Indian Patents
Title of Invention

METHOD FOR MANUFACTURING NEURAMINIC ACID DERIVATIVES
Abstract A method for manufacturing neuraminic acid derivatives is provided, also synthetic intermediates of the neuraminic acid derivatives and methods for their manufacture, and neuraminic acid derivatives having high purity. [Means for solution] A synthetic intermediate compound represented by the formula (7) is provided: [wherein R3 represents alkyl; R4 and R5 each represents H, alkyl, phenyl, or together represent tetramethylene, pentamethylene, oxo].
Full Text DESCRIPTION
Method for manufacturing neuraminic acid derivatives
[Technical Field]
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.
[Background Art]
A compound represented by the formula (I):

[wherein R1 represents a C1-C19 alkyl group and R2 represents a
C1-C4 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).
A trifluoroacetic acid salt of a compound represented by
the formula (III):

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).
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.


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.
Process X

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.

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.

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]
(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)J;
(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]
(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]
(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)].
[Patent Document 1] US Patent No. 6340702 (corresponding
to Japanese Patent No. 3209946)
[Patent Document 2] US Patent No. 6844 36 3 (corresponding
to Japanese Patent Application No. 2002-012590)
[Non-patent Document 1] T. Honda et al., Bioorganic,
Medicinal Chemistry Letters, 2002. pp. 1921-1924
[Non-patent Document 2] T. Honda et al., Bioorganic
Medicinal Chemistry Letters, 2002. pp. 1925-1928
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]
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.
The present invention provides a method for manufacturing
a neuraminic acid derivative shown by the following Process A:
In the aforementioned Process A, R1 represents a C1-C19
alkyl group, R2 represents a C1-C4 alkyl group, R3, R6 and R7,
independently from one another, represent a C1-C6 alkyl group, R4
and R5, independently from each other, represent a hydrogen
atom, a C1-C6 alkyl group or a phenyl group, or R4 and R5
together form a tetramethylene group, a pentamethylene group or
oxo group except that R4 and R5 in compound (6) do not form an 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.
According to one aspect of the present invention, there is
provided
[1] a method for manufacturing a compound represented by the
formula (7):

[wherein R3 represents a C1-C6 alkyl group, and R4 and R5,
independently from each other, represent a hydrogen atom, a C1-C6
alkyl group or a phenyl group, or R4 and R5 together form a
tetramethylene group, a pentamethylene group or an oxo group],
comprising:
allowing a compound represented by the formula (4):

[wherein R3 represents a C1-C6 alkyl group] to react with a
compound represented by the formula (5):

[wherein R4 and R5, independently from each other, represent a
hydrogen atom, a C1-C6 alkyl group or a phenyl group, or R4 and
R5 together form a tetramethylene group, a pentamethylene group
or an oxo group, and R6 represents a C1-C6 alkyl group], or with
a compound represented by the formula (6):

[wherein R4 and R5, independently from each other, represent a
hydrogen atom, a C1-C6 alkyl group or a phenyl group, or R4 and
R5 together form a tetramethylene group or a pentamethylene
group] except that R4 and R5 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
R3 is a methyl group, R4 and R5 together form an oxo group, and
the compound represented by the formula (5) is dimethyl
carbonate,
[3] a compound represented by the formula (7):

[wherein R3 represents a C1-C6 alkyl group, R4 and R5,
independently from each other, represent a hydrogen atom, a C1-C6
alkyl group or a phenyl group, or R4 and R5 together form a
tetramethylene group, a pentamethylene group or an oxo group],
[4] the compound as described in [3], wherein R3 is a methyl
group, and R4 and R5 together form an oxo group,
[5] a method for manufacturing a compound represented by the
formula (9):

[wherein R2 represents a C1-C4 alkyl group, R3 represents a C1-C6
alkyl group, and R4 and R5, independently from each other,
represent a hydrogen atom, a C1-C6 alkyl group or a phenyl group,
or R4 and R5 together form a tetramethylene group, a
pentamethylene group or an oxo group], comprising:
allowing a compound represented by the formula (8):

[wherein R2 represents a C1-C4 alkyl group, R3 represents a C1-C6
alkyl group, R4 and R5, independently from each other, represent
a hydrogen atom, a C1-C6 alkyl group or a phenyl group, or R4 and
R5 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 R2 is
a methyl group, R3 is a methyl group, R4 and R5 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) :

[wherein R2 represents a C1-C4 alkyl group], comprising:
allowing a compound represented by the formula (12):

[wherein R2 represents a C1-C4 alkyl group] to react with water,
[8] the manufacturing method as described in [ 7 ] , wherein R2 is
a methyl group,
[9] a compound represented by the formula (13):

[wherein R2 represents a C1-C4 alkyl group],
[10] the compound as described in [9], wherein R2 is a methyl
group,
[11] a method for manufacturing a compound represented by the
formula (I):

[wherein R1 represents a C1-C19 alkyl group and R2 represents a
C1-C4 alkyl group], [here, the compound represented by the
formula (I) may include a compound represented by the formula
(II):

[wherein R1 and R2 have the same meanings as in the formula
(I)]], or a pharmacologically acceptable salt thereof
comprising:
allowing a compound represented by the formula (13):

[wherein R2 represents a C1-C4 alkyl group] to react with a
compound represented by the formula R1C(OR7)3 [wherein R1
represents a C1-C19 alkyl group and R7 represents a C1-C6 alkyl,
group], or a pharmacologically acceptable salt thereof,
[12] the manufacturing method as described in [11], wherein Rl
is a 1-heptyl group, R2 is a methyl group, and R7 is a methyl
group,
[13] a method for manufacturing a compound represented by the
formula (I):

[wherein R1 represents a C1-C19 alkyl group and R2 represents a
C1-C4 alkyl group], [here, the compound represented by the
formula (I) may include a compound represented by the formula
(II):

[wherein Ra and R2 have the same meanings as in the formula
(I)]] or pharmacologically acceptable salt thereof, comprising:
allowing a compound represented by the formula (13):

[wherein R2 represents a C1-C4 alkyl group] to react with a
compound represented by the formula (15):

[wherein R1 represents a C1-Cl9 alkyl group, R7 represents a C1-C6
alkyl group, and X represents Cl, Br, I, HSO4 or NO3] , and with a
compound represented by the formula R7-OH [wherein R7 represents
a C1-C6 alkyl group],
[14] the manufacturing method as described in [13], wherein R1
is a 1-heptyl group, R2 is a methyl group, R7 is a methyl group,
and X is Cl,
[15] a method for manufacturing a compound represented by the
formula (Ib):

[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):

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):

[wherein the compound represented by the formula (Ib) may
include a compound represented by the formula (IIb):

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):

[wherein R1 represents a C1-C19 alkyl group and R2 represents a
C1-C4 alkyl group], [here, the compound represented by the
formula (I) may include a compound represented by the formula
(II):
[wherein R1 and R2 have the same meanings as in the formula (I)]]
having a chemical purity of 97wt% 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 97wt% 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 99wt% 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 99.5wt% 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 R1 is a 1-
heptyl group and R2 is a methyl group,
[21] a compound represented by the formula (I):

