U.S. patent application number 14/848787 was filed with the patent office on 2016-02-25 for method for manufacturing neuraminic acid derivatives.
This patent application is currently assigned to DAIICHI SANKYO COMPANY, LIMITED. The applicant listed for this patent is DAIICHI SANKYO COMPANY, LIMITED. Invention is credited to Masayuki MURAKAMI, Yoshitaka NAKAMURA, Kazuhiro UMEO, Masakazu WAKAYAMA, Makoto YAMAOKA.
Application Number | 20160052906 14/848787 |
Document ID | / |
Family ID | 39750971 |
Filed Date | 2016-02-25 |
United States Patent
Application |
20160052906 |
Kind Code |
A1 |
NAKAMURA; Yoshitaka ; et
al. |
February 25, 2016 |
METHOD FOR MANUFACTURING NEURAMINIC ACID DERIVATIVES
Abstract
A method for manufacturing a compound represented by the
following formula (I): ##STR00001## wherein R.sup.1 represents a
C.sub.1-C.sub.19 alkyl, R.sup.2 represents a C.sub.1-C.sub.4 alkyl,
and Ac represents an acetyl, wherein the compound of the formula
(I) is optionally contained with up to 10 wt. % of a compound
represented by the following formula (II): ##STR00002## or a
pharmacologically acceptable salt thereof, involving reacting a
compound represented by the following formula (13): ##STR00003##
wherein R.sup.2 represents a C.sub.1-C.sub.4 alkyl and Ac
represents an acetyl, with a compound represented by the formula
R.sup.1C(OR.sup.7).sub.3, wherein R.sup.1 represents a
C.sub.1-C.sub.19 alkyl and R.sup.7 represents a C.sub.1-C.sub.6
alkyl, or a pharmacologically acceptable salt thereof.
Inventors: |
NAKAMURA; Yoshitaka;
(Kanagawa, JP) ; MURAKAMI; Masayuki; (Kanagawa,
JP) ; YAMAOKA; Makoto; (Kanagawa, JP) ;
WAKAYAMA; Masakazu; (Kanagawa, JP) ; UMEO;
Kazuhiro; (Kanagawa, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DAIICHI SANKYO COMPANY, LIMITED |
Tokyo |
|
JP |
|
|
Assignee: |
DAIICHI SANKYO COMPANY,
LIMITED
Tokyo
JP
|
Family ID: |
39750971 |
Appl. No.: |
14/848787 |
Filed: |
September 9, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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|
13966863 |
Aug 14, 2013 |
|
|
|
14848787 |
|
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|
|
13795050 |
Mar 12, 2013 |
8575370 |
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|
13966863 |
|
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|
12450699 |
Oct 7, 2009 |
8455659 |
|
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PCT/JP2008/057557 |
Apr 11, 2008 |
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|
13795050 |
|
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Current U.S.
Class: |
549/424 |
Current CPC
Class: |
A61P 43/00 20180101;
C07C 41/60 20130101; C07D 309/28 20130101; A61P 31/16 20180101;
C07D 498/04 20130101; C07D 231/14 20130101; C07D 407/06 20130101;
A61K 31/351 20130101; C07C 41/60 20130101; C07C 43/32 20130101 |
International
Class: |
C07D 309/28 20060101
C07D309/28 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 11, 2007 |
JP |
2007-103585 |
Claims
1. A method for manufacturing a compound represented by the
following formula (I): ##STR00075## wherein R.sup.1 represents a
C.sub.1-C.sub.19 alkyl group, R.sup.2 represents a C.sub.1-C.sub.4
alkyl group, and Ac represents an acetyl group, wherein the
compound represented by the formula (I) is optionally contained
with up to 10 wt. % of a compound represented by the following
formula (II): ##STR00076## wherein R.sup.1, R.sup.2 and Ac have the
same meanings as in the formula (I), or a pharmacologically
acceptable salt thereof, the method comprising: reacting a compound
represented by the following formula (13): ##STR00077## wherein
R.sup.2 represents a C.sub.1-C.sub.4 alkyl group and Ac represents
an acetyl group, with a compound represented by the formula
R.sup.1C(OR.sup.7).sub.3, wherein R.sup.1 represents a
C.sub.1-C.sub.19 alkyl group and R.sup.7 represents a
C.sub.1-C.sub.6 alkyl group, or a pharmacologically acceptable salt
thereof.
2. The method according to claim 1, wherein R.sup.1 is a 1-heptyl
group, R.sup.2 is a methyl group and R.sup.7 is a methyl group.
3. A method for manufacturing a compound represented by the
following formula (I): ##STR00078## wherein R.sup.1 represents a
C.sub.1-C.sub.19 alkyl group, R.sup.2 represents a C.sub.1-C.sub.4
alkyl group and Ac represents an acetyl group, wherein the compound
represented by the formula (I) is optionally contained with up to
10 wt. % of a compound represented by the following formula (II):
##STR00079## wherein R.sup.1, R.sup.2 and Ac have the same meanings
as in the formula (I), or a pharmacologically acceptable salt
thereof, the method comprising: reacting a compound represented by
the following formula (13): ##STR00080## wherein R.sup.2 represents
a C.sub.1-C.sub.4 alkyl group and Ac represents an acetyl group,
with a compound represented by the following formula (15):
##STR00081## wherein R.sup.1 represents a C.sub.1-C.sub.19 alkyl
group, R.sup.7 represents a with a compound represented by the
formula R.sup.7--OH, wherein R.sup.7 represents a C.sub.1-C.sub.6
alkyl group.
4. The method according to claim 3, wherein R.sup.1 is a 1-heptyl
group, R.sup.2 is a methyl group, R.sup.7 is a methyl group and X
is Cl.
5. A method for manufacturing a compound represented by the formula
(Ib): ##STR00082## wherein Ac represents an acetyl group and Me
represents a methyl group, and the compound represented by the
formula (Ib) is optionally contained with a compound represented by
the following formula (IIb): ##STR00083## wherein in the formula
(IIb), Ac and Me have the same meanings as in the formula (Ib), or
a pharmacologically acceptable salt thereof, the method comprising:
reacting the following compound (4) with the following compound (5)
to produce the following compound (7) as follows: ##STR00084##
wherein R.sup.3 is a methyl group and R.sup.4 and R.sup.5 together
form an oxo group; reacting compound (7) with a compound
represented by the formula (R.sup.2O).sub.2SO.sub.2, wherein
R.sup.2 is a methyl group, in the presence of a base to produce the
following compound (8): ##STR00085## reacting compound (8) with
trimethylsilyl azide in the presence of a Lewis acid to produce the
following compound (9): ##STR00086## treating compound (9) with
triphenylphosphine and treating the compound thus obtained with a
base and water to produce the following compound (10): ##STR00087##
reacting compound (10) with the following compound (11)
##STR00088## to produce the following compound (12): ##STR00089##
wherein Boc is a tert-butoxycarbonyl group; reacting compound (12)
with water to produce the following compound (13): ##STR00090## and
reacting compound (13) with the following compound (14):
R.sup.1C(OR.sup.7).sub.3 (14) , wherein R.sup.1 is a
C.sub.1-C.sub.19 alkyl group and R.sup.7 is a C.sub.1-C.sub.6 alkyl
group, in the presence of an acid to produce the compound of
formula (Ib), which is optionally contained with the compound of
the formula (IIb).
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of application
Ser. No. 13/966,863 filed Aug. 14, 2013, which is a divisional
application of application Ser. No. 13/795,050 filed Mar. 12, 2013
(U.S. Pat. No. 8,575,370), which is a divisional application of
application Ser. No. 12/450,699 filed Oct. 7, 2009 (U.S. Pat. No.
8,455,659), which is the United States national phase application
under 35 USC 371 of International application PCT/JP2008/057557
filed Apr. 11, 2008. The entire contents of each of application
Ser. No. 13/966,863, application Ser. No. 13/795,050, application
Ser. No. 12/450,699 and International application PCT/JP2008/057557
are hereby incorporated by reference herein.
TECHNICAL FIELD
[0002] The present invention relates to a method for manufacturing
neuraminic acid derivatives which have neuraminidase inhibitory
activity, and to synthetic intermediates of the neuraminic acid
derivatives and methods for their manufacture. In addition, the
present invention relates to neuraminic acid derivatives having
high purity.
[0003] A compound represented by the formula (I):
##STR00004##
[wherein R.sub.1 represents a C.sub.1-C.sub.19 alkyl group and
R.sub.2 represents a C.sub.1-C.sub.4 alkyl group] or a
pharmacologically acceptable salt thereof is known to have
excellent neuraminidase inhibitory activity and therefore to be
useful as a drug for treatment or prevention of influenza (Patent
Document 1 or 2).
[0004] A trifluoroacetic acid salt of a compound represented by the
formula (III):
##STR00005##
is known to have excellent neuraminidase inhibitory activity and
therefore to be useful as a drug for treatment or prevention of
influenza (Non-patent Document 1 or 2).
[0005] Process W is known as a method for manufacturing a compound
represented by the formula (Ia), which is embraced in a compound
represented by the formula (I) or a pharmacologically acceptable
salt thereof, [hereinafter also referred to as "compound (Ia)"; the
same shall be applied with respect to other formulas] (Patent
Document 1). In Process W, n-Hep represents a 1-heptyl group.
##STR00006## ##STR00007##
[0006] Process X is known as a method for manufacturing compound
(Ib), which is embraced in compound (I) or a pharmacologically
acceptable salt thereof (Patent Document 2). Compound (IVk) is a
synthetic intermediate in Process W. In Process X, n-Hep represents
a 1-heptyl group.
##STR00008##
[0007] Process Y is known as a method for manufacturing compound
(IIIa), which is a trifluoroacetic acid salt of compound (III)
(Non-patent Document 1). The procedures from compound (IVc) to
compound (IVe) and from compound (IVf) to compound (IVh) in Process
Y are the same as in Process W.
##STR00009## ##STR00010##
[0008] Process Z is known as a method for manufacturing compound
(IIIa), which is a trifluoroacetic acid salt of compound (III)
(Non-patent Document 2). In Process Z, the procedure from compound
(IVf) to compound (IVh) is the same as in Process W, and the
procedure from compound (IVh) to compound (IIIa) is the same as in
Process Y.
##STR00011## ##STR00012##
[0009] From the viewpoint of industrial production, the
aforementioned Process W, Process Y, or Process Z could be improved
in points such as the following:
[Process W]
[0010] (1) the overall yield is low since a procedure with a low
yield is included [overall yield of compound (Ia): 0.2%]; (2)
N-methylation of an acetamide group occurs as a side reaction of
methylation reaction of a hydroxy group [production procedure of
compound (IVb)]; (3) an inefficient enzyme reaction is included
[production procedure of compound (IVd)]; (4) a hazardous azidation
reaction at high temperature is included [production procedure of
compound (IVg)]; or (5) in the acylation reaction, (a) protection
of a carboxyl group is necessary, (b) 2,3-diacylated product is
generated as by-product, and (c) purification by silica gel column
chromatography is necessary to remove octanoic acid derived from
the reagent [production procedure of compound (IVk)];
[Process Y]
[0011] (1) the overall yield is low since a procedure with a low
yield is included [yield of compound (Va): 34%, overall yield from
compound (Va) to compound (IIIa): 10 to 23%, resulting in 3 to 8%];
(2) an inefficient enzyme reaction is included [production
procedure of compound (IVd)]; or (3) a hazardous azidation reaction
at high temperature is included [production procedure of compound
(IVg)];
[Process Z]
[0012] (1) the overall yield is low since a procedure with a low
yield is included [yield of compound (VIa): 35%, overall yield from
compound (VIa) to compound (IIIa): 1 to 33%, resulting in 0.4 to
12%]; (2) an expensive silyl protective group is used; (3)
N-methylation of an acetamide group occurs as a side reaction of
the methylation reaction of a hydroxy group [production procedure
of compound (IVb)]; or (4) a hazardous azidation reaction at high
temperature is included [production procedure of compound (IVg)]
[0013] [Patent Document 1] U.S. Pat. No. 6,340,702 (corresponding
to Japanese Patent No. 3209946) [0014] [Patent Document 2] U.S.
Pat. No. 6,844,363 (corresponding to Japanese Patent Application
No. 2002-012590) [0015] [Non-patent Document 1] T. Honda et al.,
Bioorganic Medicinal Chemistry Letters, 2002, pp. 1921-1924 [0016]
[Non-patent Document 2] T. Honda et al., Bioorganic Medicinal
Chemistry Letters, 2002, pp. 1925-1928
[0017] As a result of conducting extensive studies on methods for
manufacturing neuraminic acid derivatives, the inventors of the
present invention have found a novel method for manufacturing
neuraminic acid derivatives via novel synthetic intermediates of
the present invention that is superior to publicly known
manufacturing methods from an industrial perspective, and have
found that neuraminic acid derivatives with high purity can be
obtained in high yield by the manufacturing method. The present
invention has been completed based on the aforementioned
findings.
SUMMARY OF THE INVENTION
[0018] The present invention provides a method for manufacturing
neuraminic acid derivatives which have neuraminidase inhibitory
activity, and synthetic intermediates of the neuraminic acid
derivatives and methods for their manufacture. In addition, the
present invention provides neuraminic acid derivatives having high
purity.
[0019] The present invention provides a method for manufacturing a
neuraminic acid derivative shown by the following Process A:
##STR00013## ##STR00014##
[0020] In the aforementioned Process A, R.sup.1 represents a
C.sub.1-C.sub.19 alkyl group, R.sup.2 represents a C.sub.1-C.sub.4
alkyl group, R.sup.3, R.sup.6 and R.sup.7, independently from one
another, represent a C.sub.1-C.sub.6 alkyl group, R.sup.4 and
R.sup.5, independently from each other, represent a hydrogen atom,
a C.sub.1-C.sub.6 alkyl group or a phenyl group, or R.sup.4 and
R.sup.5 together form a tetramethylene group, a pentamethylene
group or oxo group except that R.sup.4 and R.sup.5 in compound (6)
do not form an oxo group. Here, Ac represents an acetyl group, Boc
represents a tert-butoxycarbonyl group, and Ph represents a phenyl
group. The same applies for these three groups hereinafter.
