Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-21
2002-09-24
Chang, Ceila (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06455708
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel processes for producing 4-substituted benzopyran derivatives useful as medicines, agrichemicals and cosmetics, as well as intermediates for their synthesis and processes for producing such intermediates.
BACKGROUND ART
One of the prior art techniques known in the field contemplated by the invention is a process for synthesizing 4-substituted benzopyran derivatives via 4-bromobenzopyran drivatives (JPA Hei 7-188210).
According to JPA Hei 7-188210, a compound represented by the general formula (XVIII) (the chemical formulae embraced by the general formula (XVIII) are set forth in the List of Chemical Formulae at the end of the specification; all the chemical formulae referred to hereinafter are collectively set forth in the List of Chemical Formulae at the end of the specification) is reacted with carbon monoxide and amine in the presence of a palladium catalyst to give an amide form represented by the general formula (XXVI).
A method generally known to be applicable in the synthesis of benzopyrans is by subjecting a compound of the general formula (D) to thermal cyclization reaction to give a compound of the general formula (E) (see, for example, Australian Journal Chemistry, 1971, Vol. 24, pp. 2347-2354).
It is also known that the 4-bromobenzopyran derivative (XVIII) can be produced from a compound of the general formula (XII) in six steps (JPA Hei 5-294954). According to JPA Hei 5-294954, an acetophenone derivative represented by the general formula (XII) (where Z
5
and Z
6
which may be the same or different represent a hydrogen atom, a lower alkyl group, a lower haloalkyl group, a halogen atom, a lower haloalkoxy group, an amino group, an acylamino group, a nitro group, a cyano group, an alkoxycarbonyl group, an optionally substituted lower alkylsulfonyl group or an arylsulfonyl group or, when taken together, represent a substituent ═N—O—N═) is condensed with an acetone derivative represented by the general formula (XIII) (where Z
7
and Z
8
which may be the same or different represent a hydrogen atom, a lower alkyl group or a substituted lower alkyl group or, when taken together, represent a polymethylene group or a substituent forming a heterocycle) in the presence of a base such as pyrrolidine to give a benzopyran derivative represented by the general formula (XIV) (where Z
5
, Z
6
, Z
7
and Z
8
have the same meanings as defined above). The benzopyran derivative (XIV) is reduced with a suitable reducing agent such as sodium borohydride to give a benzopyran derivative represented by the general formula (XV) (where Z
5
, Z
6
, Z
7
and Z
8
have the same meanings as defined above). The benzopyran derivative (XV) is dehydrated with a suitable dehydrating agent such as p-toluenesulfonic acid to give a benzopyran derivative represented by the general formula (XVI) (where Z
5
, Z
6
, Z
7
and Z
8
have the same meanings as defined above). The benzopyran derivative (XVI) is brominated with a suitable brominating agent such as bromine to give a 3,4-dibromobenzopyran derivative represented by the general formula (XVII) (where Z
5
, Z
6
, Z
7
and Z
8
have the same meanings as defined above). The 3,4-dibromobenzopyran derivative (XVII) is treated with a suitable base such as sodium hydroxide to give a 4-bromobenzopyran derivative represented by the general formula (XVIII) (where Z
5
, Z
6
, Z
7
and Z
8
have the same meanings as defined above).
Other processes for producing the benzopyran derivative (XVI) as an intermediate for the general formula (XXVII) have been reported elsewhere (Tetrahedron Letters, 1993, 34, 1815-1818; The 20th Symposium on Progress in Organic Reactions and Syntheses, Shizuoka (1994)).
According to Tetrahedron Letters, 1993, 34, 1815-1818, a compound (IIf) and trimethylsilyl acetylene are subjected to cross-coupling reaction in the presence of copper(I) iodide and tetrakis(triphenylphosphine)palladium and the resulting trimethylsilyl acetylene compound is treated with potassium carbonate in methanol to give a compound represented by the formula (XIX) set forth below. This compound is reacted with hexafluoroacetone using n-butyllithium to give a compound represented by the formula (XX). This compound is reduced with a palladium-barium sulfate catalyst under a hydrogen atmosphere to give a compound represented by the formula (XXI). This compound is reacted with sodium hydride to give a benzopyran derivative represented by the formula (XXII).
According to the 20th Symposium on Progress in Organic Reactions and Syntheses, Shizuoka (1994), 4-fluoronitrobenzene and acetylene represented by the general formula (XXIII) (where Z
9
represents a methyl group or a fluoromethyl group) are reacted in the presence of sodium hydride to give a compound represented by the general formula (XXIV) (where Z
9
has the same meaning as defined above). This compound is heated in dichlorobenzene to give a benzopyran derivative represented by the general formula (XXV) (where Z
9
has the same meaning as defined above).
In the production method of the invention, phenylpropargyl ethers are one of the important intermediates for synthesis and can be produced by known methods such as those described in Synthetic Communications, 19, 1255-1259 (1989) and U.S. Pat. No. 5,463,059.
According to Synthetic Communications, 19, 1255 (1989), a phenol represented by the general formula (H) and a substituted propargyl alcohol represented by the general formula (J) are condensed in benzene in the presence of diethyl azodicarboxylate and triphenylphosphine to give a compound represented by the general formula (K).
According to U.S. Pat. No. 5,463,059, a compound represented by the general formula (L) and a substituted propargyl alcohol represented by the general formula (M) (where L represents a leaving group such as a halogen atom, a trifluoroacetoxy group or an alkoxycarbonyloxy group) are reacted in acetonitrile in the presence of an organic base and a catalytic amount of a copper salt to give a compound represented by the general formula (N).
Other prior art techniques known in the field contemplated by the invention are processes for synthesizing 4-substituted benzopyran derivatives via 4-bromobenzopyran derivatives (XVIII) (JPA Hei 7-17965, JPA Hei 7-188210 and Tetrahedron Letters, 1995, 36, 87-90). According to JPA Hei 7-17965 and JPA Hei 7-188210, the general formula (P) (where Z
a
and Z
b
which may be the same or different represent a hydrogen atom, a lower alkyl group, a lower haloalkyl group, a halogen atom, a lower haloalkoxy group, an amino group, an acylamino group, a nitro group, a cyano group, an ester group, a lower alkylsulfonyl group or a lower arylsulfonyl group or, when taken together, represent a substituent ═N—O—N═; Z
c
and Z
d
which may be the same or different represent a hydrogen atom, a lower alkyl group or a substituted alkyl group or, when taken together, represent a polymethylene group or a substituent forming a heterocycle) is reacted with carbon monoxide and amine in the presence of a palladium catalyst to give an amide form represented by the general formula (Q).
However, the reaction for the synthesis of benzopyran having a bromine-containing group introduced at 4-position involves so many steps that cumbersome treatment procedures are required. In particular, the intermediate benzopyran derivative (XIV) is a labile compound, so large amounts of decomposition products occur as by-products during the synthesis of the benzopyran and very cumbersome post-treatment procedures are involved. As a further problem, due to their labile nature, derivatives having acid- or base-sensitive functional groups such as a perfluoroalkyl group in Z
7
and Z
8
cannot be synthesized without suitable protective groups. Because of these problems, extreme difficulties have often been encountered in the synthesis of the benzopyran. In order to produce the compound (XXIV), the presence of a nitro group in para-position is essential, so the process involving the formation of this compound as an intermediate does no
Ishizawa Takenori
Khlebnikov Vladimir A.
Suzuki Yukio
Watanabe Masashi
Browdy and Neimark , P.L.L.C.
Chang Ceila
Chugai Seiyaku Kabushiki Kaisha
Small Andrea D.
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