Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
1999-02-05
2001-01-30
Shippen, Michael L. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C549S416000, C549S475000, C556S482000, C585S317000, C585S534000
Reexamination Certificate
active
06180835
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for the preparation of a cyclopropylacetylene derivative, an intermediate for the synthesis of the cyclopropylacetylene derivative and a process for the preparation of the same. The cyclopropylacetylene derivative produced by the process of the present invention is useful as an intermediate in synthesis of a compound having a cyclopropane skeleton, for example, a benzoxazinone derivative (L-743726), which has anti-HIV activity (Tetrahedron Letters, Vol. 36, page 8937 (1995)).
2. Description of the Background
Recently, a large number of physiologically active substances having a cyclopropane skeleton have been discovered. Examples of known methods of producing cyclopropylacetylene, which is useful as an intermediate for the synthesis of these compounds, include: (I) a method in which 5-chloropentyne is reacted with n-butyllithium (Tetrahedron Letters, Vol. 36, page 8937 (1995)); and (2) a method in which cyclopropyl methyl ketone is reacted with phosphorus pentachloride in carbon tetrachloride to produce 1,1-dichloro-1-cyclopropylethane, which is subsequently dehydrochlorinated by potassium tert-butoxide (Synthesis page 703 (1972)).
However, in method (1), the yield of the raw starting material 5-chloropentyne in the reaction by which it is produced is as low as 57% (Journal of American Chemical Society, Vol. 67, page 484 (1945)), and method (2) gives many byproducts and, therefore, produces relatively low yields of the target product. Therefore, these methods are of limited industrial utility for the production of cyclopropylacetylene.
Another method by which cyclopropylacetylene is prepared requires the reaction of a propynol derivative with an alkyl (di)halide in liquid ammonia in the presence of lithium amide to give an acetylene derivative (Bulletin de la Societe Chimique de France, pages 201-204 (1968)). However, no method of transforming the obtained acetylene derivative to a compound having a cyclopropane skeleton is disclosed or suggested therein.
Another reaction which is known is the ethynylation of cyclopropylacetylene with acetone or cyclopropyl methyl ketone to give 2-methyl-4-cyclopropyl-3-butyn-2-ol or 2,4-dicyclopropyl-3-butyn-2-ol (Izvetiya Akademii Nark SSSR, Seriya Khimicheskaya, pages 1339-1344 (1978)), but no description for the reverse reaction is provided.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide a method by which a cyclopropylacetylene derivative can be produced in a good yield and by a commercially advantageous method.
Another object of the present invention is to provide an intermediate, which is useful in the production of a cyclopropylacetylene derivative.
Still another object of the invention is to provide a method of preparing the intermediate.
Briefly, these objects and other objects of the present invention as hereinafter will become more readily apparent can be attained by a cyclopropylacetylene derivative having formula (V):
wherein each of R
1
, R
2
, R
3
, R
4
and R
5
is hydrogen, or an alkyl, alkenyl, aryl or aralkyl group, each of which may have a substituent (hereinafter simply referred to as cyclopropylacetylene derivative (V)), which comprises the step of subjecting a cyclopropylpropynol derivative represented by the following formula (IV):
wherein R
1
, R
2
, R
3
, R
4
and R
5
have the same meanings as defined above and each of R
6
and R
7
represents hydrogen; or an alkyl, alkenyl, aryl or aralkyl group, each of which may have a substituent, or R
6
and R
7
together may form a ring (hereinafter simply referred to as cyclopropylpropynol derivative (IV)), to retroethynylation.
A second aspect of the present invention is a process for the preparation of cyclopropylacetylene derivative (V), by the steps of: (i) reacting a propynol derivative of formula (I):
wherein R
6
and R
7
have the same meanings as defined above and R
8
is a protecting group for the hydroxyl group (hereinafter simply referred to as propynol derivative (I)) with a propane derivative having formula (VI):
wherein R
1
, R
2
, R
3
, R
4
and R
5
have the same meanings as defined above, and each of X and Y is a leaving group (hereinafter simply referred to as propane derivative (VI)), in the presence of a base in an amount of less than 2 equivalents relative to the propynol derivative (1) at a temperature of 0° C. or lower to give an acetylene derivative having formula (II):
wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
and X have the same meanings as defined above (hereinafter simply referred to as acetylene derivative (II)), (ii) reacting the acetylene derivative (II) obtained with a base to give a cyclopropane derivative having formula (III):
wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
and R
8
have the same meanings as defined above (hereinafter simply referred to as cyclopropane derivative (III)), (iii) removing the protecting group for the hydroxyl group of the obtained cyclopropane derivative (III) to give a cyclopropylpropynol derivative (IV), and (iv) subjecting the obtained cyclopropylpropynol derivative (IV) to retro-ethynylation.
A third aspect of the invention is a process for the preparation of a cyclopropylacetylene derivative (V), which comprises the steps of reacting a propynol derivative (I) with a propane derivative (VI) in the presence of a base in an amount of 2 or more equivalents relative to the propynol derivative (I) to give a cyclopropane derivative (III), removing the protecting group for the hydroxyl group of the obtained cyclopropane derivative (III) to give a cyclopropylpropynol derivative (IV), and subjecting the obtained cyclopropylpropynol derivative (IV) to retroethynylation.
A fourth aspect of the present invention is a process for the preparation of a cyclopropane derivative (III), which comprises the step of reacting an acetylene derivative (II) with a base.
A filth aspect of the invention is a process for the preparation of a cyclopropane derivative (III), which comprises the step of reacting a propynol derivative (I) with a propane derivative (VI) in the presence of a base in an amount of 2 or more equivalents relative to the propynol derivative (I).
Finally, a sixth aspect of the invention is a cyclopropane derivative of formula (III-1):
wherein R
61
is alkyl, R
71
is an alkyl group having 2 or more carbon atoms when R
61
is methyl or R
71
is alkyl when R
61
is an alkyl group having 2 or more carbon atoms, and R
81
is hydrogen or a protecting group for the hydroxyl group.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Examples of the alkyl groups of groups R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and R
7
in the above formulae include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 4-methylpentyl and the like. These alkyl groups each may have a substituent and examples of such substituents include hydroxy; methoxy, ethoxy, propoxy, butoxy and other alkoxyl groups; tert-butyldimethylsilyloxy, tert-butyldiphenylsilyloxy and other tri-substituted silyloxy groups; and phenyl, p-methoxyphenyl, p-chlorophenyl and other aryl groups.
The alkyl groups of R
61
and R
71
include, for instance, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 4-methylpentyl and the like.
Examples of the alkenyl groups of substituents R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and R
7
include vinyl, propenyl and butenyl, and examples of the aryl groups include phenyl and naphthyl, for example. Examples of the aralkyl groups include benzyl, for instance. These alkenyl groups, aryl groups and aralkyl groups each may have a substituent, and examples of such substituents include hydroxyl; methyl, ethyl, propyl, butyl and other alkyl groups; methoxy, ethoxy, propoxy, butoxy and other alkoxyl groups; tert-butyldimethylsilyloxy, tert-butyldiphenylsilyloxy and other tri-substituted silyloxy groups; and phenyl, p-methoxyphenyl, p-chlorophenyl and other aryl groups.
Examples of the ring which is formed by R
6
and R
7
taken together include cyclopentane, cyclohexane, cyclohe
Asanuma Goro
Ohzono Shigeo
Shiono Manzo
Takaki Kazuya
Kuraray Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Shippen Michael L.
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