[wherein R1 represents a C1-C19 alkyl group and R2 represents a
C1-C4 alkyl group], [here, the compound represented by the
formula (I) may include a compound represented by the formula
(II):
[wherein R1 and R2 have the same meanings as in the formula
(I)]], or a pharmacologically acceptable salt thereof,
containing a compound represented by the formula (VII):

[wherein R1 and R2 represent have the same meanings as in the
formula (I)] in an amount of 0.5wt% 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 0.3wt% 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 R1 is a 1-
heptyl group and R2 is a methyl group,
[25] a compound represented by the formula (I):

[wherein Rl represents a C1-C19 alkyl group and R2 represents a
C1-C4 alkyl group], [here, the compound represented by the
formula (I) may include a compound represented by the formula
(II):

[wherein R1 and R2 have the same meanings as in the formula
(I)]], or a pharmacologically acceptable salt thereof,
containing a compound represented by the formula (VIII):

[wherein R1 has the same meaning as the formula (I)] in an an
amount of 0.5wt% 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 0.3wt% or less,
[27] 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 an amount of 0.1wt% 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 R1 is a 1-
heptyl group and R2 is a methyl group,
[29] a compound represented by the formula (I):

[wherein R1 represents a C1-C19 alkyl group and R2 represents a
C1-C4 alkyl group], [here, the compound represented by the
formula (I) may include a compound represented by the formula
(II):

[wherein R1 and R2 have the same meanings as in the formula
(I)]], or a pharmacologically acceptable salt thereof,
containing a compound represented by the formula (13):

[wherein R2 has the same meaning as in the formula (I)] in an
amount of 0.5wt% 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 0.3wt% 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 0.1wt% 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 R1 is a 1-
heptyl group and R2 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 R1C(OR7)3
[wherein R1 represents a C1-C19 alkyl group and R7 represents a
C1-C6 alkyl group], comprising:
allowing a compound represented by the formula (15):

[wherein R1 represents a C1-C19 alkyl group, R7 represents a C1-C6
alkyl group, and X represents Cl, Br, I, HSO4 or NO3] to react
with a compound represented by the formula R7-OH [wherein R7
represents a C1-C6 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 R1 is a 1-heptyl group, R7 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):

[wherein R1 represents a C1-C19 alkyl group and R2 represents a
C1-C4 alkyl group], [here, the compound represented by the
formula (I) may include a compound represented by the formula
(II):

[wherein R1 and R2 have the same meanings as in the formula (I)]]
having a chemical purity of 97wt% 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 97wt% or higher], or a pharmacologically
acceptable salt thereof, manufactured by a method comprising:
allowing a compound represented by the formula (13):

[wherein R2 represents a C1-C4 alkyl group] to react with a
compound represented by the formula R1C(OR7)3 [wherein R1
represents a C1-C19 alkyl group and R7 represents a C1-C6 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 99wt% 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 99.5wt% or higher,
[44] the compound represented by the formula (I), which may
include the compound represented by the formula (II), as
described in any one of [41] through [43], wherein R1 is a 1-
heptyl group and R2 is a methyl group,
[45] a compound represented by the formula (I):

[wherein R1 represents a C1-C19 alkyl group and R2 represents a
C1-C4 alkyl group], [here, the compound represented by the
formula (I) may include a compound represented by the formula
(II):

[wherein R1 and R2 have the same meanings as in the formula
(I)]], or a pharmacologically acceptable salt thereof,
containing a compound represented by the formula (VII):

[wherein R1 and R2 represent have the same meanings as in the
formula (I)] in an amount of 0.5wt% or less, manufactured by a
method comprising:
allowing a compound represented by the formula (13):

[wherein R2 represents a Cl-C4 alkyl group] to react with a
compound represented by the formula R1C(OR7)3 [wherein R1
represents a C1-Cl9 alkyl group and R7 represents a C1-C6 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
anount of 0.3wt% 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 0.1wt% 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 R1 is a 1-
heptyl group and R2 is a methyl group,
[49] a compound represented by the formula (I):

[wherein R1 represents a C1-C19 alkyl group and R2 represents a
C1-C4 alkyl group], [here, the compound represented by the
formula (I) may include a compound represented by the formula
(II):

[wherein R1 and R2 have the same meanings as in the formula
(I)]], or a pharmacologically acceptable salt thereof,
containing a compound represented by the formula (VIII):

[wherein R1 has the same meaning as in the formula (I)] in an
amount of 0.5wt% or less,
manufactured by a method comprising:
allowing a compound represented by the formula (13):

[wherein R2 represents a C1-C4 alkyl group] to react with a
compound represented by the formula R1C(OR7)3 [wherein R1
represents a C1-C19 alkyl group and R7 represents a C1-C6 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 0.3wt% 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 0.1wt% 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 R1 is a 1-
heptyl group and R2 is a methyl group,
[53] a compound represented by the formula (I):

[wherein R1 represents a C1-C19 alkyl group and R2 represents a
C1-C4 alkyl group], [here, the compound represented by the
formula (I) may include a compound represented by the formula
(II):

[wherein R1 and R2 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):

[wherein R2 has the same meaning as in the formula (I)] in an
amount of 0.5wt% or less,
manufactured by a method comprising:
allowing a compound represented by the formula (13):

[wherein R2 represents a C1-C4 alkyl group] to react with a
compound represented by the formula R1C(OR7)3 [wherein Rl
represents a C1-C19 alkyl group and R7 represents a C1-C6 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 0.3wt% 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 0.1wt% 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 R1 is a 1-
heptyl group and R2 is a methyl group.
In the present invention, "Cl-C19 alkyl group" of R1
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 C5-C19 alkyl
group, more preferably a C5-C17 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.
"C1-C4 alkyl group" of R2 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.
"C1-C6 alkyl group" in R3, R4, R5, R6 and R7 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 C1-C4 alkyl group, more
preferably a methyl group or ethyl group, and most preferably a
methyl group.
R4 and R5 are preferably a hydrogen atom or a C1-C4 alkyl
group, more preferably a methyl group or ethyl group, and most
preferably a methyl group. R4 and R5 are preferably the same.
Further, R4 and R5 preferably together form an oxo group.
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 benzenesulfonic 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.
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.
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.
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.
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.
HPLC measuremen conditions (1)
Column: L-column ODS (4.6 mmID x 25 cm, particle diameter 5 µm,
manufactured by Chemicals Evaluation and Research Institute)
Column temperature: 30°C
Measurement wavelength: 210 nm
Mobile phase:
A: 0.1% PIC B-7 (Low UV, manufactured by Waters
Corporation) aqueous solution/acetonitrile (9/1, v/v)
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/1 phosphoric acid to 0.1
mol/l aqueous potassium dihydrogen phosphate solution to adjust
its pH to 3.0.]
Gradient conditions:

Flow rate: 1 ml/min
Sample concentration: approximately 1 g/l
Injection amount: 20 µl
Range detected with peak: from 0 minute to approximately 1.2
times the length of retention time of compound (I)
HPLC measurement conditions (2)
Column: L-column ODS (4.6 mmID x 25 cm, particle diameter 5 µm,
manufactured by Chemicals Evaluation and Research Institute)
Column temperature: 30°C
Measurement wavelength: 210 nm
Mobile phase:
0.1 mol/l phosphate buffer solution (pH 3.0)/acetonitrile
(23/17, 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/1 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 µl
Range detected with peak: from approximately 1.2 times to 18
times the length of retention time of compound (I)
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.
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).
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).
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)]] x 100
Composition ratio of compound (II)
= [peak area ratio of compound (II) / [peak area ratio of
compound (I) + peak area ratio of compound (II)]] x 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.
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.
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.
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.
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.
The present invention shown by Process A is superior to
publicly known manufacturing methods or synthetic intermediates,
in points given below, for example.
(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).
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.
(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°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).
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°C to 30°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).
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.
(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.
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.
(iv) Concerning the production procedure of compound (IVk)
and compound (Ia) 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). Ra
represents a C1-C4 alkyl group and the like. In the following
reaction, the reactive functional group is a hydroxyl group
only.

