Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-03
2004-12-14
Powers, Fiona T. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S266800
Reexamination Certificate
active
06831177
ABSTRACT:
TECHNICAL FIELD
The present invention relates to processes for the preparation of novel substituted propenone derivatives and their crystals, in detail processes for the preparation of their intermediates, 2-acyl-5-benzylfuran derivatives and 1,2,4-triazole-3-carboxylic acid ester derivatives.
BACKGROUND ART
2-Acyl-5-alkylfuran derivatives, which are similar to 2-acyl-5-benzylfuran derivatives, can be prepared by introducing an acyl group to 2-alkyfuran derivatives through Friedel Crafts reaction (Japanese Patent Publication (Kokoku) 1995-78056, Japanese Patent Publication (Kokoku) 1995-78056 and Japanese Patent Publication (Kokai) 1986-53275).
2-Alkylfuran derivatives can be prepared by introducing an alkyl group to furan derivatives through Priedel Crafts reaction (Chem. France. 1962, 1166).
However, the preparation of 2-acyl-5-benzylfuran derivatives is not disclosed in these documents.
On the other hand, it is known that 1,2,4-triazole-3-carboxylic acid can be prepared by converting an amino group of 3-amino-1,2,4-triazole-5-carboxylic acid to a diazo group, isolating the diazonium salt and reducing.
It is known as a reducing method that 1) a diazonium salt is reduced with sodium hypophosphite (NaH
2
PO
2
) and concentrated hydrochloric acid (HCl) under 15° C. (Khim. Geterotsikl. Soedin., 1967, 180-183) and 2) a diazonium salt is reduced at 45 to 50° C. in methanol (Khim. Geterotsikl. Soedin., 1965, 624-626).
In is known as a deaminating method of 3-amino-1,2,4-triazole that diazonation and reduction are carried out at the same time (J. Am. Chem. Soc. 76, 290, 1954).
As another process, 1,2,4-triazole-3-carboxylic acid ester can be prepared by heating acylamidrazone over its melting point (150 to 200° C.) to cyclize (Collect. Czech. Chem. Commun., 49, 1984, 2492-2495, J. Heterocyclic Chem., 25, 651-654, 1998). The document describes that a large scale of cyclization must be preformed under reduced pressure with heating over its melting point for removing the generated water.
DISCLOSURE OF INVENTION
A compound of the formula (VI-1):
wherein R
1
, R
2
and R
4
each is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy or halogen; A is CR
6
or N; and R
6
is hydrogen, optionally substituted alkyl or optionally substituted aryl, has an anti-HIV activity by inhibiting HIV integrase.
A compound of the formula (VI-1) can be prepared in the following method.
wherein R
1
, R
2
, R
4
and A are as defined above; Q is a protecting group; and L is a leaving group.
Industrial and commercial preparations of 2acyl-5-benzylfuran derivatives and 1,2,4-triazole-3-carboxylic acid ester derivatives, which are useful intermediates of the compound (VI-1), are desired.
First, the preparation of 2-acyl-5-benzylfuran derivatives is described below.
As a conventional route, for example, the following methods can be thought.
wherein any ring may be substituted with optionally substituted alkyl, optionally substituted alkoxy and/or halogen.
In method X, 2-furoic acid, a starting material is reacted with benzaldehyde. After removing the hydroxy group from the obtained compound, the carboxy group is esterified to give 2-pyridine thioester, which is reacted with methyl magnesium bromide to give 2-acetyl-5-benzylfuran. This method requires 2-pyridine thioester which is removed at the following step for converting the carboxy group to acetyl.
In method Y, furfural, a starting material, is reacted with phenyl magnesium bromide. After removing the hydroxy group of the obtained compound, 2-acetyl-5-benzylfuran is prepared through Friedel Crafts reaction. The final step of this method requires Friedel Crafts reaction which must be carried out under acidic condition. However, 2-benzylfuran is unstable under acidic condition, so 2-acyl-5-benzylfuran can not be prepared in high yield.
