Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-22
2002-04-02
Powers, Fiona T. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C562S039000, C560S070000, C558S345000, C558S390000
Reexamination Certificate
active
06365754
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing erythro-3-amino-2-hydroxybutyric acid derivatives and esters thereof, which are useful for producing medicines, agricultural chemicals and the like, and relates to a process for producing erythro-3-amino-2-hydroxybutyronitrile derivatives, which are synthetic intermediates thereof.
3-Amino-2-hydroxybutyronitrile derivatives and 3-amino-2-hydroxybutyric acid derivatives, which are derived from them, are used as synthetic intermediates of medicines, agricultural chemicals and the like, and many processes for producing them have been reported. Among them, as processes for producing nitrile derivatives by erythro selective cyanation of &agr;-aminoaldehyde derivatives, there have been disclosed (1) a process wherein N,N-dibenzylamino-L-phenylalaninal is reacted with trimethylsilyl cyanide in the presence of boron trifluoride etherate or zinc chloride in methylene chloride (Tetrahedron Lett., 29, 3295 (1988), WO 95/14653), (2) a process wherein aminoaldehyde derivatives are reacted with cyanohydrin derivatives in the presence of a metal compound, a base or an acid (Japanese Laid-open Patent Publication No. 231280/1998) and the like.
However, these processes for synthesis have the following problems in view of industrialization. Namely, the process (1) is unfit for large-scale synthesis since trimethylsilyl cyanide to be used as a cyanation agent is expensive and it is necessary to adjust reaction temperature to −10° C. or lower in order to obtain high selectivity. The process (2) is also unfit for large-scale synthesis since expensive aluminium reagents such as dichloroethylaluminium and triisobutylaluminium are required in order to carry out the reaction in high erythro selectivity.
SUMMARY OF THE INVENTION
Doing studies precisely to solve the above-mentioned problems, the present inventors found a process wherein erythro 3-amino-2-hydroxybutyric acid derivatives having desired configuration can be obtained simply and selectively using 2-aminoaldehyde derivatives as raw materials to accomplish the present invention.
A The present invention provides a process for producing an erythro-3-amino-2-hydroxybutyric acid derivative characterized in that a 2-aminoaldehyde derivative represented by the general formula [I]
(wherein R
1
is a straight-chain, branched or cyclic alkyl group having one to six carbon atoms, an alkylthio group or an arylthio group having one to eight carbon atoms, or a substituted or unsubstituted aryl group, P
1
and P
2
are, the same or different, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aralkyloxycarbonyl group, a substituted or unsubstituted arylcarbonyl group, or a substituted or unsubstituted arylsulfonyl group, and P
1
and P
2
can join each other to form a substituted or unsubstituted phthaloyl or naphthaloyl ring)
is reacted with a metal cyanide in the presence of an acid chloride and/or an acid anhydride or reacted with an organic cyanide in the presence of a Lewis acid to give stereoselectively an erythro-3-amino-2-hydroxybutyronitrile derivative represented by the general formula [II]
(wherein R
1
, P
1
and P
2
are the same as mentioned above, and R
2
is an alkylcarbonyl group, or a substituted or unsubstituted arylcarbonyl group), and then the nitrile derivative is treated with an acid in water or in a water-containing solvent to convert it into an erythro-3-amino-2-hydroxybutyric acid derivative represented by the general formula [III]
(wherein R
1
is the same as mentioned above, R
3
is hydrogen, Q
1
and Q
2
are, the same or different, hydrogen, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted arylsulfonyl group, and Q
1
and Q
2
can join each other to form a substituted or unsubstituted phthaloyl or naphthaloyl ring),
or the nitrile derivative is treated with an acid in an alcoholic solvent represented by the general formula of R
3
OH to convert it into an ester of the butyric acid represented by the above general formula [III] (in each formula, R
1
, Q
1
and Q
2
are the same as mentioned above, and R
3
is a straight-chain, branched or cyclic alkyl group having one to six carbon atoms, or a substituted or unsubstituted aralkyl group).
The reaction steps of the present invention are illustrated by the following reaction formula.
First, the first step, namely the cyanation is described.
When the 2-aminoaldehyde derivative whose amino group is protected by the bulky substituent represented by the formula [I] is cyanated, the 3-amino-2-hydroxybutyronitrile derivative [II] having erythro configuration is stereoselectively obtained. This cyanation is classified into the following two processes depending on the kind of cyanation agent to be used.
(a) When the cyanation agent is the metal cyanide, the reaction is carried out in the presence of the acid chloride and/or the acid anhydride in a two-phase solvent containing a phase-transfer catalyst.
(b) When the cyanation agent is the organic cyanide, the reaction is carried out in the presence of the Lewis acid in an aprotic solvent.
Examples of the metal cyanide to be used in the process (a) are sodium cyanide, potassium cyanide, magnesium cyanide, silver cyanide, copper cyanide and the like. Sodium cyanide and potassium cyanide are preferably used. An amount of the metal cyanide to be used is preferably one to three equivalents, more preferably one to two equivalents to a substrate (i.e. the 2-aminoaldehyde derivative [II], the same definition is applied hereinafter). Use of an excess metal cyanide does not affect a yield, but it is economically disadvantageous.
The acid chloride and/or the acid anhydride existing in the solvent in the process (a) acts as a capturing agent of alkoxide oxygen formed when the metal cyanide is added to the aldehyde as shown in the later reaction formula (A). Examples of the acid chloride are acetyl chloride, acetyl bromide, propionyl chloride, propionyl bromide, valeryl chloride, t-butylacetyl chloride, trimethylacetyl chloride, benzoyl chloride, benzoyl bromide, p-toluyl chloride, p-anisoyl chloride and the like. Acetyl chloride and benzoyl chloride are preferably used. Examples of the acid anhydride are acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, isovaleric anhydride, trimethylacetic anhydride, benzoic anhydride, p-toluic anhydride, p-anisic anhydride and the like. Acetic anhydride and benzoic anhydride are preferably used. An amount of the acid chloride and/or the acid anhydride to be used is preferably one to three equivalents, more preferably one to two equivalents to the substrate.
Unless alkoxide oxygen of a reactive intermediate formed by stereoselective addition of the cyanide to the aldehyde, i.e. the erythro-3-amino-2-hydroxybutyronitrile derivative is successively captured immediately after generation, addition of the cyanide to the aldehyde and elimination of the cyanide from the above-mentioned reactive intermediate, which is the resulting adduct, occur reversibly and racemization proceeds remarkably as shown in the following reaction formula (B). Accordingly, it is effective to add the capturing agent in order to obtain the product in high erythro configuration selectivity.
A preferred reaction solvent of the process (a) is the two-phase solvent consisting of water and a water-insoluble organic solvent. Examples of the water-insoluble organic solvent are hydrocarbon solvents such as n-hexane, benzene and toluene; ester solvents such as methyl acetate, ethyl acetate, propyl acetate and butyl acetate; ether solvents such as diethyl ether, methyl t-butyl ether and ethyl t-butyl ether; halogen solvents such as dichloromethane, chloroform and 1,2-dichloroethane; and mixed solvents thereof. Ethyl acetate, toluene, dichloromethane, 1,2-dichloroethane and methyl t-butyl ether are preferably used.
Reaction temperature of the process (a) is preferably 0 to 50° C., more preferably 0° to 25° C. The reac
Furukawa Yoshiro
Hinoue Kazumasa
Yaegashi Keisuke
Armstrong Westerman & Hattori, LLP
Daiso Co. Ltd.
Powers Fiona T.
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