[0021] According to one aspect of the present invention, there is
provided
[1] a method for manufacturing a compound represented by the
formula (7):
##STR00015##
[wherein R.sup.3 represents a C.sub.1-C.sub.6 alkyl group, and
R.sup.4 and R.sup.5, independently from each other, represent a
hydrogen atom, a C.sub.1-C.sub.6 alkyl group or a phenyl group, or
R.sup.4 and R.sup.5 together form a tetramethylene group, a
pentamethylene group or an oxo group], comprising: allowing a
compound represented by the formula (4):
##STR00016##
[wherein R.sup.3 represents a C.sub.1-C.sub.6 alkyl group] to react
with a compound represented by the formula (5):
##STR00017##
[wherein R.sup.4 and R.sup.5, independently from each other,
represent a hydrogen atom, a C.sub.1-C.sub.6 alkyl group or a
phenyl group, or R.sup.4 and R.sup.5 together form a tetramethylene
group, a pentamethylene group or an oxo group, and R.sup.6
represents a C.sub.1-C.sub.6 alkyl group], or with a compound
represented by the formula (6):
##STR00018##
[wherein R.sup.4 and R.sup.5, independently from each other,
represent a hydrogen atom, a C.sub.1-C.sub.6 alkyl group or a
phenyl group, or R.sup.4 and R.sup.5 together form a tetramethylene
group or a pentamethylene group] except that R.sup.4 and R.sup.5 in
compound (7) do not together form an oxo group when compound (6) is
used, [2] the manufacturing method as described in [1], wherein a
compound represented by the formula (7) is manufactured by the
reaction of a compound represented by the formula (4) with a
compound represented by the formula (5), and R.sup.3 is a methyl
group, R.sup.4 and R.sup.5 together form an oxo group, and the
compound represented by the formula (5) is dimethyl carbonate, [3]
a compound represented by the formula (7):
##STR00019##
[wherein R.sup.3 represents a C.sub.1-C.sub.6 alkyl group, R.sup.4
and R.sup.5, independently from each other, represent a hydrogen
atom, a C.sub.1-C.sub.6 alkyl group or a phenyl group, or R.sup.4
and R.sup.5 together form a tetramethylene group, a pentamethylene
group or an oxo group], [4] the compound as described in [3],
wherein R.sup.3 is a methyl group, and R.sup.4 and R.sup.5 together
form an oxo group, [5] a method for manufacturing a compound
represented by the formula (9):
##STR00020##
[wherein R.sup.2 represents a C.sub.1-C.sub.4 alkyl group, R.sup.3
represents a C.sub.1-C.sub.6 alkyl group, and R.sup.4 and R.sup.5,
independently from each other, represent a hydrogen atom, a
C.sub.1-C.sub.6 alkyl group or a phenyl group, or R.sup.4 and
R.sup.5 together form a tetramethylene group, a pentamethylene
group or an oxo group], comprising: allowing a compound represented
by the formula (8):
##STR00021##
[wherein R.sup.2 represents a C.sub.1-C.sub.4 alkyl group, R.sup.3
represents a C.sub.1-C.sub.6 alkyl group, R.sup.4 and R.sup.5,
independently from each other, represent a hydrogen atom, a
C.sub.1-C.sub.6 alkyl group or a phenyl group, or R.sup.4 and
R.sup.5 together form a tetramethylene group, a pentamethylene
group or an oxo group] to react with trimethylsilyl azide in the
presence of a Lewis acid, [6] the manufacturing method as described
in [5], wherein R.sup.2 is a methyl group, R.sup.3 is a methyl
group, R.sup.4 and R.sup.5 together form an oxo group, and the
Lewis acid is titanium (IV) isopropoxide, [7] a method for
manufacturing a compound represented by the formula (13)
##STR00022##
[wherein R.sup.2 represents a C.sub.1-C.sub.4 alkyl group],
comprising: allowing a compound represented by the formula
(12):
##STR00023##
[wherein R.sup.2 represents a C.sub.1-C.sub.4 alkyl group] to react
with water, [8] the manufacturing method as described in [7],
wherein R.sup.2 is a methyl group, [9] a compound represented by
the formula (13):
##STR00024##
[wherein R.sup.2 represents a C.sub.1-C.sub.4 alkyl group], [10]
the compound as described in [9], wherein R.sup.2 is a methyl
group, [11] a method for manufacturing a compound represented by
the formula (I):
##STR00025##
[wherein R.sup.1 represents a C.sub.1-C.sub.19 alkyl group and
R.sup.2 represents a C.sub.1-C.sub.4 alkyl group], [here, the
compound represented by the formula (I) may include a compound
represented by the formula (II):
##STR00026##
[wherein R.sup.1 and R.sup.2 have the same meanings as in the
formula (I)]], or a pharmacologically acceptable salt thereof
comprising: allowing a compound represented by the formula
(13):
##STR00027##
[wherein R.sup.2 represents a C.sub.1-C.sub.4 alkyl group] to react
with a compound represented by the formula R.sup.1C(OR.sup.7).sub.3
[wherein R.sup.1 represents a C.sub.1-C.sub.19 alkyl group and
R.sup.7 represents a C.sub.1-C.sub.6 alkyl group], or a
pharmacologically acceptable salt thereof, [12] the manufacturing
method as described in [11], wherein R.sup.1 is a 1-heptyl group,
R.sup.2 is a methyl group, and R.sup.7 is a methyl group, [13] a
method for manufacturing a compound represented by the formula
(I):
##STR00028##
[wherein R.sup.1 represents a C.sub.1-C.sub.19 alkyl group and
R.sup.2 represents a C.sub.1-C.sub.4 alkyl group], [here, the
compound represented by the formula (I) may include a compound
represented by the formula (II):
##STR00029##
[wherein R.sup.1 and R.sup.2 have the same meanings as in the
formula (I)]] or pharmacologically acceptable salt thereof,
comprising: allowing a compound represented by the formula
(13):
##STR00030##
[wherein R.sup.2 represents a C.sub.1-C.sub.4 alkyl group] to react
with a compound represented by the formula (15):
##STR00031##
[wherein R.sup.1 represents a C.sub.1-C.sub.19 alkyl group, R.sup.7
represents a C.sub.1-C.sub.6 alkyl group, and X represents Cl, Br,
I, HSO.sub.4 or NO.sub.3], and with a compound represented by the
formula R.sup.7--OH [wherein R.sup.7 represents a C.sub.1-C.sub.6
alkyl group], [14] the manufacturing method as described in [13],
wherein R.sup.1 is a 1-heptyl group, R.sup.2 is a methyl group,
R.sup.7 is a methyl group, and X is Cl, [15] a method for
manufacturing a compound represented by the formula (Ib):
##STR00032##
[wherein Me represents a methyl group (the same applies
hereinafter), and the compound represented by the formula (Ib) may
include a compound represented by the formula (IIb):
##STR00033##
or a pharmacologically acceptable salt thereof, which includes at
least one manufacturing method described in any one of [2], [6] and
[8] as part of the production procedure, [16] a method for
manufacturing a compound represented by the formula (Ib):
##STR00034##
[wherein the compound represented by the formula (Ib) may include a
compound represented by the formula (IIb):
##STR00035##
or a pharmacologically acceptable salt thereof, which proceeds via
at least one compound described in either one of [4] and [10], [17]
a compound represented by the formula (I):
##STR00036##
[wherein R.sup.1 represents a C.sub.1-C.sub.19 alkyl group and
R.sup.2 represents a C.sub.1-C.sub.4 alkyl group], [here, the
compound represented by the formula (I) may include a compound
represented by the formula (II):
##STR00037##
[wherein R.sup.1 and R.sup.2 have the same meanings as in the
formula (I)]] having a chemical purity of 97 wt % or higher,
[wherein in the case where the compound represented by the formula
(II) is included, the chemical purity of the mixture of the
compound represented by the formula (I) and the compound
represented by the formula (II) is 97 wt % or higher], or a
pharmacologically acceptable salt thereof, [18] the compound
represented by the formula (I), which may include the compound
represented by the formula (II), or pharmacologically acceptable
salt thereof as described in [17], wherein the chemical purity is
99 wt % or higher, [19] the compound represented by the formula
(I), which may include the compound represented by the formula
(II), or pharmacologically acceptable salt thereof as described in
[17], wherein the chemical purity is 99.5 wt % or higher, [20] the
compound represented by the formula (I), which may include the
compound represented by the formula (II), as described in any one
of [17] through [19], wherein R.sup.1 is a 1-heptyl group and
R.sup.2 is a methyl group, [21] a compound represented by the
formula (I):
##STR00038##
[wherein R.sup.1 represents a C.sub.1-C.sub.19 alkyl group and
R.sup.2 represents a C.sub.1-C.sub.4 alkyl group], [here, the
compound represented by the formula (I) may include a compound
represented by the formula (II):
##STR00039##
[wherein R.sup.1 and R.sup.2 have the same meanings as in the
formula (I)]], or a pharmacologically acceptable salt thereof,
containing a compound represented by the formula (VII):
##STR00040##
[wherein R.sup.1 and R.sup.2 represent have the same meanings as in
the formula (I)] in an amount of 0.5 wt % or less, [22] a compound
represented by the formula (I), which may include the compound
represented by the formula (II), or pharmacologically acceptable
salt thereof as described in [21], containing the compound
represented by the formula (VII) in an amount of 0.3 wt % or less,
[23] a compound represented by the formula (I), which may include
the compound represented by the formula (II), or pharmacologically
acceptable salt thereof as described in [21], containing the
compound represented by the formula (VII) in an amount of 0.1% or
less, [24] a compound represented by the formula (I), which may
include the compound represented by the formula (II), as described
in any one of [21] through [23], wherein R.sup.1 is a 1-heptyl
group and R.sup.2 is a methyl group, [25] a compound represented by
the formula (I):
##STR00041##
[wherein R.sup.1 represents a C.sub.1-C.sub.19 alkyl group and
R.sup.2 represents a C.sub.1-C.sub.4 alkyl group], [here, the
compound represented by the formula (I) may include a compound
represented by the formula (II):
##STR00042##
[wherein R.sup.1 and R.sup.2 have the same meanings as in the
formula (I)]], or a pharmacologically acceptable salt thereof,
containing a compound represented by the formula (VIII):
##STR00043##
[wherein R.sup.1 has the same meaning as the formula (I)] in an
amount of 0.5 wt % or less, [26] a compound represented by the
formula (I), which may include the compound represented by the
formula (II), or pharmacologically acceptable salt thereof as
described in [25], containing the compound represented by the
formula (VIII) in amount of 0.3 wt % or less, [27] a compound
represented by the formula (I), which may include the compound
represented by the formula (II), or pharmacologically
acceptable
[0022] salt thereof as described in [25], containing the compound
represented by the formula (VIII) in an amount of 0.1 wt % or
less,
[28] a compound represented by the formula (I), which may include
the compound represented by the formula (II) as described in any
one of [25] through [27], wherein R.sup.1 is a 1-heptyl group and
R.sup.2 is a methyl group, [29] a compound represented by the
formula (I):
##STR00044##
[wherein R.sup.1 represents a C.sub.1-C.sub.19 alkyl group and
R.sup.2 represents a C.sub.1-C.sub.4 alkyl group], [here, the
compound represented by the formula (I) may include a compound
represented by the formula (II):
##STR00045##
[wherein R.sup.1 and R.sup.2 have the same meanings as in the
formula (I)]], or a pharmacologically acceptable salt thereof,
containing a compound represented by the formula (13):
##STR00046##
[wherein R has the same meaning as in the formula (I)] in an amount
of 0.5 wt % or less, [30] a compound represented by the formula
(I), which may include the compound represented by the formula
(II), or pharmacologically acceptable salt thereof as described in
[29], containing the compound represented by the formula (13) in an
amount of 0.3 wt % or less, [31] a compound represented by the
formula (I), which may include the compound represented by the
formula (II), or pharmacologically acceptable salt thereof as
described in [29], containing the compound represented by the
formula (13) in an amount of 0.1 wt % or less, [32] a compound
represented by the formula (I), which may include the compound
represented by the formula (II) as described in any one of [29]
through [31], wherein R.sup.1 is a 1-heptyl group and R.sup.2 is a
methyl group, [33] a compound represented by the formula (I), which
may include a compound represented by the formula (II), as
described in any one of [17] through [32], wherein the composition
ratio of the compound represented by the formula (I) and the
compound represented by the formula (II) is 90:10 to 100:0 by
weight, [34] a compound represented by the formula (I), which may
include a compound represented by the formula (II), as described in
any one of [17] through [32], wherein the composition ratio of the
compound represented by the formula (I) and the compound
represented by the formula (II) is 92:8 to 100:0 by weight, [35] a
compound represented by the formula (I), which may include a
compound represented by the formula (II), as described in any one
of [17] through [32], wherein the composition ratio of the compound
represented by the formula (I) and the compound represented by the
formula (II) is 95:5 to 100:0 by weight, [36] a method for
manufacturing a compound represented by the formula
R.sup.1C(OR.sup.7).sub.3 [wherein R.sup.1 represents a
C.sub.1-C.sub.19 alkyl group and R.sup.7 represents a
C.sub.1-C.sub.6 alkyl group], comprising: allowing a compound
represented by the formula (15):
##STR00047##
[wherein R.sup.1 represents a C.sub.1-C.sub.19 alkyl group, R.sup.7
represents a C.sub.1-C.sub.6 alkyl group, and X represents Cl, Br,
I, HSO.sub.4 or NO.sub.3] to react with a compound represented by
the formula R.sup.7--OH [wherein R.sup.7 represents a
C.sub.1-C.sub.6 alkyl group] in a solvent which forms a bilayer
system, [37] the manufacturing method as described in [36], wherein
the solvent which forms the bilayer system is a hydrocarbon, [38]
the manufacturing method as described in [36], wherein the solvent
which forms the bilayer system is cyclohexane or methylcyclohexane,
[39] the manufacturing method as described in any one of [36]
through [38], wherein R.sup.1 is a 1-heptyl group, R.sup.7 is a
methyl group, and X is Cl, [40] a composition for treatment or
prevention of influenza containing as active ingredient the
compound or pharmacologically acceptable salts thereof as set forth
in any one of [17] through [35], [41] a compound represented by the
formula (I):
##STR00048##
[wherein R.sup.1 represents a C.sub.1-C.sub.19 alkyl group and
R.sup.2 represents a C.sub.1-C.sub.4 alkyl group], [here, the
compound represented by the formula (I) may include a compound
represented by the formula (II):
##STR00049##
[wherein R.sup.1 and R.sup.2 have the same meanings as in the
formula (I)]] having a chemical purity of 97 wt % or higher,
[wherein in the case where the compound represented by the formula
(II) is included, the chemical purity of the mixture of the
compound represented by the formula (I) and the compound
represented by the formula (II) is 97 wt % or higher], or a
pharmacologically acceptable salt thereof, manufactured by a method
comprising: allowing a compound represented by the formula
(13):
##STR00050##
[wherein R.sup.2 represents a C.sub.1-C.sub.4 alkyl group] to react
with a compound represented by the formula R.sup.1C(OR.sup.7).sub.3
[wherein R.sup.1 represents a C.sub.1-C.sub.19 alkyl group and
R.sup.1 represents a C.sub.1-C.sub.6 alkyl group], or a
pharmacologically acceptable salt thereof, [42] the compound
represented by the formula (I), which may include the compound
represented by the formula (II), or pharmacologically acceptable
salt thereof as described in [41], wherein the chemical purity is
99 wt % or higher, [43] the compound represented by the formula
(I), which, may include the compound represented by the formula
(II), or pharmacologically acceptable salt thereof as described in
[41], wherein the chemical purity is 99.5 wt % or higher, [44] the
compound represented by the formula (1), which may include the
compound represented by the formula (II), as described in any one
of [41] through [43], wherein R.sup.1 is a 1-heptyl group and
R.sup.2 is a methyl group, [45] a compound represented by the
formula (I):
##STR00051##
[wherein R.sup.1 represents a C.sub.1-C.sub.19 alkyl group and
R.sup.2 represents a C.sub.1-C.sub.4 alkyl group], [here, the
compound represented by the formula (I) may include a compound
represented by the formula (II):
##STR00052##
[wherein R.sup.1 and R.sup.2 have the same meanings as in the
formula (I)]], or a pharmacologically acceptable salt thereof,
containing a compound represented by the formula (VII)
##STR00053##
[wherein R.sup.1 and R.sup.2 represent have the same meanings as in
the formula (I)] in an amount of 0.5 wt % or less, manufactured by
a method comprising: allowing a compound represented by the formula
(13):
##STR00054##
[wherein R.sup.2 represents a C.sub.1-C.sub.4 alkyl group] to react
with a compound represented by the formula
R.sup.1C(OR.sup.7).sub.3[wherein R.sup.1 represents a
C.sub.1-C.sub.19 alkyl group and R.sup.7 represents a
C.sub.1-C.sub.6 alkyl group], [46] the compound represented by the
formula (I), which may include the compound represented by the
formula (II), or pharmacologically acceptable salt thereof as
described in [45], containing the compound represented by the
formula (VII) in an amount of 0.3 wt % or less, [47] the compound
represented by the formula (I), which may include the compound
represented by the formula (II), or a pharmacologically acceptable
salt thereof as described in [45], containing the compound
represented by the formula (VII) in an amount of 0.1 wt % or less,
[48] the compound represented by the formula (I), which may include
the compound represented by the formula (II), as described in any
one of [45] through [47], wherein R.sup.1 is a 1-heptyl group and
R.sup.2 is a methyl group, [49] a compound represented by the
formula (I):
##STR00055##
[wherein R.sup.1 represents a C.sub.1-C.sub.19 alkyl group and
R.sup.2 represents a C.sub.1-C.sub.4 alkyl group], [here, the
compound represented by the formula (I) may include a compound
represented by the formula (II):
##STR00056##
[wherein R.sup.1 and R.sup.2 have the same meanings as in the
formula (I)]], or a pharmacologically acceptable salt thereof,
containing a compound represented by the formula (VIII):
##STR00057##
[wherein R has the same meaning as in the formula (I)] in an amount
of 0.5 wt % or less, manufactured by a method comprising: allowing
a compound represented by the formula (13):
##STR00058##
[wherein R.sup.2 represents a C.sub.1-C.sub.4 alkyl group] to react
with a compound represented by the formula
R.sup.1C(OR.sup.7).sub.3[wherein R.sup.1 represents a
C.sub.1-C.sub.19 alkyl group and R.sup.7 represents a
C.sub.1-C.sub.6 alkyl group], [50] the compound represented by the
formula (I), which may include the compound represented by the
formula (II), or pharmacologically acceptable salt thereof as
described in [49], containing the compound represented by the
formula (VIII) in an amount of 0.3 wt % or less, [51] the compound
represented by the formula (I), which may include the compound
represented by the formula (II), or pharmacologically acceptable
salt thereof as described in [49], containing the compound
represented by the formula (VIII) in an amount of 0.1 wt % or less,
[52] the compound represented by the formula (I), which may include
the compound represented by the formula (II) as described in any
one of [49] through [51], wherein R.sup.1 is a 1-heptyl group and
R.sup.2 is a methyl group, [53] a compound represented by the
formula (I):
##STR00059##
[wherein R represents a C.sub.1-C.sub.19 alkyl group and R.sup.2
represents a C.sub.1-C.sub.4 alkyl group], [here, the compound
represented by the formula (I) may include a compound represented
by the formula (II):
##STR00060##
[wherein R.sup.1 and R.sup.2 have the same meanings as in the
formula (I)]], or a pharmacologically acceptable salt thereof,
containing an unconverted material compound represented by the
formula (13):
##STR00061##
[wherein R.sup.2 has the same meaning as in the formula (I)] in an
amount of 0.5 wt % or less, manufactured by a method comprising:
allowing a compound represented by the formula (13):
##STR00062##
[wherein R.sup.2 represents a C.sub.1-C.sub.4 alkyl group] to react
with a compound represented by the formula R.sup.1C(OR.sup.7).sub.3
[wherein R.sup.1 represents a C.sub.1-C.sub.9 alkyl group and
R.sup.7 represents a C.sub.1-C.sub.6 alkyl group], [54] the
compound represented by the formula (I), which may include the
compound represented by the formula (II), or pharmacologically
acceptable salt thereof as described in [53], containing the
compound represented by the formula (13) in an amount of 0.3 wt %
or less, [55] the compound represented by the formula (I), which
may include the compound represented by the formula (II), or
pharmacologically acceptable salt thereof as described in [53],
containing the compound represented by the formula (13) in an
amount of 0.1 wt % or less, or [56] the compound represented by the
formula (I), which may include the compound represented by the
formula (II) as described in any one of [53] through [55], wherein
R.sup.1 is a 1-heptyl group and R.sup.2 is a methyl group.
