Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-13
2002-01-15
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C568S332000, C568S345000, C568S346000, C562S433000, C562S452000
Reexamination Certificate
active
06339159
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method for producing optically active &agr;-aminonitriles and &agr;-amino acids. More specifically, the invention relates to a novel method, which enables the synthesis of optically active &agr;-aminonitriles followed by the synthesis of optically active &agr;-amino acids in high yield and high stereoselectivity.
BACKGROUND ART
Various &agr;-amino acids and &agr;-aminonitriles, as intermediates thereof, are useful substances in various fields such an pharmaceuticals, agricultural chemicals, toiletries and other such chemical products, an well an in the fold of functional polymers.
With respect to the synthesis of these useful substances, lately, there have been some reports on the method of catalytic asymmetric synthesis of &agr;-aminonitriles.
However, since such formerly reported methods of asymmetric synthesis use isolated and purified imines, in most cases, problems such as the limit in their application to imines derived from unstable aliphatic aldehydes, and low asymmetric yield exist.
Therefore, in the present invention, the object is to provide a solution to the above-mentioned problems of the conventional asymmetric synthesis, and to provide a novel method which enables the synthesis of optically active &agr;-aminonitriles, and further, the synthesis of optically active &agr;-amino acids, in high asymmetric yield, without going through imines, even when using unstable aldehydes as starting materials.
DISCLOSURE OF INVENTION
The present invention firstly provides, as a means to solve the above-mentioned problems, a method for producing optically active &agr;-aminonitriles, which comprises reacting an aldehyde compound, an amino compound and hydrogen cyanate in the presence of a chiral zirconium catalyst obtained by mixing a zirconium alkoxide with at least one optically active binaphthol compound.
Also, the present invention secondly provides a method for producing optically active &agr;-aminonitriles, wherein the optically active binaphthol compound is at least one compound selected from 3,3′-dibromo-1,1′-bi-2-naphthol and 6,6′-dibromo-1,1′-bi-2-naphthol. The invention thirdly provides a method for producing optically active &agr;-aminonitrile, wherein the reaction in conducted in the presence of an imidazole compound.
Further, the present invention fourthly provide the method for producing optically active &agr;-aminonitriles according to any one of the first to third inventions, wherein an aldehyde compound represented by the formula
R
1
CHO
(wherein R
1
represents a hydrocarbon group which may include one or more substituents) in reacted with an amino compound represented by the formula
(wherein R
2
represents a hydrogen atom or a hydrocarbon group which may include a substituent) and hydrogen cyanate to produce an optically active &agr;-aminonitrile represented by the formula
(wherein R
1
and R
2
are as described above).
Furthermore, the present invention fifthly provides a method for producing an optically active &agr;-amino acid, which comprises converting the cyano group of the optically active &agr;-aminonitrile produced by any one of the methods of the first to fourth inventions to a carboxyl group or its derivative.
Also, the invention provides, sixthly, a method for producing an optically active &agr;-amino acid ester, which comprises converting the cyano group of the &agr;-aminonitrile obtained by the method of the fourth invention to an ester group, followed by its oxidative decomposition to form an optically active &agr;-amino acid ester represented by the formula
(wherein R and R
1
are hydrocarbon groups which may include one or more substituents).
Seventhly, the present invention provides a method for producing a pipecolic acid outer represented by the formula
(wherein R is as described above) which comprises the deprotection and protection of the phenolic hydroxyl group of the &agr;-aminonitrile of the following formula
(wherein R
3
represents a protecting group), obtained by the process of the fourth invention to form the compound represented by the formula
(wherein R
4
represents a protecting group), followed by cyclization and esterification to form the ester compound represented by the formula
(wherein R
4
is an described above, and R represents a hydrocarbon group which my contain one or more substituent), which is then oxidatively decomposed.
The invention described above enables new development in the long-known Strecker synthesis. That is, although the Strecker synthesis is a method for producing synthetic amino acids wherein &agr;-aminonitriles are synthesized by the main-component condensation of ammonia, aldehyde and hydrogen cyanate, development of this method as a method of asymmetric synthesis has been an unexplored task. Under the situation, the inventors of the prevent invention have so far proposed the asymmetric Strecker-type reaction using trialkyltin cyanide as the cyano source (Japanese Patent Provisional Publication No. 255,730/1999). In the present invention, the formation of &agr;-aminonitriles by asymmetric synthesis using hydrogen cyanate as a cyano source is enabled.
In other words, the method for producing the optically active &agr;-aminonitrile of the present invention enables the realization of the asymmetric synthesis of &agr;-aminonitriles in high yield, directly from aldehyde compounds, amino compounds and hydrogen cyanate without going through an imine as in formerly known methods.
Further, the present invention also enables the production of optically active &agr;-amino acid in high yield.
BEST MODE FOR CARRYING OUT THE INVENTION
The best mode for carrying out the invention described above in as described bellow.
Basically, in the invention,
(I) an aldehyde compound,
(II) an amino compound, and
(III) hydrogen cyanate (HCN),
are used as the starting materials, reacted in the liquid phase in the presence of
(IV) a chiral zirconium catalyst to asymmetrically synthesize &agr;-aminonitrile.
The starting materials, the aldehyde compound (I) and the amino compound (II), maybe aldehydes and amines of various structures, such an aliphatic, alicyclic, aromatic, araliphatic or heterocyclic aldehydes and amines. The method of the present invention is applicable to unstable substances such as aliphatic aldehydes which were deemed to be unusable in formerly known asymmetric synthesis of &agr;-aminonitriles, which were performed via imines.
In the aldehyde compound (I), an aldehyde group (—CHO) may be bound to primary, secondary or tertiary carbon atoms, CH
2
—, CH— or C—. Further, the amino compound (II) may be a primary amine or a secondary amine with amino groups such as NH
2
and NH. It is preferable to use a primary amine (—NH
2
) compound as the amino compound (II).
The chiral zirconium catalyst (IV) used in the present invention is obtained by mixing a zirconium alkoxide of the following formula
Zr(OR)
4
(wherein R in a hydrocarbon group which may contain one or more substituents), with an optically active binaphthol compound. The hydrocarbon group constituting the alkoxy group (—OR) of the zirconium alkoxide may be aliphatic, alicyclic aromatic or other hydrocarbon groups, but is preferably an aliphatic hydrocarbon group such as an alkyl group. Appropriate examples of such alkyl group include lower alkyl groups such as a methyl group, an ethyl group, an n-propyl group (
n
Pr), an isopropyl group (
i
Pr), an n-butyl group (
n
Bu), an isobutyl group (
i
Bu), a tert-butyl group (
t
Bu), an n-pentyl group (
n
Pent), an isopentyl group (
i
Pent) and an n-hexyl group (
n
Hex).
The four alkoxide group (—OR) constituting the zirconium alkoxide (Zr(OR)
4
) may all be the same or different.
The optically active binaphthol compound to be mixed with the zirconium alkoxide may contain appropriate substituents in the naphthalene ring, and more than one optically active binaphthol compounds may be used in the mixing. Examples of the substituent are a halogen atoms such as chlorine, bromine or fluorine, alkyl groups, alkoxy groups, halo-substituted a
Ishitani Haruro
Kobayashi Shu
Covington Raymond
Japan Science and Technology Corporation
Rotman Alan L.
Wenderoth Lind & Ponack LLP
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