U.S. patent application number 17/567582 was filed with the patent office on 2022-04-21 for ointment containing an oxazole compound.
This patent application is currently assigned to OTSUKA PHARMACEUTICAL CO., LTD.. The applicant listed for this patent is OTSUKA PHARMACEUTICAL CO., LTD.. Invention is credited to Naohiko KANAI, Noriyuki KOYAMA, Kengo MATSUMOTO, Hitoshi MATSUSHITA, Yoshihiro MURAKAMI, Minoru OKADA, Yohei YUKI.
Application Number | 20220117944 17/567582 |
Document ID | / |
Family ID | 1000006066185 |
Filed Date | 2022-04-21 |
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United States Patent
Application |
20220117944 |
Kind Code |
A1 |
MURAKAMI; Yoshihiro ; et
al. |
April 21, 2022 |
OINTMENT CONTAINING AN OXAZOLE COMPOUND
Abstract
An ointment is provided. The ointment stably comprises an
oxazole compound that has specific inhibitory activity against PDE4
and that is represented by the following formula (11). The ointment
can be efficiently absorbed into the skin. ##STR00001##
Inventors: |
MURAKAMI; Yoshihiro;
(Osaka-shi, JP) ; MATSUSHITA; Hitoshi; (Osaka-shi,
JP) ; MATSUMOTO; Kengo; (Osaka-shi, JP) ;
OKADA; Minoru; (Osaka-shi, JP) ; YUKI; Yohei;
(Osaka-shi, JP) ; KOYAMA; Noriyuki; (Osaka-shi,
JP) ; KANAI; Naohiko; (Osaka-shi, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OTSUKA PHARMACEUTICAL CO., LTD. |
Tokyo |
|
JP |
|
|
Assignee: |
OTSUKA PHARMACEUTICAL CO.,
LTD.
Tokyo
JP
|
Family ID: |
1000006066185 |
Appl. No.: |
17/567582 |
Filed: |
January 3, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16782259 |
Feb 5, 2020 |
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17567582 |
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16064618 |
Jun 21, 2018 |
10588893 |
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PCT/JP2016/088843 |
Dec 27, 2016 |
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16782259 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/06 20130101; A61K
47/44 20130101; A61K 31/421 20130101; A61P 17/04 20180101; C07D
263/32 20130101 |
International
Class: |
A61K 31/421 20060101
A61K031/421; C07D 263/32 20060101 C07D263/32; A61P 17/04 20060101
A61P017/04; A61K 9/06 20060101 A61K009/06; A61K 47/44 20060101
A61K047/44 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 28, 2015 |
JP |
2015-256784 |
Claims
1. An ointment comprising an oxazole compound represented by the
following formula (11): ##STR00063##
2. The ointment according to claim 1, comprising the oxazole
compound dissolved in a base component.
3. The ointment according to claim 2, wherein the base component
comprises a solvent for dissolving the oxazole compound in the
solvent, and an ointment base for dispersing or dissolving the
solvent in the ointment base.
4. The ointment according to claim 3, wherein the ointment base
comprises a hydrocarbon.
5. The ointment according to claim 3, wherein the solvent comprises
a polar compound that is a liquid at room temperature.
6. The ointment according to claim 3, wherein the ointment base is
an ointment base for dispersing the solvent in the ointment base,
and the solvent in the form of droplets, in which the oxazole
compound is dissolved, is dispersed in the ointment base.
7. The ointment according to claim 3, wherein the ointment base
comprises at least beeswax.
8. The ointment according to claim 7, wherein the beeswax is not
chemically bleached.
9. A method for treatment and/or prevention of eczema and
dermatitis, comprising applying the ointment according to claim 1
to a subject in need thereof.
10. A method of producing an oxazole compound represented by the
following formula (11): ##STR00064## the method comprising the
following reaction scheme: ##STR00065##
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/782,259 filed Feb. 5, 2020, which is a continuation of U.S.
application Ser. No. 16/064,618 filed Jun. 21, 2018, now U.S. Pat.
No. 10,588,893, which is a National Stage of International
Application No. PCT/JP2016/088843 filed Dec. 27, 2016, claiming
priority based on Japanese Patent Application No. 2015-256784 filed
Dec. 28, 2015. The entire disclosures of the prior applications are
incorporated herein by reference.
TECHNICAL FIELD
[0002] The present invention relates to an ointment comprising an
oxazole compound.
BACKGROUND ART
[0003] PTL 1 and 2 report an oxazole compound having specific
inhibitory activity against phosphodiesterase 4 (PDE4) and a method
for producing the oxazole compound. PDE4 is predominant in
inflammatory cells. Inhibition of PDE4 increases intracellular cAMP
levels, and increased cAMP levels down-regulate inflammatory
response through expression regulation of TNF-.alpha., IL-23, or
other inflammatory cytokines. Increases in cAMP levels also
increase anti-inflammatory cytokines, such as IL-10. Thus, the
oxazole compound is thought to be suitable for use as an
anti-inflammatory agent. For example, the oxazole compound is
thought to be useful to reduce or eliminate eczema or dermatitis,
including atopic dermatitis.
