Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Description
Method for producing macrolide compound and production
intermediate thereof
Technical Field
The present invention relates to a method for producing
a 12-membered ring macrolide compound useful as a medicine and
a production intermediate thereof.
Background Art
It is known that a 12-membered ring macrolide compound and
derivatives thereof represented by Formula (1) described below
have an excellent VEGF (Vascular Endothelial Growth Factor)
production-suppressing effect, and that, in addition, they
strongly suppress the growth of solid tumor cells in vivo
experiments. It is known that a 7-position urethane derivative
thereof shows a particularly excellent activity and is expected
as a prophylactic or therapeutic agent for solid tumors and the
like (refer to WO-A 2003/099813).
OH
OH
OR21 O
O
O OR3
OR16 ~ 1 )
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(Where each of R3, R16 and R21 independently represents a hydrogen
atom or a protective group of hydroxyl group.)
As a method for producing the 7-position urethane
derivative, the method described in WO-A 2003/099813 is known.
That is, the derivative is produced through a process of
multiple steps such that, after protecting hydroxyl groups at
3-, 6-, 16- and 21-positions of the 12-membered ring macrolide
compound 11107D represented by Formula (A) below, which is a
raw material, through the use of an appropriate protective group,
a 7-position acetyl group is hydrolyzed and removed, and that
the product is then treated with a chloroformate derivative or
the like in the presence of base to induce a carbonate ester
group and, after that, the product is reacted with an intended
amine followed by removal of the protective group. Therefore,
the development of an effective method having less steps and
good yield is required.
Jo
OH
OH O
O OH
OH (A)
On the other hand, an example is known in the synthesis
of acylated derivatives of a 16-membered ring macrolide
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compound, in which a diol group of a sugar residue of a
16-membered ring macrolide compound is acetalized by using a
dialkyl tin compound and is then acylated (see JP-A 62-234093) .
However, there are no such examples as acetalizing lactone ring
diol groups of 12-membered ring macrolide compounds by using
a dialkyl tin compound, and as performing urethane
derivatization of these diol groups.
Disclosure of the Invention
The present invention provides a novel production method
for synthesizing more easily a 7-position urethane derivative
having an excellent antitumor effect, by using a 12-membered
ring macrolide compound represented by Formula (1) as a raw
material, and provides a production intermediate thereof.
For achieving the above purpose, present inventors have
worked hard to find that, by acetalizing hydroxyl groups at 6-
and 7-positions of the 12-membered ring macrolide compound
represented by Formula (1) with dialkyl tin (IV) oxide and,
after that, reacting the product with a carbamoyl halide
derivative, the 7-position urethane derivative being the target
can effectively be produced, while not necessarily protecting
hydroxyl groups at other positions. The present invention is
based on such knowledge.
Therefore, according to the present invention, inventions
[1] to [9] below are provided.
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[1] A method for producing a macrolide derivative
represented by Formula (5)
O
Rni,N~O
Rn2 OH
OH O
O OH
OH (5)
(where Rnl and Rn2 may be the same or different, and represent
a) a hydrogen atom,
b) a Cl to C22 alkyl group that may have substituent(s),
c) an unsaturated C2 to C22 alkyl group that may have
substituent(s),
d) a C6 to C14 aryl group that may have substituent(s),
e) a 5- to 14-membered ring heteroaryl group that may have
substituent(s),
f) a C7 to C22 aralkyl group that may have substituent(s),
g) a 5- to 14-membered ring heteroaralkyl group that may have
substituent(s),
h) a C3 to C14 cycloalkyl group that may have substituent(s),
i) a 3- to 14-membered non-aromatic heterocyclic group that may
have substituent(s), or
j) a 3- to 14-membered non-aromatic heterocyclic group formed
by Rnl and Rn2 with a nitrogen atom that is bonded together (the
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3- to 14-membered non-aromatic heterocyclic group may have
substituent(s))),
comprising a step of reacting a tin (IV)-containing
macrolide derivative represented by Formula (3)
Rsn,
I
O--Sn-Rsn2
O
OR21 0
O OR3
OR16 ( 3 )
(where each of R3, R16 and R21 independently represents a hydrogen
atom or a protective group of hydroxyl group, and each of Rsnl
and Rsn2 independently represents a C1 to C30 alkyl group) in
a solvent with a carbamoyl halide derivative represented by
Formula (4)
0
Rnl, N~X
Rn2 (4)
(where Rnl and Rn2 are defined in the same way as above, and
X represents a halogen atom) and, subsequently where necessary,
subjecting the product to an elimination reaction of a
protective group of hydroxyl group.
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[2] The production method according to [1] further
comprising a step of reacting a macrolide derivative
represented by Formula (1)
OH
OH
OR21 O
0
O O R3
OR~6 ~ 1 )
(where each of R3, R16 and R21 independently represents a hydrogen
atom or a protective group of hydroxyl group) in a solvent with
a dialkyl tin (IV) oxide represented by Formula (2)
Rsnl,,,, SnO
Rsn2 (2)
(where each of Rsnl and Rsn2 independently represents a Cl to
C30 alkyl group), before reacting the tin (IV)-containing
macrolide derivative represented by Formula (3) with the
carbamoyl halide derivative represented by Formula (4).
[3] The production method according to [1] or [2], wherein
the carbamoyl halide derivative represented by Formula (4) is
a derivative represented by Formula (4-1)
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O
Rni'-- N'J~ X
Rn2j ( 4 -1 )
(where Rnl' and Rn2' form a 3- to 14-membered non-aromatic
heterocyclic group with a nitrogen atom bonded together (the
3- to 14-membered non-aromatic heterocyclic group may have
substituent(s)), and X represents a halogen atom).
[ 4] The production method according to [ 1] or [ 2], wherein
the carbamoyl halide derivative represented by Formula (4) is
a derivative represented by Formula (4-2).
ic'
NJ
(4-2)
[5] A method for producing a tin (IV) -containing macrolide
derivative represented by Formula (3)
Rsn,
O--Sn-Rsn2
O
OR21 O
O
O OR3
OR (3)
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(where each of R3, R16 and R21 independently represents a hydrogen
atom or a protective group of hydroxyl group, and each of Rsnl
and Rsn2 independently represents a Cl to C30 alkyl group),
comprising a step of reacting a macrolide derivative
represented by Formula (1)
OH
OH
OR21 O
O OR3
OR16 ~ 1 )
(where each of R3, R16 and R21 independently represents a hydrogen
atom or a protective group of hydroxyl group) in a solvent with
a dialkyl tin (IV) oxide represented by Formula (2)
Rsn, \ SnO
Rsn2 (2)
(where each of Rsnl and Rsn2 independently represents a Cl to
C30 alkyl group).
[6] A tin (IV)-containing macrolide derivative
represented by Formula (3)
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Rsn,
I
O--Sn-Rsn2
O
OR21 O
o oR3
oR16 (3)
(where each of R3, R16 and R21 independently represents a hydrogen
atom or a protective group of hydroxyl group, and each of Rsnl
and Rsnz independently represents a Cl to C30 alkyl group)
[7] The tin (IV)-containing macrolide derivative
according to [6], wherein R3, R16 and R21 are hydrogen atoms.
[8] The tin (IV)-containing macrolide derivative
according to [6], wherein each of Rsnl and Rsn2 independently
represents a Cl to C10 alkyl group.
