Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-09-26
2002-12-17
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S444000, C549S048000, C549S460000
Reexamination Certificate
active
06495701
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of tricyclic amino-alcohol derivatives or salts thereof which are useful for treating and preventing diabetes, obesity, hyperlipidemia and the like and have the formula (1):
wherein
R
1
represents a lower alkyl group or a benzyl group;
*1 represents an asymmetric carbon atom;
R
2
represents a hydrogen atom, a halogen atom or a hydroxyl group; and
A represents one of the following groups:
wherein X represents NH, O or S; R
6
represents a hydrogen atom, a hydroxyl group, an amino group or an acetylamino group; and *2 represents an asymmetric carbon atom when R
6
is not a hydrogen atom. This invention also relates to intermediates useful for the preparing process.
BACKGROUND OF THE INVENTION
JP-A-9-249623 (WO 97/25311) and WO 99/01431 describe in detail processes for the preparation of the compounds of the above-mentioned general formula (1) and also describe that these compounds are very useful for treating and preventing diabetes, obesity, hyperlipidemia and the like.
Problems to be Solved
However, the study of the above known processes carried out by the present inventors showed that the said processes were not necessarily a practical process. There has been a need for a convenient, practical preparing process with low cost which comprises a small number of steps with good industrial work efficiency.
Means to Solve the Problems
The study carried out by the present inventors showed some disadvantages involved in the conventional processes for preparing a compound of the formula (1) set forth above, wherein the disadvantages were that the processes required many reaction steps and several purifying works such as chromatography, and did not necessarily provide a good yield. In addition, if an optical isomer, such as R-form of a compound of the formula (1) is to be finally obtained according to the synthesizing route disclosed in the above patent publications, the carbonyl group is reduced with borane as a reducing agent in the presence of a chiral auxiliary agent represented by the following general formula (15):
This chiral auxiliary agent is very expensive and the process for the preparation thereof is very complicated. Moreover, the chiral auxiliary agent is a hazardous combustible substance and an asymmetric reduction using the said chiral auxiliary agent requires strictly anhydrous conditions, strict temperature controls, complicated works and the like, which will become problematic when the chiral auxiliary agent is industrially used.
In order to solve the above problems, the present inventors examined a variety of synthesizing processes. As a result, the present inventors have established preferred synthesizing processes successfully and completed the present invention.
That is, the aspect of the first synthesizing route of the present invention is a process for the preparation of a compound of the formula (1):
wherein R
1
represents a lower alkyl group or a benzyl group; R
2
represents a hydrogen atom, a halogen atom or a hydroxyl group; *1 represents an asymmetric carbon atom; and A represents one of the following groups:
wherein X represents NH, O or S; R
6
represents a hydrogen atom, a hydroxyl group, an amino group or an acetylamino group; and *2 represents an asymmetric carbon atom when R
6
is not a hydrogen atom, which comprises the following steps (a) to (c):
(a)
i) reacting a compound of the formula (4):
wherein R
1
is as defined above; R
21
represents a hydrogen atom, a halogen atom, a hydroxyl group or a protected hydroxyl group; R
3
represents an amino-protecting group or a hydrogen atom, with a compound of the formula (12):
wherein R
4
represents an amino-protecting group or a hydrogen atom; and A′ represents one of the following groups:
wherein X represents NH, O or S; R
61
represents a hydrogen atom, a protected hydroxyl group, a protected amino group or an acetylamino group; and *2 represents an asymmetric carbon atom when R
61
is not a hydrogen atom, to give a compound of the formula (3):
wherein R
1
, R
21
, R
3
, R
4
and A′ are as defined above; or
ii) coupling a compound of the formula (4) with a compound of the formula (14):
wherein R
4
is as defined above, to give a compound of the formula (6):
wherein R
1
, R
21
, R
3
and R
4
are as defined above; or
iii) further converting the primary hydroxyl group of the compound of the formula (6) into a leaving group B
3
to give a compound of the formula (5):
wherein R
1
, R
21
, R
3
and R
4
are as defined above, and B
3
represents a leaving group; or
iv) further reacting the resulting compound of the formula (5) with a compound represented by A′—OH wherein A′ is as defined above to give a compound of the formula (3);
(b) then reducing the resulting compound of any one of the formulae (3), (5) and (6) to give a compound of the formula (2) as follows:
i) reducing the compound of the formula (3) to give an amino-alcohol of the formula (2):
wherein R
1
, R
21
, R
3
, R
4
and A′ are as defined above, and *1 represents an asymmetric carbon atom; or
ii) reducing the compound of the formula (5) to give a compound of the formula (7):
wherein R
1
, R
21
, R
3
, R
4
and B
3
are as defined above, and *1 represents an asymmetric carbon atom, or
iii) reducing the compound of the formula (6) to give a compound of the formula (8):
wherein R
1
, R
21
, R
3
and R
4
are as defined above, and *1 represents an asymmetric carbon atom, and converting the primary hydroxyl group of the resulting compound of the formula (8) into a leaving group B
3
to give a compound of the formula (7), then reacting the compound of the formula (7) obtained by either step as set forth above with a compound represented by A′—OH wherein A′ is as defined above to give an amino-alcohol of the formula (2); and
(c) simultaneously or sequentially removing the protecting groups of the compound of the formula (2) obtained by any one of processes as set forth above to give a compound of the formula (1).
The aspect of the first synthesizing route of the present invention is a process for the preparation of a compound of the above-mentioned general formula (1), which comprises the following steps (a) to (c):
(a) reacting a compound of the formula (4):
wherein R
1
is as defined above; R
21
represents a hydrogen atom, a halogen atom, a hydroxyl group or a protected hydroxyl group; R
3
represents an amino-protecting group or a hydrogen atom, with a compound of the formula (12):
wherein R
4
represents an amino-protecting group or a hydrogen atom; and A′ represents one of the following groups:
wherein X represents NH, O or S; R61 represents a hydrogen atom, a protected hydroxyl group, a protected amino group or an acetylamino group; and *2 represents an asymmetric carbon atom when R
61
is not a hydrogen atom, to give a compound of the formula (3):
wherein R
1
, R
21
, R
3
, R
4
and A′ are as defined above;
(b) reducing the resulting compound of the formula (3) to give an amino-alcohol of the formula (2):
wherein R
1
, R
21
, R
3
, R
4
and A′ are as defined above, and *1 represents an asymmetric carbon atom; and
(c) simultaneously or sequentially removing the protecting groups to give a compound of the formula (1).
In the aspect of the first synthesizing route set forth above, a compound represented by the formula (3) is the first preferred intermediate which is a novel compound and is relatively good in crystallinity. The said compound does not necessarily need a column chromatography purifying step and may be used in the following reaction step after being subjected to a recrystallizing treatment and the like.
Specific examples of a compound represented by the formula (3) include:
2-[N-benzyl-N-[2-(9H-carbazol-2-yloxy)]ethyl]amino-1-(3-methyl sulfonylamino)phenylethanone;
2-[N-benzyl-N-[2-(9H-carbazol-2-yloxy)]ethyl]amino-1-[3
Kida Hitoshi
Matsubara Koki
Asahi Kasei Kabushiki Kaisha
Saeed Kamal
Young & Thompson
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