[0004] However, so far there has been no ointment that stably
contains an oxazole compound having specific inhibitory activity
against PDE4 and that can be efficiently absorbed into the
skin.
CITATION LIST
Patent Literature
[0005] [PTL 1] WO2007/058338 Pamphlet (JP2009-515872A)
[0006] [PTL 2] WO2014/034958 Pamphlet (JP2015-528433A)
SUMMARY OF INVENTION
Technical Problem
[0007] An object of the present invention is to provide an ointment
that stably comprises an oxazole compound having specific
inhibitory activity against PDE4 and that can be efficiently
absorbed into the skin.
Solution to Problem
[0008] The present inventors found that dissolving a specific
oxazole compound, among oxazole compounds having specific
inhibitory activity against PDE4, in a specific solvent and
dissolving or dispersing the resulting solution in a base material
can provide an ointment that stably contains the specific oxazole
compound and that can be efficiently absorbed into the skin. The
inventors further made modification and completed the present
invention.
[0009] Specifically, the present invention encompasses, for
example, the following subject matters.
Item 1. An ointment comprising an oxazole compound represented by
the following formula (11):
##STR00002##
Item 2. The ointment according to Item 1, comprising the oxazole
compound dissolved in a base component. Item 3. The ointment
according to Item 2, wherein the base component comprises a solvent
for dissolving the oxazole compound in the solvent, and an ointment
base for dispersing or dissolving the solvent in the ointment base.
Item 4. The ointment according to Item 3, wherein the ointment base
comprises a hydrocarbon (preferably, at least one hydrocarbon
selected from the group consisting of petrolatum, paraffin, wax,
and beeswax). Item 5. The ointment according to Item 3 or 4,
wherein the solvent comprises a polar compound that is a liquid at
room temperature (preferably, at least one member selected from the
group consisting of ethylene carbonate, propylene carbonate, benzyl
alcohol, triacetin, N-methylpyrrolidone, diethyl sebacate,
diisopropyl sebacate, diethyl adipate, diisopropyl adipate,
isostearyl alcohol, and isopropyl myristate). Item 6. The ointment
according to any one of Items 3 to 5, wherein the ointment base is
an ointment base for dispersing the solvent in the ointment base,
and the solvent in the form of droplets, in which the oxazole
compound is dissolved, is dispersed in the ointment base. Item 7.
The ointment according to any one of Items 3 to 6, wherein the
ointment base comprises at least beeswax. Item 8. The ointment
according to Item 7, wherein the beeswax is not chemically
bleached. Item 9. The ointment according to any one of Items 1 to
8, for use in the treatment and/or prevention of eczema and
dermatitis (preferably atopic dermatitis). Item 10. An ointment
comprising: [0010] (I) an oxazole compound represented by formula
(11), [0011] (II) a solvent comprising at least one member selected
from the group consisting of ethylene carbonate, propylene
carbonate, benzyl alcohol, and triacetin, and [0012] (III) beeswax,
wherein component (II) in the form of droplets, in which component
(I) is dissolved, is dispersed in component (III), and the droplets
have a mean particle size of 100 .mu.m or less. Item A. A method
for producing a compound represented by formula (3)
##STR00003##
[0012] wherein X.sup.1 represents halogen, and R.sup.1 represents
an alkali metal or lower alkyl, the method comprising: [0013] (a)
reacting a compound represented by formula (1a) with a compound
represented by formula X.sup.1CF.sub.2COOR.sup.1 to produce a
compound represented by formula (2); and [0014] (b) oxidizing the
compound represented by formula (2) to produce a compound
represented by formula (3). Item B. A method for producing a
compound represented by formula (3)
##STR00004##
[0014] wherein X.sup.2 represents halogen, the method comprising:
[0015] (a) reacting a compound represented by formula (1b) with a
compound represented by formula X.sup.2CH(CH.sub.3).sub.2 to
produce a compound represented by formula (2), and [0016] (b)
oxidizing the compound represented by formula (2) to produce a
compound represented by formula (3).
Advantageous Effects of Invention
[0017] The ointment according to the present invention stably
contains an oxazole compound having specific inhibitory activity
against PDE4, and the ointment can be efficiently absorbed into the
skin.
DESCRIPTION OF EMBODIMENTS
[0018] The ointment according to the present invention comprises a
specific oxazole compound, which is preferably dissolved in a base
component. The oxazole compound can be contained in an ointment as
an active component. The base component as used here encompasses a
solvent for dissolving the oxazole compound in the solvent, and one
or more other ointment bases. The ointment base is preferably an
ointment base in which the solvent can be dispersed or
dissolved.
[0019] In other words, the ointment according to the present
invention comprises (I) a specific oxazole compound, which is
preferably dissolved in a base component, and the base component
includes (II) a solvent for dissolving the oxazole compound in the
solvent and (III) an ointment base.