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.
(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 R7-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.
(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).
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).
Therefore, the manufacturing method of compound (I) from
compound (13) contributes largely to the production of compound
(I) with high purity.
(vii) In the production of compound (14), when a compound
represented by the formula R7-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 ) .
In contrast, when compound (15) is allowed to react with a
compound represented by the formula R7-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]
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
methodes. 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]
In the present invention, the method of manufacturing
neuraminic acid derivatives can be conducted in accordance with
the following Process A through Process G.
In Process A through Process G, R1, R2, R3, R4, R5, R6, R7,
and X have the same meanings as described above.
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.
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.
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.
(Process A)
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.
(Step A-1)
Step A-1 is a procedure to allow publicly known compound
(1) to react with an alcohol represented by the formula R3OH in
the presence of acid, to produce compound (2). The alcohol
represented by the formula R3OH are either publicly known, or
can easily be produced from a publicly known compound, and is
preferably methanol.
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.
In Step A-l, a compound represented by the formula
HC(OR3)3 may be used to accelerate the reaction. The compound
represented by the formula HC(OR3)3 is either publicly known, or
can easily be produced from a publicly known compound. The
compound represented by the formula HC(OR3)3 is preferably
trimethyl orthoformate [HC(OMe)3]. R3 in the compound
represented by the formula HC(OR3)3 is preferably the same as R3
in the alcohol represented by the formula R3OH.
The solvent used is preferably an aromatic hydrocarbon, a
halogenated hydrocarbon, an ether or an alcohol represented by
the formula R3OH, more preferably an alcohol represented by the
formula R3OH, and most preferably methanol.
The reaction temperature is preferably -20°C to 100°C, and
more preferably 20°C to 60°C.
The reaction time is preferably 30 minutes to 40 hours,
and more preferably 1 to 10 hours.
(Step A-2)
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).
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 trif luorornethanesulfonic 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.
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.
The reaction temperature is preferably -20°C to 100°C, and
more preferably 0°C to 60°C.
The reaction time is preferably 30 minutes to 60 hours,
and more preferably 1 to 20 hours.
(Step A-3)
Step A-3 is a procedure to allow compound (3) to react
with a compound represented by the formula NaOR3, to produce
compound (4).
In Step A-3, the compound represented by the formula NaOR3
is preferably sodium methoxide or sodium ethoxide, and most
preferably sodium methoxide. In Step A-3, a compound
represented by the formula LiOR3 or KOR3 may be used instead of
the compound represented by the formula NaOR3. R3 in the
compound represented by the formula NaOR3, LiOR3 or KOR3 is
preferably the same as R3 of compound (3).
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 R3OH
[wherein R3 is the same as R3 of the compound represented by the
formula NaOR3].
The reaction temperature is preferably -20°C to 70°C, and
more preferably 0°C to 50°C.
The reaction time is preferably 1 minute to 5 hours, and
more preferably 5 minutes to 1 hour.
(Step A-4)
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.
In Step A-4, of compound (5) and compound (6), compound
(5) is preferably used, more preferably dimethyl carbonate
[(MeO)2CO] or diethyl carbonate, and most preferably dimethyl
carbonate.
In Step A-4, in the case where compound [(R6O)2CO], in
which R4 and R5 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-
raethylmorpholine, N-ethylmorpholine, pyridine, picoline, 4-
dimethylaminopyridine, 4-pyrrolidinopyridine, 2,6-di(tert-
butyl)-4-methylpyridine, quinoline, N,N-d±methylaniline, 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.
In Step A-4, in the case where compound (5) [except for a
compound represented by the formula (R6O)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.
In Step A-4, in the case where compound [(R6O)2CO], in
which R4 and R5 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 R6OH [wherein R6 is the same
as R6 of compound (5)]. In addition, the solvent used is
preferably an alcohol represented by the formula R6OH [wherein R6
is the same as R6 of compound (5)].
In Step A-4, in the case where compound (5) [except for a
compound represented by the formula (R6O)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 (R6O)2CO] is used and the
solvent used is a ketone, the solvent is preferably a ketone
represented by the formula (6).
The reaction temperature is preferably -30°C to 80°C, and
more preferably 0°C to 50°C.
The reaction time is preferably 30 minutes to 60 hours,
and more preferably 1 to 20 hours.
(Step A-5)
Step A-5 is a procedure to allow compound (7) to react
with a compound represented by the formula (R2O)2SO2 in the
presence of a base, to produce compound (8). The compound
represented by the formula (R2O)2SO2 is either publicly known, or
can easily be produced from a publicly known compound.
In Step A-5, the compound represented by the formula
(R2O)2SO2 is preferably dimethyl sulfuric acid [(MeO)2SO2].
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.
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.
The reaction temperature is preferably -50°C to 80°C, and
more preferably -20°C to 50°C.
The reaction time is preferably 10 minutes to 20 hours,
and more preferably 30 minutes to 10 hours.
(Step A-6)
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).
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.
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.
The reaction temperature is preferably -20°C to 60°C, and
more preferably 0°C to 30°C.
The reaction time is preferably 1 to 100 hours, and more
preferably 5 to 30 hours.
(Step A-7)
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.
(Step A-7a)
The solvent used is preferably an ether or an ester, more
preferably tetrahydrofuran or ethyl acetate, and most preferably
tetrahydrofuran.
The reaction temperature is preferably -30°C to 100°C, and
more preferably 0°C to 70°C.
The reaction time is preferably 1 minute to 20 hours, and
more preferably 5 minutes to 5 hours.
(Step A-7b)
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.
The solvent used is preferably an ether or an alcohol,
more preferably tetrahydrofuran, methanol or ethanol, and most
preferably tetrahydrofuran.
The reaction temperature is preferably -30°C to 100°C, and
more preferably 0°C to 70°C.
The reaction time is preferably 10 minutes to 20 hours,
and more preferably 30 minutes to 10 hours.
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.
(Step A-8)
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.
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.
The reaction temperature is preferably -30°C to 80°C, and
more preferably 0°C to 50°C.
The reaction time is preferably 1 to 160 hours, and more
preferably 5 to 80 hours.
(Step A-9)
Step A-9 is a procedure to allow compound (12) to react
with water to produce compound (13).
The solvent used is preferably an alcohol, water, or a
mixture thereof, more preferably methanol, water, or a mixture
thereof, and most preferably water.
The reaction temperature is preferably 0°C to 160°C, and
more preferably 50°C to 110°C.
The reaction time is preferably 30 minutes to 20 hours,
and more preferably 1 to 10 hours.
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):

