U.S. patent application number 09/424227 was filed with the patent office on 2001-05-24 for process for preparing 3-(7-amidino-2-naphthyl)-2-phenylpropionic acid derivatives.
Invention is credited to MAKINO, TORU, YOKOYAMA, YUKIO.
Application Number | 20010001802 09/424227 |
Document ID | / |
Family ID | 15306044 |
Filed Date | 2001-05-24 |
United States Patent
Application |
20010001802 |
Kind Code |
A1 |
MAKINO, TORU ; et
al. |
May 24, 2001 |
PROCESS FOR PREPARING 3-(7-AMIDINO-2-NAPHTHYL)-2-PHENYLPROPIONIC
ACID DERIVATIVES
Abstract
A process for industrially preparing intermediates of aromatic
amidine derivatives having anticoagulant activity (Japanese Patent
Application Laid-Open No. 5-208946); i.e., compounds represented by
formula (3) or salts thereof by the following reaction scheme
including (1), (2), and (3), wherein R.sup.1 represents H, an
alkanoyl group, an alkoxycarbonyl group, an aralkyl group, an
aralkyloxycarbonyl group, or the like; and R.sup.3 represents H, an
alkyl group, or an alkanoyl group. 1
Inventors: |
MAKINO, TORU; (TOKYO,
JP) ; YOKOYAMA, YUKIO; (TOKYO, JP) |
Correspondence
Address: |
OBLON SPIVAK MCCLELLAND
MAIER & NEUSTADT
1755 JEFFERSON DAVIS HIGHWAY
FOURTH FLOOR
ARLINGTON
VA
22202
|
Family ID: |
15306044 |
Appl. No.: |
09/424227 |
Filed: |
November 26, 1999 |
PCT Filed: |
May 29, 1998 |
PCT NO: |
PCT/JP98/02379 |
Current U.S.
Class: |
562/440 ;
548/541; 548/556; 548/557; 548/569 |
Current CPC
Class: |
C07D 207/12
20130101 |
Class at
Publication: |
562/440 ;
548/541; 548/556; 548/557; 548/569 |
International
Class: |
C07D 27/04; C07D
27/12 |
Foreign Application Data
Date |
Code |
Application Number |
May 30, 1997 |
JP |
9/142042 |
Claims
1. A process for producing a compound represented by formula (2) or
a salt thereof: 9wherein R.sup.1 represents a hydrogen atom or an
alkyl group; R.sup.2 represents a hydrogen atom, an alkyl group, a
formyl group, an alkanoyl group, a carbamoyl group, a
monoalkylcarbamoyl group, a dialkylcarbamoyl group, a formimidoyl
group, an alkanoimidoyl group, a benzimidoyl group, a carboxyl
group, an alkoxycarbonyl group, a carboxyalkyl group, an
alkylcarbonylalkyl group, an aminoalkyl group, an alkanoylamino
group, an alkanoylaminoalkyl group, an aralkyl group, or an
aralkyloxycarbonyl group; and R.sup.3 represents a hydrogen atom,
an alkyl group, or an alkanoyl group; which process comprises
reacting a hydroxylamine compound with a compound represented by
formula (1) or a salt thereof: 10wherein R.sup.1 and R.sup.2 have
the same meanings as defined above.
2. A process for producing a compound represented by formula (3) or
a salt thereof: 11wherein R.sup.1 and R.sup.2 have the same
meanings as defined above; which process comprises reducing a
compound represented by formula (2) or a salt thereof: 12wherein
R.sup.1, R.sup.2, and R.sup.3 have the same meanings as defined
above.
3. A process for producing a compound represented by formula (3) or
a salt thereof: 13wherein R.sup.1 and R.sup.2 have the same
meanings as defined above; which process comprises reacting a
hydroxylamine compound represented formula (1) or a salt thereof:
14wherein R.sup.1 and R.sup.2 have the same meanings as defined
above; to thereby obtain a compound represented by formula (2) or a
salt thereof: 15wherein R.sup.1, R.sup.2, and R.sup.3 have the same
meanings as defined above; and subsequently reducing the resultant
compound represented by formula (2) or a salt thereof.
4. The process according to claim 1, wherein in formulas (1) and
(2), R.sup.2 is an alkanoyl group, an alkoxycarbonyl group, an
aralkyl group, or an aralkyloxycarbonyl group.
5. The process according to claim 2, wherein in formulas (2) and
(3), R.sup.2 is an alkanoyl group, an alkoxycarbonyl group, an
aralkyl group, or an aralkyloxycarbonyl group.
6. The process according to claim 3, wherein in formulas (1), (2),
and (3), R.sup.2 is an alkanoyl group, an alkoxycarbonyl group, an
aralkyl group, or an aralkyloxycarbonyl group.
7. A process for producing
2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]ph-
enyl]-3-(7-amidino-2-naphthyl)propionic acid or a salt thereof,
which comprises: deprotecting a compound of formula (3) or a salt
thereof obtained through the process as described in claim 5,
wherein R.sup.2 is an alkanoyl group, an alkoxycarbonyl group, an
aralkyl group, or an aralkyloxycarbonyl group, to thereby yield an
alkyl
3-(7-amidino-2-naphthyl)-2-[4-[[(3S)-3-pyrrolidinyl]oxy]phenyl]propionate
or a salt thereof; reacting the alkyl
3-(7-amidino-2-naphthyl)-2-[4-[[(3S-
)-3-pyrrolidinyl]oxy]phenyl]propionate or a salt thereof with alkyl
acetimidate or a salt thereof, to thereby yield an alkyl
2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-napht-
hyl)propionate or a salt thereof; and then hydrolyzing the alkyl
2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-napht-
hyl)propionate or a salt thereof.