[9] The carbamoyl halide derivative represented by Formula
(4-2).
0
N'k CI
ONI"li
(4-2)
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In the present invention, the tin (IV)-containing
macrolide derivative represented by Formula (3) may be one that
is produced by the method described in [5].
Further, the present invention provides the macrolide
derivative represented by Formula (3) obtained by the
production method of [5].
Detailed Description of the Invention
Hereinafter, the meaning of terms, symbols and the like
described herein will be explained, and the present invention
will be explained in detail.
In the present Description, a structural formula of a
compound occasionally represents certain isomers, as a matter
of convenience. All the isomers such as geometric isomers,
optical isomers based on an asymmetric carbon, rotational
isomers, stereoisomers, and tautomers which are generated on
the basis of the structure of the compound, and isomer mixtures
are included in the present invention, which are not limited
to expediential description of a formula and may be either one
of isomers or a mixture thereof. Accordingly, the compound of
the present invention has multiple asymmetric carbon atoms in
the molecule to thereby be able to provide various diastereomers,
and is not limited to any of them.
On "the protective group of a hydroxyl group" used herein,
no limitation is imposed as long as the hydroxyl group can be
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protected. Examples thereof include a 1-ethoxyethyl group, a
tetrahydropyranyl group, a 1-methoxycyclohexyl group, a
4-methoxytetrahydropyranyl group, a
4-methoxytetrahydrothiopyranyl group, a
4-methoxytetrahydrothiopyranyl-S,S-dioxide group, a
tert-butyldimethylsilyl group, a triethylsilyl group, a
diethylisopropylsilyl group, a trimethylsilyl group, a
triisopropylsilyl group, a di-tert-butylmethylsilyl group, a
diphenylmethylsilyl group, and the like.
"The Cl to C10 alkyl group" used herein represents a linear
or branched alkyl group having 1 to 10 carbon atoms. Examples
thereof include a methyl group, an ethyl group, a n-propyl group,
an iso-propyl group, a n-butyl group, an iso-butyl group, a
sec-butyl group, a tert-butyl group, a n-pentyl group, a
1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a
2,2-dimethylpropyl group, a 1-ethylpropyl group, a
1-methylbutyl group, a 2-methylbutyl group, a n-hexyl group,
a 1-ethyl-2-methylpropyl group, a 1,1,2-trimethylpropyl group,
a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a
2,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a
2,3-dimethylbutyl group, a 1-ethylbutyl group, a 2-ethylbutyl
group, a 2-methylpentyl group, a 3-methylpentyl group, a
n-heptyl group, a n-octyl group, a n-nonyl group, a n-decyl
group, and the like.
The "Cl to C22 alkyl group" used herein represents a linear
or branched alkyl group having 1 to 22 carbon atoms. Examples
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thereof include, in addition to examples of the Cl to C10 alkyl
group, an undecanyl group, a dodecanyl group, a tridecanyl group,
a tetradecanyl group, a pentadecanyl group, a hexadecanyl group,
a heptadecanyl group, an octadecanyl group, a nonadecanyl group,
an icosanyl group, a henicosanyl group, a docosanyl group, and
the like.
"The Cl to C30 alkyl group" used herein represents a linear
or branched alkyl group having 1 to 30 carbon atoms, including,
in addition to examples of the Cl to C22 alkyl group, a tricosanyl
group, a pentacosanyl group, a hexacosanyl group, a nonacosanyl
group, a triacontanyl group, and the like.
"The unsaturated C2 to C22 alkyl group" used herein
represents a linear or branched alkenyl group having 2 to 22
carbon atoms, or a linear or branched alkynyl group having 2
to 22 carbon atoms. Examples thereof may include a vinyl group,
an allyl group, a 1-propenyl group, an isopropenyl group, a
2-methyl-l-propenyl group, a 2-methyl-2-propenyl group, a
1-butenyl group, a 2-butenyl group, a 3-butenyl group, a
1-pentenyl group, a 1-hexenyl group, a 1,3-hexadienyl group,
a 1,5-hexadienyl group, an ethynyl group, a 1-propynyl group,
a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a
3-butynyl group, a 1-ethynyl-2-propynyl group, a
2-methyl-3-butynyl group, al-pentynylgroup, a 1-hexynyl group,
a 1,3-hexadiynyl group, a 1,5-hexadiynyl group, and the like.
"The C6 to C14 aryl group" used herein means an aromatic
hydrocarbon cyclic group constituted of 6 to 14 carbon atoms,
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including a monocyclic group, and condensed rings such as a
bicyclic group and a tricyclic group. Examples thereof may
include a phenyl group, an indenyl group, a 1-naphthyl group,
a 2-naphthyl group, an azulenyl group, a heptalenyl group, an
indacenyl group, an acenaphthylenyl group, a fluorenyl group,
a phenalenyl group, a phenanthryl group, an anthryl group, and
the like.
"The 5- to 14-membered ring heteroaryl group" herein means
a monocyclic, bicyclic or tricyclic 5- to 14-membered aromatic
heterocyclic group constituted by containing one or more
hetero-atoms selected from the group consisting of a nitrogen
atom, a sulfur atom and an oxygen atom. Examples of
nitrogen-containing aromatic heterocyclic groups may include
a pyrrolyl group, a pyridyl group, a pyridazinyl group, a
pyrimidinyl group, a pyrazinyl group, a triazolyl group, a
tetrazolyl group, a benzotriazolyl group, a pyrazolyl group,
an imidazolyl group, a benzimidazolyl group, an indolyl group,
an isoindolyl group, an indolizinyl group, a purinyl group, an
indazolyl group, a quinolyl group, an isoquinolyl group, a
quinolizinyl group, a phthalazinyl group, a naphthyridinyl
group, a quinoxalyl group, a quinazolinyl group, a cinnolinyl
group, a pteridinyl group, an imidazotriazinyl group, a
pyrazinopyridazinyl group, an acridinyl group, a
phenanthridinyl group, a carbazolyl group, a carbazolinyl group,
a perimidinyl group, a phenanthrolinyl group, a phenazinyl
group, an imidazopyridyl group, an imidazopyrimidinyl group,
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a pyrazolopyridyl group, a pyrazolopyrimidinyl group, and the
like. Examples of sulfur-containing aromatic heterocyclic
groups may include a thienyl group, a benzothienyl group and
the like, and examples of oxygen-containing aromatic
heterocyclic groups may include a furyl group, a pyranyl group,
a cyclopentapyranyl group, a benzofuranyl group, an
isobenzofuranyl group and the like, and examples of aromatic
heterocyclic groups containing two or more different kinds of
hetero atoms may include a thiazolyl group, an isothiazolyl
group, a benzothiazolyl group, a benzthiadiazolyl group, a
phenothiazinyl group, an isoxazolyl group, a furazanyl group,
a phenoxazinyl group, an oxazolyl group, an isoxazoyl group,
a benzoxazolyl group, an oxadiazolyl group, a pyrazoloxazolyl
group, an imidazothiazolyl group, a thienofuranyl group, a
furopyrrolyl group, a pyridoxazinyl group and the like.