[0023] In the present invention, "C.sub.1-C.sub.19 alkyl group" of
R.sup.1 represents a linear or branched alkyl group having 1 to 19
carbon atoms, and may be for example, a methyl group, ethyl group,
propyl group, butyl group, pentyl group, hexyl group, heptyl group,
octyl group, nonyl group, decanyl group, undecanyl group, dodecanyl
group, tridecanyl group, tetradecanyl group, pentadecanyl group,
hexadecanyl group, heptadecanyl group, octadecanyl group or
nonadecanyl group, preferably a C.sub.1-C.sub.19 alkyl group, more
preferably a C.sub.5-C.sub.17 alkyl group, even more preferably a
pentyl group, heptyl group, nonyl group, undecanyl group,
tridecanyl group, pentadecanyl group or heptadecanyl group, further
preferably a 1-pentyl group, 1-heptyl group, 1-nonyl group,
1-undecanyl group, 1-tridecanyl group, 1-pentadecanyl group or
1-heptadecanyl group, and most preferably a 1-heptyl group.
[0024] "C.sub.1-C.sub.4 alkyl group" of R.sup.2 represents a linear
or branched alkyl group having 1 to 4 carbon atoms, and may be for
example, a methyl group, ethyl group, propyl group or butyl group,
preferably a methyl group or ethyl group, and most preferably a
methyl group.
[0025] "C.sub.1-C.sub.6 alkyl group" in R.sup.3, R.sup.4, R.sup.5,
R.sup.6 and R.sup.7 is a linear or branched alkyl group having 1 to
6 carbon atoms, and may be for example, a methyl group, ethyl
group, propyl group, butyl group, pentyl group or hexyl group,
preferably a C.sub.1-C.sub.4 alkyl group, more preferably a methyl
group or ethyl group, and most preferably a methyl group.
[0026] R.sup.4 and R.sup.5 are preferably a hydrogen atom or a
C.sub.1-C.sub.4 alkyl group, more preferably a methyl group or
ethyl group, and most preferably a methyl group. R.sup.4 and
R.sup.5 are preferably the same. Further, R.sup.4 and R.sup.5
preferably together form an oxo group.
[0027] In the present invention, "pharmacologically acceptable
salt" may be, for example, a hydrohalic acid salt such as
hydrofluoric acid salt, hydrochloric acid salt, hydrobromic acid
salt and hydroiodic acid salt; an inorganic acid salt such as
nitric acid salt, perchloric acid salt, sulfuric acid salt and
phosphoric acid salt; an alkanesulfonic acid salt such as
methanesulfonic acid salt, ethanesulfonic acid salt and
trifluoromethanesulfonic acid salt; an arylsulfonic acid salt such
as benzehesulfonic acid salt and p-toluenesulfonic acid salt; an
organic acid salt such as acetic acid salt, trifluoroacetic acid
salt, citric acid salt, tartaric acid salt, oxalic acid salt and
maleic acid salt; an amino acid salt such as glycine salt, lysine
salt, arginine salt, ornitine salt, glutamic acid salt and aspartic
acid salt; an alkali metal salt such as lithium salt, sodium salt
and potassium salt; an alkaline earth metal salt such as calcium
salt and magnesium salt; a metal salt such as aluminum salt, iron
salt, zinc salt, copper salt, nickel salt and cobalt salt; or an
organic amine salt or organic ammonium salt such as ammonium salt,
t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine
salt, ethylenediamine salt, guanidine salt, diethylamine salt,
triethylamine salt, dicyclohexylamine salt, procain salt,
ethanolamine salt, diethanolamine salt, piperazine salt and
tetramethylammonium salt, preferably a hydrohalic acid salt or
organic acid salt, and more preferably trifluoroacetic acid
salt.
[0028] When the compounds of the present invention are exposed to
the atmosphere or are blended with water or organic solvent, they
may form hydrates or solvates. Such hydrates and solvates are also
embraced in the compounds of the present invention. Compound (Ib)
and compound (IIb) include an anhydride and hydrates. Preferably,
the hydrate of compound (Ib) and hydrate of compound (IIb) are
monohydrates.
[0029] The compounds of the present invention have an asymmetric
carbon atom within their molecule, and thus there exist
stereoisomers (enantiomers and diastereomers are included). These
stereoisomers and mixtures thereof in an arbitrary ratio (including
racemic form) are embraced in the compounds of the present
invention.
[0030] It is known that when compound (I) is administered to a
warm-blooded animal, the acyloxy group at the 3-position of the
side chain is converted into a hydroxyl group by a metabolic
reaction such as hydrolysis, and the generated compound (III) shows
pharmacological activity (Patent Document 1 and the like). In
addition, when compound (II) is administered to a warm-blooded
animal, the acyloxy group at the 2-position of the side chain is
converted into a hydroxyl group by a metabolic reaction such as
hydrolysis, and compound (III) is generated in a similar manner.
Since both compound (I) and compound (II) are converted into the
same compound (III), which is an active metabolite, within an
organism of a warm-blooded animal, it can be considered that both
the compounds are active ingredients, from the point of view of
using a mixture of compound (I) and compound (II) as a medicament.
On the other hand, since a medicament is required to show a
constant pharmacological effect and physical and chemical
stability, it is preferable that the composition ratio of these
compounds is constant, from the point of view of the quality of a
mixture of compound (I) and compound (II) as a medicament.
[0031] In the present invention, the chemical purity of the
compound, the content of a compound as an impurity, or the
composition ratio of a mixture of compound (I) and compound (II)
may be determined by methods known in the field of organic
chemistry (for example, high performance liquid chromatography,
weight %, and the like), and is preferably determined by peak area
ratios under high performance liquid chromatography (hereinafter
also referred to as HPLC). The measurement conditions for HPLC
shall be selected appropriately; however, they are preferably as
shown hereinbelow.
[0032] HPLC Measurement Conditions (1)
Column: L-column ODS (4.6 mmID.times.25 cm, particle diameter 5
.mu.m, manufactured by Chemicals Evaluation and Research Institute)
Column temperature: 30.degree. C. Measurement wavelength: 210 nm
Mobile phase:
[0033] A: 0.1% PIC B-7 (Low UV, manufactured by Waters Corporation)
aqueous solution/acetonitrile (9/1, v/v)
[0034] B: 0.1 mol/l phosphate buffer solution (pH 3.0)/acetonitrile
(7/3, v/v)
[Here, 0.1 mol/l phosphate buffer solution (pH 3.0) is a buffer
solution prepared by adding 0.1 mol/l phosphoric acid to 0.1 mol/l
aqueous potassium dihydrogen phosphate solution to adjust its pH to
3.0.] Gradient conditions:
TABLE-US-00001 Time (min.) Mobile phase A (%) Mobile phase B (%)
0-3 100 0 3-23 100.fwdarw.0 0.fwdarw.100 23-90 0 100
Flow rate: 1 ml/min Sample concentration: approximately 1 g/l
injection amount: 20 .mu.l Range detected with peak: from 0 minute
to approximately 1.2 times the length of retention time of compound
(I)
[0035] HPLC Measurement Conditions (2)
Column: L-column ODS (4.6 mmID.times.25 cm, particle diameter 5
.mu.m, manufactured by Chemicals Evaluation and Research Institute)
Column temperature: 30.degree. C. Measurement wavelength: 210 nm
Mobile phase:
[0036] 0.1 mol/l phosphate buffer solution (pH 3.0)/acetonitrile
(23/17, v/v)
[Here, 0.1 mol/1 phosphate buffer solution (pH 3.0) is a buffer
solution prepared by adding 0.1 mol/l phosphoric acid to 0.1 mol/l
aqueous potassium dihydrogen phosphate solution to adjust its pH to
3.0.] Flow rate: 1 ml/min Sample concentration: approximately 1 g/l
Injection amount: 20 .mu.l Range detected with peak: from
approximately 1.2 times to 18 times the length of retention time of
compound (I)
[0037] By HPLC measurement conditions (1), the peak area ratios of
compound (I), compound (II), and compound as impurity, which are
detected from 0 minute to approximately 1.2 times the length of
retention time of compound (I), are measured. By HPLC measurement
conditions (2), the peak area ratio of compound as impurity, which
is detected from approximately 1.2 times to 18 times of the length
of retention time of compound (I), is measured. Here, the peaks of
the compounds as impurities represent the peaks when the peak of
compound (I), the peak of compound (II), and the peaks detected
when solvent alone is injected [for example, the peak of solvent
and the peak derived from noise], are subtracted from all of the
peaks that are detected as 0.01% or more.
[0038] The chemical purity (%) of compound (I) can be calculated
according to the following equation.
Chemical purity of compound (I)=100-sum of peak area ratio (%) of
compound as impurity Compound (I) may include compound (II), and in
the case where compound (I) includes compound (II), the chemical
purity is calculated as the mixture of compound (I) and compound
(II).
[0039] The content of compound (VII) can be calculated as the peak
area ratio under HPLC measurement conditions (2). The content of
compound (VIII) and compound (13) can be calculated as the peak
area ratio under HPLC measurement conditions (1).
[0040] The peak area ratios of compound (I) and compound (II) can
be measured in accordance with the aforementioned HPLC measurement
conditions (1). The composition ratio (%) of a mixture of compound
(I) and compound (II) can be calculated from the following
equation.
Composition ratio of compound (I)=[peak area ratio of compound
(I)/[peak area ratio of compound (I)+peak area ratio of compound
(II)]].times.100
Composition ratio of compound (II)=[peak area ratio of compound
(II)/[peak area ratio of compound (I)+peak area ratio of compound
(II)]].times.100
The chemical purity of compound (I) or pharmacologically acceptable
salt thereof is preferably 95% or more, more preferably 97% or
more, even more preferably 98% or more, further preferably 99% or
more, and most preferably 99.5% or more, by weight. Compound (I)
may contain compound (II), and in the case where compound (I)
contains compounds (II), the chemical purity is calculated by
taking both compound (I) and compound (II) as active ingredients.
It is more preferable that the content of compounds other than
compound (I) [and compound (II)] or pharmacologically acceptable
salt thereof is below the detection limit.
[0041] Concerning compound (I) which may contain compound (II), the
composition ratio of compound (I) and compound (II) is preferably
85:15 to 100:0, more preferably 90:10 to 100:0, even more
preferably 92:8 to 100:0, and most preferably 95:5 to 100:0, by
weight. The content of a compound represented by formula (II) may
be below the detection limit.
[0042] Concerning compound (I) or pharmacologically acceptable salt
thereof, the content of compound (VII) is preferably 2% or less,
more preferably 1% or less, even more preferably 0.5% or less,
further preferably 0.3% or less, and most preferably 0.1% or less,
by weight. It is more preferable that the content of compound (VII)
is below the detection limit.
[0043] Concerning compound (I) or pharmacologically acceptable salt
thereof, the content of compound (VIII) is preferably 2% or less,
more preferably 1% or less, even more preferably 0.5% or less,
further preferably 0.3% or less, and most preferably 0.1% or less,
by weight. It is more preferable that the content of compound
(VIII) is below the detection limit.
[0044] Concerning compound (I) or pharmacologically acceptable salt
thereof, the content of compound (13) is preferably 2% or less,
more preferably 1% or less, even more preferably 0.5% or less,
further preferably 0.3% or less, and most preferably 0.1% or less,
by weight. It is more preferable that the content of compound (13)
is below the detection limit.
[0045] The present invention shown by Process A is superior to
publicly known manufacturing methods or synthetic intermediates, in
points given below, for example.
[0046] (i) Concerning the production procedures of compound (IVb)
of Process W and compound (VIb) of Process Z, since an acetamide
group exists in their starting materials compound (IVa) and
compound (VIa), N-methylation occurs as a side reaction. For
example, with respect to compound (VIa), the N-methylated compound
is generated at approximately 12% (refer to data of N-methylated
compound of compound (VIa) described in Comparative Example 1).
[0047] In contrast, compound (7) has no functional group which may
be methylated other than the hydroxyl group at the 1-position of
the side chain, and thus N-methylation as a side reaction does not
occur in the methylation reaction of compound (7). In addition, the
oxazolidine ring of compound (7) simultaneously serves as a
protective group to prevent N-methylation and as a partial
structure which is to be converted into an acetamide group at the
5-position in Step A-6. Further, since compound (7) is a
crystalline solid, it can easily be purified by recrystallization.
Therefore, compound (7) contributes to the improvement of the
overall yield in Process A, by achieving efficient methylation of
the hydroxyl group at the 1-position of the side chain, and by
achieving a reduction in the number of procedures in Process A.
[0048] (ii) Concerning the production procedure of compound (IVg)
in Process W, Process Y, and Process Z, since the reaction is
carried out under a high temperature of 80.degree. C. or higher
using approximately 6 moles of sodium azide, it is extremely
hazardous especially from an industrial perspective, when the
explosive nature of azide compounds is taken into consideration. In
addition, the stereoselectivity of the reaction at the 4-position
is not enough, and thus the generation ratio of compound (IVg) and
the undesired stereoisomer in which the azide group has the
opposite configuration of compound (IVg), is approximately 7:1
(refer to Comparative Example 2).
[0049] In contrast, concerning the azidation reaction of compound
(8), by using a Lewis acid, the amount of azidation agent used is
reduced to approximately 1.5 to 2 equivalents, and the reaction
proceeds under extremely mild conditions of 0.degree. C. to
30.degree. C. In addition, the stereoselectivity of the reaction at
the 4-position is improved, and thus the generation ratio of
compound (9) and the undesired stereoisomer is improved to 15:1
(refer to data described in Step A-6 of Example 1).
[0050] Accordingly, the manufacturing method of compound (9) from
compound (8) improves the practicality of Process A from an
industrial perspective, by achieving an improvement in the safety
of the azidation reaction and stereoselective production of the
desired isomer.
[0051] (iii) Compound (IIIa) in Process Y and Process Z is a salt
of trifluoroacetic acid which is corrosive, and is an amorphous
solid, therefore being unable to be easily purified by
recrystallization.
[0052] In contrast, compound (13) is produced from compound (12),
by a reaction with only water under mild conditions. In addition,
since compound (13) is a crystalline solid, it can easily be
purified by recrystallization. From an industrial perspective, it
is extremely important to use a starting material with a purity as
high as possible in the final procedure of the production, in order
to obtain the desired compound with high purity. Therefore,
compound (13) contributes to the production of compound (I) with
high purity, by providing a starting material with high purity in
the final procedure.
[0053] (iv) Concerning the production procedure of compound (IVk)
and compound (Ta) in Process W, (a) protection of a carboxyl group
is necessary, (b) a 2,3-diacylated compound is generated as
by-product, and (c) purification by silica gel column
chromatography is required to remove the octanoic acid derived from
the reagent. Here, as an acylation reaction of a hydroxyl group
using an ortho ester, the following reaction is known (Carbohydrate
Research, 1987, Vol. 167, pp. 77-86). R.sup.a represents a
C.sub.1-C.sub.4 alkyl group and the like. In the following
reaction, the reactive functional group is a hydroxyl group
only.
##STR00063##
[0054] In contrast, no similar acylation reaction that proceeds in
the presence of a nitrogen functional group (guanidyl group), which
is considered to be more reactive, is known. In the production
procedure of compound (I) from compound (13), an acylation reaction
proceeds with a fine yield in the presence of a guanidyl group. In
the present procedure, (a') protection of a carboxyl group is
unnecessary, (b') selective mono-acylation proceeds, resulting in
scarce generation of a 2,3-diacylated compound as a by-product and
(c') removal of by-product derived from the reagent by silica gel
column chromatography is not required. Therefore, the manufacturing
method of compound (I) from compound (13) contributes largely to
the production of compound (I) with high purity.
[0055] (v) An acylation reaction of a hydroxyl group using an imino
ester is not known to present date. The production procedure of
compound (I) from compound (13) can also be conducted by using an
imino ester compound (15) and a compound represented by the formula
R.sup.7--OH, in place of an ortho ester compound (14). The
production of compound (14) by a conventional method is very low in
yield [refer to (vii) given below]. By using compound (15)
directly, the inefficient production procedure of compound (14)
from compound (15) can be omitted.
[0056] (vi) Concerning the production procedure of compound (IVk)
and compound (Ia) in Process W, compound (VII), which is a
2,3-diacylated compound, is generated as a by-product. Accordingly,
a reduction in the amount of compound (VII) contained is required
to obtain compound (Ia) with high purity (refer to Comparative
Example 3).
[0057] In the production procedure of compound (I) from compound
(13), selective monoacylation reaction can be achieved by using
compound (14) or compound (15), and thus compound (I) in which the
amount of compound (VII) contained is less to such an extent as to
be practical, can be produced (refer to Step A-10 of Example
1).
[0058] Therefore, the manufacturing method of compound (I) from
compound (13) contributes largely to the production of compound (I)
with high purity.
[0059] (vii) In the production of compound (14), when a compound
represented by the formula R.sup.7--OH is used as a reagent and as
a solvent to react with compound (15), following a publicly known
method (Journal of American Chemical Society, 1942, vol. 64, pp.
1825-1827), the yield of compound (14) is approximately 35% to 50%
(refer to Comparative Example 4).
[0060] In contrast, when compound (15) is allowed to react with a
compound represented by the formula R.sup.7--OH in a solvent which
forms a bilayer system, the yield of compound (14) is improved
remarkably to approximately 80% to 85% (refer to Example 9).
Therefore, the manufacturing method of compound (14) from compound
(15) contributes to the improvement of the overall yield of Process
A, by providing an efficient method of manufacturing compound (14),
which is used in the production of compound (I)
Effect of the Invention
[0061] The novel method of manufacturing neuraminic acid
derivatives via the novel synthetic intermediate according to the
present invention is superior from an industrial perspective,
compared with publicly known manufacturing methods. In addition,
neuraminic acid derivatives with high purity can be obtained in
high yield by the present manufacturing method.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0062] In the present invention, the method of manufacturing
neuraminic acid derivatives can be conducted in accordance with the
following Process A through Process G.
