Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-10-29
2003-12-16
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S156000, C562S561000
Reexamination Certificate
active
06664412
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing a specific, optically active lysine derivative useful as a pharmaceutical intermediate.
BACKGROUND OF THE INVENTION
Optically active lysine derivatives, such as an optically active 6,6-dimethyl lysine derivative of the formula (3)
wherein * means an asymmetric carbon atom, P
1
and P
2
are each independently an amino-protecting group or hydrogen atom where P
1
and P
2
are not hydrogen atoms at the same time, or P
1
and P
2
in combination show an amino-protecting group, and P
4
is a hydrogen atom or carboxyl-protecting group, and an optically active lysine derivative of the formula (5)
wherein *, P
1
and P
2
are as defined above, R
1
is alkyl group having 1 to 6 carbon atoms or aralkyl group having 7 to 12 carbon atoms, and P
5
is a hydrogen atom or carboxyl-protecting group, are useful as pharmaceutical intermediates.
For example, a compound having an S-configuration of asymmetric carbon atom is an important intermediate compound for a pharmaceutical compound of the following formula (25), which is useful as an antihypertensive agent having an inhibitory activity against an angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) (
Journal of Medicinal Chemistry,
1999, 42, 305-311).
As a method for producing the pharmaceutical compound of the formula (25),
Journal of Medicinal Chemistry,
1999, 42, 305-311 discloses a method shown by the following scheme using (S)-2-phthalimido-6-hydroxyhexanoic acid as a starting material.
However, this method requires many steps, and there is a demand on a production method that permits easier and simpler industrial production.
It is also known that an optically active amino acid can be generated by directly applying a microorganism enzyme system to 5-substituted hydantoin as a starting material. When a microorganism enzyme system is used, an enzyme (hydantoinase) to hydrolyze a 5-substituted hydantoin compound and produce N-carbamyl-amino acid, and an enzyme (N-carbamyl-amino-acid hydrolase) to enantio-selectively decompose the produced N-carbamyl-amino acid into optically active amino acid are required.
Conventionally, there are methods for producing D-amino acid using microorganisms containing these two kinds of enzymes, or substances containing such enzymes, such as a method comprising the use of bacteria of the genus Pseudomonas (JP-B-56-003034), a method comprising the use of bacteria of the genus Agrobacterium (JP-A-03-19696) and the like.
As a method for producing L-amino acid, there are known a method comprising the use of bacteria of the genus Flavobacterium (JP-B-56-008749), a method comprising the use of bacteria of the genus Bacillus (JP-A-63-24895), a method comprising the use of bacteria of the genus Pseudomonas (JP-A-01-071476), a method comprising the use of bacteria of the genus Arthrobacter [
J. Biotechnol.,
Vol. 46, p. 63 (1996)] and the like.
It has been also reported that optically active amino acid can be produced by isolating a genetic DNA of hydantoinase and a genetic DNA of N-carbamyl-amino-acid hydrolase from various bacteria and expressing them in
E. coli [Biotechnol. Prog.,
vol. 16, p. 564 (2000), EP515698 and the like].
It has been detailed that the substrate specificity of these hydantoinase and N-carbamyl-amino-acid hydrolase is rather broad, and by a combined use of these two kinds of enzymes under the limitation of the substrate specificity, natural or nonnatural various amino acids having optical activity can be produced from 5-substituted hydantoin compound [
Enzyme Catalysis in Organic Synthesis,
K. Drauz et al. ed., vol. 1, ch. B2.4, pp. 409-431, VCH (1995)]. Because the producible optically active amino acid is limited due to its substrate specificity, however, an optically active amino acid corresponding to 5-substituted hydantoin compound is not always generated. For example,
Microbacterium liquefaciens
AJ3940 strain (formerly classified under Flavobacterium sp.) that affords L-tryptophan in a high yield from 5-indolylmethylhydantoin (racemate) acts well on 5-substituted hydantoin having an aromatic ring, and can generate many kinds of L-enantiomer of aromatic amino acids such as L-phenylalanine, L-tyrosine and the like. However, since it does not act at all on 5-methylhydantoin, 5-sec-butylhydantoin, 5-carboxymethylhydantoin or 5-carboxyethylhydantoin, and does not produce the corresponding L-alanine, L-isoleucine, L-aspartic acid or L-glutamic acid, it is known to be specific to compounds having an aromatic ring [
Agric. Biol. Chem.,
vol. 51, p. 729 (1987)].
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide an industrial method for producing optically active lysine derivatives represented by the aforementioned formulas (3) and (5), which are useful as pharmaceutical intermediates.
The present inventors have conducted intensive studies in an attempt to solve the aforementioned problems and found a completely novel reaction sequence industrially superior as a method for producing compounds of the aforementioned formulas (3) and (5). To be specific, it has been found that the aforementioned object can be achieved by the process including protecting an amino group and, where necessary, a carboxyl group of optically active 2-amino-6-methyl-6-nitroheptanoic acid with a protecting group, after which nitro group is reduced to synthesize a 6,6-dimethyl lysine derivative of the formula (3), and further by reacting the 6,6-dimethyl lysine derivative with an acetic acid derivative to synthesize an optically active lysine derivative of the formula (5).
More particularly, the present invention provides the following.
[1] A method for producing an optically active lysine derivative of the formula (5)
wherein
* means an asymmetric carbon atom,
P
1
and P
2
are each independently an amino-protecting group or hydrogen atom where P
1
and P
2
are not hydrogen atoms at the same time, or P
1
and P
2
in combination show an amino-protecting group,
R
1
is alkyl group having 1 to 6 carbon atoms or aralkyl group having 7 to 12 carbon atoms, and
P
5
is a hydrogen atom or carboxyl-protecting group or a salt thereof, which method comprises the steps of (1) protecting an amino group or an amino group and a carboxyl group of optically active 2-amino-6-methyl-6-nitroheptanoic acid of the formula (1)
wherein * is as defined above, or a salt thereof, with a protecting group to give an optically active amino acid derivative of the formula (2)
wherein *, P
1
and P
2
are as defined above and P
3
is a hydrogen atom or carboxyl-protecting group,
(2) reducing a nitro group of the derivative of the formula (2) to give an optically active 6,6-dimethyl lysine derivative of the formula (3)
wherein *, P
1
and P
2
are as defined above and P
4
is a hydrogen atom or carboxyl-protecting group, or a salt thereof, and
(3) reacting the derivative of the formula (3) or a salt thereof with an acetate derivative of the formula (4)
wherein Y
1
is a leaving group and R
1
is as defined above.
[2] The method of [1], wherein the reduction is a catalytic reduction using a transition metal catalyst and metallic sulfate.
[3] The method of [1], wherein the reduction is a catalytic reduction using a palladium catalyst and ferrous sulfate.
[4] The method of [1], wherein either P
1
or P
2
is a tert-butoxycarbonyl group and the other is a hydrogen atom, P
3
, P
4
and P
5
are methyl groups and R
1
is a tert-butyl group.
[5] A method for producing an optically active 6,6-dimethyl lysine derivative of the aforementioned formula (3) or a salt thereof, which method comprises protecting an amino group or an amino group and a carboxyl group of optically active 2-amino-6-methyl-6-nitroheptanoic acid of the above-mentioned formula (1) or a salt thereof with a protecting group to give an optically active amino acid derivative of the above-mentioned formula (2), and reducing a
Izawa Kunisuke
Naito Masaki
Nakazawa Masakazu
Onishi Norimasa
Takahashi Daisuke
Ajinomoto Co. Inc.
Shah Mukund J.
Tucker Zachary C.
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