Since both of methods X and Y require many steps and many reagents, 2-acetyl-5-benzylfuran derivatives can not be industrially and commercially prepared.
The present inventors have solved the above problems on methods X and Y, and found out industrial and commercial processes for the preparation of 2-acyl-5-benzylfuran derivatives can be achieved through Friedel Crafts reaction of 2-acylfuran derivatives.
The present inventions of 2-acsyfuran derivatives include;
A-1) a process for the preparation of a compound of the formula (III-1):
wherein R
1
and R
2
each is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy or halogen; R
3
is optionally substituted alkyl or optionally substituted alkoxy; and R
4
is hydrogen, optionally substituted alkyl, optionally substituted alkoxy or halogen, which comprises reacting a compound of the formula (I-1):
wherein R
1
, R
2
and R
3
each is as defined above,
with a compound of the formula (II-1):
wherein R
4
is as defined above; and X is halogen,
in the presence of a Lewis acid,
A-2) the process according to the above A-1) wherein a reaction solvent is methylene chloride,
A-3) the process according to the above A-1) wherein a reaction solvent is water,
A-4) the process according to any one of the above A-1) to A-3) wherein R
3
is methyl,
A-5) the process according to any one of the above A-1) to A-4) wherein R
1
and R
2
each is hydrogen, and
A-6) the process according to any one of the above A-1) to A-5) wherein R
4
is 4-fluoro.
Second, the preparation of 1,2,4-triazole-3-carboxylic acid ester derivatives is described below.
A conventional process for the preparation of 1,2,4-triazole-3-carboxlic acid comprising a reduction of an isolated diazonium salt is accompanied with danger of explosion when a large amount of a diazonium salt is treated, so this process is not suitable to industrial production.
A process for the preparation of 1,2,4-triazole-3-carboxilic acid ester comprising a cyclization of acylamidrazone requires heating over a melting point, so this process is not suitable in an industrial scale, too.
Then, the present inventors have solved the above problems and found out processes for the preparation of 1,2,4-triazole-3-carboxilic acid ester derivatives as shown below, which are suitable in an industrial scale.
The present inventions of 1,2,4-triazole-3-carboxilic acid ester derivatives include;
B-1) a process for the preparation of a compound of the formula (IV-2):
wherein R
5
is hydrogen or optionally substituted alkyl,
which comprises reacting a compound of the formula (IV-1):
wherein R
5
is as defined above,
with an alkaline metal nitrite or an alkaline-earth metal nitrite in the presence of a reducing agent,
B-2) the process according to the above B-1) which comprises reacting a compound of the formula (IV-1) with an alkaline metal nitrite in the presence of hypophosphorous acid as the reducing agent,
B-3) the process according to the above B-1) or B-2) which is carried out under the addition of a small amount of alchol,
B-4) the process according to any one of the above B-1) to B-3) wherein R
5
is hydrogen,
B-5) a process for the preparation of a compound of the formula (IV-3):
wherein R
5
is optionally substituted alkyl,
which comprises preparing 1,2,4-triazole-3-carboxilic acid through the process according to the above B-4) and esterifing the obtained compound,
B-6) a process for a compound of the formula (IV-43):
wherein R
5
is hydrogen or optionally substituted alkyl; and R
6
is hydrogen,
optionally substituted alkyl or optionally substituted aryl,
which comprises cyclizing a compound of the formula (V):
wherein R
5
and R
6
are as defined above,
in the presence of trialkylorthoester or a catalytic amount of an acid,
B-7) the process according to the above B-6) wherein R
5
is optionally substituted alkyl,
B-8) the process according to the above B-6) wherein R
5
is optionally substituted alkyl; and R
6
is hydrogen,
B-9) a process for the preparation of a compound of the formula (IV-6):
wherein R
5
is optionally substituted alkyl; R
6
is hydrogen, optionally substituted alkyl or optionally substituted aryl; and R
12
is a group of the formula: —R
7
wherein R
7
is trityl, opt
Endoh Takeshi
Kawata Kyozo
Nagai Masahiko
Uenaka Masaaki
Powers Fiona T.
Shionogi & Co. Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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