Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-19
2004-06-01
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06743924
ABSTRACT:
This application is a 371 of PCT/JP01/06145 filed Jul. 16, 2001.
TECHNICAL FIELD
The present invention relates to production methods of intermediates for 1-substituted-1,2,3-triazole compounds having an inhibitory action on growth factor receptor tyrosine kinases (especially HER2) useful as pharmaceutical agents.
BACKGROUND ART
As a production method of an intermediate for a 1-substituted-1,2,3-triazole compound having a tyrosine kinase inhibitory action, for example, there is mentioned a method comprising condensing compound (1) of the following formula and compound (2) of the following formula in the presence of a base in a solvent inert to the reaction (e.g., aromatic hydrocarbons such as benzene, toluene, xylene etc., ethers such as tetrahydrofuran, dioxane etc., ketones such as acetone, 2-butanone etc., halogenated hydrocarbons such as chloroform, dichloromethane etc., N,N-dimethylformamide, dimethyl sulfoxide, and a mixed solvent of these) to give the objective compound (3) (JP-A-11-60571, WO 98/03505):
wherein W
1
is a leaving group, R
0
is an optionally substituted aromatic heterocyclic group, X1 is an oxygen atom, an optionally oxidized sulfur atom, —C(=O)—or —CH(OH)—, Y
1
is CH or N, ml is an integer of 0 to 10, n1 is an integer of 1 to 5, the cyclic group
is an optionally substituted aromatic azole group and the ring A1 may be further substituted.
In addition, as a production method of a 1-alkyl-1,2,3-triazole compound, for example, there is mentioned a method comprising reacting the compound (b2) of the following formula and the compound (b3) of the following formula in the presence or absence of a base (JP-A-5-170763):
wherein R
1
, R
2
, R
3
, R
4
and R
8
are the same or different and each is a hydrogen atom or a lower alkyl group, R
2
and R
3
in combination may form, together with the carbon atoms to which they are bonded, a cyclopentane ring or a cyclohexane ring, R
5
, R
6
and R
7
are the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by halogen atom(s) or a lower alkoxy group optionally substituted by halogen atom(s), Y
2
is a halogen atom, a lower alkyl sulfonyloxy group or an aryl sulfonyloxy group, and R
9
is a 5 or 6-membered heterocyclic group having 1 to 3 nitrogen atom(s), and wherein a 1H-1,2,4-triazole group is excluded and the heterocyclic group is optionally substituted by 1 to 3, the same or different halogen atom(s), lower alkyl group(s) or lower alkoxy group(s).
The aforementioned conventional production methods pose problems in that they show low reaction selectivity, and therefore, a low yield. A method using a silver salt of 1H-1,2,3-triazole shows fine selectivity but requires expensive starting materials. Therefore, there is a demand for an industrially advantageous production method of an intermediate for a 1-substituted-1,2,3-triazole compound having an inhibitory action on growth factor receptor tyrosine kinases (especially HER2).
As a production method for obtaining a 1,2,3-triazole compound useful as a starting material of pharmaceutical agents or an intermediate for printing, image processing agents, by the use of a hydrazone derivative, there is known, for example, a method comprising reacting compound (c1) of the following formula and compound (c2) under neutral or basic conditions to give compound (3) (JP-A-8-53425):
In the above formulas, R
1c
is a lower alkyl group optionally substituted by halogen atom(s), a phenyl group wherein benzene ring is optionally substituted by at least one substituent selected from halogen atom, lower alkyl group and lower alkoxy group, a benzyl group wherein benzene ring is optionally substituted by at least one substituent selected from halogen atom, lower alkyl group and lower alkoxy group, a lower alkylamino group wherein alkyl group is optionally substituted by halogen atom, a phenylamino group wherein benzene ring is optionally substituted by at least one substituent selected from halogen atom, lower alkyl group and lower alkoxy group, an ammonium group that forms a salt with an inorganic acid or a carboxyl group that forms a salt with ammonia; X is a halogen atom; R
2c
and R
3c
are each a hydrogen atom or a lower alkyl group optionally substituted by halogen atom(s); and R
4c
is a lower alkyl group optionally substituted by halogen atom(s) or a phenyl group wherein benzene ring is optionally substituted by at least one substituent selected from halogen atom, lower alkyl group and lower alkoxy group.
As a production method of an amine compound such as the above-mentioned compound (c1), there is known a method comprising reacting phthalimide butyryl chloride and chlorobenzene in the presence of anhydrous aluminum chloride, and treating the obtained 4-chloro-4-phthalimide butyrophenone with acetic acid and hydrochloric acid to give 4-chloro-4-aminobutyrophenone hydrochloride [Journal of Medicinal Chemistry (J. Med. Chem.), vol. 9, pp. 945-949 (1966)].
The conventional production method for obtaining the aforementioned compound (c3) showed lower yield from the compound (c1). A conventional production method for obtaining an amine compound, such as compound (c1), poses a problem in that it requires many steps. Therefore, there is a demand for an industrially advantageous production method of an intermediate for a 1-substituted-1,2,3-triazole compound having an inhibitory action on growth factor receptor tyrosine kinase (especially, HER2).
DISCLOSURE OF THE INVENTION
The present inventors have studied various production methods of 1-substituted-1,2,3-triazole derivatives, and first found that a reaction in a secondary or tertiary alcohol in the presence of a base or a reaction in the absence of a base unexpectedly results in the selective production of the objective 1-substituted-1,2,3-triazole derivative in a high yield, and that this production method is fully satisfactory on an industrial scale, based on which they intensively investigated and completed the present invention.
They have also found that a reaction of an alkylamine compound and a hydrazone derivative, followed by a treatment with a base, unexpectedly results in the selective production of the objective 1-substituted-1,2,3-triazole derivative in a high yield, and that this production method is fully satisfactory on an industrial scale, based on which they intensively investigated and completed the present invention.
Further, the present inventors have found that a production method via a protected 4-hydroxymethyloxazole compound as an intermediate unexpectedly results in the production of the objective product in a high yield, and that this production method is fully satisfactory on an industrial scale, based on which they intensively investigated and completed the present invention.
Accordingly, the present invention provides the following.
1. A method for producing a compound of the formula:
wherein
R
a1
and R
a2
are each a hydrogen atom, a substituted hydroxy, a substituted thiol, a substituted amino, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl;
R
a3
is a group of the formula:
wherein R
a4
and R
a5
are each a hydrogen atom, an optionally substituted hydroxy, an optionally substituted thiol, an optionally substituted amino, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl, or R
a4
and R
a5
in combination form oxo, R
a6
is an optionally substituted aromatic group, and m
a
is an integer of 0 to 10; or
two or three from R
a1
, R
a2
and R
a3
form an optionally substituted ring, together with the adjacent carbon atom; and
R
a7
and R
a8
are each a hydrogen atom, a halogen, an optionally substituted hydroxy, an optionally substituted thiol, an optionally substituted amino, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl,
which method comprises reacting a compound of the formula:
wherein X
a
is a leaving group and other symbols are as defined above, or a salt thereo
Ikemoto Tomomi
Isogami Yasushi
Ito Tatsuya
Nishiyama Hirohiko
Sawai Yasuhiro
McKane Joseph K.
Shameem Golam M M
Takeda Chemical Industries Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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