Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-10
2001-02-27
Stockton, Laura L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S333000
Reexamination Certificate
active
06194589
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel method for producing a compound of the formula [XVI]
wherein Me is methyl, Bu-t is t-butyl and Ph is phenyl, which is useful as a treatment drug of HIV-related diseases as a result of its inhibitory action on proteases derived from viruses, various novel intermediate compounds useful for producing said compound [XVI], and to the method for production thereof. These intermediate compounds can be used not only for the production of the above-mentioned compound [XVI] but also for the production of various other compounds.
BACKGROUND ART
The above-mentioned compound [XVI] useful as an HIV protease inhibitor is known as described in W095/09843. This compound [XVI] has been conventionally produced from serine as a starting material by increasing carbon and through numerous other steps inclusive of stereoselective reduction of carbonyl group. Such conventional production method is extremely complicated and inefficient, since it requires expensive starting materials and constant low temperature conditions for reactions. Accordingly, there remain many problems to be solved before the conventional synthetic method is actually put to industrial practice.
In addition, 2,2-dimethyl-6-amino-1,3-dioxepan-5-ol which is described in, for example, U.S. Pat. No. 4,439,613 is an intermediate for producing a compound useful as an X ray contrast medium, and even though the compound obtained is a racemate, resolution of the racemate itself by a method such as recrystallization has been extremely difficult. Moreover, this US patent does not suggest production of a specific enantiomer of the present invention.
Accordingly, an object of the present invention is to provide a method for stereoselectively and extremely efficiently producing the above-mentioned compound [XVI] useful as an HIV protease inhibitor upon solution of the above-mentioned problems. Another object of the present invention is to provide a novel intermediate compound useful for producing said compound, and a production method thereof.
DISCLOSURE OF THE INVENTION
The present inventors have made intensive studies in an attempt to achieve the above-mentioned objects, and found that a step comprising acetalating or ketalating (z)-2-butene-1,4-diol, and epoxidation of the obtained compound to give a 3,5,8-trioxabicyclo[5.1.0]octane derivative, which is followed by an epoxy ring-opening reaction using a chiral amine, leads to a stereospecific (5R,6S)-6-substituted amino-1,3-dioxepan-5-ol derivative or an enantiomer thereof, from which a compound of the following formula [XV], that is, a compound inclusive of the aforementioned compound [XVI] useful as an HIV protease inhibitor, can be extremely efficiently produced stereoselectively through various other steps, which resulted in the completion of the present invention.
That is, the present invention provides the following (1) to (14).
(1) A (5R, 6S)-6-substituted amino-1,3-dioxepan-5-ol derivative of the formula [VII]
wherein R
1
and R
2
are the same or different and each is a hydrogen atom, an alkyl or an aryl, or R
1
and R
2
combinedly form a cycloalkyl ring together with the adjacent carbon atom, and R
4
is an amino-protecting group, an enantiomer thereof and a salt thereof.
(2) A 1,3-dioxolan-4-yl-ethanol derivative of the formula [VIII]
wherein R
1
and R
2
are the same or different and each is a hydrogen atom, an alkyl or an aryl, or R
1
and R
2
combinedly form a cycloalkyl ring together with the adjacent carbon atom, and R
4
is an amino-protecting group, an enantiomer thereof and a salt thereof.
(3) A method for producing a 1,3-dioxolan-4-yl-ethanol derivative of the formula [VIII]
wherein R
1
, R
2
and R
4
are as defined above, and an enantiomer thereof, comprising isomerizing a (5R,6S)-6-substituted amino-1,3-dioxepan-5-ol derivative of the formula [VII]
wherein R
1
, R
2
and R
4
are as defined above, or an enantiomer thereof into a 5-membered ring in the presence of an acid.
