Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
1999-09-12
2003-10-28
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S035000, C560S038000, C560S157000, C560S161000, C560S162000, C562S422000, C568S805000, C568S030000, C568S307000
Reexamination Certificate
active
06639094
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing &agr;-amino-dihalogenated methyl ketone derivatives from N-protected &agr;-amino acid esters.
The present invention also relates to a process for producing &bgr;-amino-&agr;-hydroxycarboxylic acid derivatives from the &agr;-amino-dihalogenated methyl ketone derivatives.
It was reported that &agr;-amino-dihalogenated methyl ketone derivatives can be easily converted into &bgr;-amino-&agr;-hydroxycarboxylic acid derivatives by hydrolysis in the presence of a base (see J.P. KO-KAI No. Hei 10-59909). &bgr;-Amino-&agr;-hydroxycarboxylic acid derivatives obtained by this reaction are important compounds as intermediates for inhibitors of enzymes, such as HIV protease and renin or for some anticancer drugs (see, for example, Chem. Pharm. Bull. 1992, 40, 2251, J. Med. Chem. 1990, 33, 2707, Biochem. Pharmacol. 1983, 32, 1051, and Bull. Cancer 1993, 80, 326).
As for processes for producing &agr;-amino-dihalogenated methyl ketone derivatives, it is described in an Example of J.P. KOKAI No. Hei 10-59909 that an N-carbamate-protected &agr;-amino-dichloromethyl ketone derivative is produced by treating an &agr;-amino-monochloromethyl ketone derivative, in which the amino group is protected with a carbamate-type protecting group, with sulfuryl chloride. However, this process is unsuitable for the production of a compound having a protecting group (such as t-butoxycarbonyl group) for an amino group, which is unstable against acids, because a strong acid is formed in the reaction system. In addition, the production of N-carbamate-protected &agr;-amino-monochloromethyl ketone derivatives used as the starting material is not always easy.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide an economical, efficient process for producing &agr;-amino-dihalogenated methyl ketone derivatives and &bgr;-amino-&agr;-hydroxycarboxylic acid derivatives on an industrial scale.
After intensive investigations made for the purpose of solving the above-described problems, the inventors have found that &agr;-amino-dihalogenated methyl ketones can be easily obtained by reacting an N-protected &agr;-amino acid ester with a dihalomethyl lithium. The present invention has been completed on the basis of this finding.
Namely, the present invention provides a process for producing &agr;-amino-dihalogenated methyl ketone derivatives of the following general formula (3):
wherein B
3
and B
4
independently represent a hydrogen atom or a protecting group for an amino group, or B
3
and B
4
together form an imine-type protecting group; A represents a hydrogen atom, an unsubstituted or substituted 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, or a group corresponding thereto which contains a hetero atom in the carbon skeleton; and X
1
and X
2
independently represent a chlorine atom or a bromine atom,
which comprises the step of reacting an N-protected &agr;-amino acid ester of following general formula (1):
wherein B
1
and B
2
independently represent a hydrogen atom or a protecting group for an amino group, or B
1
and B
2
together form an imine-type protecting group (with the proviso that both B
1
and B
2
cannot be hydrogen atom at the same time), R
1
represents an unsubstituted or substituted lower alkyl group, aralkyl group or aryl group, and A is as defined above,
with a dihalomethyl lithium of general formula (2)
wherein X
1
and X
2
are as defined above.
The present invention also provides a process for producing &bgr;-amino-&agr;-hydroxycarboxylic acid derivatives of general formula (4):
wherein B
5
and B
6
independently represent a hydrogen atom or a protecting group for an amino group, or B
5
and B
6
together form an imine-type protecting group, and A represents hydrogen atom, an unsubstituted or substituted 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, or a group corresponding thereto which contains a hetero atom in the carbon skeleton,
which comprises the steps of hydrolyzing an &agr;-amino-dihalogenated methyl ketone derivative in the presence of a base and protecting or not protecting the amino group.
BEST MODE FOR CARRYING OUT THE INVENTION
In the formulae in the present invention, B
1
and B
2
independently represent a hydrogen atom or a protecting group for an amino group, or B
1
and B
2
together form an imine-type protecting group. However, both B
1
and B
2
cannot be hydrogen atom at the same time.
The protecting group for amino group is not particularly limited. For example, protecting groups described in Protecting Groups in Organic Chemistry, 2
nd
Edition (John Wiley & Sons, Inc. 1991) are usable. The protecting groups are, for example, carbamate-type protecting groups such as a methoxycarbonyl group, a ethoxycarbonyl group, a t-butoxycarbonyl group, a benzyloxycarbonyl group, and a fluorenylmethoxycarbonyl group; acyl-type protecting groups such as an acetyl group and a benzoyl group; sulfonyl-type protecting groups, such as a methanesulfonyl group, a benzenesulfonyl group, and a p-toluenesulfonyl group; alkyl-type protecting groups, such as a benzyl group and a p-methoxybenzyl group; dialkyl-type protecting groups, such as, a dibenzyl group; silyl-type protecting groups, such as, a trimethylsilyl group; and imine-type protecting groups, such as, a diphenylmethylene group, a phenylmethylene group, and a p-methoxyphenylmethylene group. Among them, carbamate-type protecting groups are preferred because they can be easily removed.
When B
1
and B
2
together form an imine-type protecting group, N-protected &agr;-amino acid esters of general formula (1) can be represented by following general formula (6):
wherein R
2
and R
3
independently represent an unsubstituted or substituted aryl group or lower alkyl group or hydrogen atom, or R
2
and R
3
may be bonded together directly or via a suitable group to form a ring structure.
Examples of the ring structures include the following structures (16) and (17):
[Formulae (16) and (17) include both protecting group formed by R
2
and R
3
and the imine structure].
Preferably R
2
and R
3
each represent an unsubstituted or substituted aryl group or one of them represents an unsubstituted or substituted aryl group and the other represents a hydrogen atom.
The unsubstituted or substituted lower alkyl group, aralkyl group or aryl group represented by R
1
in the formula in the present invention include unsubstituted or substituted, linear or branched, saturated alkyl groups having 1 to 8 carbon atoms, unsubstituted or substituted aralkyl groups having 7 to 15 carbon atoms, and unsubstituted or substituted aryl groups having 6 to 14 carbon atoms. R
1
is preferably an unsubstituted or substituted lower alkyl group, or aralkyl group. R
1
is particularly preferably a linear or branched, saturated alkyl group having 1 to 3 carbon atoms, i.e. methyl group, ethyl group, propyl group, isopropyl group or unsubstituted or substituted benzyl group. When the benzyl group is substituted, the substituent is an alkoxyl group (preferably having 1 to 7 carbon atoms), nitro group, an alkyl group (preferably having 1 to 6 carbon atoms), a halogen atom or the like.
A in the formulae in the present invention represents a hydrogen atom, an unsubstituted or substituted 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, or a corresponding group which further contains a hetero atom in the carbon skeleton. When those groups have a substituent, the substituent is an alkoxyl group (preferably having 1 to 7 carbon atoms), a nitro group, an alkyl group (preferably having 1 to 6 carbon atoms), a halogen atom or the like.
Such a group can be introduced into the compound from, e.g., an amino acid. For example, when A is hydrogen atom, it can be introduced by using glycine as the starting material. In the same way, a meth
Hirose Naoko
Izawa Kunisuke
Nakano Takashi
Nakazawa Masakazu
Onishi Tomoyuki
Ajinomoto Co. Inc.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Richter Johann
Zucker Paul A.
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