##STR00064## ##STR00065##
##STR00066##
##STR00067## ##STR00068##
##STR00069##
##STR00070##
##STR00071##
##STR00072##
[0063] In Process A through Process G, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, and X have the same meanings as
described above.
[0064] The solvent used in the reactions of each of the steps of
Process A through Process G is not limited so long as it does not
inhibit the reaction and dissolves the starting material to some
degree, and can be, for example, selected from the following
solvent group. The solvent group comprises aliphatic hydrocarbons
such as hexane, pentane, petroleum ether and cyclohexane; aromatic
hydrocarbons such as benzene, toluene and xylene; halogenated
hydrocarbons such as methylene chloride, chloroform, carbon
tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene;
ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, dimethoxyethane and diethyleneglycol dimethyl ether;
ketones such as acetone, methyl ethyl ketone, methyl isobutyl
ketone and cyclohexanone; esters such as ethyl acetate, propyl
acetate and butyl acetate; nitriles such as acetonitrile,
propionitrile, butyronitrile and isobutyronitrile; carboxylic acids
such as acetic acid and propionic acid; alcohols such as methanol,
ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol,
2-methyl-1-propanol and 2-methyl-2-propanol; amides such as
formamide, N,N-dimethylformamide, N, N-dimethylacetamide,
N-methyl-2-pyrrolidone and hexamethylphosphoroamide; sulfoxides
such as dimethyl sulfoxide; sulfones such as sulforane; water; and
mixtures thereof.
[0065] In the reactions of each of the steps of Process A through
Process G, the reaction temperature differs depending on solvent,
starting material, reagent and the like, and is selected
appropriately. In addition, the reaction time differs depending on
solvent, starting material, reagent and the like, and is selected
appropriately.
[0066] In the reactions of each of the steps of Process A through
Process G, the desired compound of each of the steps can be
isolated from a reaction mixture in accordance with ordinary
methods after completion of the reaction. The desired compound may
be obtained by, for example, (i) removing insoluble matters such as
catalyst as necessary, (ii) extracting the desired compound by
adding water and solvent which is immiscible with water (for
example, ethyl acetate and the like) to the reaction mixture, (iii)
washing the organic layer with water and drying it as necessary by
using a drying agent such as anhydrous magnesium sulfate, and (iv)
distilling off the solvent. The obtained desired compound can be
further purified as necessary, by ordinary methods (for example,
recrystallization, reprecipitation, or silicagel column
chromatography). In addition, the desired compound of each
procedure can also be used in the subsequent reaction without
purification.
[0067] (Process A)
[0068] Process A shows a method of manufacturing a compound
represented by the formula (I) [which may include a compound
represented by the formula (II)] or a pharmacologically acceptable
salt thereof.
[0069] (Step A-1)
[0070] Step A-1 is a procedure to allow publicly known compound (1)
to react with an alcohol represented by the formula R.sup.3OH in
the presence of acid, to produce compound (2). The alcohol
represented by the formula R.sup.3OH are either publicly known, or
can easily be produced from a publicly known compound, and is
preferably methanol.
[0071] The acid used is not limited so long as it is used for
esterification of a carboxyl group using an alcohol, and may be for
example, an organic acid such as acetic acid, propionic acid,
trifluoroacetic acid and pentafluoropropionic acid, an organic
sulfonic acid such as p-toluenesulfonic acid, camphorsulfonic acid
and trifluoromethanesulfonic acid, or an inorganic acid such as
hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric
acid, sulfuric acid and nitric acid, preferably an inorganic acid,
and most preferably sulfuric acid.
[0072] In Step A-1, a compound represented by the formula
HC(OR.sup.3).sub.3 may be used to accelerate the reaction. The
compound represented by the formula HC(OR.sup.3).sub.3 is either
publicly known, or can easily be produced from a publicly known
compound. The compound represented by the formula
HC(OR.sup.3).sub.3 is preferably trimethyl orthoformate
[HC(OMe).sub.3]. R.sup.3 in the compound represented by the formula
HC(OR.sup.3).sub.3 is preferably the same as R.sup.3 in the alcohol
represented by the formula R.sup.3OH.
[0073] The solvent used is preferably an aromatic hydrocarbon, a
halogenated hydrocarbon, an ether or an alcohol represented by the
formula R.sup.3OH, more preferably an alcohol represented by the
formula R.sup.3OH, and most preferably methanol.
[0074] The reaction temperature is preferably -20.degree. C. to
100.degree. C., and more preferably 20.degree. C. to 60.degree.
C.
[0075] The reaction time is preferably 30 minutes to 40 hours, and
more preferably 1 to 10 hours.
[0076] (Step A-2)
[0077] Step A-2 is a procedure to allow compound (2) to react with
acetic acid anhydride in the presence of acid, to produce compound
(3).
[0078] The acid used is not limited so long as it promotes
formation of a carbon-carbon double bond by acetic acid elimination
at the 2- and 3-positions of the tetrahydropyrane ring, formation
of an oxazoline ring at the 4- and 5-positions of the
tetrahydropyrane ring, and acetylation of the hydroxyl group at the
1-, 2-, and 3-positions of the side chain. For example, it may be
an organic acid such as acetic acid, propionic acid,
trifluoroacetic acid and pentafluoropropionic acid, an organic
sulfonic acid such as p-toluenesulfonic acid, camphorsulfonic acid
and trifluoromethanesulfonic acid, or an inorganic acid such as
hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric
acid, sulfuric acid and nitric acid, preferably an inorganic acid,
and most preferably sulfuric acid.
[0079] The solvent used is preferably a hydrocarbon, and most
preferably 1-heptane. It is also preferable that Step A-2 is
conducted in the absence of solvent.
[0080] The reaction temperature is preferably -20.degree. C. to
100.degree. C., and more preferably 0.degree. C. to 60.degree.
C.
[0081] The reaction time is preferably 30 minutes to 60 hours, and
more preferably 1 to 20 hours.
[0082] (Step A-3)
[0083] Step A-3 is a procedure to allow compound (3) to react with
a compound represented by the formula NaOR.sup.3, to produce
compound (4).
[0084] In Step A-3, the compound represented by the formula
NaOR.sup.3 is preferably sodium methoxide or sodium ethoxide, and
most preferably sodium methoxide. In Step A-3, a compound
represented by the formula LiOR.sup.3 or KOR.sup.3 may be used
instead of the compound represented by the formula NaOR.sup.3.
R.sup.3 in the compound represented by the formula NaOR.sup.3,
LiOR.sup.3 or KOR.sup.3 is preferably the same as R.sup.3 of
compound (3).
[0085] The solvent used is preferably an alcohol, more preferably
methanol or ethanol, and most preferably methanol. The solvent used
is preferably an alcohol represented by the formula R.sup.3OH
[wherein R.sup.3 is the same as R.sup.3 of the compound represented
by the formula NaOR.sup.3].
[0086] The reaction temperature is preferably -20.degree. C. to
70.degree. C., and more preferably 0.degree. C. to 50.degree.
C.
[0087] The reaction time is preferably 1 minute to 5 hours, and
more preferably 5 minutes to 1 hour.
[0088] (Step A-4)
[0089] Step A-4 is a procedure to allow compound (4) to react with
compound (5) or compound (6), to produce compound (7). Compound (5)
or compound (6) is either publicly known, or can easily be produced
from a publicly known compound.
[0090] In Step A-4, of compound (5) and compound (6), compound (5)
is preferably used, more preferably dimethyl carbonate
[(MeO).sub.2CO] or diethyl carbonate, and most preferably dimethyl
carbonate.
[0091] In Step A-4, in the case where compound
[(R.sup.6O).sub.2CO], in which R.sup.4 and R.sup.5 of compound (5)
together form an oxo group, is used, a base may be further used,
preferably. Such base is not limited so long as it is used for
conversion of 1,2-diol into cyclic carbonate, and may be for
example, an alkali metal carbonate such as lithium carbonate,
sodium carbonate, potassium carbonate and cesium carbonate; an
alkali metal hydrogencarbonate such as lithium hydrogencarbonate,
sodium hydrogencarbonate and potassium hydrogencarbonate; an alkali
metal hydroxide such as lithium hydroxide, sodium hydroxide and
potassium hydroxide; an alkaline earth metal hydroxide such as
calcium hydroxide and barium hydroxide; an alkali metal hydride
such as lithium hydride, sodium hydride and potassium hydride; an
alkali metal amide such as lithium amide, sodium amide and
potassium amide; an alkali metal alkoxide such as lithium
methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide
and potassium tert-butoxide; a lithium alkyl amide such as lithium
diisopropylamide; a lithium silyl amide such as lithium
bistrimethylsilyl amide and sodium bistrimethylsilyl amide; or an
organic amine such as triethylamine, tributylamine,
N,N-diisopropylethylamine, N-methylpiperidine, N-methylmorpholine,
N-ethylmorpholine, pyridine, picoline, 4-dimethylaminopyridine,
4-pyrrolidinopyridine, 2,6-di(tert-butyl)-4-methylpyridine,
quinoline, N,N-dimethylaniline, N,N-diethylaniline,
1,5-diazabicyclo[4,3,0]non-5-ene (DBN),
1,4-diazabicyclo[2,2,2]octane (DABCO), 1,8-diazabicyclo
[5,4,0]undec-7-ene (DBU); preferably an alkali metal carbonate, an
alkali metal alkoxide or an alkali metal hydride, more preferably
an alkali metal alkoxide, and most preferably sodium methoxide.
[0092] In Step A-4, in the case where compound (5) [except for a
compound represented by the formula (R.sup.6O).sub.2CO] or compound
(6) is used, an acid may be further used, preferably. Such acid is
not limited so long as it is used for conversion of 1,2-diol into
cyclic acetal or cyclic ketal, and may be for example, an organic
acid such as acetic acid, propionic acid, trifluoroacetic acid and
pentafluoropropionic acid, an organic sulfonic acid such as
p-toluenesulfonic acid, camphorsulfonic acid and
trifluoromethanesulfonic acid, or an inorganic acid such as
hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric
acid, sulfuric acid and nitric acid.
[0093] In Step A-4, in the case where compound
[(R.sup.6O).sub.2CO], in which R.sup.4 and R.sup.5 of compound (5)
together form an oxo group, is used, the solvent used is preferably
an alcohol, more preferably methanol or ethanol, and most
preferably methanol. In the case where compound (5) is used, the
solvent used is preferably an alcohol represented by the formula
R.sup.6OH [wherein R.sup.6 is the same as R.sup.6 of compound (5)].
In addition, the solvent used is preferably an alcohol represented
by the formula R.sup.6OH [wherein R.sup.6 is the same as R.sup.6 of
compound (5)].
[0094] In Step A-4, in the case where compound (5) [except for a
compound represented by the formula (R.sup.6O).sub.2CO] or compound
(6) is used, the solvent used is preferably a halogenated
hydrocarbon, an amide, or a ketone, more preferably a ketone, and
most preferably acetone. In a case where compound (5) [except for a
compound represented by the formula (R.sup.6O).sub.2CO] is used and
the solvent used is a ketone, the solvent is preferably a ketone
represented by the formula (6).
[0095] The reaction temperature is preferably -30.degree. C. to
80.degree. C., and more preferably 0.degree. C. to 50.degree.
C.
[0096] The reaction time is preferably 30 minutes to 60 hours, and
more preferably 1 to 20 hours.
[0097] (Step A-5)
[0098] Step A-5 is a procedure to allow compound (7) to react with
a compound represented by the formula (R.sup.2O).sub.2SO.sub.2 in
the presence of a base, to produce compound (8). The compound
represented by the formula (R.sup.2O).sub.2SO.sub.2 is either
publicly known, or can easily be produced from a publicly known
compound.
[0099] In Step A-5, the compound represented by the formula
(R.sup.2O).sub.2SO.sub.2 is preferably dimethyl sulfuric acid
[(MeO).sub.2SO.sub.2].
[0100] The base used is not limited so long as it is used for
alkylation of a hydroxyl group, and may be, for example, a base
indicated in Step A-4, preferably an alkali metal hydride, and most
preferably sodium hydride.
[0101] The solvent used is preferably an ether, an amide, or a
mixture thereof, more preferably tetrahydrofuran,
N,N-dimethylacetamide, or a mixture thereof, and most preferably a
mixture of tetrahydrofuran and N,N-dimethylacetamide.
[0102] The reaction temperature is preferably -50.degree. C. to
80.degree. C., and more preferably -20.degree. C. to 50.degree.
C.
[0103] The reaction time is preferably 10 minutes to 20 hours, and
more preferably 30 minutes to 10 hours.
[0104] (Step A-6)
[0105] Step A-6 is a procedure to allow compound (8) to react with
trimethylsilyl azide in the presence of a Lewis acid, to produce
compound (9).
[0106] The Lewis acid used is not limited so long as it promotes
azidation which is accompanied by ring opening of an oxazolidine
ring, and may be for example, a zinc halide such as zinc chloride
and zinc bromide; a boron trihalide such as boron trifluoride,
boron trichloride and boron tribromide, and their complexes with
ethers or thioethers; a titanium (IV) alkoxide such as titanium
(IV) methoxide, titanium (IV) ethoxide, titanium (IV) propoxide,
titanium (IV) isopropoxide, titanium (IV) butoxide and titanium
(IV) 2-ethylhexoxide; a zirconium (IV) alkoxide such as zirconium
(IV) ethoxide, zirconium (IV) propoxide, zirconium (IV)
isopropoxide isopropanol complex, zirconium (IV) butoxide and
zirconium (IV) tert-butoxide; a scandium (III) alkoxide such as
scandium (III) isopropoxide; a scandium salt such as scandium
trifluoromethanesulfonate; a yttrium (III) alkoxide such as yttrium
(III) isopropoxide; a yttrium salt such as yttrium
trifluoromethanesulfonate; a lanthanoid isopropoxide such as
gadolinium (III) isopropoxide, dysprosium (III) isopropoxide,
ytterbium (III) isopropoxide and erbium (III) isopropoxide; an
aluminum alkoxide such as aluminum ethoxide, aluminum butoxide,
aluminum sec-butoxide and aluminum tert-butoxide; preferably a
titanium (IV) alkoxide, and most preferably titanium (IV)
isopropoxide.
[0107] The solvent used is preferably an aromatic hydrocarbon, an
alcohol, or a mixture thereof, more preferably 2-propanol,
2-methyl-2-propanol, toluene or a mixture thereof, and most
preferably a mixture of 2-methyl-2-propanol and toluene.
[0108] The reaction temperature is preferably -20.degree. C. to
60.degree. C., and more preferably 0.degree. C. to 30.degree.
C.
[0109] The reaction time is preferably 1 to 100 hours, and more
preferably 5 to 30 hours.
[0110] (Step A-7)
[0111] Step A-7 comprises (Step A-7a), a procedure to treat
compound (9) with triphenylphosphine; and (Step A-7b), a procedure
to treat the compound obtained in Step A-7a with a base and
water.
[0112] (Step A-7a)
[0113] The solvent used is preferably an ether or an ester, more
preferably tetrahydrofuran or ethyl acetate, and most preferably
tetrahydrofuran.
[0114] The reaction temperature is preferably -30.degree. C. to
100.degree. C., and more preferably 0.degree. C. to 70.degree.
C.
[0115] The reaction time is preferably 1 minute to 20 hours, and
more preferably 5 minutes to 5 hours.
[0116] (Step A-7b)
[0117] The base used is not limited so long as it promotes
hydrolysis of an ester group and elimination of a cyclic carbonate
group, and may be for example, an alkali metal carbonate such as
lithium carbonate, sodium carbonate, potassium carbonate and cesium
carbonate; an alkali metal hydrogencarbonate such as lithium
hydrogencarbonate, sodium hydrogencarbonate and potassium
hydrogencarbonate; an alkali metal hydroxide such as lithium
hydroxide, sodium hydroxide and potassium hydroxide; or an alkaline
earth metal hydroxide such as calcium hydroxide and barium
hydroxide, preferably an alkali metal hydroxide, more preferably
sodium hydroxide or potassium hydroxide, and most preferably sodium
hydroxide.
[0118] The solvent used is preferably an ether or an alcohol, more
preferably tetrahydrofuran, methanol or ethanol, and most
preferably tetrahydrofuran.
[0119] The reaction temperature is preferably -30.degree. C. to
100.degree. C., and more preferably 0.degree. C. to 70.degree.
C.
[0120] The reaction time is preferably 10 minutes to 20 hours, and
more preferably 30 minutes to 10 hours.
[0121] In the case where a protective group of 1,2-diol of compound
(9) is a cyclic acetal or cyclic ketal, deprotection of the
1,2-diol protective group is conducted by treating the compound
obtained in Step A-7a with a base and water, and then adjusting the
pH of the reaction mixture to acidic.
[0122] (Step A-8)
[0123] Step A-8 is a procedure to allow compound (10) to react with
compound (11), to produce compound (12). Compound (11) can be
produced in accordance with Process F.
[0124] The solvent used is preferably water, an amide, a ketone, a
nitrile, an alcohol or a mixture thereof, more preferably a mixture
of water and an alcohol, and most preferably a mixture of water and
methanol.
[0125] The reaction temperature is preferably -30.degree. C. to
80.degree. C., and more preferably 0.degree. C. to 50.degree.
C.
[0126] The reaction time is preferably 1 to 160 hours, and more
preferably 5 to 80 hours.