8. A process for producing
2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]ph-
enyl]-3-(7-amidino-2-naphthyl)propionic acid or a salt thereof,
which comprises: deprotecting a compound of formula (3) or a salt
thereof obtained through the process as described in claim 6,
wherein R is an alkanoyl group, an alkoxycarbonyl group, an aralkyl
group, or an aralkyloxycarbonyl group, to thereby yield an alkyl
3-(7-amidino-2-naphthyl)-2-[4-[[(3S)-3-pyrrolidinyl]oxy]phenyl]propionate
or a salt thereof; reacting the alkyl
3-(7-amidino-2-naphthyl)-2-[4-[[(3S-
)-3-pyrrolidinyl]oxy]phenyl]propionate or a salt thereof with alkyl
acetimidate or a salt thereof, to thereby yield an alkyl
2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-napht-
hyl)propionate or a salt thereof; and then hydrolyzing the alkyl
2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-napht-
hyl)propionate or a salt thereof.
9. A compound represented by formula (2) or a salt thereof:
16wherein R.sub.1, R.sup.2, and R.sup.3 have the same meanings as
defined above.
10. Alkyl
3-[7-amino(hydroxyimino)methyl-2-naphthyl]-2-[4-[[(3S)-1-alkoxyc-
arbonyl-3-pyrrolidinyl]oxy]phenyl]-propionate or a salt
thereof.
11. Alkyl
3-[7-amino(hydroxyimino)methyl-2-naphthyl]-2-[4-[[(3S)-1-tert-bu-
toxycarbonyl-3-pyrrolidinyl]oxy]phenyl]-propionate or a salt
thereof.
12. Alkyl
3-[7-amino(hydroxyimino)methyl-2-naphthyl]-2-[4-[[(3S)-3-pyrroli-
dinyl]oxy]phenyl]propionate or a salt thereof.
13. The process according to claim 1, wherein the compound
represented by formula (1) is a compound of formula (I): 17wherein
R.sup.1 and R.sup.2 have the same meanings as defined above, and
the compound represented by formula (2) is a compound of formula
(II): 18wherein R.sup.1, R.sup.2, and R.sup.3 have the same
meanings as defined above.
14. The process according to claim 2, wherein the compound
represented by formula (2) is a compound of formula (II): 19wherein
R.sup.1, R .sup.2 and R .sup.3have the same meanings as defined
above, and the compound represented by formula (3) is a compound of
formula (III): 20wherein R.sup.1 and R.sup.2 have the same meanings
as defined above.
15. The process according to claim 3, wherein the compound
represented by formula (1) is a compound of formula (I): 21wherein
R.sup.1 and R.sup.2 have the same meanings as defined above, and
the compound represented by formula (2) is a compound of formula
(II): 22wherein R.sup.1, R.sup.2, and R.sup.3 have the same
meanings as defined above, and the compound represented by formula
(3) is a compound of formula (III): 23wherein R.sup.1 and R.sup.2
have the same meanings as defined above.
16. The process according to claim 13, wherein in formulas (I) and
(II), R.sup.2 is an alkanoyl group, an alkoxycarbonyl group, an
aralkyl group, or an aralkyloxycarbonyl group.
17. The process according to claim 14, wherein in formulas (II) and
(III), R.sup.2 is an alkanoyl group, an alkoxycarbonyl group, an
aralkyl group, or an aralkyloxycarbonyl group.
18. The process according to claim 15, wherein in formulas (I),
(II), and (III), R.sup.2 is an alkanoyl group, an alkoxycarbonyl
group, an aralkyl group, or an aralkyloxycarbonyl group.
19. A process for producing
(2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]-
oxy]phenyl]-3-(7-amidino-2-naphthyl)propionic acid or a salt
thereof, which comprises: deprotecting a compound of formula (III)
or a salt thereof obtained through the process as described in
claim 17, wherein R.sup.2 is an alkanoyl group, an alkoxycarbonyl
group, an aralkyl group, or an aralkyloxycarbonyl group, to thereby
yield an alkyl
(2S)-3-(7-amidino-2-naphthyl)-2-[4-[[(3S)-3-pyrrolidinyl]oxy]phenyl]propi-
onate or a salt thereof; reacting the alkyl
(2S)-3-(7-amidino-2-naphthyl)--
2-[4-[[(3S)-3-pyrrolidinyl]oxy]phenyl]propionate or a salt thereof
with alkyl acetimidate or a salt thereof, to thereby yield an alkyl
(2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2--
naphthyl)propionate or a salt thereof; and then hydrolyzing the
alkyl
(2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2--
naphthyl)propionate or a salt thereof.
20. A process for producing
(2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]-
oxy]phenyl]-3-(7-amidino-2-naphthyl)propionic acid or a salt
thereof, which comprises: deprotecting a compound of formula (III)
or a salt thereof obtained through the process as described in
claim 18, wherein R.sup.2 is an alkanoyl group, an alkoxycarbonyl
group, an aralkyl group, or an aralkyloxycarbonyl group, to thereby
yield an alkyl
(2S)-3-(7-amidino-2-naphthyl)-2-[4-[[(3S)-3-pyrrolidinyl]oxy]phenyl]propi-
onate or a salt thereof; reacting the alkyl
(2S)-3-(7-amidino-2-naphthyl)--
2-[4-[[(3S)-3-pyrrolidinyl]oxy]phenyl]propionate or a salt thereof
with alkyl acetimidate or a salt thereof, to thereby yield an alkyl
(2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2--
naphthyl)propionate or a salt thereof; and then hydrolyzing the
alkyl
(2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2--
naphthyl)propionate or a salt thereof.
21. A compound represented by formula (II) or a salt thereof:
24wherein R.sup.1, R.sup.2, and R.sup.3 have the same meanings as
defined above.