"The C7 to C22 aralkyl group" used herein means a group
in which a substitutable part in "the Cl to C22 alkyl group"
as defined above is substituted by "the C6 to C14 aryl group"
as defined above. Specific examples thereof may include a
benzyl group, a phenethyl group, a 3-phenylpropyl group, a
4-phenylbutyl group, a 1-naphthylmethyl group, a
2-naphthylmethyl group, and the like.
"The 5- to 14-membered ring heteroaralkyl group" used
herein means a group in which a substitutable part in "the Cl
to C22 alkyl group" as defined above is substituted by "the 5-
to 14-membered ring heteroaryl group" as defined above.
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Specific examples thereof may include a thienylmethyl group,
a furylmethyl group, a pyridylmethyl group, a pyridazylmethyl
group, a pyrimidylmethyl group, a pyrazylmethyl group, and the
like.
,, The C3 to C14 cycloalkyl group" used herein means a
cycloalkyl group constituted of 3 to 14 carbon atoms. Specific
examples thereof may include a cyclopropyl group, a cyclobutyl
group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl
group, a cyclooctyl group, and the like.
"The 3- to 14-membered non-aromatic heterocyclic group"
used herein means a monocyclic, bicyclic or tricyclic 3- to
14-membered non-aromatic heterocyclic group that may include
one or more hetero atoms selected from the group consisting of
a nitrogen atom, a sulfur atom and an oxygen atom. Examples
thereof may include an aziridinyl group, an azetidyl group, a
pyrrolidinyl group, a pyrrolyl group, a piperidyl group, a
piperazinyl group, a homopiperidinyl group, a homopiperazinyl
group, an imidazolyl group, a pyrazolidyl group, an
imidazolidinyl group, a morpholinyl group, a thiomorpholinyl
group, an imidazolinyl group, an oxazolinyl group, a
quinuclidinyl group, a tetrahydrofuranyl group, a
tetrahydrothienyl group, and the like. The non-aromatic
heterocyclic group also includes groups that are induced from
apyridone ring, and non-aromatic condensed rings (for example,
groups induced from a phthalimide ring, a succinimide ring or
the like).
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The substituent of "that may have substituent(s)" used
herein includes one or more groups selected from:
(1) a halogen atom,
(2) a hydroxyl group,
(3) a thiol group,
(4) a nitro group,
(5) a nitroso group,
(6) a cyano group,
(7) a carboxyl group,
(8) a hydroxysulfonyl group,
(9) an amino group,
(10) a C1 to C22 alkyl group (such as a methyl group, an
ethyl group, a n-propyl group, an iso-propyl group, a n-butyl
group, an iso-butyl group, a sec-butyl group or a tert-butyl
group),
(11) an unsaturated C2 to C22 alkyl group (such as a vinyl
group, an allyl group, a 1-propenyl group, an isopropenyl group,
an ethynyl group, a 1-propynyl group, a 2-propynyl group, a
1-butynyl group, a 2-butynyl group or a 3-butynyl group),
(12) a C6 to C14 aryl group (such as a phenyl group, a
1-naphthyl group or a 2-naphthyl group),
(13) a 5- to 14-membered ring heteroaryl group (such as
a thienyl group, a furyl group, a pyridyl group, a pyridadinyl
group, a pyrimidinyl group or a pyrazinyl group),
(14) a 3- to 14-membered non-aromatic heterocyclic group
(such as an aziridinyl group, an acetidyl group, a pyrrolidinyl
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group, a pyrrolyl group, a piperidyl group, a piperazinyl group,
an imidazolyl group, a pyrazolidyl group, an imidazolidinyl
group, a morpholinyl group, a thiomorpholinyl group, an
imidazolinyl group, an oxazolinyl group or a quinuclidinyl
group),
(15) a C3 to C8 cycloalkyl group (such as a cyclopropyl
group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl
group, a cycloheptyl group or a cyclooctyl group),
(16) a Cl to C22 alkoxy group (such as a methoxy group,
an ethoxy group, a n-propoxy group, an iso-propoxy group, a
n-butoxy group, an iso-butoxy group, a sec-butoxy group or a
tert-butoxy group),
(17) an unsaturated C2 to C22 alkoxy group (such as a
vinyloxy group, an allyloxy group, a 1-propenyloxy group, an
isopropenyloxy group, an ethynyloxy group, a 1-propynyloxy
group, a 2-propynyloxy group, a 1-butynyloxy group or a
2-butynyloxy group),
(18) a C6 to C14 aryloxy group (such as a phenoxy group,
a 1-naphthyloxy group or a 2-naphthyloxy group),
(19) a C7 to C22 aralkyloxy group (such as a benzyloxy group,
a phenethyloxy group, a 3-phenylpropyloxy group, a
4-phenylbutyloxy group, a 1-naphthylmethyloxy group or a
2-naphthylmethyloxy group)
(20) a 5- to 14-membered ring heteroaralkyloxy group (such
as a thienylmethyloxy group, a furylmethyloxy group, a
pyridylmethyloxy group, a pyridazinylmethyloxy group, a
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pyrimidinylmethyloxy group or a pyrazinylmethyloxy group)
(21) a 5- to 14-membered ring heteroaryloxy group (such
as a thienyloxy group, a furyloxy group, a pyridyloxy group,
a pyridazyloxy group, a pyrimidyloxy group or a pyrazyloxy
group),
(22) an aliphatic Cl to C22 acyl group (such as an acetyl
group, a propionyl group, a butyryl group, an iso-butyryl group,
a valeryl group, an iso-valeryl group, a pivaloyl group, a
caproyl group, a decanoyl group, a lauroyl group, a myristoyl
group, apalmitoyl group, a stearoyl group, an arachidoyl group,
an acrylic group, a propioloyl group, a crotonoyl group, an
iso-crotonoyl group, an oleoyl group or linolenoyl group),
(23) an aromatic C7 to C22 acyl group (such as a benzoyl
group, a 1-naphthoyl group or a 2-naphthoyl group),
(24) an aliphatic C2 to C22 acyloxy group (such as an
acetoxy group, a propionyloxy group or an acryloxy group),
(25) a C2 to C22 alkoxycarbonyl group (such as a
methoxycarbonyl group, an ethoxycarbonyl group, a
n-propoxycarbonyl group, an iso-propoxycarbonyl group, a
n-butoxycarbonyl group, an iso-butoxycarbonyl group, a
sec-butoxycarbonyl group or a tert-butoxycarbonyl group),
(26) an unsaturated C3 to C22 alkoxycarbonyl group (such
as a vinyloxycarbonyl group, an allyloxycarbonyl group, a
1-propenyloxycarbonyl group, an isopropenyloxycarbonyl group,
a propargyloxycarbonyl group or a 2-butynyloxycarbonyl group),
(27) a C1 to C22 alkylthio group (such as a methylthio group,
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an ethylthio group, a n-propylthio group or an iso-propylthio
group),
(28) a Cl to C22 alkylsulfinyl group (such as a
methylsulfinyl group, an ethylsulfinyl group, a
n-propylsulfinyl group or an iso-propylsulfinyl group),
(29) a Cl to C22 alkylsulfonyl group (such as a
methylsulfonyl group, an ethylsulfonyl group, a
n-propylsulfonyl group or an iso-propylsulfonyl group),
(30) a C6 to C14 arylsulfonyl group (such as a
benzenesulfonyl group, a 1-naphthalenesulfonyl group or a
2-naphthalenesulfonyl group),
(31) a Cl to C22 alkylsulfonyloxy group (such as a
methylsulfonyloxy group, an ethylsulfonyloxy group, a
n-propylsulfonyloxy group or an iso-propylsulfonyloxy group),
and
(32) a carbamoyl group.