[0127] (Step A-9)
[0128] Step A-9 is a procedure to allow compound (12) to react with
water to produce compound (13).
[0129] The solvent used is preferably an alcohol, water, or a
mixture thereof, more preferably methanol, water, or a mixture
thereof, and most preferably water.
[0130] The reaction temperature is preferably 0.degree. C. to
160.degree. C., and more preferably 50.degree. C. to 110.degree.
C.
[0131] The reaction time is preferably 30 minutes to 20 hours, and
more preferably 1 to 10 hours.
[0132] In Step A-8 and Step A-9, compound (13) can be produced also
by reacting compound (10) with a compound represented by the
formula (23):
##STR00073##
or a salt thereof. Compound (23) or a salt thereof is either
publicly known, or can easily be produced from a publicly known
compound.
[0133] In the present step, compound (23) or a salt thereof is
preferably the hydrochloride of compound (23). In this step, a base
(preferably an organic amine or an alkali metal hydroxide, and more
preferably an alkali metal hydroxide) may be further used for the
purpose of controlling the pH during the reaction.
[0134] The solvent used is preferably an alcohol, water, or a
mixture thereof, and most preferably a mixture of methanol and
water.
[0135] The reaction temperature is preferably -20.degree. C. to
70.degree. C., and more preferably 0.degree. C. to 50.degree.
C.
[0136] The reaction time is preferably 1 to 200 hours, and more
preferably 10 to 100 hours.
[0137] The pH during the reaction is preferably 7 to 10, and more
preferably 7 to 9.
[0138] (Step A-10)
[0139] Step A-10 is a procedure to allow compound (13) to react
with compound (14) in the presence of acid to produce compound (I)
[which may contain a compound represented by the formula (II)].
Compound (14) can be produced in accordance with Process G.
[0140] In Step A-10, compound (14) is preferably trialkyl
orthooctanoate [C.sub.7H.sub.15C(OR.sup.7).sub.3], and more
preferably trimethyl orthooctanoate.
[0141] The acid used is not limited so long as it promotes
acylation reaction of a hydroxyl group in which an ortho ester is
used, and may be for example, an organic acid such as acetic acid,
propionic acid, trifluoroacetic acid and pentafluoropropionic acid,
an organic sulfonic acid such as p-toluenesulfonic acid,
camphorsulfonic acid and trifluoromethanesulfonic acid, or an
inorganic acid such as hydrogen chloride, hydrogen bromide,
hydrogen iodide, phosphoric acid, sulfuric acid and nitric acid,
preferably an organic sulfonic acid or an inorganic acid, more
preferably p-toluenesulfonic acid, sulfuric acid or hydrogen
chloride, and most preferably hydrogen chloride.
[0142] The solvent used is preferably an alcohol, and most
preferably methanol. The solvent used is preferably an alcohol
represented by the formula R.sup.7OH [wherein R.sup.7 is the same
as R.sup.7 of compound (14)].
[0143] The reaction temperature is preferably -30.degree. C. to
80.degree. C., and more preferably 0.degree. C. to 50.degree.
C.
[0144] The reaction time is preferably 5 minutes to 20 hours, and
more preferably 10 minutes to 5 hours.
[0145] In Step A-10, compound (I) [which may contain a compound
represented by the formula (II)] may be produced also by reacting
compound (13) with compound (15) and a compound represented by the
formula R.sup.7--OH in the presence of acid. Compound (15) can be
produced in accordance with Process G.
[0146] In this step, compound (15) is preferably a compound
represented by the formula (15a):
##STR00074##
[0147] The acid used is not limited so long as it promotes the
present reaction, and is preferably the aforementioned organic
sulfonic acid or inorganic acid, more preferably p-toluenesulfonic
acid, sulfuric acid, or hydrogen chloride, and most preferably
hydrogen chloride.
[0148] The solvent used is preferably an alcohol, and most
preferably methanol. The solvent used is preferably an alcohol
represented by the formula R.sup.7OH [wherein R.sup.7 is the same
as R.sup.1 of compound (15)].
[0149] The reaction temperature is preferably -30.degree. C. to
80.degree. C., and more preferably 0.degree. C. to 50.degree.
C.
[0150] The reaction time is preferably 5 minutes to 20 hours, and
more preferably 10 minutes to 5 hours.
[0151] (Process B)
[0152] The production of compound (12) from compound (9) in Process
A can also be conducted in accordance with Process B.
[0153] (Step B-1)
[0154] Step B-1 is a procedure to reduce compound (9) by using
triphenylphosphine and water, to produce compound (16).
[0155] The solvent used is preferably an ether or an ester, more
preferably tetrahydrofuran or ethyl acetate, and most preferably
ethyl acetate.
[0156] The reaction temperature is preferably 20.degree. C. to
120.degree. C., and more preferably 50.degree. C. to 90.degree.
C.
[0157] The reaction time is preferably 10 minutes to 20 hours, and
more preferably 30 minutes to 5 hours.
[0158] (Step B-2)
[0159] Step B-2 is a procedure to allow compound (16) to react with
compound (11) to produce compound (17).
[0160] The solvent used is preferably an ether or an ester, more
preferably tetrahydrofuran or ethyl acetate, and most preferably
ethyl acetate.
[0161] The reaction temperature is preferably -30.degree. C. to
80.degree. C., and more preferably 0.degree. C. to 50.degree.
C.
[0162] The reaction time is preferably 1 to 80 hours, and more
preferably 5 to 40 hours.
[0163] (Step B-3)
[0164] Step B-3 is a procedure to treat compound (17) with a base
to produce compound (12).
[0165] The base used is not limited so long as it promotes
elimination of a cyclic carbonate group and hydrolysis of an ester
group, and may be for example, an alkali metal carbonate, an alkali
metal hydrogencarbonate, an alkali metal hydroxide, or an alkaline
earth metal hydroxide as indicated in Step A-7b, preferably an
alkali metal carbonate or an alkali metal hydroxide, more
preferably sodium carbonate or potassium carbonate, and most
preferably potassium carbonate.
[0166] The solvent used is preferably an alcohol, and more
preferably methanol. In the present step, it is preferable that
water is present.
[0167] The reaction temperature is preferably -30.degree. C. to
80.degree. C., and more preferably 0.degree. C. to 50.degree.
C.
[0168] The reaction time is preferably 30 minutes to 20 hours, and
more preferably 1 to 10 hours.
[0169] In the case where the protective group of 1,2-diol is a
cyclic acetal or a cyclic ketal, deprotection of the protective
group of 1,2-diol is conducted by treating compound (17) with a
base and then adjusting the pH of the reaction mixture to
acidic.
[0170] (Process C)
[0171] The production of compound (12) from compound (8) in Process
A can also be conducted in accordance with Process C.
[0172] (Step C-1)
[0173] Step C-1 is a procedure to allow compound (8) to react with
a compound represented by the formula NaOR.sup.3 to produce
compound (18).
[0174] In Step C-1, the compound represented by the formula
NaOR.sup.3 is preferably sodium methoxide.
[0175] Step C-1 can be conducted in a similar manner to Step
A-3.
[0176] (Step C-2)
[0177] Step C-2 is a procedure to allow compound (18) to react with
acetic acid anhydride in the presence of acid or base, to produce
compound (19).
[0178] In Step C-2, in the case where an acid is used, it can be
conducted in a similar manner to Step A-2.
[0179] In Step C-2, in the case where a base is used, the base used
is preferably an organic base as indicated in Step A-4, more
preferably triethylamine, tributylamine, N,N-diisopropylethylamine,
4-dimethylaminopyridine, or a mixture thereof, and most preferably
a mixture of triethylamine and 4-dimethylaminopyridine.
[0180] The solvent used is preferably an aromatic hydrocarbon, an
ester, or a mixture thereof, more preferably an ester, and most
preferably ethyl acetate.
[0181] The reaction temperature is preferably -30.degree. C. to
80.degree. C., and more preferably 0.degree. C. to 50.degree.
C.
[0182] The reaction time is preferably 5 minutes to 10 hours, and
more preferably 10 minutes to 5 hours.
[0183] (Step C-3)
[0184] Step C-3 is a procedure to allow compound (19) to react with
trimethylsilyl azide in the presence of a Lewis acid, to produce
compound (20).
[0185] Step C-3 can be conducted in a similar manner to Step
A-6.
[0186] (Step C-4)
[0187] Step C-4 is a procedure to reduce compound (20) by using
triphenylphosphine and water, to produce compound (21).
[0188] Step C-4 can be conducted in a similar manner to Step
B-1.
[0189] (Step C-5)
[0190] Step C-5 is a procedure to allow compound (21) to react with
compound (11) to produce compound (22).
[0191] Step C-5 can be conducted in a similar manner to Step
B-2.
[0192] (Step C-6)
[0193] Step C-6 is a procedure to treat compound (22) with a base
to produce compound (12).
[0194] Step C-6 can be conducted in a similar manner to Step
B-3.
[0195] (Process D)
[0196] The production of compound (13) from compound (9) in Process
A can also be conducted in accordance with Process D.
[0197] (Step D-1)
[0198] Step D-1 is a procedure to reduce compound (9) by using
triphenylphosphine and water to produce compound (16).
[0199] Step D-1 can be conducted in a similar manner to Step
B-1.
[0200] (Step D-2)
[0201] Step D-2 is a procedure to allow compound (16) to react with
compound (23a) to produce compound (24).
[0202] In this procedure, a base (preferably an organic amine or an
alkali metal hydroxide, more preferably an alkali metal hydroxide)
may be further used for the purpose of controlling the pH during
the reaction.
[0203] The solvent used is preferably an alcohol, water, or a
mixture thereof, and most preferably a mixture of methanol and
water.
[0204] The reaction temperature is preferably -20.degree. C. to
70.degree. C., and more preferably 0.degree. C. to 50.degree.
C.
[0205] The reaction time is preferably 1 to 200 hours, and more
preferably 10 to 100 hours.
[0206] The pH during the reaction is preferably 7 to 10, and more
preferably 7 to 9.
[0207] (Step D-3)
[0208] Step D-3 is a procedure to treat compound (24) with a base
to produce compound (13)
[0209] Step D-3 can be conducted in a similar manner to Step
B-3.
[0210] (Process E)
[0211] The production of compound (13) from compound (10) in
Process A can also be conducted in accordance with Process E.
[0212] (Step E-1)
[0213] Step E-1 is a procedure to allow compound (10) to react with
compound (23a) to produce compound (13).
[0214] Step E-1 can be conducted in a similar manner to Step
D-2.
[0215] (Process F)
[0216] Process F shows a method of manufacturing compound (11)
[0217] (Step F-1)
[0218] Step F-1 is a procedure to allow compound (23a) to react
with di-t-butyl dicarbonate (Boc.sub.2O) in the presence of a base
to produce compound (25). Compound (23a) is either publicly known,
or can easily be produced from a publicly known compound.
[0219] The base used is not limited so long as it is used for
protection of an amino group by a tert-butoxycarbonyl group, and
may be for example, an alkali metal carbonate, an alkali metal
hydrogencarbonate, an alkali metal hydroxide, an alkaline earth
metal hydroxide, an alkali metal hydride, or an organic amine as
indicated in Step A-4, preferably an organic amine, and most
preferably N,N-diisopropylethylamine.
[0220] The solvent used is preferably an amide, and most preferably
N,N-dimethylformamide.
[0221] The reaction temperature is preferably -30.degree. C. to
80.degree. C., and more preferably 0.degree. C. to 50.degree.
C.
[0222] The reaction time is preferably 30 minutes to 20 hours, and
more preferably 1 to 5 hours.
[0223] (Step F-2)
[0224] Step F-2 is a procedure to allow compound (25) to react with
a base to generate an anion of compound (25), and then allow it to
react with di-t-butyl dicarbonate to produce compound (11).
[0225] The base used is not limited so long as it is used for
protection of an imino group by a tert-butoxycarbonyl group, and
may be for example, an alkali metal carbonate, an alkali metal
hydrogencarbonate, an alkali metal hydroxide, an alkaline earth
metal hydroxide, an alkali metal hydride, an alkali metal amide, an
alkali metal alkoxide, a lithium alkyl amide, a lithium silyl
amide, or an organic amine as indicated in Step A-4, preferably an
alkali metal hydride, and most preferably sodium hydride.
[0226] The solvent used is preferably an ether, and most preferably
tetrahydrofuran.
[0227] The reaction temperature of the reaction of compound (25)
with the base is preferably -40.degree. C. to 10.degree. C., and
more preferably -20.degree. C. to 5.degree. C.
[0228] The reaction time of the reaction of compound (25) with the
base is preferably 10 minutes to 5 hours, and more preferably 30
minutes to 2 hours.
[0229] The reaction temperature of the reaction of the anion with
di-tert-butyl dicarbonate is preferably 20.degree. C. to
120.degree. C., and more preferably 50.degree. C. to 90.degree.
C.
[0230] The reaction time of the reaction of the anion with
di-tert-butyl dicarbonate is preferably 30 minutes to 10 hours, and
more preferably 1 to 5 hours.
[0231] (Process G)
[0232] Process G shows a method of manufacturing compound (14) and
compound (15).
[0233] (Step G-1)
[0234] Step G-1 is a procedure to allow compound (26) to react with
a compound represented by the formula R.sup.7OH in the presence of
an acid represented by the formula HX, to produce compound (15).
Compound (26) is either publicly known, or can easily be produced
from a publicly known compound.
[0235] In Step G-1, the acid represented by the formula HX is
preferably hydrogen chloride. In Step G-1, the compound represented
by the formula R.sup.7OH is preferably methanol.
[0236] The solvent used is preferably an ester, an aliphatic
hydrocarbon, or an aromatic hydrocarbon, more preferably an ester,
and most preferably methyl acetate.
[0237] The reaction temperature is preferably -50.degree. C. to
50.degree. C., and more preferably -20.degree. C. to 20.degree.
C.
[0238] The reaction time is preferably 1 to 100 hours, and more
preferably 5 to 50 hours.
[0239] (Step G-2)
[0240] Step G-2 is a procedure to allow compound (15) to react with
a compound represented by the formula R.sup.7OH to produce compound
(14).
[0241] In Step G-2, the compound represented by the formula
R.sup.7OH is preferably methanol. R.sup.7 in the compound
represented by the formula R.sup.1OH is preferably the same as
R.sup.7 of compound (15). The volume ratio of the compound
represented by the formula R.sup.7OH with respect to compound (15)
is preferably 0.5 to 5, and more preferably 1 to 3.
[0242] The solvent used is preferably a solvent which forms a
bilayer system. Here, formation of a bilayer system means that the
compound represented by the formula R.sup.7OH in the reaction
solution and the solvent form two layers that are not uniform and
are separate from each other, and by stirring the reaction solution
adequately, the compound present in the reaction solution,
depending on its lipid solubility or water solubility, can move to
the other layer in which the compound can be dissolved more easily.
The solvent used is preferably a carbohydrate, more preferably an
aliphatic carbohydrate or an aromatic carbohydrate, even more
preferably an aliphatic carbohydrate, further preferably
cyclohexane, methylcyclohexane or ethylcyclohexane, particularly
preferably cyclohexane or methylcyclohexane, and most preferably
methylcyclohexane. The compound represented by the formula
R.sup.7OH in excess amount can also be used as the solvent.
[0243] The mixing ratio (volume ratio) of methylcyclohexane and
methanol is preferably 10:1 to 1:2, and more preferably 5:1 to
1:1.
[0244] The reaction temperature is preferably -20.degree. C. to
90.degree. C., and more preferably 10.degree. C. to 60.degree.
C.
[0245] The reaction time is preferably 30 minutes to 30 hours, and
more preferably 2 to 15 hours.
[0246] The neuraminic acid derivative (I) according to the present
invention is known to have excellent neuraminidase inhibitory
activity and is therefore useful as a drug for treatment or
prevention of influenza (refer to the aforementioned Patent
Document 1 or 2).
[0247] In the case where the neuraminic acid derivative (I)
according to the present invention is used as a medicament,
especially as a drug for treatment or prevention of influenza, it
can be administered as such, or it can be mixed with a suitable
excipient, diluent and the like that are pharmacologically
acceptable, and administered as a tablet, capsule, granules,
powders, syrup, injection, ointment, liquid formulation,
suspension, aerosol, lozenge and the like. The medicament according
to the present invention can be administered orally or
parenterally, and it is preferable that the compound (I), which is
an active ingredient, is administered in such manner that it can be
directly delivered to the lungs or respiratory tract (which
includes intraoral and intranasal portions).
[0248] These pharmaceutical drugs are produced through known
methods by using additives such as excipients, binders,
disintegrants, lubricants, stabilizers, corrigents for taste or
smell, suspending agents, diluents and solvents for
formulation.
[0249] Although the dosage amount varies depending on symptoms,
weight, age and the like of the subject to be administered (a
warm-blooded animal, preferably a human), it is preferable to
administer it with a lower limit of 0.1 mg (preferably 1 mg) and an
upper limit of 1000 mg (preferably 500 mg) per day, once a day or
several times a day, depending on symptoms.
EXAMPLES
[0250] The present invention will be described in more detail with
reference to the following Examples; however, the scope of the
present invention is not limited to these.
Example 1
Synthesis of
(4S,5R,6R)-5-acetamide-4-guanidino-6-[(1R,2R)-2-hydroxy-1-methoxy-2-(octa-
noyloxy)propyl]-5,6-dihydro-4H-pyran-2-carboxylic acid [Compound
(Ib)]
Step A-1: Methyl N-acetylneuramate
[0251] Trimethyl orthoformate (116.67 g) and methanol (2720 ml)
were added to N-acetyl neuraminic acid (340.00 g) and suspended.
