Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-08-31
2003-05-27
Davis, Brian (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
Reexamination Certificate
active
06570039
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing &agr;-aminohalomethyl ketones or N-protected &agr;-aminohalomethyl ketones from specified 3-oxazolidin-5-one derivatives via 5-halomethyl-5-hydroxy-3-oxazolidine derivatives.
The present invention also relates to a process for producing &bgr;-aminoalcohols, N-protected &agr;-aminoalcohols or N-protected &bgr;-aminoepoxides from the &agr;-aminohalomethyl ketones or N-protected &agr;-aminohalomethyl ketones.
The &agr;-aminohalomethyl ketones and salts thereof can be converted into peptidylhalomethyl ketones by a method usually employed in peptide synthesis. These &agr;-aminohalomethyl ketones and salts thereof are useful as intermediates for synthesizing various peptidylhalomethyl ketones known as serine protease inhibitors (see, for example, W. Brandt et al., Int. J. Peptide Protein Res. 46, 1995, 73).
It was reported that the &agr;-aminohalomethyl ketones and salts thereof are also useful as intermediates for synthesizing HIV protease inhibitors (see, for example, J. Med. Chem. 1990, 33, 1285).
It is also known that N-protected &agr;-aminohalomethyl ketones, &bgr;-aminoalcohols as well as N-protected&bgr;-aminoalcohols and N-protected &bgr;-aminoepoxides derived from them are also known to be important intermediates for HIV protease inhibitors.
&agr;-Aminohalomethyl ketones were produced by removing a protecting group from N-protected &agr;-aminohalomethyl ketones (see, for example, S. Fittkau et al., J. Prakt. Chem. 1986, 529).
For the production of N-protected &agr;-aminohalomethyl ketones, for example, there is known a process wherein an amino acid ester in which the amino group is protected is reacted with a metal enolate obtained from an &agr;-haloacetic acid and a resulting product is followed by decarboxylation (WO 96/23756).
However, in this process, about 4 equivalents or more of an expensive Grignard reagent or organic lithium reagent is necessitated for 1 equivalent of the N-protected amino acid ester as shown in Examples in WO 96/23756.
Further, a process wherein an alanine ester in which the amino group is protected with dibenzyl group is reacted with a halomethyllithium is known (see J. Barluenga et al., J. Chem. Soc., Chem. Commun. 1994, 969).
However, only dibenzyl group is discussed as the protective group for the amino group in this process, and no other protective group is described therein. In addition, because no process is known for removing the protecting group from the dibenzyl group while the halogenated ketone group is kept, the process of J. Barluenga et al. cannot be employed for the production of &agr;-aminohalomethyl ketones.
There is also known another process wherein a carbamato part of an amino acid ester in which the amino group is protected with the carbamato group is further protected with a trialkylsilyl group and then this compound is reacted with a halomethyllithium (J. P. KOKAI Nos. Hei 8-99947 and Hei 8-99959).
However, also in this process, about 2.2 equivalents of an expensive organic lithium reagent is necessitated for 1 equivalent of the N-protected amino acid ester as described in Examples in J. P. KOKAI Nos. Hei 8-99947 and Hei 8-99959. Although the protecting group for the amino group used in these Examples is only methoxycarbonyl group, no process for removing the methoxycarbonyl group while keeping the halogenated ketone group is known yet. It is not yet proved that this process can be employed for the production of &agr;-aminohalomethyl ketones.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide an economical, efficient process for producing &agr;-aminohalomethyl ketones and related compounds on an industrial scale.
After intensive investigations made for the purpose of solving the above-described problems, the inventors have found that &agr;-aminohalomethyl ketones or N-protected &agr;-aminohalomethyl ketones can be obtained in a high yield by reacting a 3-oxazolidin-5-one derivative with a halomethyllithium to form a 5-halomethyl-5-hydroxy-3-oxazolidine derivative and treating this derivative with an acid.
Namely, the present invention provides a process for producing N-protected &agr;-aminohalomethyl ketones of following general formula (3):
wherein A represents 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; B
1
represents a protecting group for the amino group; and X represents a halogen atom, &agr;-aminohalomethyl ketones of following general formula (4):
wherein A and X are as defined above,
or salts thereof, which comprises the steps of reacting a 3-oxazolidin-5-one derivative of following general formula (1):
wherein R represents an unsubstituted or substituted aryl group or lower alkyl group or hydrogen atom, and A and B
1
are as defined above with a halomethyllithium and then treating the reaction product with an acid.
The present invention also provides 5-halomethyl-5-hydroxy-3-oxazolidine derivatives of following general formula (2):
wherein R represents an unsubstituted or substituted aryl group or lower alkyl group or hydrogen atom, A represents 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; B
1
represents a protecting group for the amino group; and X represents a halogen atom.
The present invention further provides 3-oxazolidin-5-one derivatives of following general formula (16)
wherein R represents an unsubstituted or substituted aryl group or lower alkyl group or hydrogen atom, and B
1
represents a protecting group for the amino group.
BEST MODE FOR CARRYING OUT THE INVENTION
In the formulae in the present invention, R represents an unsubstituted or substituted aryl group or lower alkyl group or hydrogen atom. When those groups have a substituent, the substituent is an alkoxyl group, nitro group, an alkyl group, a halogen atom or the like. The aryl group is preferably phenyl group which may have a substituent. The lower alkyl groups are preferably straight or branched, saturated alkyl groups having 1 to 4 carbon atoms.
A in the formulae in the present invention 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. When those groups have a substituent, the substituent is an alkoxyl group, nitro group, an alkyl group, 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, methyl group can be introduced by using alanine; isopropyl group can be introduced by using valine; 2-methylpropyl group can be introduced by using leucine; 1-methylpropyl group can be introduced by using isoleucine; benzyl group can be introduced by using phenylalanine; and methylthioethyl group can be introduced by using methionine.
A may be a group introduced by using an amino acid in which a functional group in a side chain thereof is protected, such as S-t-butylcysteine, S-tritylcysteine, S-(p-methylbenzyl)cysteine, S-(p-methoxybenzyl)cysteine, O-t-butylserine, O-benzylserine, O-t-butylthreonine, O-benzylthreonine, O-t-butyltyrosine or O-benzyltyrosine, as the starting material.
A is not limited to a group introduced from a starting material derived from a natural amino acid, but it may a group introduced from a starting material derived from a synthetic amino acid (such as phenylthiomethyl group). A is preferably benzyl group or phenylthiomethyl group.
X in the formulae in the present invention represents a halogen atom. The halogen atoms include fluorine
Hirose Naoko
Izawa Kunisuke
Nakano Takashi
Nakazawa Masakazu
Onishi Tomoyuki
Ajinomoto Co. Inc.
Davis Brian
LandOfFree
Process for producing &agr;-aminoketones does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for producing &agr;-aminoketones, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for producing &agr;-aminoketones will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3021642