Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2002-04-10
2004-10-19
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S555000, C562S564000
Reexamination Certificate
active
06806384
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a production method of an optically active &bgr;-amino-&agr;-hydroxycarboxylic acid. Additionally, the present invention relates to a production method of an optically active N-carbamate type protected &bgr;-amino-&agr;-hydroxycarboxylic acid.
BACKGROUND OF THE INVENTION
&bgr;-Amino-&agr;-hydroxycarboxylic acid of the formula (1)
wherein A is alkyl group having 1 to 10 carbon atoms, aryl group having 6 to 15 carbon atoms or aralkyl group having 7 to 20 carbon atoms, each optionally having substituent(s) and optionally having heteroatom(s) in the carbon skeleton, and * shows an asymmetric carbon atom, is known to be useful as an intermediate for HIV protease inhibitors, carcinostatics and the like (see, for example, B. Munoz et al., Bioorg. Med. Chem., 1994, 2 (10), 1085, R. Nishizawa et al., J. Med. Chem., 1977, 20 (4), 510).
Furthermore, as the production method of &bgr;-amino-&agr;-hydroxycarboxylic acid of the formula (1), for example, a production method shown by Scheme 1 in J. Med. Chem., 1977, 20 (4), 510 is known.
According to the above-mentioned method, however, highly toxic potassium prussiate needs to be used. Moreover, this method shows poor stereoselectivity, and the &bgr;-amino-&agr;-hydroxycarboxylic acid is obtained as a diastereomeric mixture. Accordingly, this method is not necessarily an industrially suitable production method.
As a production method of &bgr;-amino-&agr;-hydroxycarboxylic acid derivative, moreover, a production method shown by Scheme 2 in Synlett, 1996, 6, 585 is known.
The above-mentioned method requires expensive ruthenium catalyst, caesium carbonate, and also explosive sodium periodate. Accordingly, this production method is not necessarily an industrially suitable production method.
SUMMARY OF THE INVENTION
Accordingly, the present invention aims at providing industrial methods of producing an optically active &bgr;-amino-&agr;-hydroxycarboxylic acid and an optically active N-carbamate type protected &bgr;-amino-&agr;-hydroxycarboxylic acid.
The present inventors have intensively studied in an attempt to solve the aforementioned problems and obtained a specific &bgr;-amino-&agr;-hydroxycarboxylic acid by reacting an N-carbamate type protected &bgr;-aminoepoxide with an acid to give specific 5-hydroxymethyl-oxazolidin-2-one, which is oxidized in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (hereinafter sometimes to be abbreviated as TEMPO) and hypochlorite to give a specific 2-oxo-5-oxazolidinecarboxylic acid, which is then reacted with a base. Furthermore, they have found that a series of reactions proceed stereoselectively to produce the objective compound having a high optical purity in a high yield.
The present invention is based on such findings and provides the following.
A production method of &bgr;-amino-&agr;-hydroxycarboxylic acid of the formula (1)
wherein A is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, each optionally having substituent(s) and optionally having heteroatom(s) in the carbon skeleton, and * shows an asymmetric carbon atom, provided that, when the configuration of the 2-position and 3-position of &bgr;-amino-&agr;-hydroxycarboxylic acid of the formula (1) is (2R,3S), (2S,3R), (2S,3S) or (2R,3R), the configuration of the 2-position and 3-position of N-carbamate protected &bgr;-aminoepoxide of the following formula (2) is (2S,3S), (2R,3R) (2R,3S) or (2S,3R), respectively, the configuration of the 4-position and 5-position of the oxazolidin-2-one derivative of the following formula (3) is (4S, 5R), (4R, 5S), (4S, 5S) or (4R, 5R) respectively, and the configuration of the 4-position and 5-position of oxazolidin-2-one derivative of the following formula (4) is (4S, 5R), (4R, 5S), (4S, 5S) or (4R, 5R), respectively: which method comprises the following steps (a)-(c)
(a) treating an N-carbamate protected &bgr;-aminoepoxide of the formula (2)
wherein R
1
is a tert-butyl group or a benzyl group, and A and * are as defined above, with an acid to give an oxazolidin-2-one derivative of the formula (3)
wherein A and * are as defined above,
(b) oxidizing the oxazolidin-2-one derivative of the formula (3) in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy and hypochlorite to give an oxazolidin-2-one derivative of the formula (4)
wherein A and * are as defined above,
(c) treating the oxazolidin-2-one derivative of the formula (4) with a base to give the &bgr;-amino-&agr;-hydroxycarboxylic acid of the formula (1).
