(Oxazolin-4-yl) oxirane derivative

Details (Oxazolin-4-yl) oxirane derivative (Oxazolin-4-yl) oxirane derivative

2001-04-17

2001-12-25

Owens, Amelia (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06333416

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel method for producing a 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 based on its inhibitory action on proteases derived from viruses, various novel intermediates useful for producing said compound [XVI], and to the method for production of the intermediates. These intermediates can be used for not only production of the above-mentioned compound [XVI] but also for production of various compounds.
BACKGROUND ART
The above-mentioned compound [XVI] useful as an HIV protease inhibitor is known as described in WO95/09843. This compound [XVI] has been conventionally produced from serine as a starting material, by increasing carbon and 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, for example, in 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 specific enantiomers 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 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.
Thus, the present invention provides the following (1) to (15).
(1) A (5R,6S)-6-substituted amino-1,3-dioxepan-5-ol Derivative of the Formula [V]
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
3
is an aralkylamine residue or amino acid derivative residue having an (R) or (S) configuration, an enantiomer thereof and a salt thereof.
(2) A Method for Producing a (5R,6S)-6-substituted amino-1,3-dioxepan-5-ol Derivative of the Formula [V]
wherein R
1
, R
2
and R
3
are as defined above, and an enantiomer thereof, comprising subjecting a 3,5,8-trioxabicyclo[5.1.0]octane derivative of the formula [III]
wherein R
1
and R
2
are as defined above, to an epoxy ring-opening reaction using a chiral amine of the formula [IV]
R
3
—NH
2
  [IV]
wherein R
3
is as defined above, and crystallizing a produced mixture of isomers.
(3) 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, an enantiomer thereof and a salt thereof.
(4) A Method for Producing 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, an enantiomer thereof and a salt thereof, comprising subjecting a 3,5,8-trioxabicyclo[5.1.0]octane derivative of the formula [III]
Wherein R
1
and R
2
are as defined above, to an epoxy ring-opening reaction using a chiral amine of the formula [IV]
R
3
—NH
2
  [IV]
wherein R
3
is as defined above, and crystallizing a produced mixture of isomers to give a (5R,6S)-6-substituted amino-1,3-dioxepan-5-ol derivative of the formula [V]
wherein R
1
, R
2
and R
3
are as defined above, or an enantiomer thereof, and removing a substituent on an amino group of this compound to make the 6-position thereof a non-substituted amino group.
(5) An Oxazoline Derivative of the Formula [X]
wherein R
4
is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl or an optionally substituted heteroarylalkyl, R
5
is a hydrogen atom or an acyl, and Z is a substituent which functions as a leaving group together with an oxygen atom, an enantiomer thereof and a salt thereof.
(6) A Method for Producing an Oxazoline Derivative of the Formula [X]
wherein R
4
, R
5
and Z are as defined above, and an enantiomer thereof, comprising treating a 1,3-dioxepane derivative of the formula [IX]
wherein R
1
, R
2
, R
4
and Z are as defined above, or an enantiomer thereof, with a Lewis acid to form an oxazoline ring, followed by acylation as necessary.
(7) A Method for Producing an Oxazoline Derivative of the Formula [X]
wherein R
4
, R
5
and Z are as defined above, and an enantiomer thereof, comprising reacting 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, an enantiomer thereof or a salt thereof, with a reactive carboxylic acid derivative having R
4
wherein R
4
is as defined above, in the presence of a base, to give a (5R,6S)-6-acylamino-1,3-dioxepan-5-ol derivative of the formula [VIII]
wherein R
1
, R
2
and R
4
are as defined above, or an enantiomer thereof, reacting the resulting compound with a sulfonylating agent, treating the resulting compound with a Lewis acid, and acylating said compound, where necessary.
(8) An (oxazolin-4-yl)oxirane Derivative of the Formula [XI]
werein R
4
is as defined above, an enantiomer thereof and a salt thereof.
(9) A Method for Producing an (oxazolin-4-yl)oxirane Derivative of the Formula [XI]
wherein R
4
is as defined above, and an enantiomer thereof, comprising treating, with a base, an oxazoline derivative of the formula [X]
wherein R
4
, R
5
and Z are as defined above, or an enantiomer thereof.
(10) A Method for Producing an (oxazolin-4-yl)oxirane Derivative of the Formula [XI]
wherein R
4
is as defined above, and an enantiomer thereof, comprising reacting 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, an enantiomer thereof or a salt thereof, with a reactive carboxylic acid derivative having R
4
wherein R
4
is as defined above, in the presence of a base, to give a (5R,6S)-6-acylamino-1,3-dioxepan-5-ol derivative of the formula [VIII]
wherein R
1
, R
2
and R
4
are as defined above, or an enantiomer thereof, reacting the resulting compound with a sulfonylating agent, treating the resulting compound with a Lewis acid, and acylating said compound, where necessary, to give an oxazoline derivative of the formula [X]
wherein R
4
, R
5
and Z are as defined above, or an enantiomer thereof, and treating the obtained compound with a base.
(11) A 4-(2-amino-1-hydroxyethyl)oxazoline Derivative of the Formula [XIII]
Wherein R
4
is as defined above, and R
6
and R
7
are the same or different a

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