Efficient process for the preparation of a factor Xa inhibitor

Details Efficient process for the preparation of a factor Xa inhibitor Efficient process for the preparation of a factor Xa inhibitor

2003-05-07

2004-06-08

Lambkin, Deborah C. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06747158

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to an efficient process for the preparation of a benzisoxazolyl-pyrazole. Benzisoxazolyl-pyrazoles are useful as factor Xa inhibitors.
BACKGROUND OF THE INVENTION
Factor Xa inhibitors like those of Formula Ia shown below:
WO98/57951 describes the synthesis of the compound of Formula Ia, as its trifluoroacetic acid salt, as follows:
In the above procedure, the pyrazole carboxylic acid and aniline are coupled and isolated as a free base. The 3-cyano-4-fluorophenyl group of the resulting product is then converted to 1-aminobenzisoxazole. One problem with this procedure is that the acid-aniline coupling product is difficult to purify. A second problem is that the conversion to the 1-aminobenzisoxazole moiety requires the presence of a strong, expensive base such as KOt-Bu.
It can be seen that the preparation of a compound of Formula I is difficult. Thus, it is desirable to find an efficient synthesis of such a compound.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide a novel process for preparing a compound of Formula I.
It is another object of the present invention to provide intermediates that are useful in preparing a compound of Formula I.
It is another object of the present invention to provide novel salt, crystalline, and solvent forms of Formula I.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide novel compounds for use in therapy.
It is another object of the present invention to provide the use of novel compounds for the manufacture of a medicament for the treatment of a thromboembolic disorder.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Thus, in an embodiment, the present invention provides a novel process for making a compound of Formula I:
comprising:
(c) contacting a compound of Formula IVa with maleic acid to form a compound of Formula IV;
(d) converting a compound of Formula IV to a compound of Formula V; and,
(e) forming a compound of Formula I.
In a preferred embodiment, in (c), contacting with maleic acid is performed in the presence of a first solvent, ethyl acetate.
In another preferred embodiment, in (c), a second solvent, 1-chlorobutane, is added to enhance precipitation.
In another preferred embodiment, (d) is performed by contacting a compound of Formula IV with HONHCOCH
3
in the presence of a base and a solvent.
In another preferred embodiment, the base is selected from K
2
CO
3
, Na
2
CO
3
, KHCO
3
, NaHCO
3
, KF, NaOH, and KOH.
In another preferred embodiment, the base is K
2
CO
3
.
In another preferred embodiment, in (d), the solvent is selected from DMSO, DMAC, N-methylpyrrolidinone, and DMF.
In another preferred embodiment, in (d), the solvent is DMF, comprising: 0.5 to 50% by volume of water.
In another preferred embodiment, in (d), the solvent is DMF, comprising: 10, 11, 12, 13, 14, to 15% by volume of water.
In another preferred embodiment, in (d), the solvent is DMF, comprising: 15% by volume of water.
In another preferred embodiment, (e) is performed by contacting a compound of Formula V with HCl in a solvent selected from methanol, acetonitrile, isopropyl alcohol, ethanol, propanol, acetone, methyl isobutyl ketone (MIBK), 2-butanone, and water.
In another preferred embodiment, (e) is performed by contacting a compound of Formula V with HCl in ethanol.
In another preferred embodiment, the compound of Formula I is a mono-HCl salt.
In another preferred embodiment, the compound of Formula I is crystalline.
In another preferred embodiment, the compound of Formula I is a solvate selected from ethanol, propanol, isopropanol, acetone, MIBK, 2-butanone, and water.
In a more preferred embodiment, the compound of Formula I is an ethanol solvate.
In another embodiment, the present invention provides a novel process for making a compound of Formula IVa:
comprising:
(b) coupling compounds of Formulas II and III to form a compound of Formula IVa.
In another preferred embodiment, the compound of Formula IVa is used without purification in (c).
In another preferred embodiment, (b) is performed by contacting a compound of Formula II with an acid activator, in a solvent and a first base, followed by contacting the resulting solution with a compound of Formula III.
In another preferred embodiment, (b) is performed by contacting a compound of Formula II with oxalyl chloride in acetonitrile and pyridine, followed by contacting the resulting solution with a compound of Formula III.
In another preferred embodiment, after a compound of Formula II has been contacted with a compound of Formula III, a second base is added to the reaction solution.
In another preferred embodiment, the second base is diisopropylethylamine.
In another embodiment, the present invention provides a novel process for making a compound of Formula II:
comprising:
(a) contacting a compound of Formula VI with a compound of Formula VII to form a compound of Formula VIII; and,
(a
1
) converting a compound of Formula VIII to a compound of Formula II.
In another embodiment, the present invention provides a novel compound of Formula I:
wherein I is a mono-HCl salt.
In another preferred embodiment, the compound of Formula I is crystalline.
In another preferred embodiment, the compound of Formula I is an ethanol solvate.
In another embodiment, the present invention provides a novel compound of Formula IV:
In another embodiment, the present invention provides a novel compound of Formula Va:
or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a compound of the present invention for use in therapy.
In another embodiment, the present invention provides the use of a compound of the present invention for the manufacture of a medicament for the treatment of a thromboembolic disorder.
DEFINITIONS
As used herein, the following terms and expressions have the indicated meanings. It will be appreciated that the compounds of the present invention may contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, diastereomeric, and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
The processes of the present invention are contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used. Industrial scale as

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