A production method of an N-carbamate protected &bgr;-amino-&agr;-hydroxycarboxylic acid of the formula (5)
wherein R
2
is a lower alkyl group, a benzyl group or a fluorenylmethyl group, * shows an asymmetric carbon atom and A is as defined above, which method comprises obtaining &bgr;-amino-&agr;-hydroxycarboxylic acid of the formula (1) according to the above-mentioned production method, and protecting an amino group of the &bgr;-amino-&agr;-hydroxycarboxylic acid with a carbamate type protecting group, provided that when the configuration of the 2-position and 3-position of the &bgr;-amino-&agr;-hydroxycarboxylic acid of the formula (1) is (2R,3S), (2S,3R), (2S,3S) or (2R,3R), the configuration of the 2-position and 3-position of the N-carbamate protected &bgr;-amino-&agr;-hydroxycarboxylic acid of the formula (5) is (2R,3S), (2S,3R), (2S,3S) or (2R,3R), respectively.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is explained in detail in the following.
In the formulas of the present invention, A is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, each optionally having substituent(s) and optionally having heteroatom(s) in the carbon skeleton, or a hydrogen atom. When A has a substituent, the substituent is free of any particular limitation as long as it does not adversely affect the reaction in the present invention. For example, alkoxy group (preferably having 1 to 7 carbon atoms), nitro group, alkyl group (preferably having 1 to 7 carbon atoms), halogen group and the like are mentioned.
The group containing a heteroatom (nitrogen, oxygen atom and the like) in the carbon skeleton is exemplified by 4-benzyloxyphenylmethyl group and the like.
Such group can be introduced using an amino acid as a starting material. For example, when A is a methyl group, alanine is used, when it is an isopropyl group, valine is used, when it is a 2-methylpropyl group, leucine is used, when it is a 1-methylpropyl group, isoleucine is used, when it is a benzyl group, phenylalanine is used, when it is a cyclohexylmethyl group, cyclohexylalanine is used, and when it is a phenyl group, phenylglycine is used as a starting material for the introduction.
In addition, A may be a group introduced by the use, as a starting material, of an amino acid having a protected functional group of the side chain of the amino acid, such as 0-benzyl tyrosine and the like.
Furthermore, A is not limited to a group introduced from a starting material derived from a natural amino acid, and may be a group introduced from a starting material derived from a non-natural amino acid (e.g., phenyl group, cyclohexylmethyl group).
A is particularly preferably a benzyl group.
In the formulas of the present invention, R
1
is a tert-butyl group or a benzyl group. R
1
is particularly preferably a tert-butyl group.
In the formulas of the present invention, R
2
is a lower alkyl group, a benzyl group or a fluorenylmethyl group. The lower alkyl group is an alkyl group having 1 to 8 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms. For example, methyl group, ethyl group, tert-butyl group and the like are mentioned. R
2
is particularly preferably a tert-butyl group.
The N-carbamate type protected &bgr;-aminoepoxide of the formula (2) used as a starting material in the present invention is a known compound and can be produced by a known method comprising, for example, reducing N-carbamat
Oka Sachiko
Onishi Tomoyuki
Otake Yasuyuki
Takahashi Daisuke
Ajinomoto Co. Inc.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Richter Johann
Zucker Paul A.
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