In addition, the (9) amino group and (32) carbamoyl group
mentioned as the substituent in "that may have substituent (s) "
may further be substituted by one or two Cl to C22 alkyl groups,
unsaturated C2 to C22 alkyl groups or C6 to C14 aryl groups.
"The halogen atom" used herein means a fluorine atom, a
chlorine atom, a bromine atom or an iodine atom.
According to the production method of the present
invention that goes through the tin (IV) -containing macrolide
derivative represented by the above-mentioned Formula (3) as
the production intermediate, from the 12-membered ring
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macrolide compound being a raw material represented by Formula
(1), the 7-position urethane derivative that is represented by
Formula (5) and has an excellent antitumor effect can be
produced in a short production process with a good efficiency.
Reaction process 1
Process of producing the tin (IV)-containing macrolide
derivative of Formula (3) by reacting (diols at 6- and
7-positions of) the macrolide derivative of Formula (1) with
the dialkyl tin (IV) oxide of Formula (2) (Formula (1) + Formula
(2) ~ Formula (3) )
R3, R16 and R21 in the macrolide derivative of Formula (1)
being a raw material, independently of one another, are
preferably a hydrogen atom, a 1-ethoxyethyl group, a
tert-butyldimethylsilyl group or a triethylsilyl group, more
preferably a hydrogen atom or a triethylsilyl group.
As an alkyl group represented by Rsnl or Rsn2 in the dialkyl
tin (IV) oxide of Formula (2), each independently is preferably
an alkyl group having 1 to 10 carbon atoms such as a methyl group,
an ethyl group, a n-butyl group, a n-octyl group or a n-decyl
group, more preferably a n-butyl group or a n-octyl group.
On the solvent used in the reaction process 1, no limitation
is imposed, but inert solvents that do not easily react with
the raw material are desirable. Examples thereof may include
alcohols such as methanol or ethanol, ethers such as
tetrahydrofuran, diethyl ether, diisopropyl ether, methyl
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tert-butyl ether, cyclopentyl methyl ether, dioxane or
dimethoxyethane, halogenated hydrocarbons such as
dichloromethane, chloroform, carbon tetrachloride or
1,2-dichloroethane, hydrocarbons such as hexane, benzene or
toluene, ketones such as acetone or methyl ethyl ketone,
nitriles such as acetonitrile, amides such as
N,N-dimethylformamide, N,N-dimethylacetamide,
N-methyl-2-pyridone or hexamethylphosphorylamide, and
sulfoxides such as dimethyl sulfoxide, wherein acetonitrile,
tetrahydrofuran, dioxane, toluene and the like are preferable.
The reaction temperature of the reaction process 1 is from
room temperature to refluxing temperature under heating of the
solvent to be used, and is preferably 40 to 120 C. The reaction
time is preferably 10 minutes to one day, more preferably 30
minutes to 5 hours.
In the reaction process 1, dialkyl tin (IV) oxide is used
preferably at 0.3 to 5 equivalents relative to the macrolide
derivative of Formula (1), more preferably at 0.5 to 1.5
equivalents. Upon the reaction, the reaction is preferably
performed at the refluxing temperature of the solvent to be used,
and, by removing the solvent from the reaction system under
reduced pressure, the reaction progresses more effectively.
After the completion of the reaction, the solvent is
distilled off under reduced pressure, which may be further
purified, if necessary, by an ordinary method such as column
chromatography, thin-layer chromatography, crystallization or
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the like. However, usually, after the completion of the
reaction, a carbamoylating reaction below is continuously
performed in the same reaction chamber.
Meanwhile, among macrolide derivatives of Formula (1), the
derivative in which R3, R16 and R21 are hydrogen atoms may be
produced by the isolation and collectionfrom a culture solution
of Streptomyces sp, Mer-11107 (FERM BP-7812) (see WO-A
2002/060890), or it may also be produced by hydrolyzing the
7-position acetyl group of the macrolide derivative represented
by Formula (A) that can be collected in a larger amount (see
WO-A 2003/099813 and WO-A 2006/126723). It is also possible
to perform a publicly known reaction for introducing a
protective group of hydroxyl group for the macrolide derivative
represented by Formula (A), and further to hydrolyze a
7-position acetyl group to produce the macrolide derivative of
Formula (1) in which the protective group has been introduced.
The hydrolysis of the 7-position acetyl group can be
performed according to the method described in a document (see
T. W. Greene, Protective Groups in Organic Synthesis, John Wiley
& Sons, (1981)) or methods pursuant to it, for example, by
hydrolysis using acid or base, or chemical reduction using a
hydrogenated metal complex or the like. As the base, for
example, alkali metal hydroxides such as sodium hydroxide,
potassium hydroxide or lithium hydroxide, alkali metal
carbonates such as potassium carbonate, sodium carbonate,
sodium hydrogencarbonate or cesium carbonate, guanidine, and
22
CA 02692644 2010-01-05
guanidine nitrate are preferable, and a mixed salt of guanidine
and guanidine nitrate is particularly preferable. The mixed
salt of guanidine and guanidine nitrate may be used at 1.0 to
2.0 equivalents relative to a protective compound of the
hydroxyl group of Formula (A), but, preferably, 1.0 to 1.2
equivalents are favorable. On the solvent used in the process,
no particular limitation is imposed, but an inert solvent that
dissolves the raw material to some extent and that does not
easily react with the raw material is desirable. Examples
thereof include water, alcohol-based solvents such as methanol,
ethanol, isopropanol or tert-butanol, ether-based solvents
such as tetrahydrofuran, diethyl ether, diisopropyl ether,
dioxane, or 1,2-dimethoxyethane, nitrile-based solvents such
as acetonitrile, amide-based solvents such as
N,N-dimethylformamide, N,N-dimethylacetamide,
N-methyl-2-pyridone or hexamethylphosphorylamide,
sulfoxide-based solvents such as dimethyl sulfoxide, or mixed
solvents thereof. Among these, alcohol-based solvents such as
methanol or ethanol are preferable. On the reaction
temperature, no particular limitation is imposed, but a
temperature of 0 to 60 C is preferable, 10 to 30 C is more
preferable, and 24.0 to 25.0 C is furthermore preferable. The
reaction time may be 1 to 24 hours, but 3 to 10 hours is
preferable.
Reaction process 2
23
CA 02692644 2010-01-05
Process of reacting the tin (IV)-containing macrolide
derivative of Formula (3) with a carbamoyl halide derivative
of Formula (4) to produce the macrolide derivative of Formula
(5) (Formula (3) + Formula (4) ~ Formula (5) )
In the carbamoyl halide derivative of Formula (4), as X,
above-described halogen atoms are included, and a chlorine atom
or a bromine atom is preferable. As Rnl and Rn2, when
exemplifying them in the amine form in which Rnl or Rn2 is bonded
to a nitrogen atom, ones described below can be included.