22. Alkyl
(2S)-3-[7-amino(hydroxyimino)methyl-2-naphthyl]-2-[4-[[(3S)-1-al-
koxycarbonyl-3-pyrrolidinyl]oxy]phenyl]propionate or a salt
thereof.
23. Alkyl
(2S)-3-[7-amino(hydroxyimino)methyl-2-naphthyl]-2-[4-[[(3S)-1-te-
rt-butoxycarbonyl-3-pyrrolidinyl]oxy]phenyl]propionate or a salt
thereof.
24. Alkyl
(2S)-3-[7-amino(hydroxyimino)methyl-2-naphthyl]-2-[4-[[(3S)-3-py-
rrolidinyl]oxy]phenyl]propionate or a salt thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to an intermediate for
preparing aromatic amidine derivatives having excellent
anticoagulant activity based on inhibition of activated blood
coagulation factor X (Japanese Patent Application Laid-Open (kokai)
No. 5-208946), and to a process for preparing the intermediate.
BACKGROUND ART
[0002] Japanese Patent Application Laid-Open (kokai) No. 5-208946
discloses, as intermediates for preparing an aromatic amidine
derivative, a compound represented by formula (3): 2
[0003] wherein R.sup.1 represents a hydrogen atom or an alkyl
group; and R.sup.2 represents a hydrogen atom, an alkyl group, a
formyl group, an alkanoyl group, a carbamoyl group, a
monoalkylcarbamoyl group, a dialkylcarbamoyl group, a formimidoyl
group, an alkanoimidoyl group, a benzimidoyl group, a carboxyl
group, an alkoxycarbonyl group, a carboxyalkyl group, an
alkylcarbonylalkyl group, an aminoalkyl group, an alkanoylamino
group, an alkanoylaminoalkyl group, an aralkyl group, or an
aralkyloxycarbonyl group;
[0004] and salts thereof. This publication also discloses a process
for preparing the compound and salts.
[0005] The process comprises the following steps: 3
[0006] wherein R.sup.1 and R.sup.2 have the same definitions as
described above and Et represents an ethyl group. That is, the
process comprises reacting a compound represented by formula (1)
(hereinafter referred to as nitrile compound (1)) or a salt thereof
with ethanol in the presence of an acid; and reacting the
thus-formed compound represented by formula (4) or a salt thereof
with ammonia, to thereby form a compound represented by formula (3)
(hereinafter referred to as amidine compound (3)) or a salt
thereof.
[0007] However, in the process, when R.sup.2 is a substituent
cleaved by an acid (e.g., an alkoxycarbonyl group such as a
tert-butoxycarbonyl), a by-product is formed. In addition,
epimerization partially proceeds to thereby lower the optical
purity of amidine compound (3). In order to suppress epimerization,
reaction temperature must be maintained low, which requires a
period of one week or more for synthesis of amidine compound (3)
from nitrile compound (1) or a salt thereof. Moreover, the process
is not suitable for large-scale production, in that a large amount
of hydrogen chloride gas and ammonia gas must be used.
DISCLOSURE OF THE INVENTION
[0008] In view of the foregoing, the present inventors have
conducted earnest studies, and have found an industrially
advantageous process for preparing amidine compound (3) or salts
thereof, which process permits production of the compound on a
large scale at high yield and with a short reaction time without
lowering the optical purity of the target compound.
[0009] The process according to the present invention is expressed
by the following reaction scheme I or II: Reaction Scheme I 4
[0010] wherein R.sup.3 represents a hydrogen atom, an alkyl group,
or an alkanoyl group; and R.sup.1 and R.sup.2 have the same
definitions as described above.
[0011] Accordingly, the present invention is directed to a process
for producing amidine compound (3) or a salt thereof--or a compound
represented by formula (III) (hereinafter referred to as amidine
compound (III)) or a salt thereof--which process comprises reacting
nitrile compound (1) or a salt thereof--or a compound represented
by formula (I) (hereinafter referred to as nitrile compound (I)) or
a salt thereof--with a hydroxylamine compound; and reducing the
thus-formed compound represented by formula (2) (hereinafter
referred to as amidoxime compound (2)) or a salt thereof, or the
thus-formed compound represented by formula (II) (hereinafter
referred to as amidoxime compound (II)) or a salt thereof.
[0012] The present invention is also directed to amidoxime compound
(2) or salts thereof--or amidoxime compound (II) or salts
thereof--the compounds and salts being useful intermediates in the
process according to the present invention.
BEST MODE FOR CARRYING OUT THE INVENTION
[0013] The present invention will next be described in detail.
First, substituents of the compounds of the present invention will
be described.
[0014] R.sup.1 represents a hydrogen atom or an alkyl group.
Examples of the alkyl group include linear, branched, or cyclic
C1-C6 alkyl groups. Specific examples include a methyl group, an
ethyl group, a propyl group, an isopropyl group, a butyl group, an
isobutyl group, a tert-butyl group, a pentyl group, a hexyl group,
a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a
cyclohexyl group. Of these, an alkyl group is preferred, with a
methyl group or an ethyl group being more preferred as R.sup.1.
[0015] R.sup.2 represents a hydrogen atom, an alkyl group, a formyl
group, an alkanoyl group, a carbamoyl group, a monoalkylcarbamoyl
group, a dialkylcarbamoyl group, a formimidoyl group, an
alkanoimidoyl group, a benzimidoyl group, a carboxyl group, an
alkoxycarbonyl group, a carboxyalkyl group, an alkylcarbonylalkyl
group, an aminoalkyl group, an alkanoylamino group, an
alkanoylaminoalkyl group, an aralkyl group, an aralkyloxycarbonyl
group, or an alkanoyl group.