or a salt thereof. Compound (23) or a salt thereof is either
publicly known, or can easily be produced from a publicly known
compound.
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.
The solvent used is preferably an alcohol, water, or a
mixture thereof, and most preferably a mixture of methanol and
water.
The reaction temperature is preferably -20°C to 70°C, and
more preferably 0°C to 50°C.
The reaction time is preferably 1 to 200 hours, and more
preferably 10 to 100 hours.
The pH during the reaction is preferably 7 to 10, and more
preferably 7 to 9.
(Step A-10)
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.
In Step A-10, compound (14) is preferably trialkyl
orthooctanoate [C7H15C(OR7)3], and more preferably trimethyl
orthooctanoate.
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.
The solvent used is preferably an alcohol, and most
preferably methanol. The solvent used is preferably an alcohol
represented by the formula R7OH [wherein R7 is the same as R7 of
compound (14)].
The reaction temperature is preferably -30°C to 80°C, and
more preferably 0°C to 50°C.
The reaction time is preferably 5 minutes to 20 hours, and
more preferably 10 minutes to 5 hours.
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 R7-OH in the presence of acid.
Compound (15) can be produced in accordance with Process G.
In this step, compound (15) is preferably a compound
represented by the formula (15a):

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.
The solvent used is preferably an alcohol, and most
preferably methanol. The solvent used is preferably an alcohol
represented by the formula R7OH [wherein R7 is the same as R7 of
compound (15)].
The reaction temperature is preferably -30°C to 80°C, and
more preferably 0°C to 50°C.
The reaction time is preferably 5 minutes to 20 hours, and
more preferably 10 minutes to 5 hours.
(Process B)
The production of compound (12) from compound (9) in
Process A can also be conducted in accordance with Process B.
(Step B-1)
Step B-1 is a procedure to reduce compound (9) by using
triphenylphosphine and water, to produce compound (16).
The solvent used is preferably an ether or an ester, more
preferably tetrahydrofuran or ethyl acetate, and most preferably
ethyl acetate.
The reaction temperature is preferably 20°C to 120°C, and
more preferably 50°C to 90°C.
The reaction time is preferably 10 minutes to 20 hours,
and more preferably 30 minutes to 5 hours.
(Step B-2)
Step B-2 is a procedure to allow compound (16) to react
with compound (11) to produce compound (17).
The solvent used is preferably an ether or an ester, more
preferably tetrahydrofuran or ethyl acetate, and most preferably
ethyl acetate.
The reaction temperature is preferably -30°C to 80°C, and
more preferably 0°C to 50°C.
The reaction time is preferably 1 to 80 hours, and more
preferably 5 to 40 hours.
(Step B-3)
Step B-3 is a procedure to treat compound (17) with a base
to produce compound (12).
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.
The solvent used is preferably an alcohol, and more
preferably methanol. In the present step, it is preferable that
water is present.
The reaction temperature is preferably -30°C to 80°C, and
more preferably 0°C to 50°C.
The reaction time is preferably 30 minutes to 20 hours,
and more preferably 1 to 10 hours.
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.
(Process C)
The production of compound (12) from compound (8) in
Process A can also be conducted in accordance with Process C.
(Step C-1)
Step C-1 is a procedure to allow compound (8) to react
with a compound represented by the formula NaOR3 to produce
compound (18).
In Step C-1, the compound represented by the formula NaOR3
is preferably sodium methoxide.
Step C-1 can be conducted in a similar manner to Step A-3.
(Step C-2)
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).
In Step C-2, in the case where an acid is used, it can be
conducted in a similar manner to Step A-2.
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.
The solvent used is preferably an aromatic hydrocarbon, an
ester, or a mixture thereof, more preferably an ester, and most
preferably ethyl acetate.
The reaction temperature is preferably -30°C to 80°C, and
more preferably 0°C to 50°C.
The reaction time is preferably 5 minutes to 10 hours, and
more preferably 10 minutes to 5 hours.
(Step C-3)
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).
Step C-3 can be conducted in a similar manner to Step A-6.
(Step C-4)
Step C-4 is a procedure to reduce compound (20) by using
triphenylphosphine and water, to produce compound (21).
Step C-4 can be conducted in a similar manner to Step B-1.
(Step C-5)
Step C-5 is a procedure to allow compound (21) to react
with compound (11) to produce compound (22).
Step C-5 can be conducted in a similar manner to Step B-2.
(Step C-6)
Step C-6 is a procedure to treat compound (22) with a base
to produce compound (12).
Step C-6 can be conducted in a similar manner to Step B-3.
(Process D)
The production of compound (13) from compound (9) in
Process A can also be conducted in accordance with Process' D.
(Step D-1)
Step D-1 is a procedure to reduce compound (9) by using
triphenylphosphine and water to produce compound (16).
Step D-1 can be conducted in a similar manner to Step B-1.
(Step D-2)
Step D-2 is a procedure to allow compound (16) to react
with compound (23a) to produce compound (24).
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.
The solvent used is preferably an alcohol, water, or a
mixture thereof, and most preferably a mixture of methanol and
water.
The reaction temperature is preferably -20°C to 70°C, and
more preferably 0°C to 50°C.
The reaction time is preferably 1 to 200 hours, and more
preferably 10 to 100 hours.
The pH during the reaction is preferably 7 to 10, and more
preferably 7 to 9.
(Step D-3)
Step D-3 is a procedure to treat compound (24) with a base
to produce compound (13).
Step D-3 can be conducted in a similar manner to Step B-3.
(Process E)
The production of compound (13) from compound (10) in
Process A can also be conducted in accordance with Process E.
(Step E-1)
Step E-1 is a procedure to allow compound (10) to react
with compound (23a) to produce compound (13).
Step E-1 can be conducted in a similar manner to Step D-2.
(Process F)
Process F shows a method of manufacturing compound (11).
(Step F-1)
Step F-1 is a procedure to allow compound (23a) to react
with di-t-butyl dicarbonate (Boc2O) 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.
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.
The solvent used is preferably an amide, and most
preferably N,N-dimethylformamide.
The reaction temperature is preferably -30°C to 80°C, and
more preferably 0°C to 50°C.
The reaction time is preferably 30 minutes to 20 hours,
and more preferably 1 to 5 hours.
(Step F-2)
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).
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.
The solvent used is preferably an ether, and most
preferably tetrahydrofuran.
The reaction temperature of the reaction of compound (25)
with the base is preferably -40°C to 10°C, and more preferably -
20°C to 5°C.
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.
The reaction temperature of the reaction of the anion with
di-tert-butyl dicarbonate is preferably 20°C to 120°C, and more
preferably 50°C to 90°C.
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.
(Process G)
Process G shows a method of manufacturing compound (14)
and compound (15).
(Step G-1)
Step G-1 is a procedure to allow compound (26) to react
with a compound represented by the formula R7OH 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.
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 R7OH is preferably methanol.
The solvent used is preferably an ester, an aliphatic
hydrocarbon, or an aromatic hydrocarbon, more preferably an
ester, and most preferably methyl acetate.
The reaction temperature is preferably -50°C to 50°C, and
more preferably -20°C to 20°C.
The reaction time is preferably 1 to 100 hours, and more
preferably 5 to 50 hours.
(Step G-2)
Step G-2 is a procedure to allow compound (15) to react
with a compound represented by the formula R7OH to produce
compound (14).
In Step G-2, the compound represented by the formula R7OH
is preferably methanol. R7 in the compound represented by the
formula R7OH is preferably the same as R7 of compound (15). The
volume ratio of the compound represented by the formula R7OH
with respect to compound (15) is preferably 0.5 to 5, and more
preferably 1 to 3.
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 R70H 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 R7OH in excess amount can
also be used as the solvent.
The mixing ratio (volume ratio) of methylcyclohexane and
methanol is preferably 10:1 to 1:2, and more preferably 5:1 to
1:1.
The reaction temperature is preferably -20°C to 90°C, and
more preferably 10°C to 60°C.
The reaction time is preferably 30 minutes to 30 hours,
and more preferably 2 to 15 hours.
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).
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).
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.
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]
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-(octanoyloxy)propyl]-5,6-dihydro-
4H-pyran-2-carboxylic acid [compound (Ib)]
Step A-1: Methyl N-acetylneuramate
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°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°C, and the reaction solution was stirred at the same
temperature for 1 hour. After it was further stirred for 1 hour
at 0°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).
MS (FAB): m/z 324 [M+H]+
HRMS (ESI): Exact mass calcd for C12H22NO9 [M+H]+ 324.12946, Found
324.12966
IR (KBr): 3340, 2938, 1741, 1638, 1553, 1438, 1375, 1279, 1127,
1033 cm-1
1H NMR (D2O, 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).
13C NMR (D2O, 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
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°C, and concentrated
sulfuric acid (209.32 g) was added dropwise under stirring at
40°C or lower. After stirring the mixture for 4 hours at 40°C,
it was cooled to 0°C and triethylamine (431.93 g) was added
dropwise at 40°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°C under
stirring at 40°C or lower. The reaction solution was stirred for
1 hour at 25°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
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°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
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°C and then further for 5 hours at
55°C. The reaction solution was cooled to 0°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).
MS (FAB): m/z 314 [M+H]+
Anal, calcd for C13H15NO8: C, 49.84; H, 4.83; N, 4.47. Found C,
49.82; H, 4.58; N, 4.46.
IR (KBr): 3194, 1801, 1787, 1734, 1662, 1398, 1277, 1225, 1177,
1089, 988 cm-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, 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).
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
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°C.
After 60% sodium hydride (3.32 g) was added to the suspension
and the mixture was stirred for 10 minutes at 0°C, dimethyl
sulfate (11.27 g) was added, followed by stirring for 2.25 hours
at 15°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-yl]methyl)-5,6-dihydro-4H-
pyran-2-carboxylate
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°C. and the mixture was stirred for 20
hours at 20°C (stereoisomer ratio 15:1). After the reaction
solution was cooled to 0°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).
MS (FAB): m/z 371 [M+H]+
HRMS (ESI): Exact mass calcd for C14H19N4O8[M+H]+ 371.12029, Found
371.12018
IR (KBr): 3314, 2106, 1795, 1731, 1668, 1550, 1379, 1285, 1180,
1075 cm-1
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).
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.
The peak area ratios of the title compound and