Examples thereof include methylamine, ethylamine,
propylamine, butylamine, octylamine, decylamine,
cyclopropylamine, cyclopentylamine, cyclohexylamine,
dimethylamine, diethylamine, ethylmethylamine,
ethylenediamine, 1,3-propanediamine, 1,4-butanediamine,
N,N-dimethylethylenediamine,
N,N-dimethyl-l,3-propanediamine,
N,N-dimethyl-1,4-butanediamine, N,N-diethylethylenediamine,
N,N-diethyl-l,3-propanediamine,
N,N-diethyl-l,4-butanediamine,
N,N,N'-trimethylethylenediamine,
N,N,N'-trimethyl-l,3-propanediamine,
N,N,N'-trimethyl-l,4-butanediamine,
N-ethyl-N',N'-dimethylethylenediamine,
N-ethyl-N',N'-dimethyl-l,3-propanediamine,
N-ethyl-N',N'-dimethyl-l,4-butanediamine,
N,N,N'-triethylethylenediamine,
24
CA 02692644 2010-01-05
N,N,N'-triethyl-1,3-propanediamine,
N,N,N'-triethyl-l,4-butanediamine,
N,N-diethyl-N'-methylethylenediamine,
N,N-diethyl-N'-methyl-1,3-propanediamine,
N,N-diethyl-N'-methyl-1,4-butanediamine,
N,N'-dimethyl-N-phenylethylenediamine,
N,N'-dimethyl-N-phenyl-l,3-propanediamine,
N-benzyl-N,N'-dimethylethylenediamine,
N-benzyl-N,N'-dimethyl-1,3-propanediamine, morpholine,
thiomorpholine, thiomorpholine-S-oxide,
thiomorpholine-S,S-dioxide, pyrrolidine, piperidine,
piperazine, homopiperazine, 4-hydroxypiperidine,
4-methoxypiperidine, 1-methylpiperazine, 1-ethylpiperazine,
1-propylpiperazine, 1-butylpiperazine, 1-isopropylpiperazine,
1-cyclobutylpiperazine, 1-cyclopentylpiperazine,
1-cyclohexylpiperazine, 1-cycloheptylpiperazine,
1-cyclooctylpiperazine, 1-(cyclopropylmethyl)piperazine,
1-benzylpiperazine, 1-methylhomopiperazine,
1-ethylhomopiperazine, 1-(2-aminoethyl)pyrrolidine,
1-(2-(N-methylamino)ethyl)pyrrolidine,
1-(3-aminopropyl)pyrrolidine,
1-(3-(N-methylamino)propyl)pyrrolidine,
1-(2-aminoethyl)piperidine,
1-(2-(N-methylamino)ethyl)piperidine,
1-(3-aminopropyl)piperidine,
1-(3-(N-methylamino)propyl)piperidine,
CA 02692644 2010-01-05
4-(2-aminoethyl)morpholine,
4-(2-(methylamino)ethyl)morpholine,
4-(3-aminopropyl)morpholine,
4-(3-(N-methylamino)propyl)morpholine,
1-(2-aminoethyl)-4-methylpiperazine,
1-(3-aminopropyl)-4-methylpiperazine,
1-(3-(N-methylamino)propyl)-4-methylpiperazine,
1-amino-4-methylpiperidine,
1-methylamino-4-methylpiperidine,
1-ethyl-4-(N-methylamino)piperidine,
1-methylamino-4-propylpiperidine,
1-butyl-4-(N-methylamino)piperidine,
1-(N,N-dimethylamino)piperidine,
1-(N,N-diethylamino)piperidine,
4-(pyrrolidin-l-yl)piperidine, 4-(piperidin-l-yl)piperidine,
3-aminoquinuclidine, 3- (N-methylamino) quinuclidine, aniline,
N-methylaniline, N,N-dimethyl-p-phenylenediamine,
N,N,-dimethyl-m-phenylenediamine,
N,N,N'-trimethyl-p-phenylenediamine,
N,N,N'-trimethyl-m-phenylenediamine, 1-naphthylamine,
2-naphthylamine, benzylamine, N-methylbenzylamine,
phenethylamine, N-methylphenethylamine, 2-picolylamine,
3-picolylamine, 4-picolylamine, N-methyl-2-picolylamine,
N-methyl-3-picolylamine, N-methyl-4-picolylamine,
2,5-diazabicyclo[2.2.1]heptane,
2-methyl-2,5-diazabicyclo[2.2.1]heptane,
26
CA 02692644 2010-01-05
3,8-diazabicyclo[3.2.1]octane,
1,4-diazabicyclo[4.3.0]nonane, and the like. Among these,
1-methylpiperazine, 1-isopropylpiperazine,
1-cyclohexylpiperazine, 1-cycloheptylpiperazine and
N,N-diethyl-N'-methylethylenediamine are preferable.
The carbamoyl halide derivative of Formula (4) can be
obtained by reacting the amine exemplified as an amine formed
by bonding Rnl and Rn2 to a nitrogen atom, with a
chlorocarbonylating agent such as triphosgene or phosgene in
an inert solvent. On a solvent to be used for the reaction,
no particular limitation is imposed, but an inert solvent that
does not easily react with the raw material is desirable.
Examples thereof may include ethers such as tetrahydrofuran,
diethyl ether, diisopropyl ether, methyl tert-butyl ether,
cyclopentyl methyl ether, dioxane or dimethoxyethane,
halogenated hydrocarbons such as dichloromethane, chloroform,
carbon tetrachloride or 1,2-dichloroethane, hydrocarbons such
as hexane, benzene or toluene, ketones such as acetone or methyl
ethyl ketone, and nitriles such as acetonitrile, and methyl
tert-butyl ether, acetonitrile, tetrahydrofuran, dioxane,
toluene, chloroform and the like are preferable.
The reaction time of the amine and chlorocarbonylating
agent is preferably 10 minutes to 5 days, more preferably 12
to 36 hours. The reaction temperature is -20 C to the boiling
point of a solvent to be used, preferably -5 to 40 C.
As the reaction ratio of the amine and chlorocarbonylating
27
CA 02692644 2010-01-05
agent, the use of 0.8 to 10 equivalents of the
chlorocarbonylating agent relative to one equivalent of the
amine is preferable, and the use of 0. 9 to 2 equivalents is more
preferable. After the completion of the reaction, the intended
carbamoyl halide derivative is collected from the reaction
mixture according to an ordinary method. For example, when an
insoluble matter exists, the derivative can be obtained by
appropriately performing filtration and distilling off the
solvent under reduced pressure, or by diluting off the reaction
mixture with an organic solvent such as methyl tert-butyl ether,
toluene or ethyl acetate and washing the same, drying the
organic layer over anhydrous sodium sulfate or the like, and,
after that, distilling off the solvent, which may further be
purified, if necessary, by an ordinary method such as column
chromatography, thin layer chromatography, high-performance
liquid chromatography or crystallization.
As the carbamoyl halide derivative of Formula (4), the
derivative represented by Formula (4-1)
0
Rni', N'1~ X
Rn2' (4-1 )
(where, Rnl' and Rn2' represent a 3- to 14-membered non-aromatic
heterocyclic group formed with a nitrogen atom that is bonded
together (the 3- to 14-membered non-aromatic heterocyclic group
28
CA 02692644 2010-01-05
may have substituent(s)), and X represents a halogen atom) is
preferable, and, in particular, the carbamoylhalide derivative
represented by Formula (4-2) below is an extremely useful
intermediate for effectively producing an active macrolide
derivative of Formula (5).