[0016] When R.sup.2 is an alkyl group, examples thereof include the
same alkyl groups as described in relation to R.sup.1. Examples of
the alkanoyl group include a group formed of a linear, branched, or
cyclic C1-C6 alkyl group and a carbonyl group. Specific examples
include an acetyl group and a propionyl group.
[0017] Examples of the monoalkylcarbamoyl group include a carbamoyl
group in which one hydrogen atom is substituted with a linear,
branched, or cyclic C1-C6 alkyl group. Specific examples include a
monomethylcarbamoyl group, a monoethylcarbamoyl group, and a
monoisopropylcarbamoyl group.
[0018] Examples of the dialkylcarbamoyl group include a carbamoyl
group in which two hydrogen atoms are substituted with linear,
branched, or cyclic C1-C6 alkyl groups, which may be identical to
or different from each other. Specific examples include a
dimethylcarbamoyl group, a diethylcarbamoyl group, and an
ethylmethylcarbamoyl group.
[0019] The alkanoimidoyl group is a group formed of an alkyl group
and a --C(.dbd.NH)-- group. Examples include a
--C(.dbd.NH)--C.sub.1-6 alkyl group such as an acetimidoyl
group.
[0020] Examples of the alkoxycarbonyl group include a group formed
of a linear, branched, or cyclic C1-C6 alkoxyl group and a carbonyl
group. Specific examples include a methoxycarbonyl group, an
ethoxycarbonyl group, and a tert-butoxycarbonyl group.
[0021] Examples of the carboxyalkyl group include a group formed of
a carboxyl group and a linear, branched, or cyclic C1-C6 alkylene
group. Specific examples include a carboxymethyl group and a
carboxyethyl group.
[0022] Examples of the alkylcarbonylalkyl group include a group
formed of a linear, branched, or cyclic C1-C6 alkyl group, a
carbonyl group, and a linear, branched, or cyclic C1-C6 alkylene
group. Specific examples include a methylcarbonylmethyl group, a
methylcarbonylethyl group, and a ethylcarbonylmethyl group.
[0023] Examples of the aminoalkyl group include a group formed of
an amino group and a linear, branched, or cyclic C1-C6 alkylene
group. Specific examples include an aminomethyl group, an
aminoethyl group, and an aminopropyl group.
[0024] Examples of the alkanoylamino group include a group formed
of the above-described alkanoyl group and an imino group. Specific
examples include a formylamino group, an acetylamino group, and a
propionylamino group.
[0025] Examples of the alkanoylaminoalkyl group include a group
formed of the above-described alkanoylamino group and a linear,
branched, or cyclic C1-C6 alkylene group. Specific examples include
a formylaminomethyl group, an acetylaminomethyl group, a
propionylaminoethyl group.
[0026] Examples of the aralkyl group include a group formed of an
aryl group such as a phenyl group or a naphthyl group and a linear,
branched, or cyclic C1-C6 alkylene group. Specific examples include
a benzyl group, a phenethyl group, a triphenylmethyl group, and a
naphthylmethyl group.
[0027] Examples of the aralkyloxycarbonyl group include a group
formed of the above-described aralkyl group and an oxycarbonyl
group. Specific examples include a benzyloxycarbonyl group and a
p-nitrobenzyloxycarbonyl group.
[0028] In the present invention, examples of preferred R.sup.2
include a hydrogen atom, an alkanoyl group, an alkoxycarbonyl
group, an alkanoimidoyl group, an aralkyl group, or an
aralkyloxycarbonyl group. Of these, a hydrogen atom, an acetyl
group, a tert-butoxycarbonyl group, an acetimidoyl group, a benzyl
group, and a benzyloxycarbonyl group are more preferred.
[0029] R.sup.3 represents a hydrogen atom, an alkyl group, or an
alkanoyl group. When R.sup.3 is an alkyl group or an alkanoyl
group, example alkyl groups and example alkanoyl groups are the
same as described in relation to R.sup.1. In the present invention,
R.sup.3 is preferably a hydrogen atom.
[0030] The process according to the present invention will next be
described.
[0031] (Step A) Process for preparing amidoxime compound (2) or a
salt thereof or amidoxime compound (II) or a salt thereof
[0032] Amidoxime compound (2) or a salt thereof or amidoxime
compound (II) or a salt thereof can be prepared through reaction of
a hydroxylamine compound with nitrile compound (1) or a salt
thereof or nitrile compound (I) or a salt thereof, wherein nitrile
compound (1) or a salt thereof or nitrile compound (I) or a salt
thereof is prepared through a method described, for example, in
Japanese Patent Application Laid-Open (kokai) No. 5-208946.
[0033] Examples of the hydroxylamine compound include hydroxylamine
or a salt thereof and an O-alkylhydroxylamine or a salt thereof
such as O-methylhydroxylamine or O-ethylhydroxylamine. Such
hydroxylamines may be represented by formula NH.sub.2OR.sup.3,
wherein R.sup.3 has the same definition as described above. These
hydroxylamines may be used as such; e.g., in the form of liquid,
solid, or gas, in the reaction. When the hydroxylamine compound is
liquid, the compound may be used as a mixture with an appropriate
solvent, whereas when the compound is solid, it may be used as a
solution which is prepared by dissolving the compound in an
appropriate solvent.
[0034] Examples of preferred hydroxylamine compounds in the present
invention include hydroxylamine and a salt thereof. Specific
examples include hydroxylamine, hydroxylammonium chloride, and
hydroxylammonium sulfate. When they are used in the reaction, an
aqueous solution of hydroxylamine, hydroxylammonium chloride and/or
hydroxylammonium sulfate dissolved in an aqueous solution of sodium
hydroxide is preferable.
[0035] Reaction of a hydroxylamine compound with nitrile compound
(1) or a salt thereof or nitrile compound (I) or a salt thereof is
preferably carried out in a solvent.
