Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-13
2004-09-14
Tsang, Cecilia (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C568S435000, C568S436000
Reexamination Certificate
active
06790964
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a production method of 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester. 7-Azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester, such as ethyl (1&agr;,5&agr;,6&agr;)-5-(1-ethylpropoxy)-7-azabicyclo[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 and treatment of influenza based on the action to prevent viral growth by inhibiting neuraminidase present on the surface of influenza virus (hereinafter to be generally referred to as anti-influenza drug) [see Journal of Organic Chemistry (J. Org. Chem.), vol. 63, p. 4545 (1998); Journal of American Chemical Society (J. Am. Chem. Soc.), vol. 119, p. 681 (1997)].
BACKGROUND ART
As a conventional synthetic method of 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester, such as ethyl (1&agr;,5&agr;,6&agr;)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate, a synthetic method wherein shikimic acid is used as a starting material [see Journal of Organic Chemistry (J. Org. Chem.), vol. 63, p. 4545 (1998); WO 99/14185; WO 98/07685], and a synthetic method wherein guinic acid is used as a starting material [see Journal of American Chemical Society (J. Am. Chem. Soc.), vol. 119, p. 681 (1997)] and the like are known.
The shikimic acid and quinic acid used as a starting material for the conventional synthetic method of ethyl (1&agr;,5&agr;,6&agr;)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate are produced in less amounts and expensive. All the above-mentioned methods require many reaction steps. As widely known, influenza often becomes an epidemic disease worldwide, and an anti-influenza drug is required to be economical and 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 INVENTION
It is therefore an object of the present invention to provide a production method of a 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester, such as ethyl (1&agr;,5&agr;,6&agr;)-5-(1-ethylpropoxy)-7-azabicyclo[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 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester of the formula (VII)
wherein R
1
is an alkyl group optionally having substituents, a cycloalkyl group optionally having substituents, an aryl group optionally having substituents or an aralkyl group optionally having substituents and R
3
is 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 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester (VII)], which comprises the steps of
(A) reacting a 5-hydroxy-7-oxabicyclo[4.1.0]hept-2-ene-3-carboxylic acid ester of the formula (I)
wherein R
1
is as defined above [hereinafter to be abbreviated as epoxide (I)] with an amine of the formula (II)
R
2
NH
2
(II)
wherein R
2
is a hydrogen atom, 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 amine (II)] to give a 3-amino-4,5-dihydroxy-1-cyclohexene-1-carboxylic acid ester of the formula (III)
wherein R
1
and R
2
are as defined above [hereinafter to be abbreviated as aminodiol (III)],
(B) reacting the obtained aminodiol (III) with a sulfonylating agent in the presence of a base to give a 5-sulfonyloxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylic acid ester of the formula (IV)
wherein R
1
and R
2
are as defined above and A is an organic sulfonyl group [hereinafter to be abbreviated as azabicyclohept-2-ene (IV)],
(C) reacting the obtained azabicyclohept-2-ene (IV) with an alcohol of the formula (V)
R
3
OH (V)
wherein R
3
is as defined above [hereinafter to be abbreviated as alcohol (V)] in the presence of a Lewis acid to give a 5-oxy-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester of the formula (VI)
wherein R
1
, R
2
and R
3
are as defined above [hereinafter to be abbreviated as azabicyclohept-3-ene (VI)], and
(D) when R
2
is 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, eliminating the 7-position substituent R
2
of the obtained azabicyclohept-3-ene (VI),
(2) a production method of a 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester (VII), which comprises the steps of
(A) reacting epoxide (I) with amine (II) to give aminodiol (III),
(B) protecting an amino group of the obtained aminodiol (III) to give a 3-amino-4,5-dihydroxy-1-cyclohexene-1-carboxylic acid ester of the formula (VIII)
wherein R
1
and R
2
are as defined above and R
4
is an amino-protecting group [hereinafter to be abbreviated as aminodiol (VIII)],
(C) reacting the obtained aminodiol (VIII) with a sulfonylating agent in the presence of a base to give a 3-amino-4,5-disulfonyloxy-1-cyclohexene-1-carboxylic acid ester of the formula (IX)
wherein R
1
, R
2
and R
4
are as defined above and A is an organic sulfonyl group [hereinafter to be abbreviated as disulfonate (IX)],
(D) removing the amino-protecting group from the obtained disulfonate (IX) to give a 3-amino-4,5-disulfonyloxy-1-cyclohexene-1-carboxylic acid ester of the formula (X)
wherein R
1
, R
2
and A are as defined above [hereinafter to be abbreviated as disulfonate (X)],
(E) reacting the obtained disulfonate (X) with a base to give azabicyclohept-2-ene (IV),
(F) reacting the obtained azabicyclohept-2-ene (IV) with alcohol (V) in the presence of a Lewis acid to give azabicyclohept-3-ene (VI), and
(G) when R
2
is 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, eliminating the 7-position substituent R
2
from the obtained azabicyclohept-3-ene (VI),
(3) a production method of a 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester (VII), which comprises eliminating the 7-position substituent R
2′
, from a 5-oxy-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester of the formula (VI′)
wherein R
2′
, is 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, and R
1
and R
3
are as defined above,
(4) a production method of azabicyclohept-3-ene (VI), which comprises reacting azabicyclohept-2-ene (IV) with alcohol (V) in the presence of a Lewis acid,
(5) a production method of azabicyclohept-2-ene (IV), which comprises reacting aminodiol (III) with a sulfonylating agent in the presence-of a base,
(6) a production method of azabicyclohept-2-ene (IV), which comprises re
Ishiwata Akihiro
Terashima Shiro
Ujita Katsuji
Sackey Ebenezer
Sagami Chemical Research Center
Tsang Cecilia
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