N-heterocyclic methylpropylamine derivatives, process for...

Details N-heterocyclic methylpropylamine derivatives, process for... N-heterocyclic methylpropylamine derivatives, process for...

2000-03-10

2001-08-07

Seaman, D. Margaret (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C544S336000, C548S202000, C548S235000, C548S335500, C548S561000, C504S205000, C504S244000, C504S266000, C504S270000, C504S275000, C504S284000

Reexamination Certificate

active

06271385

ABSTRACT:

TECHNICAL FIELD
This invention relates to novel propylamine derivatives having physiological activities, and particularly it relates to novel N-heterocyclicmethylpropylamine derivatives that can be utilized as the effective ingredients of fungicides (such as those for use in farming and horticulture).
BACKGROUND ART
Commercially available fungicides include, as 3-phenylpropylamines, N-[3-p-t-butylphenyl-2-methyl-1-propyl]-cis-2,6-dimethylmorpholine (fenpropimorph), a compound described in Japanese Unexamined Patent Publication No. SHO 53-77070, and N-[3-p-t-butylphenyl-2-methyl-1-propyl]piperidine (fenpropidine), a compound described in Japanese Unexamined Patent Publication No. SHO 53-68785 and No. SHO 53-68786.
The nitrogen atom of the amino group in each of the aforementioned compounds forms part of a ring. In contrast, the only compounds known wherein the nitrogen atom of the amino group does not form part of a ring and a heterocyclicmethyl group is bonded to the nitrogen atom, are those with a tetrahydrofurfuryl group as described in Japanese Unexamined Patent Publication No. SHO 63-258867, those with heterocyclicmethyl groups containing oxygen or sulfur, such as thenyl, and the following compounds listed in Pestic. Sci., 35, 339 (1992):
N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-(t-butyl)-3-pyridylmethylamine;
N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-butyl-3-pyridylmethylamine; and
N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-methyl-3-pyridylmethylamine.
DISCLOSURE OF THE INVENTION
However, except for the aforementioned compounds having a 3-pyridylmethyl group, no compounds are known wherein a heterocycle containing at least one nitrogen atom as the hetero atom and having an optional substituent on the ring is bonded to the nitrogen atom of the amino group via methylene, such as in the N-heterocyclicmethylpropylamine derivatives represented by the following formula (I):
Moreover, no compounds with substituents on the heterocycle have yet been reported, and consequently no studies have yet been conducted on the usefulness of such compounds.
It is an object of this invention to provide a novel N-heterocyclicmethylpropylamine derivative that is useful as a physiologically active substance in a fungicide, for example. It is another object of the invention to provide a process for preparation of the N-heterocyclicmethylpropylamine derivatives described above and utility therefor.
According to this invention, there is provided a N-heterocyclicmethylpropylamine derivative of formula (I):
or an acid addition salt thereof;
wherein R
1
represents at least one moiety selected from the group consisting of hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
6
alkenyl, C
1
-C
6
halogenated alkyl, C
1
-C
6
alkoxy, C
1
-C
6
halogenated alkoxy, hydroxyl, cyano, nitro, phenyl optionally having a substituent on a ring thereof and phenoxy; n represents an integer of 0-5; when n is 2 or greater, each R
1
may be the same or different and two R
1
groups may be bonded together into a ring or crosslinked; R
2
represents a heterocycle containing at least one nitrogen atom as the hetero atom and optionally having a substituent on a ring thereof; and R
3
represents at least one moiety selected from the group consisting of hydrogen and C
1
-C
5
alkyl,
with the proviso that the following compounds are excluded:
N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-(t-butyl)-3-pyridylmethylamine,
N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-butyl-3-pyridylmethylamine, and
N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-methyl-3-pyridylmethylamine.