Concentrated sulfuric acid (8.63 g) was added to the suspension
under stirring at room temperature, and the mixture was stirred for
3 hours at 40.degree. C. The solvent was distilled off under
reduced pressure until the amount of solution became approximately
1530 ml, dibutyl ether (4420 ml) was added to the reaction solution
at 30.degree. C., and the reaction solution was stirred at the same
temperature for 1 hour. After it was further stirred for 1 hour at
0.degree. C., crystals were filtered. The crystals were washed with
a mixture of methanol (170 ml) and dibutyl ether (510 ml) and dried
under reduced pressure to give the title compound as a white solid
(342.11 g, 96.3% yield).
[0252] MS (FAB): m/z 324 [M+H].sup.+
[0253] HRMS (ESI): Exact mass calcd for C.sub.12H.sub.22NO.sub.9
[M+H].sup.+ 324.12946. Found 324.12966.
[0254] IR (KBr): 3340, 2938, 1741, 1638, 1553, 1438, 1375, 1279,
1127, 1033 cm.sup.-1
[0255] .sup.1H NMR (D.sub.2O, 500 MHz): 1.80 (1H, dd, J=12.1, 12.9
Hz), 1.94 (3H, s), 2.20 (1H, dd, J=5.0, 12.9 Hz), 3.44 (1H, dd,
J=1.0, 9.2 Hz), 3.51 (1H, dd, J=6.2, 11.8 Hz), 3.62 (1H, ddd,
J=2.8, 6.2, 9.2 Hz), 3.73 (1H, dd, J=2.8, 11.8 Hz), 3.73 (3H, s),
3.81 (1H, dd, J=10.2, 10.2 Hz), 3.95 (1H, ddd, J=5.0, 10.2, 12.1
Hz), 3.96 (1H, dd, J=1.0, 10.2 Hz).
[0256] .sup.13C NMR (D.sub.2O, 125 MHz): 22.2, 38.7, 52.1, 53.6,
63.2, 66.7, 68.3, 70.2, 70.4, 95.4, 171.5, 174.9.
Step A-2: Methyl
(3aS,4R,7aR)-4-[(1S,2R)-1,2,3-triacetoxypropyl]-2-methyl-3a,7a-dihydro-4H-
-pyrano[3,4-d][1,3]oxazole-6-carboxylate
[0257] Heptane (600 ml) and anhydrous acetic acid (814.70 g) were
added to the compound obtained in Step A-1 (300.00 g) and
suspended. The suspension was cooled to 0.degree. C., and
concentrated sulfuric acid (209.32 g) was added dropwise under
stirring at 40.degree. C. or lower. After stirring the mixture for
4 hours at 40.degree. C., it was cooled to 0.degree. C. and
triethylamine (431.93 g) was added dropwise at 40.degree. C. or
lower. The reaction solution was added dropwise to a mixture of
water (1800 ml), 26% aqueous ammonia (916.79 g) and toluene (4500
ml) which was cooled to 0.degree. C. under stirring at 40.degree.
C. or lower. The reaction solution was stirred for 1 hour at
25.degree. C. After the reaction solution was allowed to stand, the
organic layer was separated and the solvent was distilled off under
reduced pressure until the amount of solution became approximately
900 ml to give a toluene solution of the title compound.
Step A-3: Methyl
(3aS,4R,7aR)-4-[(1R,2R)-1,2,3-trihydroxypropyl]-2-methyl-3a,7a-dihydro-4H-
-pyrano[3,4-d][1,3]oxazole-6-carboxylate
[0258] Methanol (1800 ml) and 25.4% methanol solution of sodium
methoxide (15.79 g) were added to the toluene solution of the
compound obtained in Step A-2 at room temperature, and the reaction
solution was stirred for 15 minutes at 25.degree. C. The solvent of
the reaction solution was distilled off until the amount of
solution became approximately 900 ml to give a methanol solution of
the title compound.
Step A-4: Methyl
(3aS,4R,7aR)-4-{(S)-hydroxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-2-methyl-
-3a, 7a-dihydro-4H-pyrano[3,4-d][1, 3]oxazole-6-carboxylate
[0259] Dimethyl carbonate (961.26 g) was added to the methanol
solution of the compound obtained in Step A-3, and the mixture was
stirred for 1 hour at 25.degree. C. and then further for 5 hours at
55.degree. C. The reaction solution was cooled to 0.degree. C.,
stirred for 5 minutes at the same temperature, and crystals were
filtered. The crystals were washed with methanol (600 ml) and dried
under reduced pressure to give the title compound as a white solid
(234.32 g, 80.6% yield).
[0260] MS (FAB): m/z 314 [M+H].sup.+
[0261] Anal. calcd for C.sub.13H.sub.15NO.sub.8: C, 49.84; H, 4.83;
N, 4.47. Found C, 49.82; H, 4.58; N, 4.46.
[0262] IR (KBr): 3194, 1801, 1787, 1734, 1662, 1398, 1277, 1225,
1177, 1089, 988 cm.sup.-1 1H NMR (DMSO-d6, 500 MHz): 1.89 (3H, s),
3.24 (1H, dd, J=2.0, 10.2 Hz), 3.72 (3H, s), 4.07 (1H, dd, J=2.0,
0.2.9 Hz), 4.15 (1H, dd, J=8.4, 10.2 Hz), 4.52 (1H, dd, J=7.2, 12.8
Hz), 4.54 (1H, dd, J=8.2, 12.8 Hz), 4.90 (1H, dd, J=4.2, 8.4 Hz),
4.98 (1H, ddd, J=2.9, 7.2, 8.2 Hz), 6.15 (1H, s), 6.27 (1H, d,
J=4.2 Hz).
[0263] .sup.13C NMR (DMSO-d6, 125 MHz): 14.3, 53.0, 61.0, 65.9,
67.5, 72.3, 78.3, 78.8, 108.1, 146.8, 155.3, 162.2, 166.3.
Step A-5: Methyl
(3aS,4R,7aR)-4-{(S)-methoxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-2-methyl-
-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate
[0264] Tetrahydrofuran (80 ml) and N,N-dimethylacetamide (20 ml)
were added to the compound obtained in Step A-4 (20.00 g) and
suspended. The suspension was stirred for 15 minutes at 0.degree.
C. After 60% sodium hydride (3.32 g) was added to the suspension
and the mixture was stirred for 10 minutes at 0.degree. C.,
dimethyl sulfate (11.27 g) was added, followed by stirring for 2.25
hours at 15.degree. C. Acetic acid (3.83 g) and toluene (200 ml)
were added to the reaction solution, the mixture was washed with 5%
aqueous sodium hydrogencarbonate (100 ml), and the organic layer 1
and aqueous layer 1 were separated. The organic layer 1 was washed
with water (10 ml), and the organic layer 2 and aqueous layer 2
were separated. The aqueous layer 1 and aqueous layer 2 were
combined, extracted with toluene (200 ml), and the organic layer 3
was separated. The organic layer 2 and organic layer 3 were
combined and the solvent was distilled off under reduced pressure
until the amount of solution became approximately 60 ml to give a
toluene solution of the title compound.
Step A-6: Methyl
(4S,5R,6R)-5-acetamide-4-azide-6-{(S)-methoxy[(4R)-2-oxo-1,3-dioxolan-4-y-
l]methyl}-5,6-dihydro-4H-pyran-2-carboxylate
[0265] 2-Methyl-2-propanol (20 ml) and trimethylsilyl azide (14.71
g) were added to the compound obtained in Step A-5 at room
temperature. Subsequently, titanium (IV) isopropoxide (5.44 g) was
added at 10.degree. C., and the mixture was stirred for 20 hours at
20.degree. C. (stereoisomer ratio 15:1). After the reaction
solution was cooled to 0.degree. C., it was stirred for 1 hour at
the same temperature, and then crystals were filtered. After the
crystals were washed with toluene (40 ml) and dried under reduced
pressure to give the title compound as a pale yellowish white solid
(20.73 g, 87.7% yield, stereoisomer ratio 66:1).
[0266] MS (FAB): m/z 371 [M+H].sup.+
[0267] HRMS (ESI): Exact mass calcd for
C.sub.14H.sub.19N.sub.4O.sub.8 [M+H].sup.+ 371.12029. Found
371.12018.
[0268] IR (KBr): 3314, 2106, 1795, 1731, 1668, 1550, 1379, 1285,
1180, 1075 cm.sup.-1
[0269] .sup.1H NMR (DMSO-d6, 500 MHz): 1.89 (3H, s), 3.36 (3H, s),
3.71 (3H, s), 3.88 (1H, dd, J=1.3, 2.0 Hz), 3.99 (1H, ddd, J=8.9,
9.2, 10.6 Hz), 4.20 (1H, dd, J=1.3, 10.6 Hz), 4.29 (1H, dd, J=2.5,
9.2 Hz), 4.54 (1H, dd, J=7.9, 12.2 Hz), 4.56 (1H, dd, J=7.9, 12.2
Hz), 5.06 (1H, ddd, J=2.0, 7.9, 7.9 Hz), 5.81 (1H, d, J=2.5 Hz),
8.16 (1H, d, J=8.9 Hz).
[0270] .sup.13C NMR (DMSO-d6, 125 MHz): 23.4, 47.0, 53.0, 59.0,
61.7, 66.1, 76.7, 77.7, 79.1, 108.6, 144.7, 155.0, 161.7,
170.1.
[0271] The peak area ratios of the title compound and stereoisomer
thereof were measured under the following HPLC measurement
conditions.
HPLC Measurement Conditions (3)
[0272] Column: L-column ODS (4.6 mmID.times.250 mm, particle
diameter 5 .mu.m, manufactured by Chemicals Evaluation and Research
Institute) Column temperature: 40.degree. C. Measurement
wavelength: 254 nm Mobile phase: acetonitrile:0.02 mol/l aqueous
ammonium acetate solution=65:35 Flow rate: 1 ml/min Retention time
of the title compound: approximately 6.3 minutes Retention time of
stereoisomer: approximately 6.6 minutes.
Step A-7:
(4S,5R,6R)-5-Acetamide-4-amino-6-[(1R,2R)-2,3-dihydroxy-1-methox-
ypropyl]-5,6-dihydro-4H-pyran-2-carboxylic acid
[0273] Triphenylphosphine (3.90 g) and tetrahydrofuran (20 ml) were
added to the compound obtained in Step A-6 (5.00 g) at room
temperature, and the mixture was stirred for 10 minutes at
50.degree. C. To the reaction solution were added water (12.5 ml)
and 25% aqueous sodium hydroxide (6.48 g) at 50.degree. C.,
followed by stirring for 2 hours at the same temperature. The
reaction solution was cooled to 0.degree. C., concentrated
hydrochloric aid (2.74 g) was added and the mixture was allowed to
stand. Subsequently, the aqueous layer was separated to give an
aqueous solution of the title compound.
Step A-8:
(4S,5R,6R)-5-Acetamide-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-
-6-[(R,2R)-2,3-dihydroxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxyli-
c acid
[0274] tert-Butyl
(tert-butoxycarbonyliminopyrazol-1-yl-methyl)carbamate (4.19 g) and
methanol (40 ml) were added to the aqueous solution of the compound
obtained in Step A-7 at room temperature, and the mixture was
stirred for 43 hours at the same temperature. To the reaction
solution was added water (12.5 ml) and the pH was adjusted to 8.35
by concentrated hydrochloric acid. Subsequently, the solvent was
distilled off under reduced pressure until the amount of solution
became approximately 25 ml. The obtained solution was washed with
ethyl acetate (25 ml) 3 times, and the aqueous layer was separated.
After the pH of the aqueous layer was adjusted to 2.75 with
concentrated hydrochloric acid, it was extracted with ethyl acetate
(45 ml) twice. The organic layers were combined, and the solvent
was distilled off under reduced pressure until the amount of
solution became approximately 20 ml. Water (20 ml) was added to the
concentrated solution, and the solvent was distilled off until the
amount of solution became approximately 20 ml to give an aqueous
solution of the title compound.
Step A-9:
(4S,5R,6R)-5-Acetamide-4-guadino-6-[(1R,2R)-2,3-dihydroxy-1-meth-
oxypropyl]-5,6-dihydro-4H-pyran-2-carboxylic acid
[0275] The aqueous solution of the compound obtained in Step A-8
was stirred for 3.7 hours at 80.degree. C. After the reaction
solution was cooled to 0.degree. C., methanol (50 ml) was added
thereto, the mixture was stirred for 1.25 hours at the same
temperature, and crystals were filtered. The crystals were washed
with methanol (10 ml) and dried under reduced pressure to give the
title compound as a white solid (3.34 g, 71.4% yield).
[0276] MS (FAB): m/z 347[M+H].sup.+
[0277] Anal. calcd for C.sub.13H.sub.22N.sub.4O.sub.7: C, 45.08; H,
6.40; N, 16.18. Found C, 44.85; H, 6.16; N, 16.09.
[0278] IR (KBr): 3440, 3375, 3256, 1699, 1653, 1587, 1401, 1329,
1284, 1171, 1087, 1029 cm.sup.-1
[0279] .sup.1H NMR (D.sub.2O, 500 MHz): 1.94 (3H, s), 3.31 (3H, s),
3.45 (1H, dd, J=1.5, 8.6 Hz), 3.57 (1H, dd, J=5.6, 12.0 Hz), 3.78
(1H, dd, J=3.0, 12.0 Hz), 3.88 (1H, ddd, J=3.0, 5.6, 8.6 Hz), 4.10
(1H, dd, J=9.7, 9.7 Hz), 4.30 (1H, dd, J=1.5, 9.7 Hz), 4.30 (1H,
dd, J=2.2, 9.7 Hz), 5.52 (1H, d, J=2.2 Hz).
[0280] .sup.13C NMR (D.sub.2O, 125 MHz): 22.1, 47.7, 51.8, 60.5,
62.5, 69.6, 75.7, 77.8, 104.0, 149.4, 157.0, 169.0, 174.2.
Step A-10:
(4S,5R,6R)-5-Acetamide-4-guadino-6-[(1R,2R)-2-hydroxy-1-methoxy-
-2-(octanoyloxy)propyl]-5,6-dihydro-4H-pyran-2-carboxylic acid
[Compound (Ib)]
[0281] Methanol (15 ml) and trimethyl orthooctanoate (5.31 g) were
added to the compound obtained in Step A-9 (3.00 g) and suspended.
To the suspension was added a 1 mol/1 hydrogen chloride methanol
solution (9.3 ml) at room temperature, followed by stirring for 1
hour at the same temperature. The solvent was distilled off under
reduced pressure until the amount of solution became approximately
10.5 ml, and water (30 ml) was added to the reaction solution and
the mixture was washed with ethyl acetate (15 ml) twice. The
aqueous layer was separated, and pH was adjusted to 7 with a 16.5%
aqueous sodium carbonate solution. After stirring the reaction
solution for 10 minutes at room temperature, pH was adjusted to 8.8
with a 16.5% aqueous sodium carbonate solution, and then the
reaction solution was stirred for 2 hours while maintaining the
same pH. Subsequently, pH was adjusted to 5.7 with concentrated
hydrochloric acid at room temperature, and the reaction solution
was stirred for 1 hour at 0.degree. C. while maintaining the same
pH. Crystals were filtered, washed with water (12 ml), and dried
under reduced pressure. The crystals were allowed to absorb
moisture at room temperature in the atmosphere for 5 hours to give
the crude title compound as white crystals (3.89 g, 95.1% yield).
Methanol (12 ml) was added to the crude title compound (2.00 g) to
dissolve it at 37.degree. C. After methanol (2 ml) and water (28
ml) were added to the solution at the same temperature, the
solution was stirred for 1 hour at 25.degree. C., and then crystals
were filtered. The crystals were washed with a mixture of methanol
(2 ml) and water (4 ml), followed by drying under reduced pressure.
The crystals were allowed to absorb moisture at room temperature in
the atmosphere for 5 hours to give the title compound as a white
crystal (1.84 g, 92.0% yield, chemical purity: 99.72%, compound
(Ib):compound (IIb)=97:3, content of compound (13) [R.sup.232
methyl group]: 0.02%, content of compound (VII) [R.sup.1=1-heptyl
group, R.sup.2=methyl group]: 0.08%, content of compound (VIII)
[R.sup.1=1-heptyl group]: 0.04%).
[0282] MS (FAB): m/z 473[M+H].sup.+
[0283] KF moisture value: 3.9%
[0284] Anal. calcd for C.sub.21H.sub.36 N.sub.4O.sub.8.
0.1.065H.sub.2O: C, 51.29; H, 7.82; N, 11.39. Found C, 51.21; H,
7.82; N, 11.32.
[0285] IR (KBr): 3334, 3289, 2929, 1736, 1665, 1640, 1401, 1325,
1283, 1173, 1114 cm.sup.-1 1H NMR (CD.sub.3OD, 500 MHz): 0.88 (3H,
t, J=7.0 Hz), 1.25-1.34 (8H, m), 1.62 (2H, tt, J=7.2, 7.5 Hz), 1.99
(3H, s), 2.35 (2H, t, J=7.5 Hz), 3.38 (3H, s), 3.45 (1H, dd, J=2.5,
8.2 Hz), 4.09-4.14 (2H, m), 4.23 (1H, dd, J=9.0, 9.0 Hz), 4.29-4.36
(3H, m), 5.55 (1H, d, J=2.5 Hz).
[0286] .sup.13C NMR (CD.sub.3OD, 125 MHz): 13.1, 21.5, 22.3, 24.7,
28.8, 28.9, 31.5, 33.7, 47.8, 51.4, 60.0, 65.5, 67.4, 76.1, 78.9,
102.3, 150.3, 157.6, 168.1, 172.2, 174.1.