[0036] Examples of the solvent include C1-C6 alcohols such as
methanol, ethanol, propanol, and butanol; ethers such as
tetrahydrofuran and diisopropyl ether; aprotic polar solvents such
as dimethylformamide and dimethyl sulfoxide; ketones such as
acetone; and water. These solvents may be used singly or in
combination of two or more species.
[0037] In the present invention, the solvent is preferably a C1-C6
alcohol or a solvent mixture containing a C1-C6 alcohol, more
preferably ethanol or a solvent mixture containing ethanol.
[0038] The solvent is used in an amount of 2-50 ml based on 1 g of
nitrile compound (1) or a salt thereof or nitrile compound (I) or a
salt thereof, preferably 5-15 ml. The reaction is carried out in
the temperature range of 0.degree. C. to the boiling point of an
employed solvent for 0.1-48 hours. Preferably, the reaction mixture
is refluxed for 1-6 hours.
[0039] The thus-formed amidoxime compound (2) or amidoxime compound
(II) can be isolated through crystallization, which is carried out
by cooling the reaction mixture. Alternatively, amidoxime compound
(2) or amidoxime compound (II) may also be crystallized from the
reaction mixture as a salt. Examples of the salt include mineral
acid salts such as hydrochloride and sulfate, and organic
sulfonates such as methanesulfonate and p-toluenesulfonate.
[0040] The reaction mixture may optionally be subjected to
extraction with a solvent such as ethyl acetate, chloroform,
dichloromethane, dichloroethane, toluene, or butanol. The resultant
extract containing amidoxime compound (2) or amidoxime compound
(II) may be used as is in the subsequent step.
[0041] (Step B) Process for preparing amidine compound (3) or a
salt thereof or amidine compound (III) or a salt thereof
[0042] Amidine compound (3) or a salt thereof may be prepared
through reduction of amidoxime compound (2) or a salt thereof, and
amidine compound (III) or a salt thereof may be prepared through
reduction of amidoxime compound (II) or a salt thereof.
Specifically, amidoxime compound (2) or a salt thereof or amidoxime
compound (II) or a salt thereof may be reduced by 1) hydrogenation
by use of a metallic catalyst, or 2) reduction in the presence of a
metal such as zinc, iron, or titanium.
[0043] Examples of metallic catalysts used in hydrogenation include
nickel catalysts, palladium catalysts, platinum catalysts, and
rhodium catalysts. A nickel catalyst refers to a nickel compound
and a nickel compound carried by carbon, barium sulfate, or
diatomaceous earth. The same applies to the case of other metallic
catalysts such as palladium, platinum, and rhodium catalysts.
[0044] In the process, a palladium catalyst is preferably used.
Examples of palladium catalysts include palladium black,
palladium-barium sulfate with barium sulfate serving as a carrier,
and palladium-carbon. Of these, palladium-carbon is preferably
used.
[0045] The amount of a metallic catalyst used in the process may be
appropriately determined, and, for example, 0.001-0.5 g of 10%
palladium-carbon may be used with respect to 1 g of amidoxime
compound (2) or a salt thereof or amidoxime compound (II) or a salt
thereof.
[0046] For hydrogenation by use of a metallic catalyst, examples of
a hydrogen source include hydrogen gas, isopropanol, silane, formic
acid, and a formic acid salt. Of these, formic acid is preferably
used. The hydrogen source may be used in an amount of 1 equivalent
or more, and, for example, when the hydrogen source is formic acid,
formic acid may be used in an amount of 2-10 equivalents.
[0047] Hydrogenation is preferably performed in a solvent. Examples
of the solvent include chloroform; dichloromethane; dichloroethane;
toluene; C1-C6 alcohols such as methanol, ethanol, propanol,
isopropanol, and butanol; ethers such as diethyl ether, diisopropyl
ether, and tetrahydrofuran; esters such as ethyl acetate and ethyl
formate; N,N-dimethylformamide; dimethylsulfoxide; and water. These
solvents may be used singly or in combination of two or more
species. In the process, C1-C6 alcohols and esters are preferably
used, and, of these, ethanol or ethyl acetate is particularly
preferred.
[0048] The amount of a solvent used in the reaction is 2-25 ml
based on 1 g of amidoxime compound (2) or a salt thereof or
amidoxime compound (II) or a salt thereof, preferably 2-15 ml. The
reaction temperature is between 0.degree. C. and the boiling point
of a used solvent, preferably between 5 and 30.degree. C. The
reaction time is 0.1-24 hours, preferably 0.5-5 hours.
[0049] Reduction in the presence of a metal such as zinc, iron, or
titanium is performed in the presence of an acid such as
hydrochloric acid or sulfuric acid, or a salt such as ammonium
hydrochloride, and the metal is used in an amount of 1 equivalent
or more. Reduction in the presence of a metal is preferably
performed in a solvent. Examples of the solvent include C1-C6
alcohols such as methanol, ethanol, propanol, isopropanol, and
butanol; N,N-dimethylformamide; dimethylsulfoxide; and water. These
solvents may be used singly or in combination of two or more
species. In the process, C1-C6 alcohols are preferably used, and of
these, methanol or ethanol is particularly preferred.
[0050] The amount of the solvent is 2-50 ml based on 1 g of
amidoxime compound (2) or a salt thereof or amidoxime compound (II)
or a salt thereof, preferably 5-15 ml. The reduction temperature is
between 0.degree. C. and the boiling point of the employed solvent,
preferably at the reflux temperature. The reduction time is 0.1-24
hours, preferably 2-8 hours. When reduction is performed in the
presence of a metal, a proton source is preferably used. Examples
of the proton source include mineral acids such as hydrochloric
acid, sulfuric acid, and nitric acid; salts of the mineral acids;
organic acids such as formic acid and acetic acid; and salts of the
organic acids. Of these, hydrochloric acid salts such as ammonium
hydrochloride are preferably used.