[0020] More preferably, the ointment according to the present
invention is an ointment wherein component (II) in the form of
droplets, in which component (I) is dissolved, is dissolved or
dispersed in component (III).
[0021] Examples of oxazole compound (I) include compounds
represented by the following formulae (11) and (11a) to (11s). In
particular, the compound represented by formula (11) is
preferable.
##STR00005##
TABLE-US-00001 TABLE 1 Formula Number Structural Formula 11a
##STR00006## 11b ##STR00007## 11c ##STR00008## 11d ##STR00009## 11e
##STR00010## 11f ##STR00011## 11g ##STR00012## 11h ##STR00013## 11i
##STR00014## 11j ##STR00015## 11k ##STR00016## 11l ##STR00017## 11m
##STR00018## 11n ##STR00019## 11o ##STR00020## 11p ##STR00021## 11q
##STR00022## 11r ##STR00023## 11s ##STR00024##
[0022] These oxazole compounds can be used singly or in a
combination of two or more. Specifically, the ointment of the
present invention comprises at least one oxazole compound selected
from the group consisting of compounds represented by formulae (11)
and (11a) to (11s).
[0023] Although there is no particular limitation, oxazole compound
(I) is present in the ointment in an amount of preferably 0.01 to
10 parts by weight, more preferably 0.05 to 7.5 parts by weight,
still more preferably 0.1 to 5 parts by weight, per 100 parts by
weight of the ointment.
[0024] As stated above, the oxazole compound is preferably
dissolved in solvent (II). The solvent is preferably a polar
compound that is a liquid at room temperature. Specific examples of
the solvent include ethylene carbonate, propylene carbonate, benzyl
alcohol, triacetin, diethyl sebacate, diisopropyl sebacate, diethyl
adipate, diisopropyl adipate, isostearic acid, olive oil,
hexyldodecanol, decyl oleate, isostearyl alcohol, and isopropyl
myristate. Ethylene carbonate, propylene carbonate, benzyl alcohol,
and triacetin are more preferable, and propylene carbonate and
triacetin are still more preferable. Of these, propylene carbonate
is preferable. These solvents can be used singly or in a
combination of two or more. In particular, it is preferable to use
ethylene carbonate or propylene carbonate alone, or a combination
of ethylene carbonate or propylene carbonate with benzyl alcohol
and/or triacetin.
[0025] Solvent (II) is present in the ointment in an amount of
preferably more than 2 parts by weight, more preferably 2.1 parts
by weight or more, and still more preferably 2.2 parts by weight or
more, per part by weight of oxazole compound (I). The upper limit
of the amount of solvent (II) is not particularly limited, as long
as the effect of the present invention is produced. For example,
the upper limit is preferably 30 parts by weight or less, more
preferably 20 parts by weight or less, and still more preferably 15
parts by weight or less.
[0026] Solvent (II) is present in the ointment in an amount of
preferably 0.1 to 50 parts by weight, more preferably 0.2 to 25
parts by weight, and still more preferably 0.5 to 20 parts by
weight, per 100 parts by weight of the ointment.
[0027] A solution of the oxazole compound in the solvent is
preferably dissolved or dispersed in the form of droplets in
ointment base (III), and more preferably dispersed in the form of
droplets in ointment base (III).
[0028] Known ointment bases for use in the production of ointments
can be used as ointment base (III). Examples of ointment bases
include hydrocarbons, and more specific examples include grease
bases, particularly natural wax, petroleum wax, and other
hydrocarbons. Examples of natural wax include beeswax (e.g.,
unbleached beeswax, non-chemically bleached beeswax, and chemically
bleached beeswax), and carnauba wax. Examples of petroleum wax
include paraffin and microcrystalline wax. Examples of other
hydrocarbons include liquid paraffin and petrolatum (e.g., white
petrolatum and yellow petrolatum). These ointment bases can be used
singly or in a combination of two or more.
[0029] Ointment base (III) is present in the ointment in an amount
of preferably 5 to 5000 parts by weight, more preferably 10 to 2500
parts by weight, and still more preferably 20 to 1000 parts by
weight, per part by weight of oxazole compound (I).
[0030] Ointment base (III) is present in the ointment in an amount
of preferably 50 to 99 parts by weight, more preferably 70 to 98
parts by weight, and still more preferably 80 to 97 parts by
weight, per 100 parts by weight of the ointment.
[0031] Ointment base (III) preferably comprises at least beeswax.
The beeswax for use is preferably beeswax that is not chemically
bleached, including, for example, beeswax that is non-chemically
bleached (non-chemically bleached beeswax) and beeswax that is not
bleached (unbleached beeswax).
[0032] The beeswax is present in the ointment in an amount of
preferably 0.05 to 50 parts by weight, more preferably 0.1 to 40
parts by weight, and still more preferably 0.2 to 35 parts by
weight, per part by weight of oxazole compound (I).