1ci
NJ
(4-2)
On the solvent used in the reaction process 2, no particular
limitation is imposed, but an inert solvent that does not easily
react with the tin (IV)-containing macrolide derivative of
Formula (3) and the carbamoyl halide derivative of Formula (4)
is desirable. Examples thereof include ethers such as
tetrahydrofuran, diethyl ether, diisopropyl ether, methyl
tert-butyl ether, cyclopentyl methyl ether, dioxane or
dimethoxyethane, halogenated hydrocarbons such as
dichloromethane, chloroform, carbon tetrachloride or
1,2-dichloroethane, hydrocarbons such as hexane, benzene or
toluene, ketones such as acetone or methyl ethyl ketone,
nitriles such as acetonitrile, amides such as
N,N-dimethylformamide, N,N-dimethylacetamide,
N-methyl-2-pyridone or hexamethylphosphorylamide, and
29
CA 02692644 2010-01-05
sulfoxides such as dimethylsulfoxide. Acetonitrile,
tetrahydrofuran, dioxane, toluene and the like are preferable.
The reaction temperature of the reaction process 2 is 0 C
to the refluxing temperature under heating of the solvent to
be used, and is preferably 5 to 90 . The reaction time is
preferably 10 minutes to 5 days, more preferably 30 minutes to
48 hours.
In the reaction process 2, the carbamoyl halide derivative
of Formula (4) is used preferably at 1 to 10 equivalents relative
to the tin (IV) -containing macrolide derivative of Formula (3),
more preferably 1 to 4 equivalents.
In the reaction process 2, when the reaction rate is low
only by the addition of the carbamoyl halide derivative of
Formula (4), it is possible to heighten the reaction rate by
heating or adding a base, or by both operations. As the base,
organic bases or the like are included, and, for example,
diisopropylethylamine, 4-dimethylaminopyridine,
triethylamine, pyridine, 2, 6-lutidine or the like is preferably
used.
In order to check the completion of the reaction, a part
of the reaction liquid is suspended in acetonitrile, which is
filtrated and then subjected to HPLC analysis, and the instant,
when the area dimension of the macrolide of Formula (5), or of
a macrolide derivative having a protective group of hydroxyl
group at 3-position, 16-position and/or 21-position becomes
constant, is determined to be the completion of the reaction.
CA 02692644 2010-01-05
After the completion of the reaction, where necessary,
that is, when R3, R16 and/or R21 is a protective group, the
obtained reaction product is subjected to an elimination
reaction of the protective group of hydroxyl group to give the
macrolide derivative of Formula (5).
The process is achieved by performing a deprotection
treatment as shown below for the obtained compound in an inert
solvent. The deprotection reaction of the protective group of
hydroxyl group differs depending on the kind of the protective
group, and can be performed by a method well known in synthetic
organic chemistry.
For example, the deprotection of respective hydroxyl
groups such as 1-ethoxyethyl, tetrahydropyranyl,
1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,
4-methoxytetrahydrothiopyranyl and
4-methoxytetrahydrothiopyranyl-S,S-dioxide is easily
performed by an acid treatment in an inert solvent. Examples
of acids may include organic acids such as pyridinium p-toluene
sulfonate (PPTS), p-toluene sulfonic acid, camphor sulfonic
acid, acetic acid, trifluoroacetic acid or methane sulfonic
acid, and inorganic acids such as hydrogen chloride, nitric acid,
hydrochloric acid or sulfuric acid. Preferable are, for
example, pyridinium p-toluene sulfonate, p-toluene sulfonic
acid, camphor sulfonic acid and the like. On the solvent to
be used for the reaction, no limitation is imposed, but one that
does not easily react with the raw materials is desirable. For
31
CA 02692644 2010-01-05
example, alcohol-based solvents such as methanol, ethanol,
isopropanol or tert-butanol are preferable, and these and the
above-described inert solvent may also be used in mixture. The
amount of the acid used for the reaction is 0. 5 to 5 equivalents
relative to the macrolide derivative having the protective
group, preferably 1 to 3 equivalents. The reaction time is 10
minutes to 10 days, preferably 1 day to 4 days. The reaction
temperatureis-78 Ctothe ref luxing temperature under heating,
preferably -10 C to 50 C.
When it is protected by other protective groups such as
tert-butyldimethylsilyl, triethylsilyl,
diethylisopropyllsilyl, trimethylsilyl, triisopropylsilyl,
di-tert-butylmethylsilyl and diphenylmethylsilyl, the
deprotection is possible by, for example, a treatment with a
fluorine anion or acid. Examples of the fluorine anion may
include tetrabutylammonium fluoride, hydrogen fluoride,
potassium fluoride, pyridinium hydrogen fluoride and the like,
and examples of the acid may include the above-described organic
acid, inorganic acids and the like. Preferable examples
include acetic acid, formic acid, trifluoroacetic acid,
pyridinium p-toluene sulfonate, camphor sulfonic acid and the
like. On the solvent used for the reaction, no particular
limitation is imposed, but one that does not easily react with
the raw material is desirable, and the above-described inert
solvents are included. For example, tetrahydrofuran, diethyl
ether, water or the like is preferably used. The amount of the
32
CA 02692644 2010-01-05
fluorine anion and the acid used for the reaction are 1 to 5
equivalents and 0.5 to 5 equivalents, respectively, relative
to the macrolide derivative having the protective group,
preferably 1 to 4 equivalents and 0.5 to 3 equivalents,
respectively. The reaction time is 10 minutes to 30 hours,
preferably 1 to 2 hours. The reaction temperature is -78 C to
the refluxing temperature under heating, preferably -10 C to
50 C .
After the completion of the reaction, the intended
macrolide derivative represented by Formula (5) is collected
from the reaction mixture according to an ordinary method. For
example, when an insoluble matter exists, the derivative can
be obtained by appropriately filtering off and distilling off
the solvent under reduced pressure, or by diluting the reaction
mixture with an organic solvent such as ethyl acetate and
washing the same with water, drying the organic layer over
anhydrous sodium sulfate or the like, and, after that,
distilling off the solvent, which may further be purified, if
necessary, by an ordinary method such as column chromatography,
thin layer chromatography, high-performance liquid
chromatography or crystallization.
Examples
Hereinafter, the present invention will be described based
on examples. But, the present invention is not limited to the
embodiments below.
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Example 1
Synthesis of
(8E,12E,14E)-3,6,7,16,21-pentahydroxy-6,10,12,16,20-
pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide
(Reference Example)
OH
OH
OH O
o OH
OH
To a methanol solution (41.3%) of
(8E,12E,14E)-7-acetoxy-6,10,12,16,20-pentamethyl-3,6,16,21-
tetrahydroxy-18,19-epoxytricosa-8,12,14-trien-ll-olide
(1.92 g, 3.47 mmol), methanol (19 ml) was added and stirred,
to which potassium carbonate (0.72 g, 5.21 mmol) was added and
stirred for 1 hour under cooling with water. The reaction
mixture was diluted with ethyl acetate (95 ml ), and washed twice
with a 25% salt solution (50 ml) . The obtained organic layer
was dried over sodium sulfate, filtrated and then concentrated
under reduced pressure to give the crudely purified subject
compound (2.29 g) as white powder.
