Processes for the preparation of bicyclic aminoalcohols

Details Processes for the preparation of bicyclic aminoalcohols Processes for the preparation of bicyclic aminoalcohols

2002-01-02

2004-04-20

Davis, Brian (Department: 1621)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06723857

ABSTRACT:

TECHNICAL FIELD
The present invention relates to processes for the preparation of bicyclic aminoalcohols.
BACKGROUND ART
The following scheme is disclosed in Chem. Pharm. Bull., 37(6), 1524-1533 (1989) as processes for the preparation of a bicyclic aminoalcohol (IV).
A starting material, myrtenol, is reacted with ethyl orthoformate to give an exomethylene derivative. The exomethylene derivative is oxidized by ozone to give a ketone derivative, compound (II-1), which is further reacted with O-methylhydroxyamine to give an O-methyloxime derivative, compound (III-1). The obtained O-methyloxime derivative is reduced in n-propanol with metallic sodium to give a bicyclic aminoalcohol, compound (IV).
It is disclosed in the above document that alkylation of nopinone, compound (I), gives a mixture of the starting material, a di-substituted product and a mono-substituted product as shown below. Moreover, the mono-substituted product is disclosed as a mixture of two stereo isomers.
DISCLOSURE OF INVENTION
There are some problems in the above process for the preparation of the bicyclic aminoalcohol that the starting material, myrtenol, is expensive and not preferable in view of supply. Thus, another process for the preparation of the ketone derivative, compound (II-1), is desired. In the above method, the purity of the bicyclic aminoalcohol (compound (IV)) obtained through reduction of the O-methyloxime derivative (compound (III-1)) is not so high. When the bicyclic aminoalcohol is crystallized and purified as a salt with benzoic acid, the yield is only 39.6%.
A benzothiophene carboxamide derivative, compound (VIII):
wherein R
3
is hydrogen, alkyl, acyl, alkylsulfonyl or arylsulfonyl, R
4
is hydrogen or alkyl, and a double bond represents E- or Z-configuration, is a high selective PGD
2
receptor antagonist. WO 98/25919 discloses the following process for the preparation of the compound (VIII).
wherein R
3
is hydrogen, alkyl, acyl, alkylsulfonyl or arylsulfonyl, R
4
is hydrogen or alkyl, and a double bond represents E- or Z-configuration.
The bicyclic aminoalcohol of the formula (IV):
is useful as an intermediate of the compound (VIII) and should be prepared at a low cost and stably provided.
But, a prior art of process for the preparation of the bicyclic aminoalcohol (IV) has the above problems.
On the other hand, as shown below, a method using an alkaline metal- or alkaline earth metal-substituted borohydride in the presence of a Lewis acid is known as a reduction of an O-methyloxime derivative (compound (III-1)) to a bicyclic aminoalcohol (compound (IV)).
But the above method using such borohydrides is accompanied with production of diborane, so this method has a problem in view of safety for an industrial process.
The present inventors have found out a process for the preparation of the ketone derivative (compound (II)) from nopinone (compound (I)) and a novel process for the reduction of the O-methyloxime derivative or a more inexpensive oxime derivative (compound (III)) to the bicyclic aminoalcohol (compound (IV)), to develop a safe process for the preparation of the bicyclic aminoalcohol.
The present invention provides;
1) a process for the preparation of a compound (II):
wherein R
1
is alkyl, which comprises reacting a compound (I):
with XCH
2
COOR
1
wherein X is halogen, and R
1
is as defined above in the presence of an additive and a base,
2) a process for the preparation of a compound (IV):
which comprises reducing a compound (III):
wherein R
1
is as defined above, and R
2
is hydrogen or alkyl, with an aluminum hydride,
3) a process for the preparation of a compound (IV):
which comprises reacting a compound (II):
wherein R
1
is as defined above, with NH
2
OR
2
wherein R
2
is as defined above to give a compound (III):
wherein R
1
and R
2
are as defined above, and reducing the compound (III) with an aluminum hydride,
4) a process for the preparation of a compound (III):
wherein R
1
and R
2