[0033] The beeswax is present in the ointment in an amount of
preferably 0.1 to 10 parts by weight, more preferably 0.2 to 9
parts by weight, still more preferably 0.4 to 8 parts by weight,
even still more preferably 0.5 to 7.5 parts by weight, and
particularly preferably 1 to 5 parts by weight, per 100 parts by
weight of the ointment.
[0034] When other ointment bases are combined with beeswax, the
combination is not particularly limited. However, for example, the
combination preferably comprises at least one member selected from
the group consisting of petrolatum (preferably white petrolatum),
liquid paraffin, and paraffin and beeswax.
[0035] In addition to the ointment base, the ointment may comprise
other additives for use in ointments (in particular, pharmaceutical
additives), such as aroma components, colorants, preservatives,
absorption promoters including higher alkene acids (e.g., oleic
acid), or medicaments effective for treating other skin
diseases.
[0036] As stated above, the ointment of the present invention is
preferably an ointment wherein solvent (II), in which oxazole
compound (I) is dissolved, is dissolved or dispersed in the form of
droplets in ointment base (III). Examples of the method for
producing this ointment include a method comprising preparing a
solution of component (I) in component (II), and mixing the
solution with component (III) with stirring. Mixing with stirring
can be performed with, for example, a homomixer, a paddle mixer, or
a combination of these mixers.
[0037] In the use of multiple types of ointment bases (component
(III)), it is preferable to mix the multiple ointment bases
beforehand. In the formulation of component (III) containing
multiple types of ointment bases, it is preferable to mix the
ointment bases with heating to melt the solids, such as beeswax.
For example, when beeswax and other ointment bases are used in
combination, beeswax and other ointment bases are preferably mixed
beforehand, preferably with heating.
[0038] In the case of an ointment wherein component (II), in which
component (I) is dissolved, is dispersed in the form of droplets in
component (III), the particle size of the droplets observed with a
polarizing microscope is 100 .mu.m or less, preferably about 40
.mu.m or less, more preferably about 25 .mu.m or less, and still
more preferably about 20 .mu.m or less. In particular, there exist
preferably no droplets having a particle size of more than 100
.mu.m, more preferably no droplets having a particle size of more
than 40 .mu.m, still more preferably no droplets having a particle
size of more than 25 .mu.m, and even still more preferably no
droplets having a particle size of more than 20 .mu.m. A desired
mean particle size of the droplets is achieved by adjusting the
stirring rate at which the solution is mixed with component (III)
with stirring.
[0039] The oxazole compound represented by formula (11) is a known
compound disclosed in PTL 1 and 2, and can be produced in
accordance with the procedure described in PTL 1 or 2.
[0040] The oxazole compound represented by formula (11) can also be
produced as described below. The compounds used as starting
materials below are known or easily produced from known
compounds.
[0041] Specifically, compound (3) is first synthesized, and then
compound (7) is synthesized from compound (3). Subsequently,
compound (11) is synthesized from compound (7). In this
specification, a compound represented by formula A may be indicated
as compound A or compound (A).
##STR00025##
Production of Compound (3)
[0042] Compound (3) can be produced, for example, through the
reaction steps illustrated in the following reaction scheme.
##STR00026##
Compound (1a)+Compound X.sup.1CF.sub.2COOR.sup.1.fwdarw.Compound
(2)
[0043] Compound (2) can be produced by reacting compound (1a) with
compound X.sup.1CF.sub.2COOR.sup.1 in the presence of a base.
[0044] In compound X.sup.1CF.sub.2COOR.sup.1, X.sup.1 represents
halogen, and the halogen includes fluorine, chlorine, bromine, and
iodine, with chlorine, bromine, and iodine being preferable, and
chlorine being more preferable.
[0045] R.sup.1 represents an alkali metal or lower alkyl. The
alkali metal includes lithium, sodium, and potassium, with sodium
being preferable. The lower alkyl includes C1-C6 (in particular,
C1-C4) linear or branched alkyl. Specific examples include methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, 1-ethyl propyl, n-pentyl, neopentyl, n-hexyl, isohexyl,
and 3-methyl pentyl, with methyl and ethyl being preferable.
[0046] The reaction can be performed in the presence of a common
solvent. The solvent can be any solvent that does not adversely
affect the reaction. Examples of the solvent include ketone
solvents (e.g., acetone and methyl ethyl ketone), ether solvents
(e.g., tetrahydrofuran, dioxane, diethyl ether, and diglyme), ester
solvents (e.g., methyl acetate and ethyl acetate), aprotic polar
solvents (e.g., acetonitrile, N,N-dimethylformamide, and dimethyl
sulfoxide), halogenated hydrocarbon solvents (e.g., methylene
chloride and ethylene chloride), and combinations of these
solvents. The solvent is preferably N,N-dimethylformamide.
