Process for producing benzopyran carboxamide

Details Process for producing benzopyran carboxamide Process for producing benzopyran carboxamide

2002-08-08

2003-11-25

Solola, Taofiq (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S407000

Reexamination Certificate

active

06653488

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a process for producing fluorine-containing benzopyran carboxamide derivatives, which are useful as medicines. Furthermore, it relates to a process for stabilizing 3-aminopropionitrile, which is a useful compound as an intermediate for medicines and agricultural chemicals.
There are several processes for producing an acid amide, N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-(perfluoroalkyl)-2H-1-benzopyran-4-carboxamide, represented by the following general formula [1].
where R is a straight-chain or non-straight-chain perfluoroalkyl group represented by C
n
F
2n+1
where n is an integer of 1-10.
Of such processes, there are the following three (3) processes using 3-aminopropionitrile as a raw material. In the first process of Bioorg. Med. Chem. (2000), 8(6), 1393-1405, 2-2-bis(fluoromethyl)-6-(trifluoromethyl)-2H-1-benzopyran-4-carboxylic acid is reacted with 3-aminopropionitrile in tetrahydrofuran in the presence of a dehydration and condensation agent (e.g., 1,1′-carbonyldiimidazole). In the second process of WO/00/18754, 4-bromo-2,2-bis(fluoromethyl)-6-(perfluoroalkyl)-2H-1-benzopyran is reacted with 3-aminopropionitrile in the presence of palladium acetate in N,N-dimethylacetoamide, under an atmosphere of carbon monoxide. In the third process of WO/00/18754, an acid halide represented by the following general formula [2] is reacted with 3-aminopropionitrile in the presence of a base.
where R is defined as above, and X is fluorine, chlorine, bromine or iodine.
Although 3-aminopropionitrile, which is used in Bioorg. Med. Chem. (2000), 8(6), 1393-1405 and WO/00/18754, is a less stable compound at normal temperature (e.g., room temperature), its storing and handling methods are not described in these publications.
It is possible to produce an acid amide compound represented by the general formula [1] by the above first to third processes efficiently under a small-scale, laboratory condition. It is described in The Merck Index Twelfth Edition, Page 82 that 3-aminopropionitrile tends to gradually decompose under storage at normal temperature, and in particular may polymerize rapidly upon contact with the air. Thus, it is general to store it in tightly stoppered bottles under refrigeration to prevent its deterioration. Therefore, it is difficult to store and transport 3-aminopropionitrile, and its handling is cumbersome in case that the above-mentioned first to third processes are conducted in an industrial scale, resulting in low productivity. In other words, it is difficult to use 3-aminopropionitrile in a large amount in an industrial scale.
As mentioned above, 3-aminopropionitrile is a useful compound as an intermediate for medicines and agricultural chemicals. Organic Synthesis Collective Volume Vol. III (1955) p. 34 discloses that 3-aminopropionitrile is added in a dropwise manner to a barium hydroxide aqueous solution, followed by addition of hot water and by saturation with carbon dioxide, thereby synthesizing &bgr;-alanine, which is a useful compound in industry.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a process for stabilizing 3-aminopropionitrile, thereby allowing its easy use in an industrial scale.
According to a first aspect of the present invention, there is provided a process for stabilizing 3-aminopropionitrile, comprising turning said 3-aminopropionitrile into a sulfate of said 3-aminopropionitrile (e.g., 3-aminopropionitrile.½ sulfate represented by the formula N≡CCH
2
CH
2
NH
2
.½(H
2
SO
4
)). In fact, the present inventors unexpectedly found that the sulfate obtained by this process is remarkably improved in stability and is significantly easier in storage and handling, as compared with 3-aminopropionitrile itself. Therefore, industrial use of 3-aminopropionitrile is made much easier.
It is another object of the present invention to provide a process for producing a benzopyran carboxamide easily in an industrial scale.
According to a second aspect of the present invention, there is provided a first process for producing a benzopyran carboxamide represented by the general formula [1] (hereinafter the benzopyran carboxamide [1]). The first process comprises reacting 3-aminopropionitrile.½ sulfate represented by the formula N≡CCH
2
CH
2
NH
2
.½(H
2
SO
4
), with a benzopyran carboxylic halide represented by the general formula [2] (hereinafter the benzopyran carboxylic halide [2]), in the presence of a base,
where R is a straight-chain or non-straight-chain perfluoroalkyl group represented by C
n
F
2n+1
where n is an integer of 1-10, and
X is fluorine, chlorine, bromine or iodine.
According to the second aspect of the present invention, there is provided a second process for producing the benzopyran carboxamide [1]. The second process comprises the steps of:
(a) reacting 3-aminopropionitrile.½ sulfate represented by the formula N≡CCH
2
CH
2
NH
2
.½(H
2
SO
4
), with a base, thereby forming 3-aminopropionitrile; and
(b) reacting said 3-aminopropionitrile with the benzopyran carboxylic halide [2], thereby producing said benzopyran carboxamide.
In fact, the present inventors unexpectedly found that it is possible to easily produce the benzopyran carboxamide [1] by the first or second process using the above-mentioned 3-aminopropionitrile.½ sulfate (a novel compound). It is not necessary in the first and second processes to handle 3-aminopropionitrile itself (an unstable compound) outside the reaction system.


REFERENCES:
patent: 0995438 (2000-04-01), None
patent: 1120412 (2001-08-01), None
patent: 00/18754 (2000-04-01), None
Naoki Taka, et al., “6-Substituted 2,2-Bis(fluoromthyl)-benzopyran-4-carboxamide K+ Channel Openers” Bioorganic Medicinal Chemistry 8(6), 2000.
Organic Synthesis Collection vol. III, p. 34, 1955.
Naoki Taka, et al., “6-Substituted 2,2-Bis(fluoromethyl)-benzopyran-4-carboxamide K+ Channel Openers” Bioorganic and Medicinal Chemistry, vol. 8, 2000, pp. 1393-1405.

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