Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-27
2001-01-09
Lambkin, Deborah C. (Department: 1613)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S532000
Reexamination Certificate
active
06172234
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel useful intermediates for producing optically active cyclic amino acids (for example, optically active proline, pipecolic acid, etc.), which are useful for producing pharmaceuticals, agrochemicals and the like, and to processes for producing and using the same.
2. Description of Related Art
Heretofore, a process has been known as processes for producing racemic proline and pipecolic acid, in which process pyrrolecarboxylic acid or pyridinecarboxylic acid is hydrogenated [Journal of Organic Chemistry, 1990, 55, 738].
Although processes in which racemic proline or pipecolic acid is optically resolved with tartaric acid have been known [Bulletin Chemical Society of Japan, 64, 3251 (1991)], such processes have a problem in separation of proline or pipecolic acid from the resolving agents.
Processes also have been known in which proline or pipecolic acid is first converted into N-(benzyloxycarbonyl)proline or N-(benzyloxycarbonyl)pipecolic acid, which is then subjected to optical resolution with optically active tyrosine hydrazide, and then a hydrogenolysis [Monatshefte fur Chemie 101, 1177 (1970)], but such processes have drawbacks in that they require expensive and not readily available resolving agent in an industrial scale.
As a process for producing optically active pipecolic acid, a process also has been known in which process optically active lysine is used [Chem. Pharm. Bull., 24, 621 (1976), Japanese unexamined patent publication No. Hei 2-229152], but it is not always satisfactory in an optical purity.
SUMMARY OF THE INVENTION
An object of the invention is to provide a novel process for producing an optically active cyclic amino acid ester compound, which can be further derivatized to the optically active cyclic amino acids, by using readily available inexpensive di-substituted aliphatic carboxylic acids and resolving agents.
It is also an object of the invention to provide the novel optically active cyclic amino acid and its derivatives.
A further object of the invention is to provide processes for producing the optical active cyclic amino acids from the novel derivatives.
The present invention provides:
1. A process for producing the optically active cyclic amino acid ester derivative of the formula (I):
wherein R
1
represents a C1-C8 alkyl group;
R
2
represents a hydrogen atom, a C1-C8 alkyl group, a halogen atom, a hydroxy group or a C1-C8 alkoxy group;
R
3
represents an aryl group or a C1-C8 alkyl group, which alkyl group may be substituted with an aryl group;
“n” represents an integer from 1 to 4; and
“a” and “b” independently represent R or S,
which comprises the steps of:
(a) contacting a cyclic amino acid ester derivative of the formula (II):
wherein R
1
, R
2
, R
3
, “n” and “a” represent the same as defined above, with an optically active carboxylic acid of the formula (III):
wherein R
4
represents:
a C1-C8 linear or branched alkyl group which may be substituted with at least one group selected from a phenyl group, a hydroxy group, a C1-C8 alkoxy group, a phenoxy group, an acyloxy group (e.g., C1-C8 alkanoyloxy and C7-C11 arylcarbonyloxy) a hydroxycarbonyl group, an C1-C8 alkoxycarbonyl group and a halogen atom;
a phenyl group which may be substituted with at least one group selected from a C1-C8 alkyl group, a phenyl group, a hydroxy group, a C1-C8 alkoxy group, a phenoxy group, an acyloxy group (e.g., C1-C8 alkanoyloxy and C7-C11 arylcarbonyloxy) and a halogen atom; or a halogen atom;
R
5
represents:
a C1-C8 linear or branched alkyl group which may be substituted with at least one group selected from a phenyl group, a hydroxy group, a C1-C8 alkoxy group, a phenoxy group, an acyloxy group (e.g., C1-C8 alkanoyloxy and C7-C11 arylcarbonyloxy) and a halogen atom;
a phenyl group which may be substituted with at least one group selected from a C1-C8 alkyl group, a phenyl group, a hydroxy group, a C1-C8 alkoxy group, a phenoxy group, an acyloxy group (e.g., C1-C8 alkanoyloxy and C7-C11 arylcarbonyloxy), a halogen atom and a nitro group;
an acyl group (e.g., C1-C8 alkanoyl and C7-C11 arylcarbonyl) which may be substituted with at least one group selected from a C1-C8 alkyl group, a phenyl group, a hydroxy group, a C1-C8 alkoxy group, a phenoxy group, an acyloxy group (e.g., C1-C8 alkanoyloxy and C7-C11 arylcarbonyloxy), a halogen atom and a nitro group; or
a hydrogen atom;
“c” represents R or S;
(b) isolating a resulting salt comprising the compounds of the formulae (I) and (III); and
(c) treating the isolated salt with an acid or a base.