[0047] The base for use can be known inorganic bases or organic
bases. Examples of inorganic bases include alkali metals (e.g.,
sodium and potassium), alkali metal hydrogen carbonates (e.g.,
lithium hydrogen carbonate, sodium hydrogen carbonate, and
potassium hydrogen carbonate), alkali metal hydroxides (e.g.,
lithium hydroxide, sodium hydroxide, potassium hydroxide, and
cesium hydroxide), alkali metal carbonates (e.g., lithium
carbonate, sodium carbonate, potassium carbonate, and cesium
carbonate), alkali metal lower (C1-C3) alkoxides (e.g., sodium
methoxide and sodium ethoxide), and alkali metal hydrides (e.g.,
sodium hydride and potassium hydride). Examples of organic bases
include trialkyl amines (e.g., trimethylamine, triethylamine, and
N,N-diisopropylethylamine), pyridine, quinoline, piperidine,
imidazole, picoline, 4-dimethylaminopyridine, N,N-dimethylaniline,
N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicyclo[2.2.2]octane (DABCO), and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). When these bases are a
liquid, these bases can also be used as a solvent. These bases are
used singly or in a combination of two or more. The base is
preferably an alkali metal carbonate (in particular, sodium
carbonate or potassium carbonate).
[0048] The amount of the base for use is typically 1 to 10 moles,
and preferably 1 to 6 moles, per mole of compound (1a).
[0049] The reaction can be performed by optionally adding an alkali
metal iodide, such as potassium iodide or sodium iodide, as a
reaction accelerator to the reaction system.
[0050] When a reaction accelerator is used, the amount of the
reaction accelerator is typically at least 0.01 moles, and
preferably about 0.1 to 2 moles, per mole of
X.sup.1CF.sub.2COOR.sup.1.
[0051] The proportion of compound (1a) and compound
X.sup.1CF.sub.2COOR.sup.1 is typically at least 1 mole, preferably
about 1 to 5 moles of compound X.sup.1CF.sub.2COOR.sup.1, per mole
of compound (1a).
[0052] The reaction temperature is not particularly limited, and
the reaction can be typically performed under any of the following
conditions: with cooling, at room temperature, or with heating. The
reaction is preferably performed at a temperature of about 80 to
120.degree. C. for 1 to 30 hours.
Compound (2).fwdarw.Compound (3)
[0053] Compound (3) can be produced by oxidizing compound (2).
Specifically, for example, compound (3) is produced by subjecting
compound (2) to reaction in a solvent in the presence of an
oxidant.
[0054] When compound (2) is reacted in a solvent in the presence of
an oxidant, examples of the solvent for use include water;
alcohols, such as methanol, ethanol, propanol, isopropyl alcohol,
n-butanol, tert-butanol, and ethylene glycol; halogenated
hydrocarbons, such as dichloromethane, chloroform, and carbon
tetrachloride; ethers, such as diethyl ether, tetrahydrofuran,
dioxane, monoglyme, and diglyme; ketones, such as acetone and
methyl ethyl ketone; aromatic hydrocarbons, such as benzene,
o-dichlorobenzene, toluene, and xylene; esters, such as methyl
acetate, ethyl acetate, and butyl acetate; aprotic polar solvents,
such as acetonitrile, N,N-dimethylformamide, and
hexamethylphosphoric triamide; and combinations of these
solvents.
[0055] Oxidants include halous acids, such as chlorous acid, iodous
acid, and bromous acid; alkali metal salts of halous acids, such as
sodium chlorite, sodium iodite, sodium bromite, potassium chlorite,
potassium iodite, and potassium bromite; alkali metal salts of
permanganic acid, such as potassium permanganate; chromic acid or
alkali metal salts thereof, such as chromium oxide (VI), sodium
dichromate, and potassium dichromate; and nitric acid. When using
an alkali metal salt of permanganic acid, it is preferable to
perform reaction in the presence of an inorganic base, such as
potassium hydroxide, sodium hydroxide, sodium carbonate, or
potassium carbonate. When using chromic acid or an alkali metal
salt thereof, it is preferable to perform reaction in the presence
of a mineral acid such as sulfuric acid, or an organic acid such as
acetic acid. Of these, in particular, halous acids, and alkali
metal salts of halous acids are particularly preferable.
[0056] The amount of the oxidant for use is typically 0.5 to 1 mole
or more, and preferably 1 to 10 moles, per mole of compound
(2).
[0057] The reaction temperature is typically about -20 to
50.degree. C., and preferably about -20.degree. C. to room
temperature (25.degree. C.). The reaction time is about 1 to 30
hours.
[0058] Compound (3) can be produced through the reaction steps
illustrated in the following reaction scheme.
##STR00027##
Compound (1b)+Compound X.sup.2CH(CH.sub.3).sub.2.fwdarw.Compound
(2)
[0059] Compound (2) can also be produced by reacting compound (1a)
with compound X.sup.2CH(CH.sub.3).sub.2 in the presence of a
base.
