Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-22
2002-01-08
Solola, T. A. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06337405
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for preparing intermediates of aromatic amidine derivatives which have anticoagulation action based on excellent activated coagulation factor X (hereinafter abbreviated as FXa) inhibitory action and are described in Japanese Patent Application Laid-Open (kokai) No. 5-208946.
BACKGROUND ART
As intermediates of the aromatic amidine derivatives described in Japanese Patent Application Laid-Open (kokai) No. 5-208946, compounds of the following formulas (V), (Va), and (Vb), and salts thereof have conventionally been known:
[wherein R
1
represents a protective group for a nitrogen atom and R
3
represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms];
[wherein R
1
and R
3
have the same meanings as described above]; and
[wherein R
1
and R
3
have the same meanings as described above]. Processes for preparing the above compounds are also described in the cited publication.
A typical process for preparing these intermediates comprises the following steps:
brominating 7-methyl-2-naphthalenecarbonitrile to thereby form 7-bromomethyl-2-naphthalenecarbonitrile (first step);
further converting the 7-bromomethyl-2-naphthalenecarbonitrile to a phosphonium salt, [(7-cyano)-2-naphthyl)methyl]triphenylphosphonium bromide (second step);
synthesizing ethyl 2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidinyl]oxy]phenyl]-2-oxoacetate using a Mitsunobu reaction of ethyl 2-(4-hydroxyphenyl)-2-oxoacetate and (3R)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine (third step);
subjecting the obtained ethyl 2-[4-[[(3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidinyl]oxy]phenyl]-2-oxoacetate and the [(7-cyano)-2-nahpthyl)methyl]-triphenylphosphonium bromide to a Wittig reaction (fourth step);
further performing catalytic hydrogenation to thereby form compounds represented by formula (V) or (Va) (fifth step); and
dissolving compounds represented by formula (Va) in ethanol with heat, adding a small amount of sodium hydride thereto, and causing crystallization while stirring the mixture at room temperature, to thereby obtain compounds represented by formula (Vb) (sixth step).
However, the above-described prior art process has the following drawbacks:
1) bromination in the first step is performed in tetrachloromethane, which is a suspected carcinogen;
2) the product of the first step, i.e., 7-bromomethyl-2-naphthalenecarbonitrile, causes skin irritation when isolated as crystals;
3) comparatively expensive reagents, diethyl azodicarboxylate and 1,8-diazabicyclo[5.4.0]-7-undecene, are used;
4) by-products formed both in the third step and the fourth step behave as catalyst poisons in the catalytic hydrogenation of the fifth step, and in order to remove the by-products, it requires purification by silica gel column chromatography;
5) palladium oxide monohydrate-barium sulfate, which is a catalyst of the catalytic hydrogenation, must be prepared upon use; and
6) the yield of the sixth step is low and sodium hydride, which involves a safety problem, is used.
Briefly, the prior art process is unsatisfactory as an industrial process.
Accordingly, an object of the present invention is to provide an industrially satisfactory process for preparing compounds represented by formulas (V), (Va), and (Vb) and salts thereof, by use of safe, inexpensive, and easily available starting material(s) and auxiliary material(s) and without a silica gel chromatographic purification step, as well as to provide an industrial process for preparing intermediates of aromatic amidine derivatives which are described in Japanese Patent Application Laid-Open (kokai) No. 5-208946.
DISCLOSURE OF THE INVENTION
In view of the foregoing, the present inventors have conducted earnest studies and have found
that halogenation can be effectively performed in an alkylnitrile solvent in a first step, which permits the reaction to proceed to the next step without isolation of the product;
that use of a pyrrolidinyloxyphenylacetic acid derivative, obtained through condensation of 4-hydroxyphenylacetic acids and sulfonyloxypyrrolidines, as one starting material provides a compound represented by formula (V) or (Va) without requiring reaction to form a phosphonium salt and catalytic hydrogenation, and further without need for preparation of an expensive reagent or a reagent required upon use; and
that applying a base to a diasteromeric mixture of compounds represented by formula (Va) results in easy formation of compounds represented by formula (Vb). The present invention was accomplished based on these findings.
The present invention is generally represented by the following reaction schemes I and II:
[wherein R
1
represents a protective group for a nitrogen atom; R
2
represents a methanesulfonyl group or a p-toluenesulfonyl group; R
3
represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms; and X
1
represents a leaving group].
Accordingly, the present invention provides a process for preparing a compound represented by formula (III) or (IIIa) or salts thereof through reaction of a compound represented by formula (I) or (Ia) and a compound represented by formula (II) in the presence of a base.
The present invention also provides a process for preparing a compound represented by formula (V) (or (Va)) or salts thereof through reaction of a compound represented by formula (III) (or (IIIa)) or a salt thereof and a compound represented by formula (IV) in the presence of a base.
The present invention further provides a process for preparing a compound represented by formula (Vb) through reaction of a compound represented by formula (Va) and a base.
The present invention still further provides a process for preparing a compound represented by formula (IVa):
[wherein X
2
represents a halogen atom]; through halogenation of a compound represented by formula (VII) in an alkylnitrile solvent.
Of the compounds appearing in the above-described reaction schemes, some are novel compounds that have been newly found in the present invention. Accordingly, the present invention is also directed to such novel compounds which are useful as synthesis intermediates.
The present invention further provides compounds represented by formula (III):
[wherein R
1
and R
3
have the same meanings as described above], and salts thereof.
The present invention further provides compounds represented by formula (IIIa):
[wherein R
1
and R
3
have the same meanings as described above], and salts thereof.
The present invention still further provides compounds represented by formula (Vc):
[wherein R
1c
represents a tertiary butoxycarbonyl group and R
3c
represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms(other than an ethyl group)], and salts thereof.
The present invention yet further provides compounds represented by formula (Vd):
[wherein R
1d
represents a benzyl group and R
3d
represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms], and salts thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
The present will next be described in detail. Firstly, the substituents of the compounds according to the present invention are described.
R
1
represents a protective group for the nitrogen atom. Protective groups which are typically used may be employed for the protective group. Examples include a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a benzyl group, a formyl group, an acetyl group, and a triphenylmethyl group. In the present invention, a tert-butoxycarbonyl group or a benzyl group is preferred.
R
2
represents a methanesulfonyl group or a p-toluenesulfonyl group.
The alkyl group having 1 to 6 carbon atoms represented by R
3
may be linear, branched, or cyclic, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group,
Kobayashi Tatsuya
Koyama Takeo
Yokoyama Yukio
Daiichi Pharmaceutical Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Solola T. A.
Wright Sonya N.
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