Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-07
2001-07-31
Davis, Zinna Northington (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S346000
Reexamination Certificate
active
06268503
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to 4-(pyridin-2-yl)benzaldehyde hydrazone, a production method of this compound, and a method of producing N-(tert-butoxycarbonyl)-N′-[4-(pyridin-2-yl)phenylmethylidene]hydrazine from this compound. The present invention moreover relates to a salt of 2-(4-bromomethylphenyl)pyridine, 2,-(4-dibromomethylphenyl)pyridine and a salt thereof, methods for the production of these compounds and a method of producing 4-(pyridin-2-yl)benzaldehyde, which is a production intermediate for 4-(pyridin-2-yl)benzaldehyde hydrazone, from these compounds. The above-mentioned hydrazine derivative is a compound useful as a production intermediate for compound (A) to be mentioned later, which is an anti-HIV drug.
BACKGROUND OF THE INVENTION
N-(tert-Butoxycarbonyl)-N′-[4-(pyridin-2-yl)phenylmethylidene]hydrazine in the present invention is useful as a synthetic intermediate for compound (A) represented by the following formula
which is an anti-HIV drug, and the method for the production of the pharmaceutical compound (A) via the intermediate is described in, for example, WO97/40029.
WO97/40029 discloses a production method comprising reacting 4-(pyridin-2-yl)benzaldehyde with tert-butyl carbazate [tBuOC(═O)NHNH
2
wherein tBu is tert-butyl] to give N-(tert-butoxycarbonyl)-N′-[4-(pyridin-2-yl)phenylmethylidene]hydrazine, therefor 4-(pyridin-2-yl)benzaldehyde is important as an intermediate for a pharmaceutical product.
The method for the production of 4-(pyridin-2-yl)benzaldehyde includes a method disclosed in, for example, Japanese Patent Unexamined Publication No. 95157/1991 and WO97/40029, wherein Grignard reagent prepared from 4-bromobenzaldehyde dimethyl acetal and 2-bromopyridine are reacted using [1,3-bis(diphenylphosphino)propane] nickel(II) chloride as a catalyst. With regard to the above-mentioned production method, 4-bromobenzaldehyde dimethyl acetal and 2-bromopyridine, which are reaction reagents, are relatively expensive, and [1,3-bis(diphenylphosphino)propane] nickel(II) chloride, which is a catalyst, is extremely expensive and industrially hard to obtain. Thus, it is desired to have a method of producing 4-(pyridin-2-yl)benzaldehyde at a lower cost.
Inasmuch as tert-butyl carbazate used as the reagent in the aforementioned hydrazine derivative production method (WO97/40029) is expensive, a production method for producing N-(tert-butoxycarbonyl)-N′-[4-(pyridin-2-yl)phenylmethylidene]hydrazine industrially and economically has been awaited.
It is therefore an object of the present invention is to provide an economical method for the production of 4-(pyridin-2-yl)benzaldehyde, to provide an intermediate for producing 4-(pyridin-2-yl)benzaldehyde, and a method for the production of this intermediate. Another object of the present invention is to provide a method for producing N-(tert-butoxycarbonyl)-N′-[4-(pyridin-2-yl)phenylmethylidene]hydrazine economically and easily, as well as an intermediate (4-(pyridin-2-yl)benzaldehyde hydrazone) useful for producing this hydrazine derivative and a production method of this intermediate compound.
SUMMARY OF THE INVENTION
The present inventors have found that 4-(pyridin-2-yl)benzaldehyde can be produced economically by reacting a salt of 2-(4-bromomethylphenyl)pyridine, 2-(4-dibromomethylphenyl)pyridine or salt thereof, all of which being novel compounds, with hexamethylenetetramine and water, and further that a salt of 2-(4-bromomethylphenyl)pyridine, 2-(4-dibromomethylphenyl)pyridine and a salt thereof can be obtained by reacting a salt of 2-(4-tolyl)pyridine with a brominating agent. In addition, they have found that N-(tert-butoxycarbonyl)-N′-[4-(pyridin-2-yl)phenylmethylidene]hydrazine can be produced more economically and easily by reacting 4-(pyridin-2-yl)benzaldehyde hydrazone with di-tert-butyl dicarbonate, and that 4-(pyridin-2-yl)benzaldehyde hydrazone can be obtained from 4-(pyridin-2-yl)benzaldehyde.