[0060] In compound X.sup.2CH(CH.sub.3).sub.2, X.sup.2 represents
halogen, and the halogen includes fluorine, chlorine, bromine, and
iodine, with chlorine, bromine, and iodine being preferable, and
bromine being more preferable.
[0061] The reaction can be performed in the presence of a common
solvent. The solvent can be any solvent that does not adversely
effect the reaction. Examples of the solvent include ketone
solvents (e.g., acetone and methyl ethyl ketone), ether solvents
(e.g., tetrahydrofuran, dioxane, diethyl ether, and diglyme), ester
solvents (e.g., methyl acetate and ethyl acetate), aprotic polar
solvents (e.g., acetonitrile, N,N-dimethylformamide, and dimethyl
sulfoxide), halogenated hydrocarbon solvents (e.g., methylene
chloride and ethylene chloride), and combinations of these
solvents. The solvent is preferably N,N-dimethylformamide.
[0062] The base for use can be known inorganic bases or organic
bases. Examples of inorganic bases include alkali metals (e.g.,
sodium and potassium), alkali metal hydrogen carbonates (e.g.,
lithium hydrogen carbonate, sodium hydrogen carbonate, and
potassium hydrogen carbonate), alkali metal hydroxides (e.g.,
lithium hydroxide, sodium hydroxide, potassium hydroxide, and
cesium hydroxide), alkali metal carbonates (e.g., lithium
carbonate, sodium carbonate, potassium carbonate, and cesium
carbonate), alkali metal lower (C1-C3) alkoxides (e.g., sodium
methoxide and sodium ethoxide), and alkali metal hydrides (e.g.,
sodium hydride and potassium hydride). Organic bases include
trialkyl amines (e.g., trimethylamine, triethylamine, and
N,N-diisopropylethylamine), pyridine, quinoline, piperidine,
imidazole, picoline, 4-dimethylaminopyridine, N,N-dimethylaniline,
N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicyclo[2.2.2]octane (DABCO), and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). When these bases are a
liquid, these bases can also be used as a solvent. These bases are
used singly or in a combination of two or more. The base is
preferably an alkali metal carbonate (in particular, sodium
carbonate or potassium carbonate).
[0063] The amount of the base for use is typically 1 to 10 moles,
and preferably 1 to 6 moles, per mole of compound (1b).
[0064] The reaction can be performed by optionally adding an alkali
metal iodide, such as potassium iodide or sodium iodide, as a
reaction accelerator to the reaction system.
[0065] When a reaction accelerator is used, the amount of the
reaction accelerator is typically at least 0.01 moles, and
preferably about 0.1 to 2 moles, per mole of
X.sup.2CH(CH.sub.3).sub.2.
[0066] The proportion of compound (1b) and compound
X.sup.2CH(CH.sub.3).sub.2 for use may be typically at least 1 mole,
and preferably about 1 to 5 moles of compound
X.sup.2CH(CH.sub.3).sub.2, per mole of compound (1b).
[0067] The reaction temperature is not particularly limited, and
the reaction can be typically performed under any of the following
conditions: with cooling, at room temperature, or with heating. The
reaction is preferably performed at a temperature within the range
of around room temperature to about 85.degree. C. for 1 to 30
hours.
[0068] The method for producing compound (3) from compound (2) is
as described above.
Production of Compound (7)
[0069] Compound (7) can be produced, for example, through the
reaction steps illustrated in the following reaction scheme.
##STR00028##
Compound (3).fwdarw.Compound (4)
[0070] Compound (4) can be produced by subjecting compound (3) to
condensation reaction with ammonia (amidation reaction). The
reaction can be typically performed by reacting compound (3) with
ammonia in a solvent in the presence of a condensation agent.
[0071] The solvent can be any solvent that does not adversely
effect the reaction. Examples of the solvent include halogenated
aliphatic hydrocarbon solvents (e.g., methylene chloride,
chloroform, and ethylene chloride), ketone solvents (e.g., acetone
and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran,
dioxane, diethyl ether, dimethoxyethane, and diglyme), aromatic
hydrocarbons (e.g., toluene and xylene), aprotic polar solvents
(e.g., acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone,
and dimethyl sulfoxide), and combinations of these solvents. The
solvent is preferably acetonitrile.
[0072] Examples of the condensation agent include 1,1'-carbonyl
diimidazole (CDI), dicyclohexyl carbodiimide (DCC), diisopropyl
carbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (EDC or WSC), diphenylphosphoryl azide (DPPA),
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium salts (e.g.,
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate), and 2-chloro-4,6-dimethoxytriazine (CDMT).
The condensation agent is preferably CDI.
[0073] The amount of the condensation agent for use is typically at
least 1 mole, and preferably about 1 to 5 moles, per mole of
compound (3).
[0074] Together with the condensation agent, an additive
(activator), such as 1-hydroxy benzotriazole (HOBt) and N-hydroxy
succinimide (HOSu), may optionally be used.
