ring system which may contain one additional heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur, wherein any sulfur present in the ring is thio or can be oxidized to sulfoxide or sulfur dioxide by which said cyclic tertiary amine, which ring is directly attached via the ring nitrogen to the remainder of the molecule or is attached through the linker —(CH
2
)
n
N(R
5
)—. The cyclic tertiary amine may contain three to five carbon atoms. When the ring is substituted it is preferably substituted at the heteroatom, for example N-alkyl-piperazine. Examples of such rings include pyrrol-1-yl, imidazol-1-yl, piperidin-1-yl, piperazin-1-yl, which is optionally substituted by lower alkyl, morpholin-4-yl, thiomorpholin-4-yl; 1-oxo-thiomorpholin-4-yl or 1,1-dioxo-thiomorpholin-4-yl. Preferred cyclic tertiary amines are the piperazinyl and the morpholinyl groups.
The term “aryl” means a monocyclic or bicyclic aromatic ring, such as phenyl, benzyl, naphthyl and the like. Preferred is the phenyl group.
The term a “5-6 membered hetercyclic ring” is a ring system which contains from 1 to 4 heteroatoms, selected form the group consisting of oxygen, nitrogen, and sulfur, and with one of the carbon atoms in said ring being unsubstituted or substituted with an oxo group. Examples of such rings are pyrimidine, oxadiazole, triazole, tetrazole, pyridine, thiazole, thiene, furane, pyrane, pyrrole, imidazole, pyrazole, isothiazole, piperazine or piperidine.
The term “pharmaceutically acceptable acid addition salts” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods described in or analogous to those in EP1035115, for example, by processes described in schemes 1 and 2 below:
In the schemes the following abbreviations have been used:
PivCl
pivaloyl chloride
THF
tetrahydrofuran
TMEDA
N,N,N′,N′-tetramethylethylene diamine
DIPEA
N-diisopropylethyl-amine
KHMDS
potassium hexamethyldisilazide
wherein the definition of substituents is given above.
The definition of the other substituents is given above.
As it is seen in the above described known methods in schemes 1 and 2, the introduction of the group R
1
, which may be lower alkyl or optionally substituted aryl, is carried out with an activated pyridine ring, wherein the activating group is a halogen atom, such as bromo or iodo.
Now, it has surprisingly be

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