Example 2
Synthesis of 4-cycloheptylpiperazine carbonyl chloride
(Example)
34
CA 02692644 2010-01-05
O
N'it, CI
GNJ
To a solution of 1-cycloheptylpiperazine 100 mg (0.549
mmol) in methyl-tert-butyl ether (MTBE) 5 ml, triphosgene 162
mg (0.549 mmol) was added and stirred over night under ice
cooling. After the addition, white precipitate was generated.
The reaction solution was diluted with MTBE, and the MTBE
solution was washed twice with saturated sodium bicarbonate
water and was then dried over anhydrous sodium sulfate. The
solvent was removed to give a pale yellow solid 122.8 mg. By
TLC (hexane:ethyl acetate = 2:1), slight impurities were
confirmed, and, therefore, the pale yellow solid was dissolved
again in MTBE, which was washed twice with saturated sodium
bicarbonate water and then dried over anhydrous sodium sulfate.
The solvent was removed to give a white solid of
4-cycloheptylpiperazine carbonyl chloride 100.8 mg (yield:
75.1%).
Rf value 0.57 (TLC; Merck 1.05715, developing solvent;
hexane:ethyl acetate = 2:1)
13C-NMRSpectrum(CDC13r 125MHz) b(ppm) : 148.28, 65. 13, 49. 30, 48. 47,
47.86,46.90,30.01,28.03,25.54.
1H-NMRSpectrum(CDC13,500MHz)b(ppm):1.35-1.60(m,8H),
CA 02692644 2010-01-05
1.64-1.70(m,2H),1.78-1.81(m,2H),2.56(brs,5H),3.61(brs,2H),
3. 70 (brs, 2H)
ESI-MS m/z 245(M+H)+.
Example 3
Synthesis of (8E,12E,14E)-6,7-(dibutylstannylene)dioxy-
6,10,12,16,20-pentamethyl-3,16,21-trihydroxy-18,19-
epoxytricosa-8,12,14-trien-l1-olide (Example)
C4Hg
O--Sn-CqHg
O
OH O
O OH
OH
To a solution of crudely purified
(8E,12E,14E)-3,6,7,16,21-pentahydroxy-6,10,12,16,20-pentame
thyl-18,19-epoxytricosa-8,12,14-trien-ll-olide (0.18 g, 0.35
mmol) in a mixture of tetrahydrofuran (4 ml) and toluene (20
ml) , dibutyl tin (IV) oxide (97. 0 mg, 0. 39 mmol) was added. The
mixture was refluxed under heating for 4 hours (at this time,
the system was set so that the cooled solvent was dehydrated
with calcium chloride and returned to the reaction solution).
After cooling the reaction mixture to room temperature, it was
concentrated under reduced pressure to give the subject
compound as a pale yellow oil.
36
CA 02692644 2010-01-05
1H-NMRSpectrum(CDC13r500MHz)b(ppm):0.88-1.00(16H,m),
1.01-1.78(16H,m),1.12(3H,s),1.64(3H,s),1.77(3H,s),
2.02-2.08(1H,m),2.42-2.58(3H,m),2.74-2.78(1H,m),
2.96-3.00(1H,m),3.45(1H,d,J=10.4Hz),3.62-3.76(3H,m),
5. 11 (1H, d, J=10 . 5Hz ), 5. 27 (1H, dd, J=9 . 7, 15 . 2Hz ),
5.45(1H,dd,J=9.6,15.3Hz),5.85(1H,d,J=15.1Hz),
6.09-6.14(1H,m),6.53(1H,dd,J=11.2,14.9Hz).
Example 4
Synthesis of (8E,12E,14E)-7-
((4-cycloheptylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-
pentamethyl-3,6,16,21-tetrahydroxy-18,19-epoxytricosa-
8,12,14-trien-11-olide (Example)
O
N~O
OH N O OH
O
O OH
OH
The crudely purified ((8E,12E,14E)-6,7-
(dibutylstannylene)dioxy-6,10,12,16,20-pentamethyl-3,16,21-
trihydroxy-18,19-epoxytricosa-8,12,14-trien-l1-olide
obtained in Example 3 was suspended and dissolved in toluene
(9.3 ml), to which triethylamine (0.17 ml, 1.20 mmol) and
4-cycloheptylpiperazine carbonyl chloride (0.17 g, 0.69 mmol)
37
CA 02692644 2010-01-05
were added. The mixture was stirred at 70 to 80 C for 40 hours.
The reaction mixture was cooled to room temperature and
concentrated under reduced pressure and then methanol (10 ml)
was added to form a solution. The solution was measured by HPLC
analysis (Chemicals Evaluation and Research Institute,
L-column ODS, 4. 6 x 250 mm, mobile phase; acetonitrile/ (1. 5 mM
potassium dihydrogen phosphate + 50 mM sodium perchlorate) =
35/65, flow rate; lml/min, detection wavelength; 241nm, column
temperature; a constant temperature near 23 C) to confirm the
subject compound (retention time; 14.6 min, relative purity;
75.90) .
Example 5
Synthesis of (8E,12E,14E)-7-
((4-cycloheptylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-
pentamethyl-3,6,16,21-tetrahydroxy-18,19-epoxytricosa-
8,12,14-trien-ll-olide (Example)
O
NO
N OH
OH O
O
O OH
OH
To crudely purified (8E,12E,14E)-3,6,7,16,21-
pentahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-
38
CA 02692644 2010-01-05
8, 12, 14-trien-11-olide (0.74 g, 1. 4 mmol) in a mixed liquid of
tetrahydrofuran (4 ml) and toluene (15 ml), dioctyl tin (IV)
oxide (0.54 g, 1.5 mmol) was added. The mixture was stirred
at 90 C for 30 minutes. The solution was concentrated (exterior
temperature 90 C) to about 5 ml under reduced pressure, to which
toluene (15 ml) was added and the solution further concentrated
to about 5 ml under reduced pressure (exterior temperature 90 C)
After cooling the solution to room temperature, tetrahydrofuran
(11 ml), 4-dimethylaminopyridine (0.18 g, 1.5 mmol) and
4-cycloheptylpiperazine carbonyl chloride (0.73 g, 3.0 mmol)
were added. The mixture was stirred at room temperature for
25 hours. To the reaction mixture, toluene (12 ml) and
tetrahydrofuran (4 ml) were added. The mixture was washed with
a 5% ammonium chloride aqueous solution (15 ml) twice, and with
25% salt water (15 ml) . The obtained organic layer was dried
over sodium sulfate, filtrated and then concentrated under
reduced pressure to give a crudely purified subject compound
(0.87 g, 1.2 mmol) as a yellow product (5.06 g).
Example 6
Synthesis of (8E,12E,14E)-7-((4-methylpiperazin-1-yl)-
carbonyl)oxy-6,10,12,16,20-pentamethyl-3,6,16,21-
tetrahydroxy-18,19-epoxytricosa-8,12,14-trien-ll-olide
(Example)
39
CA 02692644 2010-01-05
O
N~O
r H
NJ O
OH O
O
O O H
OH
The subject compound (colorless oil) was synthesized in
the same manner as Example 4, except for using
4-methylpiperazine carbonyl chloride hydrochloride in place of
4-cycloheptylpiperazine carbonyl chloride.