stereoisomer thereof were measured under the following HPLC
measurement conditions.
HPLC measurement conditions (3)
Column: L-column ODS (4.6 mmID x 250 mm, particle diameter 5 µm,
manufactured by Chemicals Evaluation and Research Institute)
Column temperature: 40°C
Measurement wavelength: 254 nm
Mobile phase: acetonitrile:0.02 mol/1 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-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylic
acid
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°C.
To the reaction solution were added water (12.5 ml) and 25%
aqueous sodium hydroxide (6.48 g) at 50°C, followed by stirring
for 2 hours at the same temperature. The reaction solution was
cooled to 0°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-[(1R,2R)-2,3-dihydroxy-1-
methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylic acid
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 8.3 5 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-methoxypropyl]-5, 6-dihydro-4H-pyran-2-carboxylic
acid
The aqueous solution of the compound obtained in Step A-8
was stirred for 3.7 hours at 80°C. After the reaction solution
was cooled to 0°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).
MS (FAB): m/z 347[M+H]+
Anal, calcd for C13H22N407: C, 45.08; H, 6.40; N, 16.18. Found C,
44.85; H, 6.16; N, 16.09.
IR (KBr): 3440, 3375, 3256, 1699, 1653, 1587, 1401, 1329, 1284,
1171, 1087, 1029 cm-1
1H NMR (D2O, 500 MHz): 1.94 (3H, s), 3.31 (3H, s), 3.45 (1H, dd,
3 = 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).
13C NMR (D2O, 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-Acetarnide-4-guadino-6-[(1R,2R)-2-
hydroxy-1-methoxy-2-(octanoyloxy)propyl]-5,6-dihydro-4H-pyran-2-
carboxylic acid [compound (1b)]
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/l 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°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°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°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) [R2 = methyl group] : 0.02%, content of
compound (VII) [R1 = 1-heptyl group, R2 = methyl group] : 0.08%,
content of compound (VIII) [R1 = 1-heptyl group] : 0.04%).
MS (FAB): m/z 473[M+H]+
KF moisture value: 3.9%
Anal, calcd for C21H36 N4O8.1.065H2O: C, 51.29; H, 7.82; N, 11.39.
Found C, 51.21; H, 7.82; N, 11.32.
IR (KBr): 3334, 3289, 2929, 1736, 1665, 1640, 1401, 1325, 1283,
1173, 1114 cm-1 1H NMR (CD3OD, 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).
13C NMR (CD3OD, 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) [R4,R5 =
oxo group])
Step A-1: Methyl N-acetylneuramate
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"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 20DC, the mixture was
stirred for 0.5 hours at 30°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°C, crystals were
filtered, and the crystals were washed with ethyl acetate (30
ml) which was cooled to 0°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
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°C or
lower. After stirring the reaction solution for 5 hours at 40°C,
the reaction solution was cooled to 0°C, and triethylamine
(13.64 g) was added dropwise at 40°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°C or lower. The
reaction solution was further stirred for 1 hour at 25°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
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°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-
trihydroxypropy1]-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-
l,3-dioxolan-4-yl]methyl}-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-
d][1,3]oxazole-6-carboxylate
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°C, and further stirred for 5 hours at
55°C. The reaction solution was cooled to 0°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) [R2 = methyl group])
Step B-1: Methyl (4S,5R,6R)-5-acetamide-4-amino-6-{(S)-
methoxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-5,6-dihydro-4H-
pyran-2-carboxylate
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°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)-methoxy[(4R)-2-oxo-1,3-
dioxolan-4-yl]methyl}-5,6-dihydro-4H-pyran-2-carboxylate
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-l 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-carboxylic acid
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°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-[(lR,2R)-2.3-
dihydroxy-1-methoxypropyl]-5, 6-dihydro-4H-pyran-2-carboxylic
acid (compound (13) [R2 = methyl group])
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) [R2 = methyl group])
Step C-1: Methyl (3aS,4R,7aR)-4-[(1R,2R)-2,3-dihydroxy-1-
methoxypropyl]-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-
d][l,3]oxazole-6-carboxylate
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][l,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-dihydro-4H-pyrano[3,4-
d][1,3]oxazole-6-carboxylate
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°C or lower, and the
mixture was stirred for 1 hour at room temperature. Toluene
(4 60 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
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
trirnethylsilyl azide (23.92 g) were added, followed by stirring
for 4 hours at 20oC. 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°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-
[(lS,2R)-2,3-diacetoxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-
carboxylate
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°C, and the mixture was stirred for 2 hours at 72°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-[(lS,2R)-2,3-diacetoxy-1-
methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylate
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-carboxylic acid
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°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
(42 3 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-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylic
acid (compound (13) [R2 = methyl group])
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) [R2 = methyl group])
Step D-1: Methyl (4S,5R,6R)-5-acetamide-4-arnino-6-{(S)-
methoxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-5,6-dihydro-4H-
pyran-2-carboxylate
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°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)-methoxyl(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-5,6-dihydro-
4H-pyran-2-carboxylate
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-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylic
acid (compound (13) [R2 = methyl group))
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 o£ the title compound generated was
measured by HPLC (amount generated 0.59 g, yield 63.3%).
HPLC measurement conditions (4)
Column: L-column ODS (4.6 mmID x 250 mm, particle diameter 5 µm,
manufactured by Chemicals Evaluation and Research Institute)
Column temperature: 40°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) [R2 = methyl group])
Step E-1: To an aqueous solution of a compound obtained by
subjecting methyl (4S,5R,6R)-5-acetamide-4-azide-6-{(S)-
methoxy[(4R)-2-oxo-l,3-dioxolan-4-yl]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-(octanoyloxy)propyl]-5,6-dihydro-4H-pyran-
2-carboxylic acid [compound (Ib)]
Methanol (20 ml) was added to methyl octaneimidoate
hydrochloride (8.39 g), and the mixture was stirred for 3 hours
at 35°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/1 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 (lb) : compound (IIb) = 95:5,
content of compound (13) [R2 = methyl group]: compound (VII) [R1 = 1-heptyl group, R2 = methyl group]: 0.06%,
content of compound (VIII) [R1 = 1-heptyl group]: 0.09%).
(Example 8)
Synthesis of tert-butyl (tert-butoxycarbonyliminopyrazol-
1-yl-methyl)carbamate [compound (11)]
Step F-1: 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)]
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°C to 0°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°C
to 0°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).
1H NMR (CDCl3, 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).
13C NMR (CDCl3, 125MHz): 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) [R1 =
1-heptyl group, R7 = methyl group])
Step G-1: Methyl octanimidate hydrochloride
Methanol (2.81 g) and methyl acetate (30 ml) were added to
octanenitrile (10.00 g), and the mixture was cooled to 0°C.
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).
MS (FAB): m/z 158 [M+H]+
HRMS (ESI): Exact mass calcd for C9H20NO [M+H]+ 158.15449, Found
158.15433
IR (KBr): 3139, 3109, 2925, 2857, 1712, 1627, 1474, 1411, 1213,
1100 cm-1
1H NMR (CDCl3, 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).
13C NMR (CDCl3, 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) [R1 = 1-
heptyl group, R7 = methyl group])
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°C. The reaction solution was
cooled to 10°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°C) to give the title compound as a
colorless transparent oil (35.37 g, 83.8% yield).
MS (ESI): rn/z 227 [M+Na] +
HRMS (ESI): Exact mass calcd for C11H2403Na [M+Na]+227.16231,
Found 227.16138
IR (neat): 2955, 2928, 2854, 1466, 1241, 1153, 1078, 1047, 977
cm-1
1H NMR (CDCl3, 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).
13C NMR (CDCl3, 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)-methoxy[(4R)-2,2-
dimethyl-1,3-dioxolan-4-yl]methyl}-tetrahydro-4H-pyran-2-
carboxylate [compound (VIb)]
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°C. The mixture was stirred for 5
minutes at the same temperature and dimethyl sulfate (0.31 g)
was added at 0°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°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%).
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)
Column: L-column ODS (4.6 mmID x 250 mm, particle diameter 5 µm,
manufactured by Chemicals Evaluation and Research Institute)
Column temperature: 40°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)]
N,N-dimethylformamide (250 ml), DOWEX° 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°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).
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)
Column: L-column ODS (4.6 mmID x 250 mm, particle diameter 5 µm,
manufactured by Chemicals Evaluation and Research Institute)
Column temperature: 40°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,2R)-2-hydroxy-1-
methoxy-3-(octanoyloxy)propyl]-5,6-dihydro-4H-pyran-2-
carboxylate [compound (IVk)]
Dichloromethane (20 ml) and triethylamine (0.10 g) were
added to compound (IVj) (0.50 g) of Process W at 0°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%).
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 x 250 mm, particle diameter 5 µm,
manufactured by Chemicals Evaluation and Research Institute)
Column temperature: 40°C
Measurement wavelength: 254 nm
Mobile phase: acetonitrile : 0.02 mol/1 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)[R1 =
1-heptyl group, R7 = methyl group])
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°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°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-(octanoyloxy)propyl]-5,6-dihydro-4H-pyran-2-carboxylic
acid [compound (Ib)]
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)
[R2 = methyl group]: 3.54%, content of compound (VII) [R1 = 1-
heptyl group, R2 = methyl group]: 0.51%, content of compound
(VIII) [R1= 1-heptyl group]: 0.97%
(Preparation Example 1) Liquid formulation 1
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
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
A powder formulation is prepared containing the compound
of Example 1 40% (w/w) and lactose 60% (w/w).
(Preparation Example 4) Aerosol
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]
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.
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.
We claim:
1. A method for manufacturing a compound represented by the
formula (7):