2. An optically active cyclic amino acid ester derivative of the formula (I) as described above;
3. A salt comprising the optically active cyclic amino acid ester derivative of the formula (I) as defined above and an optically active carboxylic acid of the formula (III) as defined above;
4. An optically active cyclic amino acid derivative of the formula (IV):
wherein R
1
, R
2
, “n”, “a” and “b” respectively have the same meaning as defined above;
5. A process for producing the optically active cyclic amino acid derivative of the formula (IV) as defined above,
which comprises:
hydrolyzing the optically active cyclic amino acid ester derivative of the formula (I) as defined above in the presence of an acid or a base.
6. A process for producing an optically active cyclic amino acid of the formula (V):
wherein “n” is an integer of 1 to 4, and “b” represents R or S, which comprises:
subjecting the optically active cyclic amino acid derivative of the formula (IV) as defined above to a hydrogenolysis reaction in the presence of a catalyst;
7. A cyclic amino acid ester derivative of the formula (II):
wherein R
1
, R
2
, R
3
and “a” represent the same as defined above, and “n” represents an integer from 2 to 4;
8. A process for producing an optically active cyclic amino acid ester derivative of the formula (I) as defined above,
which comprises:
reacting a di-substituted aliphatic carboxylic acid ester of the formula (VI):
wherein Y represents a leaving group,
R
3
and “n” have the same meaning defined above, with an optically active amine of the formula (VII):
wherein R
1
, R
2
and “a” have the same meaning defined above.
DETAILED DESCRIPTION OF THE INVENTION
In the present invention, the C1-C8 alkyl group in the formula (I) through (VII) includes a methyl group, an ethyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group and an octyl group.
The C1-C8 alkoxyl group includes a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, a butoxy group, a pentyloxy group, a hexyloxy group, a heptyloxy group and an octyloxyl group.
The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
Examples of the aryl group for R
3
include a C6-C10 aryl group such as a phenyl group, a tolyl group and a naphthyl group.
Examples of the C1-C8 alkyl group which may be substituted with an aryl group for R
3
include a C1-C8 alkyl group which may be substituted a phenyl group or a tolyl group.
In the chemical formula of the present invention, “a”, “b” and “c” mean either R or S configuration around the carbon atom to which the notations are attached.
Next, a description will be made to the process for producing the optically active cyclic amino acid ester derivative of the formula (I) as defined above,
which comprises the steps of:
(a) contacting a diastereomeric mixture of cyclic amino acid ester derivative of the formula (II) as defined above with an optically active carboxylic acid of the formula (III) as defined above
(b) isolating a resulting salt comprising the compounds of the formulae (I) and (III); and
(c) treating the isolated salt with an acid or a base.
Specific examples of such an optically active cyclic amino acid ester derivative of the formula (I) include N-[(S)-&agr;-methylbenzyl]-(S)-proline methyl ester, N-[(S)-&agr;-methylbenzyl]-(R)-proline methyl ester, N-[(R
Honda Yukihiro
Kurimoto Isao
Oikawa Miyuki
Lambkin Deborah C.
Sughrue Mion Zinn Macpeak & Seas, PLLC
Sumitomo Chemical Company Limited
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