[0075] When the additive is used, the amount of the additive is
typically at least 1 mole, and preferably about 1 to 5 moles, per
mole of the condensation agent.
[0076] The reaction can also be performed by optionally adding a
base. Examples of the base include tertiary amines, such as
triethylamine and N,N-diisopropylethylamine; and
nitrogen-containing aromatic compounds, such as pyridine and
4-dimethylaminopyridine.
[0077] When a base is used, the amount of the base is typically at
least 1 mole, and preferably about 1 to 5 moles, per mole of
compound (5).
[0078] Ammonia is typically used as ammonia water. The amount of
ammonia for use is typically at least 1 mole, and preferably about
1 to 10 moles, per mole of compound (3).
[0079] The reaction is typically performed by reacting compound (3)
with a condensation agent, optionally with an additive, to prepare
an activated ester, and reacting the activated ester with
ammonia.
[0080] The reaction temperature for the preparation of the
activated ester and subsequent reaction with ammonia is not
particularly limited. The preparation and the reaction can be
typically performed under any of the following conditions: with
cooling, at room temperature, or with heating. The reaction is
preferably performed at a temperature within the range of ice
cooling temperature to about room temperature for 1 to 30
hours.
Compound (4).fwdarw.Compound (5)
[0081] Compound (5) can be produced by reacting compound (4) with
compound CO(CH.sub.2X.sup.3).sub.2.
[0082] In compound CO(CH.sub.2X.sup.3).sub.2, X.sup.3 represents
halogen. The halogen represented by X.sup.3 includes fluorine,
chlorine, bromine, and iodine, with chlorine, bromine, and iodine
being preferable.
[0083] The reaction can be performed in the presence of a common
solvent. The solvent can be any solvent that does not adversely
effect the reaction. Examples of the solvent include halogenated
aliphatic hydrocarbon solvents (e.g., methylene chloride,
chloroform, and ethylene chloride), ketone solvents (e.g., acetone
and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran,
dioxane, diethyl ether, dimethoxyethane, and diglyme), aromatic
hydrocarbons (e.g., toluene and xylene), aprotic polar solvents
(e.g., acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone,
and dimethyl sulfoxide), and combinations of these solvents. The
solvent is preferably an aromatic hydrocarbon (e.g., toluene and
xylene).
[0084] The proportion of compound (4) and compound
CO(CH.sub.2X.sup.3).sub.2 for use is typically at least 1 mole,
preferably about 1 to 5 moles of compound
CO(CH.sub.2X.sup.3).sub.2, per mole of compound (4).
[0085] Optionally, a dehydrating agent may be used. Examples of the
dehydrating agent include synthetic zeolite, which specifically
includes molecular sieves (MS)3A, MS4A, and other similar zeolite
with fine pores.
[0086] The reaction temperature is not particularly limited, and
the reaction can be typically performed under any of the following
conditions: with cooling, at room temperature, or with heating. The
reaction is preferably performed at a temperature within the range
of around room temperature to about 200.degree. C. for 1 to 30
hours. The use of this method enables the oxazole ring to foam at a
high yield.
Compound (5).fwdarw.Compound (6)
[0087] Compound (6) can be produced by reacting compound (5) with
compound R.sup.2OM.sup.1. In compound R.sup.2OM.sup.1, R.sup.2
represents alkanoyl, and M.sup.1 represents an alkali metal.
[0088] The alkanoyl represented by R.sup.2 includes C1-C6 (in
particular, C1-C4) linear or branched alkanoyl. Specific examples
of the alkanoyl include formyl, acetyl, n-propionyl, isopropionyl,
n-butyryl, isobutyryl, sec-butyryl, tert-butyryl, and hexanoyl,
with formyl, acetyl, n-propionyl, and isopropionyl being
preferable, and acetyl being more preferable.
[0089] The alkali metal represented by M.sup.1 includes lithium,
sodium, and potassium, with sodium and potassium being
preferable.
[0090] Specific examples of compound R.sup.2OM.sup.1 include sodium
acetate and potassium acetate.
[0091] The reaction can be performed in the presence of a common
solvent. The solvent can be any solvent that does not adversely
affect the reaction. Examples of the solvent include ketone
solvents (e.g., acetone and methyl ethyl ketone), ether solvents
(e.g., tetrahydrofuran, dioxane, diethyl ether, and diglyme), ester
solvents (e.g., methyl acetate and ethyl acetate), aprotic polar
solvents (e.g., acetonitrile, N,N-dimethylformamide, and dimethyl
sulfoxide), halogenated hydrocarbon solvents (e.g., methylene
chloride and ethylene chloride), and combinations of these
solvents. The solvent is preferably N,N-dimethylformamide.
[0092] The proportion of compound (5) and compound R.sup.2OM.sup.1
for use is typically at least 1 mole, and preferably about 1 to 5
moles of compound R.sup.2OM.sup.1, per mole of compound (5).
