Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-21
2004-09-28
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S545000, C549S546000
Reexamination Certificate
active
06797832
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a production method of 5-oxy-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester. 5-Oxy-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester, such as ethyl (1&bgr;,5&agr;,6&bgr;)-5-(1-ethylpropoxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate, obtained by the present invention, is useful as a synthetic intermediate for GS4104 represented by the following formula.
GS4104 is a compound under development as a novel agent for the prophylaxis or treatment of influenza based on its action to prevent viral growth by inhibiting neuraminidase present on the surface of influenza virus (hereinafter to be generally referred to as an anti-influenza drug) [see The Journal of Organic Chemistry (J. Org. Chem.), vol. 63, p. 4545 (1998); organic Process Research & Development, vol. 3, p. 266 (1999)].
BACKGROUND ART
As a conventional synthetic method of 5-oxy-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester, such as ethyl (1&bgr;,5&agr;,6&bgr;)-5-(1-ethylpropoxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate, a synthetic method wherein shikimic acid is used as a starting material [see The Journal of Organic Chemistry (J. Org. Chem.), vol. 63, p. 4545 (1998); Organic Process Research & Development, vol. 3, p. 266 (1999); WO 99/14185; WO 98/07685], and a synthetic method wherein quinic acid is used as a starting material [see Organic Process Research & Development, vol. 3, p. 266 (1999)] and the like are known.
The shikimic acid and quinic acid used as a starting material for the conventional synthetic method of ethyl (1&bgr;,5&agr;,6&bgr;)-5-(1-ethylpropoxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate are produced in less amounts and expensive. As widely known, influenza often becomes an epidemic disease worldwide, and an anti-influenza drug is required to be economical and to be supplied in a large amount. The above-mentioned production methods are not necessarily advantageous as a production method of the intermediate for GS4104 under development as an anti-influenza drug from the industrial viewpoint, and there is a demand for a synthetic method capable of economical production in a large amount.
DISCLOSURE OF THE INVENTION
It is therefore an object of the present invention to provide a production method of a 5-oxy-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester, such as ethyl (1&bgr;,5&agr;,6&bgr;)-5-(1-ethylpropoxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate, useful as a synthetic intermediate for GS4104 under development as an anti-influenza drug, economically, industrially advantageously and efficiently in a large amount.
According to the present invention, the above-mentioned objects can be achieved by providing
(1) a production method of a 5-oxy-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester of the formula (X)
wherein R
1
and R
3
are independently an alkyl group optionally having substituents, a cycloalkyl group optionally having substituents, an alkenyl group optionally having substituents, an aryl group optionally having substituents or an aralkyl group optionally having substituents [hereinafter to be abbreviated as 5-oxy-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester (X)], which comprises:
reacting a 2-halogeno-7-oxabicyclo[2.2.1]heptane-5,3-carbolactone of the formula (I)
wherein X is a halogen atom [hereinafter to be abbreviated as halolactone (I)] with a base,
reacting the resulting compound with alkyl halide optionally having substituents, cycloalkyl halide optionally having substituents, alkenyl halide optionally having substituents, aryl halide optionally having substituents or aralkyl halide optionally having substituents to give a 2,3-epoxy-7-oxabicyclo[2.2.1]heptane-5-carboxylic acid ester of the formula (III)
wherein R
1
is as defined above [hereinafter to be abbreviated as epoxy ester (III)],
