Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-01-15
2001-03-06
Kight, John (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S351000, C546S352000
Reexamination Certificate
active
06197966
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing an intermediate for the production of the compound of the formula [XVI]
wherein Me is methyl, Bu-t is t-butyl and Ph is phenyl, which has a virus-derived protease inhibitory activity and which is a useful therapeutic agent for HIV infectious diseases.
BACKGROUND OF THE INVENTION
The above-mentioned compound [XVI] useful as an HIV protease inhibitor has been known from WO95/09843, and the production methods thereof have been known from WO97/11937 and WO97/11938.
However, these production methods cannot impart stereoselectivity to intermediates, and thus, they are not satisfactory in view of low yields of the objective intermediates. In addition, these methods require heating to 80-90° C. during reaction, as well as purification due to crystallization, since the resulting intermediate compound is a 1:1 mixture of isomers.
SUMMARY OF THE INVENTION
The present invention aims at solving the above-mentioned problems, and producing an optically active amino alcohol compound, an enantiomer thereof and a salt thereof stereoselectively at high yields as a highly pure salt.
The present inventors have conducted intensive studies in an attempt to solve the above-mentioned problems, and found that a ring opening of a mesoepoxide compound, using chiral or achiral amine and a mixed catalyst of a proton donor and a Lewis acid under mild temperature conditions leads to stereoselective production of an optically active amino alcohol compound, an enantiomer thereof and a salt thereof at high yields. In addition, they have found that the use of a chiral proton donor enables production of an amino alcohol at sufficient asymmetric yields by ring opening of an epoxy compound using achiral amine. They have also found that an important intermediate compound [5] and an enantiomer thereof to be mentioned later can be produced stereoselectively and highly efficiently in large amounts as crystalline salts having high purity by isomerizing the 7-membered moiety of said amino alcohol to a 5-membered structure and then removing the substituent(s) R
4
and/or R
5
on the nitrogen atom, which resulted in the completion of the present invention.
Accordingly, the present invention provides the following (1) to (10).
(1) A method for producing an optically active amino alcohol compound of the formula [3]
wherein
R
1
, R
2
and R
3
are the same or different and each is a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted aralkyl, or R
1
and R
1
or R
2
and R
3
in combination may form an optionally substituted ring; and
R
4
and R
5
are the same or different and each is a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted aryl, an optionally substituted aralkyl or an acyl, or R
4
and R
5
in combination may form an optionally substituted ring together with the adjacent nitrogen atom, or R
4
and R
5
in combination may form an imide group or an azide group together with the adjacent nitrogen atom,
an enantiomer thereof or a salt thereof, comprising reacting a mesoepoxide compound of the formula [1]
wherein R
1
, R
2
and R
3
are as defined above, with a compound of the formula [2]
wherein R
4
and R
5
are as defined above, and R
6
is a hydrogen atom or a silyl group, in the presence of a mixed catalyst comprising a Lewis acid and a proton donor.
(2) The method according to (1) above, for producing an optically active amino alcohol compound of the formula [3′]
wherein
R
2
′ and R
3
′ are the same or different and each is a hydrogen atom, an optionally substituted lower alkyl or an aryl, or R
2
′ and R
3
′ in combination may form a cycloalkyl ring together with the adjacent carbon atom; and
R
4
and R
5
are the same or different and each is a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted aryl, an optionally substituted aralkyl or an acyl, or R
4
and R
5
in combination may form an optionally substituted ring together with the adjacent nitrogen atom, or R
4
and R
5
in combination may form an imide group or an azide group together with the adjacent nitrogen atom,
an enantiomer thereof or a salt thereof, comprising reacting a mesoepoxide compound of the formula [1′]
wherein R
2
′ and R
3
′ are as defined above, with a compound of the formula [2]
wherein R
4
and R
5
are as defined above and R
6
is a hydrogen atom or a silyl group, in the presence of a mixed catalyst comprising a Lewis acid and a proton donor.
(3) A method for producing an optically active 1,3-dioxolane compound of the formula [4]
wherein
R
2
′ and R
3
′ are the same or different and each is a hydrogen atom, an optionally substituted lower alkyl or an aryl, or R
2
′ and R
3
′ in combination may form a cycloalkyl ring together with the adjacent carbon atom; and
R
4
and R
5
are the same or different and each is a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted aryl, an optionally substituted aralkyl or an acyl, or R
4
and R
5
in combination may form an optionally substituted ring together with the adjacent nitrogen atom, or R
4
and R
5
in combination may form an imide group or an azide group together with the adjacent nitrogen atom,
or an enantiomer thereof, comprising reacting a mesoepoxide compound of the formula [1′]
wherein R
2
′ and R
3
′ are as defined above, with a compound of the formula [2]
wherein R
4
and R
5
are as defined above and R
6
is a hydrogen atom or a silyl group, in the presence of a mixed catalyst comprising a Lewis acid and a proton donor, to give an optically active amino alcohol compound of the formula [3′]
wherein R
2
′, R
3
′, R
4
and R
5
are as defined above, an enantiomer thereof or a salt thereof, and isomerizing the resulting compound to a 5-membered ring in the presence of an acid.
(4) A method for producing an optically active amino alcohol compound having 1,3-dioxolane, which is represented by the formula [5]
wherein
R
2
′ and R
3
′ are the same or different and each is a hydrogen atom, an optionally substituted lower alkyl or an aryl, or R
2
′ and R
3
′ in combination may form a cycloalkyl ring together with the adjacent carbon atom,
an enantiomer thereof or a salt thereof, comprising reacting a mesoepoxide compound of the formula [1′]
wherein R
2
′ and R
3
′ are as defined above, with a compound of the formula [2]
wherein R
4
and R
5
are the same or different and each is a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted aryl, an optionally substituted aralkyl or an acyl, or R
4
and R
5
in combination may form an optionally substituted ring together with the adjacent nitrogen atom, or R
4
and R
5
in combination may form an imide group or an azide group together with the adjacent nitrogen atom; and
R
6
is a hydrogen atom or a silyl group,
in the presence of a mixed catalyst comprising a Lewis acid and a proton donor, to give an optically active amino alcohol compound of the formula [3′]
wherein R
2
′, R
3
′, R
4
and R
5
are as defined above, an enantiomer thereof or a salt thereof; converting the resulting compound to an optically active 1,3-dioxolane compound of the formula [3]
wherein R
2
′, R
3
′, R
4
and R
5
are as defined above, or an enantiomer thereof, in the presence of an acid, and eliminating the substituent(s) R
4
and/or R
5
on the nitrogen atom.
(5) The production method of (1) or (2) above, wherein the proton donor is at least one member selected from the group consisting of (R)-1,1-bi-2-naphthol, (S)-1,1′-bi-2-naphthol, catechol and 4-tert-butylcatechol, and the Lewis acid is at least one member selected from the group consisting of titan
Abe Hiroyuki
Inaba Takashi
Sagawa Shoichi
Covington Raymond
Foley & Lardner
Japan Tobacco Inc.
Kight John
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