Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-07-25
2002-12-31
Davis, Brian J. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S271000, C564S272000, C564S275000, C564S278000, C564S415000, C564S468000, C564S489000
Reexamination Certificate
active
06500985
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing an &agr;-aminohalomethylketone from an N-protected &agr;-amino acid ester with an amino group protected as an imine via a novel N-protected-&agr;-aminohalomethylketone.
Further, the invention relates to a process for producing an N-protected-&agr;-aminohalomethylketone, a &bgr;-aminoalcohol, an N-protected-&bgr;-aminoalcohol or an N-protected-&bgr;-aminoepoxide derived from the &agr;-aminohalomethylketone.
Still further, the invention relates to an N-carbamate-protected-&agr;-aminohalomethylketone, an N-carbamate-protected-&bgr;-aminoalcohol or an N-carbamate-protected-&bgr;-aminoepoxide derived from the &agr;-aminohalomethylketone.
An &agr;-aminohalomethylketone (compound of formula (3) to be described later) and its salt can be converted into peptidylhalomethylketones by the method which is ordinarily used in the peptide synthesis, and they are compounds useful as intermediates for synthesis of various peptidylhalomethylketones which are known as serine protease inhibitors (refer to, for example, W. Brandt et al., Int. J. Peptide Protein Res. 1995, 46, 73).
In addition, they are reported to be useful as intermediates for synthesis of HIV protease inhibitors (refer to, for example, J. Med. Chem. 1990, 33, 1285).
Furthermore, an N-protected-&agr;-aminohalomethylketone (compound of formula (7) or (10) to be described later), a &bgr;-aminoalcohol (compound of formula (13) to be described later) and an N-protected-&bgr;-aminoalcohol (compound of formula (8), (11) or (14) to be described later) and an N-protected-&bgr;-aminoepoxide (compound of formula (9), (12) or (15) to be described later) derived therefrom are likewise known to be important compounds as medical intermediates of HIV protease inhibitors.
An &agr;-aminohalomethylketone has been so far produced by deprotecting an N-protected-&agr;-aminohalomethylketone (refer to, for example, S. Fittkau et al., J. Prakt. Chem. 1986, 529).
As a method for producing N-protected-&agr;-aminohalomethylketones, for example, a method has been known in which N-protected &agr;-amino acid ester is reacted with a metallic enolate formed from an &agr;-haloacetic acid and decarboxylation is conducted (refer to WO 96/23756).
In this method, however, as described in Examples of WO 96/23756, a costly Grignard reagent or an organolithium reagent has to be used in an amount of more than approximately 4 equivalents based on N-protected amino acid ester.
A method is also known in which production is conducted such that an alanine ester having an amino group protected with a dibenzyl group is reacted with a halomethyllithium (refer to J. Barluengaetal., J. Chem. Soc., Chem. Commun. 1994, 969).
In this method, however, groups other than a dibenzyl group are not studied as a protecting group of the amino group, and a method in which elimination of the dibenzyl group is conducted while maintaining a halogenated ketone moiety is unknown. Thus, the method cannot be used as a method for producing an &agr;-aminohalomethylketone.
A method is also known in which production is conducted such that a carbamate site of an amino acid ester having an amino group protected with a carbamate group is further protected with a trialkylsilyl group, and then reacted with a halomethyllithium (refer to Japanese Patent Laid-Open Nos. 99,947/1996 and 99,959/1996).
Nevertheless, in this method also, as described in Examples of Japanese Patent Laid-Open Nos. 99,947/1996 and 99,959/1996, a costly organolithium reagent has to be used in an amount of approximately 2.2 equivalents based on N-protected amino acid ester. Further, the protecting group of the amino group used in Examples thereof is only a methoxycarbonyl group. However, a method in which elimination of the methoxycarbonyl group is conducted while maintaining a halogenated ketone moiety is unknown. Thus, it is unclear whether the method can be used in the production of an &agr;-aminohalomethylketone.
DISCLOSURE OF THE INVENTION
The invention aims to provide a process for producing an &agr;-aminohalomethylketone and its related compounds which is suited for industrial production, economical and efficient.
The present inventors have assiduously conducted investigations to solve the problems, and have consequently found that a novel N-protected-&agr;-aminohalomethylketone is obtained in high yield by protecting an amino group of an &agr;-amino acid ester as an imine (Schiff base) and then reacting it with a halomethyllithium.
Further, it has been found that this N-protected-&agr;-aminohalomethylketone is easily deprotected through the treatment with an acid to form an &agr;-aminohalomethylketone.
This &agr;-aminohalomethylketone can be converted into an N-protected-&bgr;-aminoepoxide via an N-protected-&agr;-aminohalomethylketone and an N-protected-&bgr;-aminoalcohol.
Moreover, the inventors have found a process for producing an N-protected-&bgr;-aminoepoxide from an &agr;-aminohalomethylketone via a &bgr;-aminoalcohol and an N-protected-&bgr;-aminoalcohol.
Besides, the inventors have found a method in which an amino group of an &agr;-aminohalomethylketone is protected with a carbamate group (especially a tert-butoxycarbonyl group).
The inventors have completed the invention based on these findings.
That is, the invention provides a process for producing an &agr;-aminohalomethylketone represented by formula (3)
wherein
A represents an optionally substituted alkyl group having 1 to 10 carbon atoms, an optionally substituted aryl group having 6 to 15 carbon atoms, an optionally substituted aralkyl group having 7 to 20 carbon atoms, or a group in which heteroatom is contained in these carbon skeletons, and
X represents a halogen atom or its salt, which comprises reacting an N-protected-&agr;-amino acid ester represented by formula (1)
wherein
R
1
and R
2
, independently from each other, represent an optionally substituted aryl group or lower alkyl group, or a hydrogen atom,
R
3
represents an optionally substituted lower alkyl group, aralkyl group or aryl group, and
A is as defined above,
provided R
1
and R
2
may together form a ring structure with a halomethyllithium, and then treating this with an acid.
REFERENCES:
patent: 4638080 (1987-01-01), Raizon et al.
patent: 5481011 (1996-01-01), Chen et al.
patent: WO 00/44706 (2000-08-01), None
patent: WO 98/45271 (1998-10-01), None
Greene, Theodora W., et al, “Protective Groups in Organic Synthesis”, Second Edition, John Wiley & Sons, Inc., 1991, pp. 368-371.
Hirose Naoko
Izawa Kunisuke
Nakano Takashi
Nakazawa Masakazu
Onishi Tomoyuki
Ajinomoto Co. Inc.
Davis Brian J.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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