wherein R3 represents a C1-C6 alkyl group, and R4 and R5,
independently from each other, represent a hydrogen atom, a C1-C6
alkyl group or a phenyl group, or R4 and R5 together form a
tetramethylene group, a pentamethylene group or an oxo group,
comprising:
allowing a compound represented by the formula (4):

wherein R3 represents a C1-C6 alkyl group, to react with a compound
represented by the formula (5):

wherein R4 and R5, independently from each other, represent a
hydrogen atom, a C1-C6 alkyl group or a phenyl group, or R4 and R5
together form a tetramethylene group, a pentamethylene group or an
oxo group, and R6 represents a C1-C6 alkyl group, or with a
compound represented by the formula (6):

wherein R4 and R5, independently from each other, represent a
hydrogen atom, a C1-C6 alkyl group or a phenyl group, or R4 and R5
together form a tetramethylene group or a pentamethylene group,
except that R4 and R5 in compound (7) do not together form an oxo
group when compound (6) is used.
2. The manufacturing method according to Claim 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
R3 is a methyl group, R4 and R5 together form an oxo group, and the
compound represented by the formula (5) is dimethyl carbonate.
3. A compound represented by the formula (7):

wherein R3 represents a C1-C6 alkyl group, R4 and R5, independently
from each other, represent a hydrogen atom, a C1-C6 alkyl group or
a phenyl group, or R4 and R5 together form a tetramethylene group,
a pentamethylene group or an oxo group.
4. The compound according to Claim 3, wherein R3 is a
methyl group, and R4 and R5 together form an oxo group.
5. A method for manufacturing a compound represented by the
formula (9):