[0051] In accordance with needs, the reaction mixture after
reduction may be extracted by use of solvents for extraction such
as ethyl acetate, chloroform, dichloromethane, dichloroethane,
toluene, and butanol, and subsequently washed with water to thereby
remove an unnecessary acid and salt, and the thus-treated reaction
mixture may be used in the next step.
[0052] Amidine compound (3) or amidine compound (III) may be
purified by crystallization as a salt thereof from the reaction
mixture or the above-treated reaction mixture. Examples of salts of
amidine compound (3) or amidine compound (III) include mineral acid
salts such as hydrochlorides, hydrobromides, hydroiodides,
tetrafluoroboronates, perchlorates, nitrates, and sulfates; organic
sulfonates such as methanesulfonates, 2-hydroxyethanesulfonates,
p-toluenesulfonates, and benzenesulfonates; and carboxylic acid
salts such as formates, acetates, propionates, butyrates,
pivalonates, oxalates, malonates, succinates, glutarates, adipates,
tartrates, maleates, malates, mandelates, and benzoates. Of these,
methanesulfonates, acetates, fumarates, maleates, succinates,
mandelates, and benzoates are preferably used, and particularly
maleates are preferably used.
[0053] When R.sup.3 refers to a hydrogen atom, reduction of
amidoxime compound (2) or amidoxime compound (II) may be performed
after o-acylation by use of an acylating agent. After o-acylation,
reduction may be easily performed, which is preferable. In this
case, previously-acylated amidoxime compound (2) or amidoxime
compound (II) may be reduced, or these compounds may be reduced in
the presence of an acylating agent. Preferably, reduction is
performed in the presence of an acylating agent, in consideration
of convenience.
[0054] Examples of acylating agents include acid anhydrides such as
acetic anhydride, benzoic anhydride, maleic anhydride, and phthalic
anhydride; mixed acid anhydrides prepared from different carboxylic
acids or from carboxylic acids and acid anhydrides; and acid
chlorides such as benzoyl chloride and acetyl chloride. Specific
examples of mixed acid anhydrides include a mixture prepared from
formic acid and acetic anhydride. In the process, an acid anhydride
and a mixed acid anhydride are preferably used as an acylating
agent.
[0055] The amount of acylating agent used in acylation is 1
equivalent or more with respect to amidoxime compound (2) or
amidoxime compound (II). In the process, acetic anhydride or a
mixed acid anhydride prepared from formic acid and acetic anhydride
is preferably used, and the amount of the acylating agent is
equivalent to that of the amidoxime compound (2) or amidoxime
compound (II).
[0056] In order to convert the substituent (R.sup.2) on the
nitrogen atom of the pyrrolidinyl group of amidine compound (3) or
a salt thereof or amidine compound (III) or a salt thereof into a
hydrogen atom, deprotection may be performed on amidine compound
((3) or (III)) or a salt thereof, wherein R.sup.2 is a protective
group of the nitrogen atom of the pyrrolidine ring, including
alkoxycarbonyl groups such as a tert-butoxycarbonyl group; aralkyl
groups such as a benzyl group; aralkyloxycarbonyl groups such as a
benzyloxycarbonyl group; and alkanoyl groups such as an acetyl
group. Specifically, deprotection may be performed by use of known
reactions and methods, such as a method described in "Protective
Groups in Organic Synthesis. 2nd Edition" by T. W. Green and P. G.
M. Wuts. For example, in the case of an alkoxycarbonyl group,
deprotection proceeds easily by reaction with an acid. Examples of
employed acids include inorganic acids such as hydrochloric acid
and sulfuric acid, and organic acids such as methanesulfonic acid
and p-toluenesulfonic acid. The acid may be used in an equiamount
or more, or in great excess with respect to amidine compound ((3)
or (III)). The reaction is preferably carried out in a solvent, and
examples of employed solvents include ethanol, ethyl acetate,
toluene, and N,N-dimethylformamide. These solvents may be used
singly or in combination of two or more species. The reaction
temperature is between -10.degree. C. and the boiling temperature
of an employed solvent, and the reaction time is between five
minutes and 10 hours.
[0057] For example, when hydrochloric acid is used as an acid in
deprotection, 1-10 ml of an ethanol solution containing 30 wt. %
hydrochloric acid is used with respect to 1 g of amidine compound
(3) or a salt thereof or amidine compound (III) or a salt thereof.
In this case, deprotection may be performed at room temperature or
less for five minutes to two hours. When sulfuric acid,
methanesulfonic acid, or p-toluenesulfonic acid is used as an acid
in deprotection, the acid is used in an amount of 1-5 equivalents
and deprotection may be performed in ethanol for 1-5 hours with
refluxing.
[0058] A compound corresponding to amidine compound (3) wherein the
substituent (R.sup.2) on the nitrogen atom of the pyrrolidinyl
group is a hydrogen atom is represented by the following formula
(3'): 5
[0059] wherein R.sup.1 is the same as described above.
[0060] A compound corresponding to amidine compound (III) wherein
the substituent (R.sup.2) on the nitrogen atom of the pyrrolidinyl
group is a hydrogen atom is represented by the following formula
(III'): 6
[0061] wherein R.sup.1 is the same as described above.
[0062] After reaction or concentration, the compound prepared
through the above-described reaction may be purified by isolation
as a salt of the compound. Examples of the salts include mineral
acid salts such as hydrochlorides, hydrobromides, hydroiodides,
tetrafluoroboronates, perchlorates, nitrates, and sulfates; organic
sulfonates such as methanesulfonates, 2-hydroxyethanesulfonates,
p-toluenesulfonates, and benzenesulfonates; and carboxylic acid
salts such as formates, acetates, propionates, butyrates,
pivalonates, oxalates, malonates, succinates, glutarates, adipates,
tartrates, maleates, malates, mandelates, and benzoates.
