Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2000-12-07
2003-03-25
Davis, Brian J. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S343000
Reexamination Certificate
active
06538160
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing, from &agr;-aminodihalomethyl ketone derivatives, the corresponding &agr;-aminohalomethyl ketone derivatives; a process for producing the corresponding &bgr;-aminoalcohol derivatives by reducing the &agr;-aminohalomethyl ketone derivatives; and a process for producing the corresponding &bgr;-aminoepoxide derivatives by treating the &bgr;-aminoalcohol derivatives with a base.
BACKGROUND ART
Optically active a-aminohalomethyl ketones are known to be important compounds as an intermediate for the synthesis of an HIV protease inhibitor or the like (Refer to, for example, D. P. Getman, et al., Journal of Medicinal Chemistry, 36, 288(1993); Y. Okada, et al., Chemical and Pharmaceutical Bulletin, 36, 4794(1988); European Patent EP 346867; P. Raddatz, et al., Journal of Medicinal Chemistry, 34, 3267(1991)). There are accordingly demands for the development of a process for producing &agr;-aminohalomethyl ketones which is economical and efficient, and is therefore suited for industrial production.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a process for producing &agr;-aminohalomethyl ketones and compounds related thereto which process is economical and efficient and is therefore suited for industrial production.
With a view to attaining the above-described object, the present inventors have carried out an extensive investigation. As a result, it has been found that catalytic reduction of an &agr;-aminodihalomethyl ketone derivative readily yields the intended &agr;-aminohalomethyl ketone derivative. Based on such a finding, the present invention has been completed.
Accordingly, the present invention relates to a process for producing the &agr;-aminohalomethyl ketone derivative represented by the general Formula (2) below which comprises subjecting the corresponding &agr;-aminodihalomethyl ketone derivative represented by the general Formula (1) below to catalytic reduction; a process for producing the &bgr;-aminoalcohol derivative which comprises reducing such an &agr;-aminohalomethyl ketone derivative; and a process for producing the &bgr;-aminoepoxide derivative which comprises treating such a &bgr;-aminoalcohol with a base.
wherein, B
1
and B
2
represent, each independently, a hydrogen atom or an amino-protecting group, or B
1
and B
2
are coupled together to represent an imino type protecting group (with the proviso that B
1
and B
2
do not represent a hydrogen atom at the same time), A
1
represents a C
1-10
alkyl group, C
6-15
aryl group or C
7-20
aralkyl group which groups may be optionally substituted thereon, or a group containing, in the carbon skeleton of such group, a hetero atom, and X
1
represents a chlorine atom or a bromine atom.
wherein, B
3
and B
4
represent, each independently, a hydrogen atom or an amino-protecting group and A
1
and X
1
have the same meanings as described above, respectively.
The present invention will now be described more specifically hereinafter.
In the general Formulas in the present description, A
1
represents a hydrogen atom, a C
1-10
alkyl group, C
6-15
aryl group or C
7-20
aralkyl group, these groups being able to have a substituent thereon, or a group containing, in the carbon skeleton of such group, a hetero atom. Examples of the groups containing a hetero atom in the carbon skeleton include methylthioethyl, t-butylthiomethyl, tritylthiomethyl, (p-methylbenzyl)thiomethyl, (p-methoxybenzyl)thiomethyl, t-butoxymethyl, benzyloxymethyl, t-butoxyethyl, benzyloxyethyl, 4-(t-butoxy)phenylmethyl, 4-benzyloxyphenylmethyl, phenylthiomethyl and the like groups. When the above-exemplified groups have one or more substituents, there are imposed no particular limitations on the substituent(s) insofar as it does or they do not adversely affect the reaction of the present invention. Examples thereof include alkoxyl groups, nitro group, alkyl groups, halogen atoms and the like.
Such a group can be introduced, for example, using an amino acid as a starting material. When A
1
represents, e.g., a hydrogen atom, a methyl group, an isopropyl group, a 2-methylpropyl group, a 1-methylpropyl group, a benzyl group and a methylthioethyl group, such groups can be introduced by using, as a starting material, glycine, alanine, valine, leucine, isoleucine, phenylalanine and methionine, respectively.
Alternatively, A
1
may be a group introduced by using, as a starting material, an amino acid which has a functional group protected on the side chain of the amino acid. Examples of such amino acid include 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 and O-benzyltyrosine.
A
1
is not limited to a group introduced from a starting material derived from a natural amino acid, but may be a group introduced from a starting material derived from a non-natural amino acid (for example, a cyclohexylmethyl group, a phenyl group, a phenylthiomethyl group, or the like).
In the general Formulas given in the present description, X
1
represents a chlorine atom or a bromine atom.
In the general Formulas given in the present description, B
1
and B
2
represent, each independently, a hydrogen atom or an amino-protecting group, or B
1
and B
2
are coupled together to represent an imino type protecting group. B
1
and B
2
, however, do not represent a hydrogen atom at the same time.
There are no particular limitations imposed on the amino-protecting groups. For example, amino-protecting groups as described in “Protecting Groups in Organic Chemistry, 2nd edition” (John Wiley & Sons, Inc. 1991) or the like can be employed. Examples thereof include carbamate type protecting groups such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl and the like; acyl type protecting groups such as acetyl, benzoyl and the like; sulfonyl type protecting groups such as methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl and the like; alkyl type protecting groups such as benzyl, p-methoxybenzyl and the like; dialkyl type protecting groups such as dibenzyl and the like; silyl type protecting groups such as trimethylsilyl and the like; and imine type protecting groups such as diphenylmethylene, phenylmethylene, p-methoxyphenylmethylene and the like. Among them, the carbamate type protecting groups are preferred because they can be eliminated easily.
When B
1
and B
2
are coupled together to represent an imino type protecting group, the &agr;-aminodihalomethyl ketone derivative of the general Formula (1) can, in turn, be represented by the following general Formula (9):
wherein, R
2
and R
3
represent, each independently, an aryl group or lower alkyl group which groups may be optionally substituted, or a hydrogen atom. Alternatively, R
2
and R
3
may be coupled together directly or via a proper group to represent a cyclic structure.
In the general Formulas given in the present description, B
3
and B
4
represent, each independently, a hydrogen atom or an amino-protecting group. Examples of the amino-protecting group can be the same as those exemplified above.
The &agr;-aminodihalomethyl ketone derivatives represented by the general Formula (1) can be prepared by reacting, as illustrated in the below-described scheme, an &agr;-amino acid ester derivative of the general Formula (10) with a dihalomethyl lithium represented by the general Formula (11). As the dihalomethyl lithium of the general Formula (11), dichloromethyl lithium or dibromomethyl lithium can be used.
wherein, B
9
and B
10
represent, each independently, a hydrogen atom or an amino-protecting group, or B
9
and B
10
may be coupled together to represent an imino type protecting group with the proviso that B
9
and B
10
do not represent a hydrogen atom at the same time. As the amino-protecting group, those exemplified above can be employed.
In the general Formula (10), R
4
represents a lower alkyl or aralkyl group which groups may be op
Izawa Kunisuke
Nakazawa Masakazu
Onishi Tomoyuki
Otake Yasuyuki
Ajinomoto Co. Inc.
Davis Brian J.
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