Example 2
Synthesis of methyl
(3aS,4R,7aR)-4-{(S)-hydroxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-2-methyl-
-3a,7a-dihydro-4H-pyrano[3,4-d][1, 3]oxazole-6-carboxylate
(compound (7) [R.sup.4,R.sup.5 oxo group])
Step A-1: Methyl N-acetylneuramate
[0287] Trimethyl orthoformate (5.14 g) and methanol (120 ml) were
added to N-acetyl neuraminic acid (1) (15.00 g) and suspended.
Concentrated sulfuric acid (0.38 g) was added at room temperature
under stirring, and the reaction solution was stirred for 3 hours
at 40.degree. C. After the completion of the reaction,
N,N-dimethylacetamide (15 ml) was added to the reaction solution,
and then the solvent was distilled off under reduced pressure until
the amount of solution became approximately 40 ml. Water (7.5 ml)
and ethyl acetate (150 ml) were added to the concentrated solution
at 200.degree. C., the mixture was stirred for 0.5 hours at
30.degree. C., and then ethyl acetate (150 ml) was added and
stirred for another 0.5 hours at the same temperature. After
stirring for 2 hours at 0.degree. C., crystals were filtered, and
the crystals were washed with ethyl acetate (30 ml) which was
cooled to 0.degree. C. to give moist crystals of the title compound
(15.65 g).
Step A-2: Methyl
(3aS,4R,7aR)-4-[(1S,2R)-1,2,3-triacetoxypropyl]-2-methyl-3a,7a-dihydro-4H-
-pyrano[3,4-d][1, 3]oxazole-6-carboxylate
[0288] Anhydrous acetic acid (25.72 g) was added to the moist
crystals obtained in Step A-1 (10.08 g) and suspended, and then
concentrated sulfuric acid (6.61 g) was slowly added dropwise under
stirring while maintaining the temperature at 40.degree. C. or
lower. After stirring the reaction solution for 5 hours at
40.degree. C., the reaction solution was cooled to 0.degree. C.,
and triethylamine (13.64 g) was added dropwise at 40.degree. C. or
lower. This reaction solution was added dropwise to a cooled
solution mixture of water (50 ml), 28% aqueous ammonia (27.27 g),
and toluene (140 ml) while maintaining the temperature at
40.degree. C. or lower. The reaction solution was further stirred
for 1 hour at 25.degree. C. After the reaction solution was allowed
to stand, the separated organic layer was washed twice with water
(20 ml). The solvent was distilled off under reduced pressure until
the amount of solution became approximately 30 ml to give a toluene
solution of the title compound.
Step A-3: Methyl
(3aS,4R,7aR)-4-[(1R,2R)-1,2,3-trihydroxypropyl]-2-methyl-3a,7a-dihydro-4H-
-pyrano[3,4-d][1,3]oxazole-6-carboxylate
[0289] Methanol (60 ml) and a 28% sodium methoxide methanol
solution (0.45 g) were added to the toluene solution of the
compound obtained in Step A-2 at room temperature, and the mixture
was stirred for 15 minutes at 25.degree. C. Subsequently, the
reaction solution was concentrated under reduced pressure until the
amount of solution became approximately 30 ml to give a methanol
solution of methyl
(3aS,4R,7aR)-4-[(1R,2R)-1,2,3-trihydroxypropyl]-2-methyl-3a,7a-dihydro-4H-
-pyrano[3,4-d][1,3]oxazole-6-carboxylate (4).
Step A-4: Methyl
(3aS,4R,7aR)-4-{(S)-hydroxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-2-methyl-
-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate
[0290] Dimethyl carbonate (30.35 g) was added to the methanol
solution of the compound obtained in Step A-3. The mixture was
stirred for 1 hour at 25.degree. C., and further stirred for 5
hours at 55.degree. C. The reaction solution was cooled to
0.degree. C., stirred for 5 minutes at the same temperature, and
then crystals were filtered. The crystals were washed with methanol
(20 ml) and dried under reduced pressure to give the title compound
as a white solid (7.06 g, 76.9% yield).
Example 3
Synthesis of
(4S,5R,6R)-5-acetamide-4-guadino-6-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl-
]-5,6-dihydro-4H-pyran-2-carboxylic acid (Compound (13)
[R.sup.2=methyl group])
Step B-1: Methyl
(4S,5R,6R)-5-acetamide-4-amino-6-{(S)-methoxy[(4R)-2-oxo-1,3-dioxolan-4-y-
l]methyl}-5,6-dihydro-4H-pyran-2-carboxylate
[0291] Ethyl acetate (40 ml), triphenylphosphine (7.79 g), and
water (1.94 g) were added to the compound (10.00 g) obtained in
Step A-6 of Example 1 at room temperature, followed by stirring for
2.5 hours at 72.degree. C. The reaction solution was cooled to room
temperature to give an ethyl acetate solution of the title
compound.
Step B-2: Methyl
(4S,5R,6R)-5-acetamide-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-6-{(S)-m-
ethoxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-5,6-dihydro-4H-pyran-2-carboxy-
late
[0292] tert-Butyl
(tert-butoxycarbonyliminopyrazol-1-yl-methyl)carbamate (8.80 g) was
added to the ethyl acetate solution of the compound obtained in
Step B-1 at room temperature, and the mixture was stirred for 17.5
hours at the same temperature. The solvent was distilled off under
reduced pressure until the amount of solution became approximately
30 ml, toluene (100 ml) was added, and then insoluble matter was
filtered. The filtrate was washed twice with water (30 ml), and the
solvent of the separated organic layer was distilled off under
reduced pressure until the amount of solution became approximately
40 ml to give a toluene solution of the title compound.
Step B-3:
(4S,5R,6R)-5-Acetamide-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-
-6-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxyl-
ic acid
[0293] Methanol (50 ml), water (23 ml), and potassium carbonate
(11.20 g) were added to the toluene solution of the compound
obtained in Step B-2 at room temperature, and the mixture was
stirred for 4 hours at the same temperature. The reaction solution
was cooled to 5.degree. C., water (50 ml) was added, and then pH
was adjusted to 8.3 by 7% hydrochloric acid. The solvent of the
reaction solution was distilled off under reduced pressure until
the amount of solution became approximately 110 ml, followed by
washing with ethyl acetate (50 ml) 3 times, and the aqueous layer
was separated. The pH of the aqueous layer was adjusted to 2.7 with
7% hydrochloric acid, followed by extracting with ethyl acetate (90
ml) twice. The organic layers were combined, and the solvent was
distilled off until the amount of solution became approximately 40
ml. Water (40 ml) was added to the concentrated solution, and the
solvent was distilled off under reduced pressure until the amount
of solution became approximately 40 ml to give an aqueous solution
of the title compound.
Step A-9:
(4S,5R,6R)-5-Acetamide-4-guadino-6-[(1R,2R)-2,3-dihydroxy-1-meth-
oxypropyl]-5,6-dihydro-4H-pyran-2-carboxylic acid (Compound (13)
[R.sup.2=methyl group])
[0294] The aqueous solution of the compound obtained in Step B-3
was subjected to a similar operation to Step A-9 of Example 1 to
give the title compound as a white solid (6.71 g, 71.8% yield).
Example 4
Synthesis of
(4S,5R,6R)-5-acetamide-4-guadino-6-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl-
]-5,6-dihydro-4H-pyran-2-carboxylic acid (Compound (13)
[R.sup.2=methyl group])
Step C-1: Methyl
(3aS,4R,7aR)-4-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl]-2-methyl-3a,7a-dih-
ydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate
[0295] Methanol (460 ml) and a 25.4% sodium methoxide methanol
solution (14.36 g) were added to a toluene solution (approximately
675 ml) of a compound, which was obtained by subjecting methyl
(3aS,4R,7aR)-4-{(S)-hydroxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-2-methyl-
-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate (46.00 g)
to Step A-5 of Example 1, at room temperature, and the mixture was
stirred for 30 minutes at the same temperature. The solvent of the
reaction solution was distilled off under reduced pressure until
the amount of solution became approximately 138 ml, methanol (460
ml) was added, and the reaction solution was stirred for 30 minutes
at room temperature. After acetic acid (4.41 g) was added to the
reaction solution and the solvent was distilled off under reduced
pressure until the amount of solution became approximately 138 ml,
toluene (230 ml) was added to the reaction solution and then the
solvent was distilled off again under reduced pressure until the
amount of solution became 138 ml to give a toluene suspension of
the title compound.
Step C-2: Methyl
(3aS,4R,7aR)-4-[(1S,2R)-2,3-diacetoxy-1-methoxypropyl]-2-methyl-3a,7a-dih-
ydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate
[0296] Ethyl acetate (184 ml) was added to the toluene suspension
of the compound obtained in Step C-1 and the mixture was stirred
for 30 minutes at room temperature. Subsequently, triethylamine
(66.69 g), N,N-dimethylaminopyridine (0.90 g), and anhydrous acetic
acid (34.47 g) were added at 20.degree. C. or lower, and the
mixture was stirred for 1 hour at room temperature. Toluene (460
ml) and 5% aqueous sodium hydrogencarbonate (230 ml) were added to
the reaction solution, followed by stirring for 1 hour at room
temperature. After allowing the reaction solution to stand, the
organic layer was separated and washed with 5% aqueous sodium
hydrogencarbonate (230 ml). The organic layer was separated, the
solvent was distilled off under reduced pressure until the amount
of solution became approximately 230 ml, and then insoluble matter
was filtered. The residue was washed with 138 ml of toluene, the
filtrate and the solution used for washing were combined, and the
solvent was distilled off under reduced pressure until the amount
of solution became approximately 138 ml to give a toluene solution
of the title compound.
Step C-3: Methyl
(4S,5R,6R)-5-acetamide-4-azide-6-[(1S,2R)-2,3-diacetoxy-1-methoxypropyl]--
5,6-dihydro-4H-pyran-2-carboxylate
[0297] 2-Methyl-2-propanol (47 ml) was added to the toluene
solution of the compound obtained in Step C-2. After cooling the
mixture, titanium (IV) isopropoxide (8.68 g) and trimethylsilyl
azide (23.92 g) were added, followed by stirring for 4 hours at
20.degree. C. An aqueous sodium nitrite solution (sodium nitrite
14.32 g, water 329 ml) and hydrochloric acid (concentrated
hydrochloric acid 23.77 g, water 74 ml) were added to the reaction
solution at 10.degree. C. or lower, and the reaction solution was
stirred for 30 minutes at room temperature. Subsequently, the
solvent was distilled off under reduced pressure until the amount
of solution became approximately 494 ml. The concentrated solution
was extracted with ethyl acetate (471 ml), and organic layer 1 and
aqueous layer 1 were separated. Aqueous layer 1 was extracted with
ethyl acetate (471 ml), and organic layer 2 was separated. Organic
layer 1 was washed twice with 5% aqueous sodium hydrogencarbonate
(235 ml), and organic layer 3 was separated. Aqueous layer 2 and
aqueous layer 3 were combined, extracted with organic layer 2, and
organic layer 4 was separated. Organic layer 3 and organic layer 4
were combined, ethyl acetate (80 ml) was added, and the solvent was
distilled off under reduced pressure until the amount of solution
became approximately 245 ml to give an ethyl acetate solution of
the title compound.
Step C-4: Methyl
(4S,5R,6R)-5-acetamide-4-amino-6-[(1S,2R)-2,3-diacetoxy-1-methoxypropyl]--
5,6-dihydro-4H-pyran-2-carboxylate
[0298] Triphenylphosphine (35.23 g) and water (8.80 g) were added
to the ethyl acetate solution of the compound obtained in Step C-3
at 0.degree. C., and the mixture was stirred for 2 hours at
72.degree. C. The reaction solution was cooled to room temperature
to give an ethyl acetate solution of the title compound.
Step C-5: Methyl
(4S,5R,6R)-5-acetamide-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-6-[(1S,2-
R)-2,3-diacetoxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylate
[0299] tert-Butyl
(tert-butoxycarbonyliminopyrazol-1-yl-methyl)carbamate (39.79 g)
was added to the ethyl acetate solution of the compound obtained in
Step C-4 at room temperature, the mixture was stirred for 1 hour at
the same temperature, and was then allowed to stand for 17 hours.
After the solvent was distilled off under reduced pressure until
the amount of solution became approximately 141 ml, toluene (471
ml) was added to the reaction solution, followed by washing with
water (141 ml) and a 10% aqueous sodium chloride solution (141 ml).
The solvent of separated organic layer was distilled off under
reduced pressure until the amount of solution became approximately
188 ml to give a toluene solution of the title compound.
Step C-6:
(4S,5R,6R)-5-Acetamide-4-[2,3-bis(tert-Butoxycarbonyl)guanidino]-
-6-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxyl-
ic acid
[0300] Methanol (235 ml), water (108 ml), and potassium carbonate
(50.63 g) were added to the toluene solution of the compound
obtained in Step C-5, and the mixture solution was stirred for 4.5
hours at room temperature. Water (235 ml) was added at 30.degree.
C. or lower, and then the pH of the mixture was adjusted to 8.3
with 7% hydrochloric acid. The solvent was distilled off under
reduced pressure until the amount of solution became approximately
518 ml, the reaction solution was washed with ethyl acetate (235
ml) 3 times, and the aqueous layer was separated. The pH of the
aqueous layer was adjusted to 2.7 with 7% hydrochloric acid,
followed by extracting with ethyl acetate (423 ml) twice. The
organic layers were combined, the solvent was distilled off under
reduce pressure until the amount of solution became approximately
282 ml, and the insoluble matter was filtered. The residue was
washed with ethyl acetate (376 ml), the filtrate and the solution
used for washing were combined, and then the solvent was distilled
off under reduced pressure until the amount of solution became
approximately 188 ml. Water (188 ml) was added to the concentrated
solution, the solvent was distilled off until the amount of
solution became approximately 188 ml to give an aqueous solution of
the title compound.
Step A-9:
(4S,5R,6R)-5-acetamide-4-guadino-6-[(1R,2R)-2,3-dihydroxy-1-meth-
oxypropyl]-5,6-dihydro-4H-pyran-2-carboxylic acid (compound (13)
[R.sup.2=methyl group])
[0301] The aqueous solution of the compound obtained in Step C-6
was subjected to a similar operation to Step A-9 of Example 1 to
give the title compound as a white solid (30.97 g, 62.3%
yield).
Example 5
Synthesis of
(4S,5R,6R)-5-acetamide-4-guadino-6-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl-
]-5,6-dihydro-4H-pyran-2-carboxylic acid (Compound (13)
[R.sup.2=methyl group])
Step D-1: Methyl
(4S,5R,6R)-5-acetamide-4-amino-6-{(S)-methoxy[(4R)-2-oxo-1,3-dioxolan-4-y-
l]methyl}-5,6-dihydro-4H-pyran-2-carboxylate
[0302] Ethyl acetate (4 ml), water (0.194 g), and
triphenylphosphine (0.78 g) were added to the compound (1.00 g)
obtained in Step A-6 of Example 1, and the mixture was stirred for
2 hours at 70.degree. C. The reaction solution was cooled to room
temperature, and then the solvent was distilled off under reduced
pressure to give the crude title compound.
Step D-2: Methyl
(4S,5R,6R)-5-acetamide-4-guanidino-6-{(S)-methoxy[(4R)-2-oxo-1,3-dioxolan-
-4-yl]methyl}-5,6-dihydro-4H-pyran-2-carboxylate
[0303] Water (4 ml), methanol (1 ml), and
1H-pyrazole-1-carboxamidine hydrochloride (0.52 g) were added to
the crude compound obtained in Step D-1, and the mixture was
stirred for 65 hours at room temperature to give a solution of the
title compound.
Step D-3:
(4S,5R,6R)-5-acetamide-4-guadino-6-[(1R,2R)-2,3-dihydroxy-1-meth-
oxypropyl]-5,6-dihydro-4H-pyran-2-carboxylic acid (Compound (13)
[R.sup.2=methyl group])
[0304] Methanol (1 ml) and potassium carbonate (0.75 g) were added
to the compound obtained in Step D-2, and after the mixture was
stirred for approximately 23 hours at room temperature, the amount
of the title compound generated was measured by HPLC (amount
generated 0.59 g, yield 63.3%).
HPLC Measurement Conditions (4)
[0305] Column: L-column ODS (4.6 mmID.times.250 mm, particle
diameter 5 .mu.m, manufactured by Chemicals Evaluation and Research
Institute) Column temperature: 40.degree. C. Measurement
wavelength: 210 nm Mobile phase: 0.01M potassium dihydrogen
phosphate buffer (pH 3)/methanol/PIC B-7 (Low UV, manufactured by
Waters Corporation) (950/50/1) Flow rate: 1 ml/min Retention time
of the title compound: approximately 4.1 minutes.
Example 6
Synthesis of
(4S,5R,6R)-5-acetamide-4-guadino-6-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl-
]-5,6-dihydro-4H-pyran-2-carboxylic acid (Compound (13)
[R.sup.2=methyl group])
Step E-1
[0306] To an aqueous solution of a compound obtained by subjecting
methyl
(4S,5R,6R)-5-acetamide-4-azide-6-{(S)-methoxy[(4R)-2-oxo-1,3-dioxolan-4-y-
l]methyl}-5,6-dihydro-4H-pyran-2-carboxylate (1.00 g) to a similar
operation to Step A-7, was added 1H-pyrazole-1-carboxamidine
hydrochloride (1.01 g) in two portions. The mixture was stirred for
approximately 100 hours at room temperature while maintaining the
pH in the range of 7 to 9. The amount of the title compound
generated was measured under the HPLC measurement conditions (4)
(amount generated 0.53 g, yield 56.5%).