reacting the obtained epoxy ester (III) with a base to give a 5-hydroxy-7-oxabicyclo[4.1.0]hept-2-ene-3-carboxylic acid ester of the formula (IV)
wherein R
1
is as defined above [hereinafter to be abbreviated as oxabicyclohept-2-ene (IV)],
protecting a hydroxyl group of the obtained oxabicyclohept-2-ene (IV) to give a 5-oxy-7-oxabicyclo[4.1.0]hept-2-ene-3-carboxylic acid ester of the formula (V)
wherein R
1
is as defined above and R
2
is a hydroxyl-protecting group [hereinafter to be abbreviated as oxabicyclohept-2-ene (V)],
reacting the obtained oxabicyclohept-2-ene (V) with an alcohol of the formula (VI)
R
3
OH (VI)
wherein R
3
is as defined above [hereinafter to be abbreviated as alcohol (VI)] in the presence of a Lewis acid to give a 4-hydroxy-3,5-dioxy-1-cyclohexene-1-carboxylic acid ester of the formula (VII)
wherein R
1
, R
2
and R
3
are as defined above [hereinafter to be abbreviated as cyclohexene ester (VII)],
reacting the obtained cyclohexene ester (VII) with a sulfonylating agent in the presence of a base to give a 3,5-dioxy-4-sulfonyloxy-1-cyclohexene-1-carboxylic acid ester of the formula (VIII)
wherein R
1
, R
2
and R
3
are as defined above and A is an organic sulfonyl group [hereinafter to be abbreviated as cyclohexene ester (VIII)],
removing the R
2
from the obtained cyclohexene ester (VIII) to give a 5-hydroxy-3-oxy-4-sulfonyloxy-1-cyclohexene-1-carboxylic acid ester of the formula (IX)
wherein A, R
1
and R
3
are as defined above [hereinafter to be abbreviated as hydroxy ester (IX)], and
reacting the obtained hydroxy ester (IX) with a base,
(2) a production method of 5-oxy-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester (X), which comprises:
reacting halolactone (I) with a base to give a 2,3-epoxy-7-oxabicyclo[2.2.1]heptane-5-carboxylic acid of the formula (II)
[hereinafter to be abbreviated as epoxy carboxylic acid (II)],
reacting the obtained epoxy carboxylic acid (II) with an esterification agent to give epoxy ester (III),
reacting the obtained epoxy ester (III) with a base to give oxabicyclohept-2-ene (IV),
protecting a hydroxyl group of the obtained oxabicyclohept-2-ene (IV) to give oxabicyclohept-2-ene (V),
reacting the obtained oxabicyclohept-2-ene (V) with an alcohol (VI) in the presence of a Lewis acid to give cyclohexene ester (VII),
reacting the obtained cyclohexene ester (VII) with a sulfonylating agent in the presence of a base to give cyclohexene ester (VIII),
removing the R
2
from the obtained cyclohexene ester (VIII) to give hydroxy ester (IX), and
reacting the obtained hydroxy ester (IX) with a base,
(3) a production method of epoxy carboxylic acid (II), which comprises reacting halolactone (I) with a base,
(4) a production method of a 2,3-epoxy-7-oxabicyclo[2.2.1]heptane-5-carboxylic acid ester of the formula (III-1)
wherein R
1
is as defined above, or the formula (III-2)
wherein R
1
is as defined above, which comprises reacting a 2,3-epoxy-7-oxabicyclo[2.2.1]heptane-5-carboxylic acid of the formula (II-1)
or the formula (II-2)
with an esterification agent,
(5) a production method of epoxy ester (III), which comprises reacting halolactone (I) with a base, and
reacting the resulting compound with alkyl halide optionally having substituents, cycloalkyl halide optionally having substituents, alkenyl halide optionally having substituents, aryl halide optionally having substituents or aralkyl halide optionally having substituents,
(6) a production method of oxabicyclohept-2-ene (IV), which comprises reacting epoxy ester (III) with a base,
(7) a production method of cyclohexene ester (VII), which comprises protecting a hydroxyl group of oxabicyclohept-2-ene (IV) to give oxabicyclohept-2-ene (V), and
reacting the obtained oxabicyclohept-2-ene (V) with an alcohol (VI) in the presence of a Lewis acid,
(8) a production method of cyclohexene ester (VII
Kanehira Koichi
Kuwayama Tomoya
Shimizu Kazuya
Sugioka Takashi
Terashima Shiro
Sagami Chemical Research Center
Trinh Ba K.
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