are as defined above, which comprises preparing a compound (II):
wherein R
1
is as defined above, through the process according to the above 1), and reacting the compound (II) with NH
2
OR
2
wherein R
2
is as defined above,
5) a process for the preparation of a compound (IV):
which comprises preparing a compound (III):
wherein R
1
and R
2
are as defined above through the process according to the above 4), and reducing the compound (III) with an aluminum hydride,
6) the process according to the above 2), 3) or 5) wherein the aluminum hydride is prepared by reacting a Lewis acid with lithium aluminum hydride or reacting concentrated sulfuric acid with lithium aluminum hydride,
7) a process for the preparation of a compound (IX):
wherein R
5
each is independently alkyl, which comprises reacting a compound (I):
with (R
5
)
3
SiX wherein R
5
is as defined above, and X is halogen, in the presence of a base,
8) a process for the preparation of a compound (X):
wherein R
6
each is independently alkyl, which comprises reacting a compound (IX):
wherein R
5
each is independently alkyl, with CH
2
═CHOR
6
wherein R
6
is as defined above in the presence of ceric ammonium nitrate (IV) in a solvent of R
6
OH wherein R
6
is as defined above,
9) a process for the preparation of a compound (X):
wherein R
6
is as defined above, which comprises preparing a compound (IX):
wherein R
5
is as defined above through the process according to the above 7), and reacting the compound (IX) with CH
2
═CHOR
6
wherein R
6
is as defined above in the presence of ceric ammonium nitrate (IV) in a solvent of R
6
OH wherein R
6
is as defined above,
10) a process for the preparation of a compound (VI):
wherein R
3
is hydrogen, alkyl, acyl, alkylsulfonyl or arylsulfonyl, which comprises preparing a compound (IV):
through the process according to any one of the above 2), 3), 5) and 6), and reacting the compound (IV) or its salt with a compound (V):
wherein R
3
is as defined above or its reactive derivative,
11) a process for the preparation of a compound (VII):
wherein R
3
is as defined above, which comprises preparing a compound (VI):
wherein R
3
is as defined above through the process according to the above 10), and oxidizing the compound (VI),
12) a process for the preparation of a compound (VII):
wherein R
3
is as defined above, which comprises preparing a compound (X):
wherein R
6
is as defined above through the process according to the above 8) or 9), reacting the compound (X) with NH
2
OR
2
wherein R
2
is as defined above to give a compound (XI):
wherein R
2
and R
6
are as defined above, reducing the compound (XI) to give a compound (XII):
wherein R
6
is as defined above, reacting the compound (XII) with a compound (V):
wherein R
3
is as defined above or its reactive derivative to give a compound (XIII):
wherein R
3
and R
6
are as defined above, and reacting the compound (XIII) with an acid,
13) a process for the preparation of a compound (VIII):
wherein R
3
is as defined above, R
4
is hydrogen or alkyl, and a double bond represents E- or Z-configuration, a pharmaceutically acceptable salt or hydrate thereof, which comprises preparing a compound (VII):
wherein R
3
is as defined above through the process according to the above 11) or 12), reacting the compound (VII) with an ylide of the formula: Ph
3
P═CH(CH
2
)
3
COOR
4
wherein R
4
is as defined above, and if desired, deprotecting.
The term “alkyl” includes straight or branched C1 to C6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl or the like. Preferred is methyl or ethyl.
The term “acyl” includes carbonyl substituted with hydrogen or the above alkyl, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl or the like. Preferred is formyl or acetyl.
The term “alkylsulfonyl” includes sulfonyl substituted with the above alkyl, for example, methanesulfonyl, ethanesulfonyl or the like.
The term “arylsulfonyl” includes sulfony

Affiliated with

Also associated with

Rating

Processes for the preparation of bicyclic aminoalcohols does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Processes for the preparation of bicyclic aminoalcohols, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Processes for the preparation of bicyclic aminoalcohols will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3267346