Example 7
Synthesis of
(4S,5R,6R)-5-acetamide-4-guadino-6-[(1R,2R)-2-hydroxy-1-methoxy-2-(octano-
yloxy)propyl]-5,6-dihydro-4H-pyran-2-carboxylic acid [Compound
(Ib)]
[0307] Methanol (20 ml) was added to methyl octaneimidoate
hydrochloride (8.39 g), and the mixture was stirred for 3 hours at
35.degree. C. Subsequently, the compound (5.00 g) obtained in Step
A-9 of Example 1 and methanol (5 ml) were added at room
temperature, and suspended. A 1.6 mol/l hydrogen chloride methanol
solution (10.4 ml) was added to this suspension at room
temperature, followed by stirring for 2 hours at the same
temperature. The solvent was distilled off until the amount of
solution became approximately 20 ml, and water (60 ml) was added,
followed by washing twice with ethyl acetate (25 ml). The aqueous
layer was separated, and the pH was adjusted to 7 with a 20%
aqueous sodium carbonate solution, followed by stirring for 5
minutes at room temperature. Subsequently, the pH was adjusted to
8.7 with a 20% aqueous sodium carbonate solution, the reaction
solution was stirred for 1.5 hours, and then crystals were
filtered. The crystals were washed with water (10 ml), and then
dried under reduced pressure to give the crude title compound as
white crystal (6.21 g, 91.3% yield, chemical purity: 99.51%
compound (Ib):compound (IIb)=95:5, content of compound (13)
[R.sup.2=methyl group]: <0.01%, content of compound (VII)
[R.sup.1=1-heptyl group, R.sup.2=methyl group]: 0.06%, content of
compound (VIII) [R.sup.1=1-heptyl group]: 0.09%).
Example 8
Synthesis of tert-butyl
(tert-butoxycarbonyliminopyrazol-1-yl-methyl)carbamate [Compound
(11)]
Step F-1
[0308] N,N-dimethylformamide (350 ml) and N,N-diisopropyl
ethylamine (125 ml) were added to
tert-butyl(iminopyrazol-1-yl-methyl)carbamate
1H-pyrazole-1-carboxamidine hydrochloride (100 g), and then a
N,N-dimethylformamide (50 ml) solution of ditert-butyl dicarbonate
(152 g) was added over 40 minutes at room temperature. After the
mixture was stirred for 2 hours at the same temperature, water (500
ml) was added, the mixture was extracted with toluene (500 ml), and
organic layer 1 and aqueous layer 1 were separated. Organic layer 1
was further washed twice with water (300 ml), and organic layer 2
was separated. Aqueous layer 1 was extracted with toluene (500 ml),
and organic layer 3 was separated. Organic layer 2 and organic
layer 3 were combined, and the solvent was distilled off under
reduced pressure until the amount of the solution became
approximately 300 ml. Hexane (500 ml) was added to the resulting
solution at room temperature, the mixture was stirred for 30
minutes, followed by stirring for 30 minutes under ice-cooling, and
then crystals were filtered. The crystals were washed with hexane
(100 ml), and then dried under reduced pressure to give the title
compound (120.3 g, 83.9% yield).
Step F-2: tert-Butyl
(tert-butoxycarbonyliminopyrazol-1-yl-methyl)carbamate [Compound
(11)]
[0309] A tetrahydrofuran (100 ml) solution of the compound (50 g)
obtained in Step B-1 was added to a tetrahydrofuran (100 ml)
suspension of 60% sodium hydride (9.99 g) over 1 hour while
maintaining the temperature in the range of -5.degree. C. to
0.degree. C. After the mixture was stirred for 30 minutes at the
same temperature, a tetrahydrofuran (100 ml) solution of
ditert-butyl dicarbonate (57.1 g) was added while maintaining the
temperature from -5.degree. C. to 0.degree. C., and then
tetrahydrofuran (250 ml) was added. After the reaction solution was
stirred for 2 hours under reflux, acetic acid (20.4 ml) was added
at room temperature, and the solvent was distilled off under
reduced pressure until the amount of solution became approximately
150 ml. A 5% aqueous sodium hydrogencarbonate solution (500 ml) was
added to the resulting solution and the mixture was extracted with
ethyl acetate (500 ml). The organic layer was washed with water
(150 ml), and the solvent was distilled off until the amount of
solution became approximately 75 ml. Hexane (200 ml) was added to
the residue at room temperature, and seed crystal was inoculated.
After stirring the solution for 40 minutes under ice-cooling,
crystals were filtered, washed with hexane (50 ml), and dried under
reduced pressure to give the title compound (54.47 g, 73.8%
yield).
[0310] .sup.1H NMR (CDCl.sub.3, 500 MHz): 1.49 (9H, s), 1.55 (9H,
s), 6.41 (1H, dd, J=1.5, 2.7 Hz), 7.62 (1H, dd, J=0.7, 1.5 Hz),
8.30 (1H, dd, J=0.7, 2.7 Hz), 8.93 (1H, brs).
[0311] .sup.13C NMR (CDCl.sub.3, 125 MHz): 28.1, 28.2, 81.4, 83.4,
109.8, 129.0, 139.2, 142.8, 149.4, 157.4.
Example 9
Synthesis of trimethyl orthooctanoate (Compound (14)
[R.sup.1=1-heptyl group, R.sup.7=methyl group])
Step G-1: Methyl octanimidate hydrochloride
[0312] Methanol (2.81 g) and methyl acetate (30 ml) were added to
octanenitrile (10.00 g), and the mixture was cooled to 0.degree.
C.
[0313] Hydrogen chloride (7.50 g) was added and the mixture was
stirred for 25 hours at the same temperature. Methylcyclohexane (60
ml) was added to the reaction solution, and then the solvent was
distilled off under reduced pressure. Methylcyclohexane (20 ml) was
added to the residue, the mixture was stirred for 1.5 hours at room
temperature, and then crystals were filtered. The crystals were
washed with methylcyclohexane and dried under reduced pressure to
give the title compound as a white solid (14.45 g, 93.4%
yield).
[0314] MS (FAB): m/z 158 [M+H].sup.+
[0315] HRMS (ESI): Exact mass calcd for C.sub.9H.sub.20NO
[M+H].sup.+ 158.15449. Found 158.15433.
[0316] IR (KBr): 3139, 3109, 2925, 2857, 1712, 1627, 1474, 1411,
1213, 1100 cm.sup.-1
[0317] .sup.1H NMR (CDCl.sub.3, 500 MHz): 0.82 (3H, t, J=7.0 Hz),
1.19-1.33 (8H, m), 1.67 (2H, tt, J=7.5, 7.8 Hz), 2.70 (2H, t, J=7.8
Hz), 4.24 (3H, s), 11.52 (1H, brs), 12.46 (1H, brs). .sup.13C NMR
(CDCl.sub.3, 125 MHz): 14.1, 22.6, 25.7, 28.7, 28.8, 31.5, 32.9,
60.7, 180.5.
Step G-2: Trimethyl orthooctanoate (Compound (14) [R.sup.1=1-heptyl
group, R.sup.7=methyl group])
[0318] Methylcyclohexane (240 ml) and methanol (80 ml) were added
to the compound (40.00 g) obtained in Step G-1, and the mixture was
stirred for 6 hours at 35.degree. C. The reaction solution was
cooled to 10.degree. C., and methylcyclohexane (20 ml) was added,
followed by washing with 5% aqueous sodium hydrogencarbonate (280
ml). The reaction solution was further washed with 5% aqueous
sodium hydrogencarbonate (120 ml), and the organic layer was
separated. The insoluble matter was filtered, and the residue was
washed with methylcyclohexane. (20 ml). Then, the filtrate and the
solution used for washing were combined, and the solvent was
distilled off under reduced pressure. The residue was purified by
distillation under reduced pressure (1.5-1.8 torr, b.p.
85-90.degree. C.) to give the title compound as a colorless
transparent oil (35.37 g, 83.8% yield).
[0319] MS (ESI): m/z 227 [M+Na].sup.+
[0320] HRMS (ESI): Exact mass calcd for C.sub.11H.sub.24O.sub.3Na
[M+Na].sup.+227.16231. Found 227.16138.
[0321] IR (neat): 2955, 2928, 2854, 1466, 1241, 1153, 1078, 1047,
977 cm.sup.-1
[0322] .sup.1H NMR (CDCl.sub.3, 500 MHz): 0.86 (3H, t, J=6.8 Hz),
1.23-1.33 (8H, m), 1.67-1.71 (2H, m), 3.21 (9H, s).
[0323] .sup.13C NMR (CDCl.sub.3, 125 MHz): 14.1, 22.7, 22.8, 29.3,
29.5, 30.5, 31.9, 49.4, 116.0.
Comparative Example 1
Synthesis of methyl
(4S,5R,6R)-5-acetamide-4-tert-butyldimethylsilyloxy-2-methoxy-6-{(S)-meth-
oxy[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-tetrahydro-4H-pyran-2-carb-
oxylate [compound (VIb)]
[0324] 60% Sodium hydride (0.16 g) was added to a
N,N-dimethylformamide (10 ml) solution of compound (VIa) (1.00 g)
described in Process Z at 0.degree. C. The mixture was stirred for
5 minutes at the same temperature and dimethyl sulfate (0.31 g) was
added at 0.degree. C., followed by further stirring for 2 hours at
room temperature (peak area ratio of the title compound: 41.6%,
peak area ratio of N-methylated compound: 12.2%). A saturated
aqueous ammonium chloride solution (10 ml) and water (2 ml) were
added to the reaction solution, and the mixture was extracted with
ethyl acetate (20 ml) 3 times. The organic layer was washed once
with 5% aqueous sodium hydrogencarbonate (10 ml) and with water (10
ml) twice. Subsequently, the solvent was distilled off under
reduced pressure. Diisopropyl ether (2 ml) was added to the
residue, the mixture was stirred for 10 minutes at room
temperature, and the mixture was further stirred for 30 minutes at
0.degree. C. After that crystals were filtered. The crystals were
washed with diisopropyl ether (2 ml), and dried under reduced
pressure to give the title compound as a white solid (0.28 g, 27.3%
yield, peak area ratio of the title compound: 97.2%, peak area
ratio of N-methylated compound: 0.3%).
[0325] The peak area ratios of the title compound and the
N-methylated compound were measured in accordance with the
following HPLC measurement conditions.
HPLC Measurement Conditions (4)
[0326] Column: L-column ODS (4.6 mmID.times.250 mm, particle
diameter 5 .mu.m, manufactured by Chemicals Evaluation and Research
Institute) Column temperature: 40.degree. C. Measurement
wavelength: 195 nm Mobile phase: acetonitrile: 0.02 M aqueous
potassium dihydrogen phosphate solution=60:40 Flow rate: 1 ml/min
Retention time of the title compound: approximately 8.6 minutes
Retention time of the N-methylated compound: approximately 15.4
minutes
Comparative Example 2
Synthesis of methyl
(4S,5R,6R)-5-acetamide-4-azide-6-[(1S,2R)-2,3-diacetoxy-1-methoxypropyl]--
5,6-dihydro-4H-pyran-2-carboxylate [Compound (IVg)]
[0327] N,N-dimethylformamide (250 ml), DOWEX.sup.o 50W-X8 (10.0 g),
and sodium azide (10.0 g) were added to compound (IVf) (10.0 g)
described in Process W, Process Y, and Process Z, and the mixture
was stirred for 7 hours at 80.degree. C. (stereoisomer ratio 7:1).
The reaction solution was cooled to room temperature, and was
filtered through an ion exchange resin. The resin was washed with
methanol (50 ml), the solvent used for washing was combined with
the filtrate, and the solvent was distilled off under reduced
pressure. Dichloromethane (100 ml), saturated aqueous sodium
hydrogencarbonate (50 ml), and water (50 ml) were added to the
concentrated residue, and the organic layer was separated after
stirring. The organic layer was washed with 10% aqueous sodium
chloride (100 ml) and the solvent was distilled off under reduced
pressure to give the unpurified title compound (10.34 g,
stereoisomer ratio 6:1).
[0328] The peak area ratios of the title compound and the
stereoisomer were measured in accordance with the following HPLC
measurement conditions.
HPLC Measurement Conditions (5)
[0329] Column: L-column ODS (4.6 mmID.times.250 mm, particle
diameter 5 .mu.m, manufactured by Chemicals Evaluation and Research
Institute) Column temperature: 40.degree. C. Measurement
wavelength: 254 nm Mobile phase: acetonitrile:water=60:40 Flow
rate: 1 ml/min Retention time of the title compound: approximately
6.2 minutes Retention time of stereoisomer: approximately 6.6
minutes
Comparative Example 3
Synthesis of diphenylmethyl
(4S,5R,6R)-5-acetamide-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-6-[(1R,2-
R)-2-hydroxy-1-methoxy-3-(octanoyloxy)propyl]-5,6-dihydro-4H-pyran-2-carbo-
xylate [compound (IVk)]
[0330] Dichloromethane (20 ml) and triethylamine (0.10 g) were
added to compound (IVj) (0.50 g) of Process W at 0.degree. C.,
octyl chloride (0.14 g) was added dropwise at the same temperature,
and the mixture was stirred for 3.5 hours. Ethyl acetate (50 ml)
was added to the reaction solution, and the mixture was washed with
saturated aqueous sodium hydrogencarbonate (30 ml) and saturated
aqueous sodium chloride (10 ml). The organic layer was separated,
dried with anhydrous sodium sulfate, and the solvent was distilled
off under reduced pressure to give the unpurified title compound
(0.57 g, 97.0% yield, peak area ratio of the title compound: 63.2%,
peak area ratio of diacylated compound: 5.6%).
[0331] The peak area ratios of the title compound and the
diacylated compound were measured in accordance with the following
HPLC measurement conditions.
HPLC measurement conditions (6) Column: L-column ODS (4.6
mmID.times.250 mm, particle diameter 5 .mu.m, manufactured by
Chemicals Evaluation and Research Institute) Column temperature:
40.degree. C. Measurement wavelength: 254 nm Mobile phase:
acetonitrile: 0.02 mol/l aqueous ammonium acetate=90:10 Flow rate:
1 ml/min Retention time of the title compound: approximately 6.8
minutes Retention time of the diacylated compound: approximately
24.6 minutes
Comparative Example 4
Synthesis of trimethyl orthooctanoate (Compound (14)
[R.sup.1=1-heptyl group, R.sup.7=methyl group])
[0332] Methanol (330 ml) and petroleum ether (1 L) were added to
the compound (160.44 g) obtained in accordance with Step G-1 of
Example 9, and the mixture was stirred for 18 hours under reflux.
The reaction solution was cooled to 0.degree. C., and was allowed
to stand for 2 hours at the same temperature. The insoluble matter
was filtered, and the solvent was distilled off under reduced
pressure. The residue was purified by distillation under reduced
pressure (2.2 torr, b.p. 93-96.degree. C.) to give the title
compound as a colorless transparent oil (78.60 g, 44.7% yield).
Comparative Example 5
(4S,5R,6R)-5-Acetamide-4-guadino-6-[(1R,2R)-2-hydroxy-1-methoxy-2-(octanoy-
loxy)propyl]-5,6-dihydro-4H-pyran-2-carboxylic acid [Compound
(Ib)]
[0333] Compound (Vd) of Process Z was converted into compound (IVj)
by the diphenylmethyl esterification reaction of Process W [the
third reaction in the conversion procedure of compound (IVi) into
compound (IVj)], then converted into compound (Ia) by Process W,
and then the title compound was synthesized from compound (Ia) in
accordance with the process described in the Example of Patent
Document 2. The quality of the synthesized title compound was as
follows: Chemical purity: 91.88%, compound (Ib):compound
(IIb)=85:15, content of compound (13) [R.sup.2=methyl group]:
3.54%, content of compound (VII) [R.sup.1=1-heptyl group,
R.sup.2=methyl group]: 0.51%, content of compound (VIII)
[R.sup.1=1-heptyl group]: 0.97%
Preparation Example 1
Liquid Formulation 1
[0334] A liquid formulation is prepared containing the compound of
Example 1 10% (w/w), benzalkonium chloride 0.04% (w/w), phenethyl
alcohol 0.40% (w/w), and purified water 89.56% (w/w).
Preparation Example 2
Liquid Formulation 2
[0335] A liquid formulation is prepared containing the compound of
Example 1 10% (w/w), benzalkonium chloride 0.04% (w/w),
polyethylene glycol 400 10% (w/w), propylene glycol 30% (w/w), and
purified water 49.96% (w/w)
Preparation Example 3
Powders
[0336] A powder formulation is prepared containing the compound of
Example 1 40% (w/w) and lactose 60% (w/w).
Preparation Example 4
Aerosol
[0337] An aerosol is prepared containing the compound of Example 1
10% (w/w), lecithin 0.5% (w/w), Freon 11 34.5% (w/w) and Freon 12
55% (w/w)
INDUSTRIAL APPLICABILITY
[0338] The novel method for manufacturing neuraminic acid
derivatives via novel synthetic intermediates according to the
present invention is superior from an industrial perspective,
compared with known manufacturing methods. In addition, neuraminic
acid derivatives with high purity can be obtained in high yield by
the present manufacturing method.
[0339] Since neuraminic acid derivative with high purity, which is
obtained by the present production method, has excellent
neuraminidase inhibitory activity, it is useful as a drug for
prevention or treatment of influenza.
* * * * *