(4) A method for producing a 1,3-dioxolan-4-yl-ethanol derivative of the formula [VIII]
wherein R
1
, R
2
and R
4
are as defined above, and an enantiomer thereof, comprising protecting an amino group of a (5R,6S)-6-amino-1,3-dioxepan-5-ol derivative of the formula [VI]
wherein R
1
and R
2
are as defined above, or an enantiomer thereof, to give a (5R,6S)-6-substituted amino-1,3-dioxepan-5-ol derivative of the formula [VII]
wherein R
1
, R
2
and R
4
are as defined above, an enantiomer thereof or a salt thereof, and isomerizing the obtained compound into a 5-membered ring in the presence of an acid.
(5) A 1,3-dioxolan-4-yl-ethylthio derivative of the formula [IX]
wherein R
1
, R
2
and R
4
are as defined above, and R
5
is a hydrogen atop, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl or an optionally substituted aralkyl, an enantiomer thereof and a salt thereof.
(6) A method for producing a 1,3-dioxolan-4-yl-ethylthio derivative of the formula [IX]
wherein R
1
, R
2
, R
4
and R
5
are as defined above, comprising reacting a 1,3-dioxolan-4-yl-ethanol derivative of the formula [VIII]
wherein R
1
, R
2
and R
4
are as defined above, or an enantiomer thereof, with a halogenating agent or a sulfonylating agent, and reacting the obtained compound with a mercaptan of the formula
R
5
SH
wherein R
5
is as defined above, for thioetherification.
(7) A 3-substituted aminobutane-1,2-diol derivative of the formula [X]
wherein R
4
and R
5
are as defined above, an enantiomer thereof and a salt thereof.
(8) A method for producing a 3-substituted aminobutane-1,2-diol derivative of the formula [X]
wherein R
4
and R
5
are as defined above, and an enantiomer thereof, comprising hydrolyzing a 1,3-dioxolan-4-yl-ethylthio derivative of the formula [IX]
wherein R
1
, R
2
, R
4
and R
5
are as defined above, or an enantiomer thereof in the presence of an acid.
(9) A 3-substituted aminobutane derivative of the formula [XI]
wherein R
4
and R
5
are as defined above, R
6
is a hydroxy-protecting group and Z is a substituent which functions as a leaving group with an oxygen atom, an enantiomer thereof and a salt thereof.
(10) A method for producing a 3-substituted aminobutane derivative of the formula [XI]
wherein R
4
, R
5
, R
6
and Z are as defined above, and an enantiomer thereof, comprising protecting a primary hydroxy of a 3-substituted aminobutane-1,2-diol derivative of the formula [X]
wherein R
4
and R
5
are as defined above, or an enantiomer thereof, and, with or without isolating the obtained compound, converting a secondary hydroxy to a leaving group.
(11) A substituted 1-butene oxide derivative of the formula [XII]
wherein R
4
and R
5
are as defined above, an enantiomer thereof and a salt thereof.
(12) A method for producing a substituted 1-butene oxide derivative of the formula [XII]
wherein R
4
and R
5
are as defined above, and an enantiomer thereof, comprising treating a 3-substituted aminobutane derivative of the formula [XI]
wherein R
4
, R
5
, R
6
and Z are as defined above, or an enantiomer thereof, in the presence of a base, and simultaneously conducting epoxidation and deprotection of primary hydroxy.
(13) A method for producing a substituted 1-butene oxide derivative of the formula [XII]
wherein R
4
and R
5
are as defined above, and an enantiomer thereof, comprising protecting a primary hydroxy of a 3-substituted aminobutane-1,2 diol derivative of the formula [X]
wherein R
4
and R
5
are as defined above, or an enantiomer thereof, converting, with or without isolating the obtained compound, a secondary hydroxy to a leaving group to give a 3-substituted aminobutane derivative of the formula [XI]
wherein R
4
, R
5
, R
6
and Z are as defined above, or an enantiomer the
Inaba Takashi
Yamada Yasuki
Japan Tobacco Inc.
Stockton Laura L.
Wenderoth , Lind & Ponack, L.L.P.
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