[0063] In the process, a compound and/or a salt of the compound
comprises a solvate of the compound and a solvate of the salt of
the compound. Examples of solvents include water and C1-C6
alcohols.
[0064] The thus-obtained amidine compound ((3') or (III')) or a
salt thereof is reacted with alkyl acetimidate or a salt thereof,
to thereby produce alkyl
2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-a-
midino-2-naphthyl)propionate (an acetimidoyl compound), which is a
compound wherein the nitrogen atom on the pyrrolidine ring or the
acetimidoyl group of amidine compound ((3') or (III')) is
substituted, or to thereby produce a salt of the compound. In
addition, the thus-produced acetimidoyl compound or a salt thereof
is hydrolyzed to thereby prepare
2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-napht-
hyl)propionic acid or a salt thereof. In this case,
acetimidoylation is performed, for example, by reaction between
amidine compound (3') or a salt thereof and alkyl acetimidate or a
salt thereof in an appropriate solvent in the presence of a base
such as triethylamine, sodium hydroxide, or potassium hydroxide.
The thus-prepared acetimidoyl compound or a salt thereof is
hydrolyzed in the presence of a mineral acid such as hydrochloric
acid or sulfuric acid or an organic acid such as p-toluenesulfonic
acid at -20.degree. C. to the reflux temperature. The
aforementioned acetimidoylation and hydrolysis are described in
Japanese Patent Application Laid-Open (kokai) No. 5-208946.
EXAMPLE 1
[0065] Ethyl
(2S)-3-[7-amino(hydroxyimino)methyl-2-naphthyl]-2-[4-[[(3S)-1-
-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]phenyl]propionate
[0066] Hydroxylammonium sulfate (32.83 g) was dissolved in a 5N
aqueous solution of sodium hydroxide (76 ml) at room temperature.
The solution was added to ethanol (520 ml) with stirring. Ethyl
(2S)-2-[4-[[(3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cy-
ano-2-naphtyl)propionate (51.46 g) was suspended in the resultant
solution at room temperature, followed by refluxing for 2 hours
with stirring under heat. After completion of reaction was
confirmed through TLC (chloroform:acetone=3:1), the resultant
mixture was left to cool, and a precipitated inorganic salt was
removed through filtration. The filtrate was subjected to
crystallization at room temperature overnight with stirring. Water
(520 ml) was added to the thus-formed suspension and the resultant
mixture was further stirred for 3 hours at room temperature. The
formed crystals were collected through filtration with suction.
After being air-dried for one day, the crystals were dried at
50.degree. C. under reduced pressure for 8 hours, to thereby yield
53.14 g of the target compound (colorless crystals).
[0067] .sup.1H-NMR (DMSO-d.sub.6, ref. TMS=0. 00 ppm) .delta.: 1.00
(3H, t, J=7 Hz), 1.38 (9H, d, J=5 Hz), 1.9.about.2.2 (2H, m),
3.1.about.3.6 (6H, m), 3.9.about.4.1 (3H, m), 4.95 (1H, m) , 5.91
(2H, br), 6.89 (2H, d, J=8 Hz), 7.29 (2H, d, J=8 Hz), 7.39 (1H, d,
J=9 Hz), 7.67 (1 H, s) 7.7.about.7.9 ( 3H, m) , 8.09 (1H, s), 9.76
(1H, br).
[0068] FAB-MS: 548 (M+1), 532
EXAMPLE 2
[0069] Ethyl
(2S)-3-(7-amidino-2-naphtyl)-2-[4-[[(3S)-1-tert-butoxycarbony-
l-3-pyrrolidinyl]oxy]phenyl]propionate maleic acid salt
[0070] Ethyl
(2S)-3-[7-amino(hydroxyimino)methyl-2-naphtyl]-2-[4-[[(3S)-1--
tert-butoxycarbonyl-3-pirrolidinyl]oxy]phenyl]propionate (5.476 g)
and 10% palladium-carbon (0.548 g) were suspended in ethanol (50
ml). Acetic anhydride (0.95 ml) and formic acid (1.90 ml) were
added to the suspension at room temperature with stirring. The
resultant mixture was stirred at room temperature for 2 hours.
After completion of reaction was confirmed, palladium-carbon was
removed through filtration. After the filtrate was concentrated
under reduced pressure, ethyl acetate (100 ml) and maleic acid
(1.161 g) were added to the residue. The resultant mixture was
heated at 85.degree. C. for 10 minutes with stirring. After the
mixture was cooled, precipitated crystals were collected through
filtration. The crystals were dried at 50.degree. C. under reduced
pressure, to thereby yield 5.168 g of the target compound.
[0071] .sup.1H-NMR (DMSO-d.sub.6, ref. TMS=0. 00 ppm) .delta.: 1.00
(3H, t, J=7 Hz) , 1.39 (9H, d, J=6 Hz) 1.9.about.2.2 (2H, m),
3.1.about.3.6 (6H, m), 3.9.about.4.2 ( 3H, m), 4.95 (1H, m) , 6.02
(2H, s), 6.89 (2H, d, J=9 Hz), 7.29 (2H, d, J=9 Hz), 7.62 (1H, d d,
J=8,1 Hz), 7.74 (1H, d d, J=8,1 Hz), 7.85 (1H, s), 7.96 (1H, d, J=8
Hz), 8.08 (1H, d, J=8 Hz), 8.34 (1H, s) ,8.96, 9.40 (each 2H,
br).
