Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-27
2004-06-08
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C562S512000
Reexamination Certificate
active
06747157
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method for producing oxo-oxazoline derivatives using a simple and inexpensive method.
BACKGROUND ART
Oxo-oxazoline derivatives are critical intermediates for compounds (WO98/08867) which are TRH (thyrotropin releasing hormone) derivatives represented by the following general formula (VIII):
wherein R
A
is a hydrogen atom or optionally substituted lower alkyl; Y is an optionally substituted alkyl.
Further, compounds represented by the following general formulas (III-A), (III-B), (IV-A), or (IV-B):
wherein R
1
is an optionally substituted lower alkyl, an optionally substituted aryl, an alkynyl, or an optionally substituted heteroaryl, and derivatives thereof, are useful as tools for combinatorial chemistry.
Conventionally, as a method for producing oxo-oxazoline derivatives having a lower alkyloxycarbonyl group or a carboxyl group, a method of cyclizing a starting material while retaining its stereochemistry, and a method using cyclization reaction without reference to stereoselectivity are known.
An example of the method of cyclizing a starting material while retaining its stereochemistry is the following:
(Tetrahedron, 48, 2507, 1992). In this reaction, L-allo-threonine used as a starting material is allowed to react with phosgene and potassium hydroxide in toluene at 0° C. for one hour, thereby obtaining a cyclized product which retains its stereochemisty. Unfortunately, this method encounters a problem in industrialization since the method employs L-allo-threonine which is more expensive than its natural type, and phosgene which is toxic to the human body.
An example of the cyclization method without reference to stereoselectivity is the following:
(Japanese Laid-Open Publication No. 60-34955). In this reaction, a starting material is allowed to react with potassium carbonate in water at 60° C. for 1.5 hours to obtain a cyclized product. It is believed that the stereochemistry of the material is maintained in view of the mechanism of this method. Therefore, it is considered that allo-threonine needs to be used as a starting material in order to obtain a cis-form cyclized product.
Although a resultant cyclized product is an oxo-oxazoline derivative which does not have a lower alkyloxycarbonyl group or a carboxyl group, the following method is known:
(Bull. Chem. Soc. Japan., 44, 2515, 1971). In this reaction, a starting material is allowed to react in thionyl chloride at 60° C. for 24 hours without solvent, thereby obtaining a cyclized product at a yield of 65%. In this method, similar to the method of the present invention, the position of an ethyl group is inverted after the reaction. However, the starting material is not an amino acid derivative, and the relationship between the amino group and the hydroxyl group of the starting material is different from that of a starting material used in the method of the present invention. Moreover, since the reaction is conducted in thionyl chloride, the yield is as low as 65%.
Similar to the method of the present invention, a cyclization reaction with inversion is known:
(Heterocycl. Commun., 2, 55, 1996). An example in which trifluoroacetic anydride is used in the first step is disclosed. Although in the method of the present invention, the yield of a cyclization reaction is as high as 83%, the yield of the cyclization reaction disclosed in the above-described publication is as low as 40% in both a method using tosyl chloride and a method using trifluoroacetic anydride. Moreover, the method of the present invention is superior in regard to simplicity of reaction.
DISCLOSURE OF THE INVENTION
The objective of the present invention is to provide a method for producing oxo-oxazoline derivatives in a simple, inexpensive and stereoselective manner. The oxo-oxazoline derivatives are useful as intermediates for pharmaceuticals and tools for combinatorial chemistry. Moreover, the oxo-oxazoline derivatives in an open-circular form are also useful as tools for combinatorial chemistry.
The inventors found a method for producing oxo-oxazoline derivatives in a stereoselective manner, which is suitable for large-scale synthesis.
That is, the present invention relates to
I) A method for the production of a compound represented by a general formula (I-A) or a general formula (I-B), comprising the step of treating a compound represented by a general formula (II-A) or a general formula (II-B) with thionyl chloride as follows:
wherein R
1
is an optionally substituted lower alkyl, an optionally substituted aryl, an alkynyl, or an optionally substituted heteroaryl; R
2
is a lower alkyl, an optionally substituted aralkyl, or an optionally substituted heteroarylalkyl; and R
3
is a lower alkyl.
More specifically, the present invention relates to following II) to X).
II) A method for the production according to I), wherein the compound represented by the general formula (II-A) or the general formula (II-B) is allowed to react with 1.0 to 5.0 equivalents of thionyl chloride in a solvent of toluene, ethyl acetate, cyclohexane, or acetonitrile at 30° C. to reflux temperature.
III) A method for the production according to I), wherein the compound represented by the general formula (II-A) or the general formula (II-B) is allowed to react with 1.0 to 3.0 equivalents of thionyl chloride in a solvent of toluene, ethyl acetate, cyclohexane, or acetonitrile at 60° C. to 80° C.
IV) A method for the production of a compound represented by a general formula (III-A) or a general formula (III-B), comprising the step of subjecting a compound represented by a general formula (I-A) or a general formula (I-B) obtained by a method according to any of I) to III) to a hydrolysis as follows:
wherein R
1
and R
3
are as described above.
V) A method for the production of a compound represented by a general formula (IV-A) or a general formula (IV-B), comprising the step of subjecting a compound represented by a general formula (III-A) or a general formula (III-B) obtained by a method according to IV) to a hydrolysis as follows:
wherein R
1
is as described above.
VI) A method for the production of a compound represented by a general formula (I-A) or a general formula (I-B), comprising the step of protecting the amino group of a compound represented by a general formula (V-A) or a general formula (V-B) with R
2
OC(═O)—, wherein R
2
is as described above, esterifying the carboxyl group thereof, and treating with thionyl chloride as follows:
wherein R
1
and R
3
are as described above.
VII) A method for production of a compound represented by a general formula (VI):
wherein R
1
is as described above, and Y is an optionally substituted alkyl, comprising the step of subjecting a compound represented by a general formula (III-A) or a general formula (III-B) obtained by a method according to IV) to a peptide bond formation.
VIII) A method for the production according to IV), wherein R
1
is phenyl, 5-imidazolyl, methyl, isopropyl, ethynyl, or 1-propynyl.
IX) A method for the production according to IV), wherein R
2
is a lower alkyl, an aralkyl, or a heteroarylalkyl.
X) A method for the production according to IV), wherein R
2
is an aralkyl.
XI) A method for the production according to IV), wherein R
1
is methyl and R
2
is benzyl.
“Halogen” as used herein refers to fluorine, chlorine, bromine, and iodine. Chlorine and bromine are preferable.
The term “lower alkyl” as herein used alone or in combination with other words comprises C
1
-C
6
straight chained or branched alkyl. Examples of the lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and t-butyl, and the like. Methyl and ethyl are preferable.
“Alkynyl” as used herein comprises C
2
-C
8
straight or branched chain monovalent hydrocarbon group having one or two or more triple bonds. The alkynyl may have a double bond. Examples of the alkynyl include ethynyl, 1-propynyl, 2-propynyl, 6-heptynyl, 7-octynyl, and 8-nonyl, and the like. Ethynyl and 1-propynyl are preferable.
The term “aryl” as herein used alone or in combination
Kobayashi Makoto
Koike Haruo
Nagai Masahiko
McKane Joseph K.
Saeed Kamal
Shionogi & Co. Ltd.
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