wherein R2 represents a C1-C4 alkyl group, R3 represents a C1-C6
alkyl group, R4 and R5, independently from each other, represent
a hydrogen atom, a C3-C6 alkyl group or a phenyl group, or R4 and
R5 together form a tetramethylene group, a pentamethylene group or
an oxo group, and Ac represents an acetyl group, comprising:
allowing a compound represented by the formula (8):

wherein R2 represents a C1-C4 alkyl group, R3 represents a C1-C6
alkyl group, R4 and R5, independently from each other, represent a
hydrogen atom, a C1-C6 alkyl group or a phenyl group, or R4 and R5
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 according to Claim 5, wherein
R2 is a methyl group, R3 is a methyl group, R4 and R5 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):

wherein R2 represents a C1-C4 alkyl group and Ac represents an
acetyl group, comprising:
allowing a compound represented by the formula (12):

wherein R2 represents a C1-C4 alkyl group, Ac represents an acetyl
group and Boc represents a tert-butoxycarbonyl group, to react
with water.
8. The manufacturing method according to Claim 7, wherein
R2 is a methyl group.
9. A compound represented by the formula (13):

wherein R2 represents a C1-C4 alkyl group and Ac represents an
acetyl group.
10. The compound according to Claim 9, wherein R2 is a
methyl group.
11. A method for manufacturing a compound represented by
the formula (I):

wherein R1 represents a C1-C19 alkyl group, R2 represents a C1-C4
alkyl group, and Ac represents an acetyl group, and the compound
represented by the formula (I) may include a compound represented
by the formula (II):

wherein R1, R2 and Ac have the same meanings as in the formula
(I), or a pharmacologically acceptable salt thereof, comprising:
allowing a compound represented by the formula (13):

wherein R2 represents a C1-C4 alkyl group and Ac represents an
acetyl group, to react with a compound represented by the formula
R1C(OR7)3 wherein R1 represents a C1-C19 alkyl group and R7
represents a C1-C6 alkyl group, or a pharmacologically acceptable
salt thereof.
12. The manufacturing method according to Claim 11, wherein
R1 is a 1-heptyl group, R2 is a methyl group and R7 is a methyl
group.
13. A method for manufacturing a compound represented by
the formula (I):

wherein R1 represents a C1-C19 alkyl group, R2 represents a C1-C4
alkyl group and Ac represents an acetyl group, and the compound
represented by the formula (I) may include a compound represented
by the formula (II):

wherein R1, R2 and Ac have the same meanings as in the formula
(I) , or a pharmacologically acceptable salt thereof, comprising:
allowing a compound represented by the formula (13):

wherein R2 represents a C1-C4 alkyl group and Ac represents an
acetyl group, to react with a compound represented by the formula
(15) :
wherein R1 represents a C1-C19 alkyl group, R7 represents a C1-C6
alkyl group and X represents Cl, Br, I, HSO4 or NO3, and with a
compound represented by the formula R7-OH wherein R7 represents a
C1-C6 alkyl group.
14. The manufacturing method according to Claim 13, wherein
R1 is a 1-heptyl group, R2 is a methyl group, R7 is a methyl group
and X is Cl.
15. A method for manufacturing a compound represented by
the formula (Ib):

wherein Ac represents an acetyl group, and Me represents a methyl
group, and the compound represented by the formula (Ib) may
include a compound represented by the formula (IIb):

wherein in the formula (IIb), Ac and Me have the same meanings as
in the formula (Ib), or a pharmacologically acceptable salt
thereof, wherein at least one manufacturing method according to
any one of Claims 2, 6 and 8 is included as part of the production
procedure.
16. A method of manufacturing a compound represented by the
formula (Ib):

wherein Ac represents an acetyl group, Me represents a methyl
group, and the compound represented by the formula (Ib) may
include a compound represented by the formula (IIb):

wherein in the formula (IIb), Ac and Me have the same meanings as
in the formula (Ib), or a pharmacologically acceptable salt
thereof, which proceeds via at least one compound according to
either one of Claims 4 and 10.
17. A compound represented by the formula (I):

wherein R1 represents a C1-C19 alkyl group, R2 represents a C1-C4
alkyl group and Ac represents an acetyl group, and the compound
represented by the formula (I) may include a compound represented
by the formula (II):

wherein R1, R2 and Ac have the same meanings as in the formula
(I), having a chemical purity of 97wt% 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 97wt% or higher, or a pharmacologically acceptable
salt thereof.
18. A compound represented by the formula (I):

wherein R1 represents a C1-C19 alkyl group, R2 represents a C1-C4
alkyl group and Ac represents an acetyl group, and the compound
represented by the formula (I) may include a compound represented
by the formula (II):

wherein Ra, R2 and Ac have the same meanings as in the formula
(I), or a pharmacologically acceptable salt thereof, containing a
compound represented by the formula (VII):

wherein Ra, R2 and Ac have the same meanings as in the formula (I)
in an amount of 0.5wt% or less.
19. A compound represented by the formula (I):

wherein R1 represents a C1-C19 alkyl group, R2 represents a C1-C4
alkyl group and Ac represents an acetyl group, and the compound
represented by the formula (I) may include a compound represented
by the formula (II):

wherein R1, R2 and Ac have the same meanings as in the formula
(I), or a pharmacologically acceptable salt thereof, containing a
compound represented by the formula (VIII):

wherein R1 and Ac have the same meanings as the formula (I) in an
amount of 0.5wt% or less.
20. A compound represented by the formula (I):

wherein R1 represents a C1-C19 alkyl group, R2 represents a C1-C4
alkyl group and Ac represents an acetyl group, and the compound
represented by the formula (I) may include a compound represented
by the formula (II):

wherein R1, R2 and Ac have the same meanings as in the formula
(I), or a pharmacologically acceptable salt thereof, containing a
compound represented by the formula (13):

wherein R2 and Ac have the same meanings as in the formula (I) in
an amount of 0.5wt% or less.
21. A compound represented by the formula (I), which may
include a compound represented by the formula (II), according to
any one of Claims 17 to 20, 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.
22. A compound represented by the formula (I), which may
include a compound represented by the formula (II), according to
any one of Claims 17 to 20, 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.
23. A compound represented by the formula (I), which may
include a compound represented by the formula (II), according to
any one of Claims 17 to 20, 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.
24. A method of manufacturing a compound represented by the
formula R1C(OR7)3 wherein R1 represents a C1-C19 alkyl group and R7
represents a C1-C6 alkyl group, comprising:
allowing a compound represented by the formula (15):

wherein R1 represents a C1-C19 alkyl group, R7 represents a C1-C6
alkyl group and X represents Cl, Br, I, HSO4 or NO3, to react with
a compound represented by the formula R7-OH wherein R7 represents
a C1-C6 alkyl group, in a solvent which forms a bilayer system.
25. The manufacturing method according to Claim 24, wherein
the solvent which forms the bilayer system is a hydrocarbon.
26. The manufacturing method according to Claim 24, wherein
the solvent which forms the bilayer system is cyclohexane or
methylcyclohexane.
27. The manufacturing method according to any one of Claims
24 to 26, wherein R1 is a 1-heptyl group, R7 is a methyl group and
X is Cl.
28. A composition for treatment or prevention of influenza
containing as active ingredient the compound or pharmacologically
acceptable salt thereof as set forth in any one of Claims 17 to
23.
29. A compound represented by the formula (I):

wherein R1 represents a C1-C19 alkyl group and R2 represents a C1-C4
alkyl group, and the compound represented by the formula (I) may
include a compound represented by the formula (II):

wherein R1 and R2 have the same meanings as in the formula (I),
having a chemical purity of 97wt% 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 97wt% or higher, or a pharmacologically acceptable salt
thereof, manufactured by a method comprising:
allowing a compound represented by the formula (13):