Optical isomers may exist for the N-heterocyclicmethylpropylamine derivative of formula (I) of the invention as described above, because there is an asymmetric carbon at the 2-position of its propyl group, regardless of any asymmetry due to other substituents. Consequently, a compound of formula (I) of the invention naturally encompasses either of single optical isomers and any mixtures of the optical isomers.
According to the invention, there is also provided a process for preparation comprising reductive amination between a 3-phenylpropionaldehyde derivative of formula (II) and a heterocyclicmethylamine derivative of formula (III) to obtain an N-heterocyclicmethylpropylamine derivative of formula (I):
(in formulae (I), (II) and (III) R
1
, R
2
, R
3
and n are as previously defined).
According to the invention, reductive amination may be employed to synthesize a 3-phenylpropylamine derivative of formula (IV) from a 3-phenylpropionaldehyde derivative of formula (II) and an aminating agent of formula (VIII) or, alternatively, a 3-phenylpropionamide derivative of formula (XII) may be reduced to synthesize a 3-phenylpropylamine derivative of formula (IV); and an N-heterocyclicmethylpropylamine derivative of formula (I) is synthesized from this compound (IV) and a heterocycle-methylating agent of formula (V). On the other hand, reductive amination may also be used to synthesize an N-heterocyclicmethylpropylamine derivative of formula (I) from a compound of (IV) and a heterocyclicaldehyde derivative of formula (VI):
(in the above formulae R
1
, R
2
, R
3
and n are as previously defined, and X represents a leaving group).
BEST MODE FOR CARRYING OUT THE INVENTION
This invention will be explained in greater detail hereinbelow.
N-heterocyclicmethylpropylamine Derivatives
In the N-heterocyclicmethylpropylamine derivatives of formula (I) above, R
1
represents at least one moiety selected from the group consisting of hydrogen, halogen, C
1
-C
6
alkyl, C
1
-C
6
alkenyl, C
1
-C
6
halogenated alkyl, C
1
-C
6
alkoxy, C
1
-C
6
halogenated alkoxy, hydroxyl, cyano, nitro, phenyl optionally having a substituent on a ring thereof, and phenoxy. The halogen atom may be fluorine, chlorine, bromine or iodine. The alkyl portion of the C
1
-C
6
alkyl, C
1
-C
6
halogenated alkyl, C
1
-C
6
alkoxy or C
1
-C
6
halogenated alkoxy group may be primary, secondary or tertiary.
Among these groups for R
1
preferred are halogen atoms, halogenated alkyl, halogenated alkoxy and tertiary alkyl groups, examples of which include chlorine, fluorine and bromine atoms, and trifluoromethyl, trifluoromethoxy and 1,1-dimethylethyl (equivalent to t-butyl) groups. The position of substitution on the phenyl ring of R
1
is not particularly limited, but the 3-position and 4-position are preferred.
“n” represents an integer of 0-5, and n is preferably 1 or 2. When n is 2 or greater, each R
1
may be the same or different. Also, two R
1
groups may be bonded together into a ring or crosslinked, and for example, they may together with the benzene ring form indane, 1,2-methylenedioxybenzene or naphthalene.
R
2
represents a heterocycle containing at least one nitrogen atom as the hetero atom and optionally having a substituent on a ring thereof. This heterocycle R
2
contains at least one nitrogen atom as the hetero atom, although it may also have one or more other hetero atoms (oxygen, sulfur, etc.), and the heterocycle R
2
is preferably a 5- or 6-membered ring. As specific preferred examples of the heterocycle R
2
there may be mentioned pyridine, pyrazine, pyrimidine, thiazole, oxazole, pyrazole and pyrrole.
As a substituent on the heterocycle, there may be mentioned halogen (which may be fluorine, chlorine, bromine or iodine), alkyl (among which a C
1
-C
4
alkyl group is preferred, and methyl, ethyl or 1-methylethyl is particularly preferred), halogenated alkyl (a group wherein at least one of the hydrogen atoms of the alkyl group is substituted with a halogen atom: fluorine is preferred as the halogen atom and C
1
-C
4
alkyl as the number of carbon atoms, with trifluoromethyl being particularly preferred), alkoxy (among which a C
1
-C
4
alkoxy group is preferred, and methoxy is particularly preferred), a di(C
1
-C
4
alkyl)amino group and nitro. The number of substituents is not particularly limited, but is preferably 1 or 2. When two or more substituents are bonded to the heterocycle, they may be the same or different.
R
3
represents a

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