1H-NMRSpectrum(CD30D,400MHz)b(ppm):0.89(3H,d,J=6.8Hz),0.90
(3H,d,J=6.8Hz),0.94(3H,t,J=7.6Hz),1.19-1.28(4H,m),1.32-1.68
(10H,m),1.77(3H,d,J=0.8Hz),1.86(1H,dd,J=5.6,14.4Hz),2.30
(3H,S),2.36-2.44(4H,m),2.50-2.64(3H,m),2.66(1H,dd,J=2.4,
8.0Hz),2.89(1H,dt,J=2.4,6.0Hz),3.38-3.70(5H,m),3.75-3.81
(1H,m), 4.93(1H,d,J=10.OHz),5.06(1H,d,J=10.8Hz),5.57 (1H,dd,
J=10.0,15.2Hz),5.71(1H,dd,J=9.6,15.2Hz),5.87(1H,d,J=15.2Hz),
6.13(1H,d,J=10.8Hz),6.53(1H,dd,J=11.2,15.2Hz)
ESI-MS m/z 637(M+H)+.
Example 7
Synthesis of (8E,12E,14E)-3,6,7,16,21-pentahydroxy-
6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-
trien-ll-olide (Reference Example)
CA 02692644 2010-01-05
OH
OH
OH O
O
O OH
OH
To a methanol solution (100.3 g) of
(8E,12E,14E)-7-acetoxy-6,10,12,16,20-pentamethyl-3,6,16,21-
tetrahydroxy-18,19-epoxytricosa-8,12,14-trien-11-olide
(30. 0 g) , methanol (306 ml) was added. The mixture was stirred,
to which potassium carbonate (0.72 g, 5.21 mmol) was added. The
mixture was stirred under room temperature for 4.5 hours. The
reaction mixture was diluted with ethyl acetate (1529 ml) , which
was washed twice with 25% salt water (917 ml). The obtained
organic layer was dried over sodium sulfate, filtrated and then
concentrated under reduced pressure. To the concentrated
product, acetonitrile (305 ml) was added and concentrated again
under reduced pressure, to the concentrated product
acetonitrile (30 ml) and tetrahydrofuran (30 ml) were added to
give a solution (90.5 g, content 25.1 g) of the crudely purified
subject compound.
Example 8
Synthesis of (8E,12E,14E)-7-
((4-cycloheptylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-
pentamethyl-3,6,16,21-tetrahydroxy-18,19-epoxytricosa-
8,12,14-trien-ll-olide (Example)
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O
N~O
NJ
OH O OH
O
O OH
OH
To crudely purified (8E, 12E, 14E) -3, 6, 7, 16, 21-
pentahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-
8,12,14-trien-11-olide (25.1 g, 49.2 mmol) in a mixed liquid
of tetrahydrofuran (258 ml) and toluene (203 ml), dioctyl tin
(IV) oxide (13.18 g, 36.5 mmol) was added, and the solution
concentrated with heating to 100 C for 30 minutes with stirring.
Further, after cooling it to 40 C, tetrahydrofuran (430 ml),
4-dimethylaminopyridine (5.5 g, 44.9 mmol) and
4-cycloheptylpiperazine carbonyl chloride (27.5 g, 112 mmol)
were added. The mixture was stirred at 40 C for 3 hours. To
the reaction mixture, toluene (287 ml) and tetrahydrofuran (287
ml) were added, the mixture was washed with a 5% ammonium
chloride aqueous solution (573 ml) twice and with 25% salt water
(573 ml). The obtained organic layer was dried over sodium
sulfate, filtrated and then concentrated under reduced pressure
to give a toluene solution (278 g, content 27.7 g) of the crudely
purified subject compound.
Example 9
Purification of (8E,12E,14E)-7-
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((4-cycloheptylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-
pentamethyl-3,6,16,21-tetrahydroxy-18,19-epoxytricosa-
8,12,14-trien-ll-olide (Example)
O
N~O
N.J
OH O OH
O O H
OH
To the toluene solution (278 g) of the crudely purified
(8E,12E,14E)-7-((4-cycloheptylpiperazin-1-yl)carbonyl)oxy-
6,10,12,16,20-pentamethyl-3,6,16,21-tetrahydroxy-18,19-
epoxytricosa-8,12,14-trien-11-olide (27.7 g) obtained in
Example 8, methanol (420 ml) was added. The mixture was stirred
at room temperature for 30 minutes, to which methanol (580 ml)
was dropped under -10 C and the mixture was stirred for
additional 1 hour at that temperature. The obtained suspension
was filtrated by using a filtration auxiliary agent (Roka Help,
Mitsui Mining And Smelting Company, Limited) . The resultant
was then subjected to washing with methanol (138 ml) to give
a methanol solution (1500 ml) of (8E,12E,14E)-7-
((4-cycloheptylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-
pentamethyl-3,6,16,21-tetrahydroxy-18,19-epoxytricosa-
8,12,14-trien-ll-olide (28.3 g). The obtained methanol
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solution (500 ml) of the crude product (10.0 g) of the subject
compound was filtrated with an activated charcoal filter
(ZetaCarbon, 90 mm~, CUNO) . The resultant was then subjected
to washing with methanol (1000 ml) . The filtrate and washing
solution were mixed together and concentrated under reduced
pressure to give a crude product of the subject compound
(content 9.6 g) . By the same operation, the remaining methanol
solutions of the crude product were treated (total three batches,
content 27.6 g). The obtained crude product of the subject
compound was diluted with ethyl acetate (94 ml) and was
filtrated by using silica gel (139 g, Chromatorex NH-DM2035,
FUJI SILYSIA CHEMICAL LTD.) and then subjected to washing with
methanol:ethyl acetate = 3:97 (2770 ml). The filtrate and
washing solution were mixed together and concentrated under
reduced pressure to give the crude product of the subject
compound 42. 9 g (content 27.4 g) . To the obtained crude product
of the subject compound (content 8. 2 g) , chloroform (58 ml) was
added. The mixture was purified by using silica gel column
chromatography (Chromatorex NH-DM2035, FUJI SILYSIA CHEMICAL
LTD., elution solvents were 1) ethyl acetate:heptane = 70:30,
2) ethyl acetate:heptane = 85:15, 3) ethyl acetate, 4)
methanol:ethyl acetate = 3:97, in this order). The purified
fraction was collected and concentrated under reduced pressure
to give (8E,12E,14E)-7-((4-cycloheptylpiperazin-1-yl)-
carbonyl)oxy-6,10,12,16,20-pentamethyl-3,6,16,21-
tetrahydroxy-18,19-epoxytricosa-8,12,14-trien-11-olide
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(content 7.9 g).
1H-NMRSpectrum (CD3OD, 400MHz ) b(ppm) : 0. 89 (3H, d, J=6. 8Hz) , 0. 90
(3H,d,J=6.8Hz),0.94(3H,t,J=7.2Hz),1.10-1.77(24H,m), 1.77
(3H,brs),1.79-1.90(3H,m),2.42-2.74(9H,m),2.85-2.92(1H,m),
3.36-3.70(SH,m),3.72-3.84(1H,m), 4.92(1H,dd,J=9.6,15.2Hz),
5.71(1H,dd,J=9.0,15.2Hz), 5.87(1H,d,J=15.2Hz),
6. 13 (1H, d, J=11. 2Hz ), 6. 52 (1H, dd, J=11. 2, 15 . 2Hz )
ESI-MS m/z 719(M+H)+