Accordingly, the present invention provides the following. (1) 4-(Pyridin-2-yl)benzaldehyde hydrazone. (2) A method for the production of N-(tert-butoxycarbonyl)-N′-[4-(pyridin-2-yl)phenylmethylidene]hydrazine of the formula (VI)
wherein tBu is tert-butyl, comprising reacting 4-(pyridin-2-yl)benzaldehyde hydrazone of the formula (V)
with di-tert butyl dicarbonate of the formula: [tBuOC(═O)]
2
O wherein tBu is as defined above. (3) The production method of the above-mentioned (2), wherein 4-(pyridin-2-yl)benzaldehyde hydrazone is obtained by reacting 4-(pyridin-2-yl)benzaldehyde of the formula (III)
with hydrazine. (4) The production method of the above-mentioned (3), wherein 4-(pyridin-2-yl)benzaldehyde is obtained by reacting at least one member selected from the group consisting of a salt of 2-(4-bromomethylphenyl)pyridine of the formula (I)
2-(4-dibromomethylphenyl)pyridine of the formula (II)
a salt thereof with hexamethylenetetramine and water. (5) The production method of the above-mentioned (3), wherein 4-(pyridin-2-yl)benzaldehyde is obtained by reacting a salt of 2-(4-bromomethylphenyl)pyridine of the formula (I)
and/or a salt of 2-(4-dibromomethylphenyl)pyridine of the formula (II)
with hexamethylenetetramine and water. (6) A method for the production of N-(tert-butoxycarbonyl)-N′-[4-(pyridin-2-yl)phenylmethylidene]hydrazine comprising reacting at least one member selected from the group consisting of a salt of 2-(4-bromomethylphenyl)pyridine of the formula (I)
2-(4-dibromomethylphenyl)pyridine of the formula (II)
and a salt thereof, with hexamethylenetetramine and water to give 4-(pyridin-2-yl)benzaldehyde of the formula (III)
and reacting this compound with tert-butyl carbazate of the formula: tBuOC(═O)NHNH
2
wherein tBu is tert-butyl. (7) The production method of the above-mentioned (6), wherein 4-(pyridin-2-yl)benzaldehyde is obtained by reacting a salt of 2-(4-bromomethylphenyl)pyridine of the formula (I)
and/or a salt of 2-(4-dibromomethylphenyl)pyridine of the formula (II)
with hexamethylenetetramine and water. (8) A method for the production of 4-(pyridin-2-yl)benzaldehyde hydrazone comprising reacting 4-(pyridin-2-yl)benzaldehyde with hydrazine. (9) A method for the production of 4-(pyridin-2-yl)benzaldehyde of the formula (III)
comprising reacting at least one member selected from the group consisting of a salt of 2-(4-bromomethylphenyl)pyridine of the formula (I)
2-(4-dibromomethylphenyl)pyridine of the formula (II)
and a salt thereof, with hexamethylenetetramine and water. (10) The production method of the above-mentioned (9), wherein the salt of 2-(4-bromomethylphenyl)pyridine of the formula (I)
and/or the salt of 2-(4-dibromomethylphenyl)pyridine of the formula (II)
and hexamethylenetetramine and water are reacted. (11) A salt of 2-(4-bromomethylphenyl)pyridine, 2-(4-dibromomethylphenyl)pyridine or a salt thereof. (12) A method for the production of a salt of 2-(4-bromomethylphenyl)pyridine, 2-(4-dibromomethylphenyl)pyridine or a salt thereof, comprising reacting a salt of 2-(4-tolyl)pyridine of the formula (IV)
wherein X is halogen atom or sulfonic acid residue, with a brominating agent. (13) The production method of the above-mentioned (12), wherein X is halogen atom. (14) The production method of the above-mentioned (12), wherein brominating agent is bromine.
In the production of a salt of 2-(4-bromomethylphenyl)pyridine, 2-(4-dibromomethylphenyl)pyridine, and a salt thereof, all of which are novel compounds, bromination of 2-(4-tolyl)pyridine without convertion into a salt results in an unintended product, because substituted benzyl bromide once generated reacts with the nitrogen atom in the molecule. The present inventors converted 2-(4-tolyl)pyridine into a salt and subjected the salt to bromination, whereby a salt of 2-(4-bromomethylphenyl)pyridine, 2-(4-dibromomethylphenyl)pyridine, and a salt thereof were afforded without producing and unintended
Itaya Nobushige
Matsui Kozo
Shintaku Tetsuya
Sugi Kiyoshi
Umemoto Yoshihide
Davis Zinna Northington
Leydig , Voit & Mayer, Ltd.
Sumika Fine Chemicals Co., Ltd.
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