EXAMPLE 3
[0072] Ethyl
(2S)-3-(7-amidino-2-naphtyl)-2-[4-[[(3S)-3-pyrrolidinyl]oxy]p-
henyl]propionate dihydrochloride
[0073] Hydroxylammonium sulfate (1.64 g) was dissolved in a 5N
aqueous solution of sodium hydroxide (3.8 ml) at room temperature.
The resultant solution was added to ethanol (52 ml) with stirring.
In the resultant mixture was suspended ethyl
(2S)-2-[4-[[(3S)-1-tert-butoxycarbonyl-3-pyrr-
olidinyl]oxy]phenyl]-3-(7-cyano-2-naphtyl) propionate (5.15 g). The
suspension was heated with stirring and refluxed for 4 hours. After
completion of reaction was confirmed through TLC
(chloroform:acetone=3:1)- , the resultant mixture was left to cool
and concentrated under reduced pressure. The residue was dissolved
by addition of ethyl acetate (50 ml) and water (50 ml). The ethyl
acetate phase was separated and washed with water (50 ml), to
thereby obtain a solution of ethyl
(2S)-3-[7-amino(hydroxyimino)methyl-2-naphtyl]-2-[4-[[(3S)-1-tert-butoxyc-
arbonyl-3-pyrrolidinyl]oxy]phenyl]propionate in ethyl acetate. 10%
Palladium-carbon (0.548 g) was suspended in the solution. To the
thus-formed suspension were added acetic anhydride (0.95 ml) and
formic acid (1.90 ml) at 15.degree. C. with stirring. After the
mixture was stirred at 15.degree. C. for 2 hours and completion of
reaction was confirmed, 30% hydrogen chloride-ethanol (27 ml) was
added and the resultant mixture was further subjected to stirring
at 15.degree. C. for 30 minutes. After completion of reaction was
confirmed through HPLC, the solvent was concentrated to about half
the amount under reduced pressure. Ethanol (27 ml) was added to the
thus-concentrated solution and the resultant mixture was diluted,
followed by filtration for removal of palladium-carbon. The
filtrate was concentrated at reduced pressure. The residue was
added to water (50 ml) and allowed to dissolve at room temperature.
The thus-formed solution was purified though column chromatography
employing a highly porous polymer type synthesized adsorbent
(styrene-divinylbenzene polymer; DIAION HP-20) while a mixture of
water and acetonitrile was used as a solvent. A small amount of
diluted hydrochloric acid was added to the fraction containing the
target compound. The resultant mixture was dried to solidify under
reduced pressure to thereby obtain 4.62 g of the target compound.
The thus-obtained ethyl
(2S)-3-(7-amidino-2-naphtyl)-2-[4-[[(3S)-3-pyrrolidin-
yl]oxy]phenyl]propionate dihydrochloride was found to be identical
to the compound obtained from synthesis described in Example 34 of
Japanese Patent Application Laid-Open (kokai) No. 5-208946.
Reference Example 1
[0074]
(2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amid-
ino-2-naphtyl)propionic acid dihydrochloride.
[0075]
((2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-ami-
dino-2-naphtyl)propionis acid dihydrochloride (103.6 g) was
obtained through the method described in Example 34, 40, or 46 of
Japanese Patent Application Laid-Open (kokai) No. 5-208946, by use
of ethyl
(2S)-2-[4-[[(3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cy-
ano-2-naphtyl)propionate (123.1 g, Optical purity: 99.7%). Optical
purity of the thus-obtained compound was 94.8%de when measured
under the HPLC conditions described in Example 46 of the
specification of the above publication.
EXAMPLE 4
[0076]
(2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amid-
ino-2-naphtyl)propionic acid dihydrochloride.
[0077] Ethyl
(2S)-3-(7-amidino-2-naphtyl)-2-[4-[[(3S)-3-pyrrolidinyl]oxy]p-
henyl]propionate dihydrochloride (4.60 g) obtained from the
synthesis described in Example 3 was used in the method described
in Example 40 or 46 of Japanese Patent Application Laid-Open
(kokai) No. 5-208946, to thereby obtain the target compound (4.35
g). Optical purity of the thus-obtained compound was 99.1% de when
measured under the HPLC conditions described in Example 46 of the
specification of the above publication. Further, through treatment
similar to that described in Example 52 of the specification of the
above publication,
(2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2--
naphtyl)propionic acid hydrochloride pentahydrate was obtained.
[0078] Industrial Applicability
[0079] Through a process disclosed in Japanese Patent Application
Laid-Open (kokai) No. 5-208946; i.e., 7
[0080] {wherein Et represents an ethyl group and Boc represents a
tert-butoxycarbonyl group}, a
(2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidin-
yl]oxy]phenyl]-3-(7-amidino-2-naphthyl)propionic acid
dihydrochloride represented by formula (IIIa) is derived from ethyl
(2S)-2-[4-[[(3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-cy-
ano-2-naphthyl)propionate represented by (Ia) and having an optical
purity of 99.7% de. In this case, the obtained compound (IIIa) has
an optical purity of 94.8% de (see Reference Example 1).
[0081] In contrast, through a process according to the present
invention; i.e., 8
[0082] {wherein Et and Boc have the same definitions as described
above}, compound (IIIa) is derived from compound (Ia) having an
optical purity of 99.7 % de. In this case, the obtained compound
(IIIa) has an optical purity of 99.1% de and a high optical purity
is maintained (see Example 4). Briefly, substantial epimerization
was not observed in the process according to the present
invention.
[0083] The process according to the present invention is
advantageous in that it can produce, on an industrial scale,
intermediates for preparing aromatic amidine derivatives described
in Japanese Patent Application Laid-Open (kokai) No. 5-208946
without lowering the optical purity.
* * * * *