(13)
wherein R2 represents a C1-C4 alkyl group, to react with a compound
represented by the formula R1C(OR7)3 wherein R1 represents a C1-C19
alkyl group and R7 represents a C1-C6 alkyl group, or a
pharmacologically acceptable salt thereof.
30. The compound represented by the formula (I), which may
include the compound represented by the formula (II) , or
pharmacologically acceptable salt thereof according to Claim 17 or
Claim 29, wherein the chemical purity is 99wt% or higher.
31. The compound represented by the formula (I), which may
include the compound represented by the formula (II), or the
pharmacologically acceptable salt thereof as according to Claim 17
or Claim 29, wherein the chemical purity is 99.5wt% or higher.
32. A compound represented by the formula (I):

wherein R1 represents a C1-C19 alkyl group and R2 represents a C1-C4
alkyl group, and the compound represented by the formula (I) may
include a compound represented by the formula (II):

wherein R1 and R2 have the same meanings as the formula (I), or a
pharmacologically acceptable salt thereof, containing a compound
represented by the formula (VII):

wherein R1 and R2 represent have the same meanings as in the
formula (I) in an amount of 0.5wt% or less, manufactured by a
method comprising:
allowing a compound represented by the formula (13):

wherein R2 represents a C1-C4 alkyl group, to react with a compound
represented by the formula R1C(OR7)3 wherein R1 represents a C1-C19
alkyl group and R7 represents a C1-C6 alkyl group.
33. The compound represented by the formula (I), which may
include the compound represented by the formula (II), or
pharmacologically acceptable salt thereof according to Claim 18 or
Claim 32, containing the compound represented by the formula (VII)
in an amount of 0.3wt% or less.
34. The compound represented by the formula (I), which may
include the compound represented by the formula (II), or
pharmacologically acceptable salt thereof according to Claim 18 or
Claim 32, containing the compound represented by the formula (VII)
in an amount of 0.1wt% or less.
35. A compound represented by the formula (I):

wherein R1 represents a C1-C19 alkyl group and R2 represents a C1-C4
alkyl group, and the compound represented by the formula (I) may
include a compound represented by the formula (II):

wherein R1 and R2 have the same meanings as in the formula (I), or
a pharmacologically acceptable salt thereof, containing a compound
represented by the formula (VIII):

wherein R1 has the same meaning as in the formula (I) in an amount
of 0.5wt% or less,
manufactured by a method comprising:
allowing a compound represented by the formula (13):

wherein R2 represents a C1-C4 alkyl group, to react with a compound
represented by the formula R1C(OR7)3 wherein R1 represents a C1-C19
alkyl group and R7 represents a C1-C6 alkyl group.
36. The compound represented by the formula (I), which may
include the compound represented by the formula (II), or
pharmacologically acceptable salt thereof according to Claim 19 or
Claim 35, containing the compound represented by the formula
(VIII) in an amount of 0.3wt% or less.
37. The compound represented by the formula (I), which may
include the compound represented by the formula (II), or
pharmacologically acceptable salt thereof according to Claim 19 or
Claim 35, containing the compound represented by the formula
(VIII) in an amount of 0.1wt% or less.
38. A compound represented by the formula (I):

wherein R1 represents a C1-C19 alkyl group and R2 represents a C1-C4
alkyl group, and the compound represented by the formula (I) may
include a compound represented by the formula (II):

wherein R1 and R2 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):

wherein R2 has the same meaning as the formula (I) in an amount of
0.5wt% or less,
manufactured by a method comprising:
allowing a compound represented by the formula (13):

wherein R2 represents a C1-C4 alkyl group, to react with a compound
represented by the formula R1C(OR7)3 wherein R1 represents a C1-C19
alkyl group and R7 represents a C1-C6 alkyl group.
39. The compound represented by the formula (I), which may
include the compound represented by the formula (II), or
pharmacologically acceptable salt thereof according to Claim 20 or
Claim 38, containing the compound represented by the formula (13)
in an amount of 0.3wt% or less.
40. The compound represented by the formula (I), which may
include the compound represented by the formula (II), or
pharmacologically acceptable salt thereof according to Claim 20 or
Claim 38, containing the compound represented by the formula (13)
in an amount of 0.1wt% or less.
41. The compound represented by the formula (I), which
may include the compound represented by the formula (II),
according to any one of Claims 17 to 20 and 29 to 40, wherein R1
is a 1-heptyl group and R2 is a methyl group.

A method for manufacturing neuraminic acid derivatives is provided, also
synthetic intermediates of the neuraminic acid derivatives and methods for their
manufacture, and neuraminic acid derivatives having high purity. [Means for
solution] A synthetic intermediate compound represented by the formula (7) is
provided: [wherein R3 represents alkyl; R4 and R5 each represents H, alkyl,
phenyl, or together represent tetramethylene, pentamethylene, oxo].

Documents:

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Patent Number 268840
Indian Patent Application Number 3530/KOLNP/2009
PG Journal Number 39/2015
Publication Date 25-Sep-2015
Grant Date 18-Sep-2015
Date of Filing 09-Oct-2009
Name of Patentee DAIICHI SANKYO COMPANY, LIMITED
Applicant Address 3-5-1, NIHONBASHI HONCHO, CHUO-KU, TOKYO 103-8426, JAPAN
Inventors:
# Inventor's Name Inventor's Address
1 MURAKAMI, MASAYUKI C/O. DAIICHI SANKYO COMPANY, LIMITED, 1-12-1, SHINOMIYA, HIRATSUKA-SHI, KANAGAWA 254-0014, JAPAN
2 NAKAMURA, YOSHITAKA C/O. DAIICHI SANKYO COMPANY, LIMITED, 1-12-1, SHINOMIYA, HIRATSUKA-SHI, KANAGAWA 254-0014, JAPAN
3 YAMAOKA, MAKOTO C/O. DAIICHI SANKYO COMPANY, LIMITED, 1-12-1, SHINOMIYA, HIRATSUKA-SHI, KANAGAWA 254-0014, JAPAN
4 YAKAYAMA, MASAKAZU C/O. DAIICHI SANKYO COMPANY, LIMITED, 1-12-1, SHINOMIYA, HIRATSUKA-SHI, KANAGAWA 254-0014, JAPAN
5 UMEO, KAZUHIRO C/O DAIICHI SANKYO CHEMICAL PHARMA CO., LTD. 4-4-8, NISHIYAWATA, HIRATSUKA-SHI, KANAGAWA 254-0073, JAPAN
PCT International Classification Number C07D309/28; A61K31/351; C07C41/00
PCT International Application Number PCT/JP2008/057557
PCT International Filing date 2008-04-11
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2007-103585 2007-04-11 Japan