Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-03-14
2004-01-13
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06677464
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a production method of 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivatives. An endo form of a 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative obtained by the method of the present invention is useful as a starting material for the synthesis of medicine, agricultural chemical and the like. For example, an endo form of 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid is a useful compound as a synthetic intermediate for Cyclophellitol, an anti-HIV drug [see Tetrahedron Letters, vol. 37, p. 3043 (1996)], as a synthetic intermediate for Validamycin A, an antibiotic [see Carbohydrate Research, vol. 58, p. 240 (1977)], and as a synthetic intermediate for GS4104, an anti-influenza drug [see Journal of the American Chemical Society (J. Am. Chem. Soc.), vol. 119, p. 681 (1997); The Journal of organic Chemistry (J. Org. Chem.), vol. 63, p. 4545 (1998); specification of WO 01/47906].
BACKGROUND ART
A number of physiologically active substances derived from an oxanorbornene skeleton have been found in recent years. Known production methods of 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative useful as a synthetic intermediate for these compounds include (1) a method comprising a reaction of acrylic acid with furan in the presence of hydroquinone [see Carbohydrate Research, vol. 58, p. 240 (1977)], (2) a method comprising a reaction of an acrylic acid derivative with furan in the presence of tetrakis(acetonitrile)copper(I) tetrafluoroborate and hydroquinone [see The Journal of organic Chemistry (J. Org. Chem.), vol. 48, p. 1105 (1983)], (3) a method comprising a reaction of an acrylic acid derivative with furan under high pressure conditions of 1 to 2 MPa (10 to 20 kbar) [see The Bulletin of the Chemical Society of Japan (Bull. Chem. Soc. Japan), vol. 55, p. 4969 (1982)], (4) a method comprising a reaction of an acrylic acid ester with furan in the presence of zinc chloride, zinc iodide or titanium chloride [see Journal of Molecular Catalysis A: Chemical (J. Mol. Catal. A: Chem.), vol. 123, p. 43 (1997)], and then hydrolysis of the ester moiety of the obtained compound [see Journal of Heterocyclic Chemistry (J. Heterocycl. Chem.), vol. 9, p. 561 (1972)] and the like.
The reaction to form the 7-oxabicyclo[2.2.1]hept-5-ene skeleton by Diels-Alder reaction of dienophile such as an acrylic acid derivative with furan has been considered to resist promotion of the reaction by heating, because cycloaddition products are unstable to heat. In the above-mentioned methods (1) and (2), therefore, the reaction is carried out for a long time in the presence of hydroquinone as a polymerization inhibitor, and in the above-mentioned method (3), the reaction is carried out under high pressure conditions.
However, the method of the above-mentioned (1) is problematic in that the reaction time is extremely long (75 days) and the yield is as low as 33%. In addition, the method of the above-mentioned (2) is also problematic in that the reaction time is long (9 days) and the yield is as low as 48%, and the method of the above-mentioned (3) essentially requires a pressure reactor, which increases costs of facilities. Furthermore, the method of the above-mentioned (4) requires a Diels-Alder reaction step of an acrylic acid ester with furan and a hydrolysis step of the ester moiety, thus problematically having many steps. Therefore, it is difficult to say that these methods are industrially advantageous production methods of 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivatives.
DISCLOSURE OF THE INVENTION
It is therefore an object of the present invention to provide a production method capable of industrially advantageously producing a 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative under mild conditions in a high yield. In other words, in the method of producing a 7-oxabicyclo [2.2.1]hept-5-ene-2-carboxylic acid derivative directly from an acrylic acid derivative and a furan derivative, the present invention aims at providing a method for producing the objective compound in a shorter reaction time in a high yield under mild conditions (without the need for heating at a high temperature or pressurizing).
The present invention provides a production method of a 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative of the formula (III)
wherein
R
1
, R
2
and R
3
are each independently a hydrogen atom, a halogen atom, a formyl group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an acyl group, an acyloxy group, an organic sulfinyl group, an organic sulfonyl group or an alkyl group optionally having substituents, or R
1
and R
2
may form a ring together with the carbon atoms they are bonded to, and
R
4
, R
5
, R
6
and R
7
are independently a hydrogen atom, an alkoxyl group, an alkylthio group or an alkyl group optionally having substituents, or R
4
and R
5
, and R
5
and R
6
may form a ring together with the carbon atoms they are bonded to, or the formula (IV)
wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and R
7
are as defined above 5 [hereinafter to be abbreviated as 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative (III) and 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative (IV), respectively], which comprises:
reacting an &agr;,&bgr;-unsaturated carboxylic acid of the formula (I)
wherein R
1
, R
2
and R
3
are as defined above [hereinafter to be abbreviated as &agr;,&bgr;-unsaturated carboxylic acid (I)], with a furan derivative of the formula (II)
wherein R
4
, R
5
, R
6
and R
7
are as defined above [hereinafter to be abbreviated as furan derivative (II)], in the presence of a Lewis acid.
The present invention provides a production method of a 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative of the formula (III-1)
wherein
R
11
, R
21
and R
31
are each independently a hydrogen atom, a halogen atom or a carboxyl group, or R
11
and R
21
may form a ring together with the carbon atoms they are bonded to, and
R
41
, R
51
, R
61
and R
71
are each independently a hydrogen atom or an alkyl group optionally having substituents, or R
41
and R
51
, and R
51
and R
61
may form a ring together with the carbon atoms they are bonded to, or the formula (IV-1)
wherein R
11
, R
21
, R
31
, R
41
, R
51
, R
61
and R
71
are as defined above [hereinafter to be abbreviated as 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative (III-1) and 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative (IV-1), respectively], which comprises:
reacting an &agr;,&bgr;-unsaturated carboxylic acid of the formula (I-,1)
wherein R
11
, R
21
and R
31
are as defined above [hereinafter to be abbreviated as &agr;,&bgr;-unsaturated carboxylic acid (I-1)], with a furan derivative of the formula (II-1)
wherein R
41
, R
51
, R
61
and R
71
are as defined above [hereinafter to be abbreviated as furan derivative (II-1)], in the presence of a Lewis acid.
In a preferable embodiment, a boron compound having Lewis acidity is used as a Lewis acid. In a preferable embodiment, a Lewis acid selected from the group consisting of a borane-tetrahydrofuran complex, a borane-dimethyl sulfide complex, a boron trifluoride-diethyl ether complex, triacetoxyborane and lo tripropionyloxyborane can be also used as a Lewis acid. Alternatively, in another embodiment, a Lewis acid selected from the group consisting of anhydrous aluminum chloride, anhydrous ferric chloride and zinc chloride can be used as a Lewis acid.
The halogen atom represented by R
1
, R
2
, R
3
, R
11
, R
21
and R
31
in the above-mentioned formulas is exemplified by a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
The alkyl group represented by R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
41
, R
51
, R
61
and R71 is exemplified by a stra
Kuwayama Tomoya
Shimizu Kazuya
Terashima Shiro
Ujita Katsuji
Kuraray Co. Ltd.
Morris Patricia L.
LandOfFree
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