[0093] The reaction temperature is not particularly limited, and
the reaction can be typically performed under any of the following
conditions: with cooling, at room temperature, or with heating. The
reaction may be preferably performed at a temperature within the
range of around room temperature to about 120.degree. C. for 1 to
30 hours.
Compound (6).fwdarw.Compound (7)
[0094] Compound (7) can be produced by hydrolyzing compound (6).
The hydrolysis of compound (6) can be typically performed in a
solvent in the presence of a base.
[0095] The solvent can be any solvent that does not adversely
affect the reaction. Examples of the solvent include water, alcohol
solvents (e.g., methanol, ethanol, isopropanol, and n-butanol),
ketone solvents (e.g., acetone and methyl ethyl ketone), ether
solvents (e.g., tetrahydrofuran, dioxane, diethyl ether,
dimethoxyethane, and diglyme), and acetonitrile. Preferable
examples of the solvent include a combination solvent of water and
an alcohol solvent (methanol or ethanol). Alcohol solvents (in
particular, methanol and ethanol) are preferable.
[0096] Examples of the base include alkali metal hydroxides (e.g.,
lithium hydroxide, sodium hydroxide, potassium hydroxide, and
cesium hydroxide). Typically, alkali metal hydroxides can be used
in the form of an aqueous solution. Examples of the aqueous
solution include sodium hydroxide aqueous solution.
[0097] The amount of the base for use is typically at least 1 mole,
and preferably about 1 to 5 moles, per mole of compound (6).
[0098] The reaction temperature is not particularly limited, and
the reaction can be typically performed under any of the following
conditions: with cooling, at room temperature, or with heating. The
reaction is preferably performed at a temperature within the range
of around room temperature to about 85.degree. C. for 1 to 30
hours.
Production of Compound (11)
[0099] Compound (11) can be produced, for example, through the
reaction steps illustrated in the following reaction scheme.
##STR00029##
Compound (7).fwdarw.Compound (8)
[0100] Compound (8) can be produced by converting the hydroxy group
of compound (7) into leaving group (X.sup.4).
[0101] Examples of the leaving group represented by X.sup.4 include
halogen (e.g., fluorine, chlorine, bromine, and iodine) and organic
sulfonyloxy (e.g., p-toluenesulfonyloxy, methanesulfonyloxy,
trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, and
o-nitrobenzolsulfonyloxy). Halogen is preferable, and bromine is
more preferable.
[0102] Compound (8'), wherein the leaving group represented by
X.sup.4 is an organic sulfonyloxy, can be produced by reacting
compound (7) with an organic sulfonyl halide or organic sulfonic
acid anhydride containing the organic sulfonyl group in a solvent
in the presence of a base.
[0103] The solvent can be any solvent that does not adversely
affect the reaction. Examples of the solvent include ketone
solvents (e.g., acetone and methyl ethyl ketone), ether solvents
(e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane,
and diglyme), ester solvents (e.g., methyl acetate and ethyl
acetate), aprotic polar solvents (e.g., acetonitrile,
dimethylformamide, and dimethyl sulfoxide), halogenated hydrocarbon
solvents (e.g., methylene chloride and ethylene chloride), and
combinations of these solvents. The solvent is preferably ester
solvents (in particular, ethyl acetate etc.).
[0104] The base for use can be known inorganic bases or organic
bases. Examples of the inorganic bases include alkali metal
hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium
hydrogen carbonate, and potassium hydrogen carbonate), alkali metal
hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium
hydroxide, and cesium hydroxide), alkali metal carbonates (e.g.,
lithium carbonate, sodium carbonate, potassium carbonate, and
cesium carbonate), and alkali metal hydrides (e.g., sodium hydride
and potassium hydride). The organic bases include trialkyl amines
(e.g., trimethylamine, triethylamine, and
N,N-diisopropylethylamine), pyridine, quinoline, piperidine,
imidazole, picoline, 4-dimethylaminopyridine, N,N-dimethylaniline,
N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicyclo[2.2.2]octane (DABCO), and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). When these bases are a
liquid, these bases can also be used as a solvent. These bases can
be used singly or in a combination of two or more. The base is
preferably N,N-diisopropylethylamine, and triethylamine, and more
preferably N,N-diisopropylethylamine. In particular,
N,N-diisopropylethylamine is preferable because the use of
N,N-diisopropylethylamine can significantly increase the yield.
[0105] Examples of the organic sulfonyl halide include
p-toluenesulfonyl halide, methanesulfonyl halide,
trifluoromethanesulfonyl halide, nonafluorobutanesulfonyl halide,
and o-nitrobenzolsulfonyl halide. Examples of the halide include
chloride and bromide, with chloride being preferable. Particularly
preferable organic sulfonyl halide includes methanesulfonyl
chloride.
[0106] Examples of the organic sulfonic acid anhydride include
p-toluenesulfonic acid anhydride, methanesulfonic acid anhydride,
trifluorosulfonic acid anhydride, nonafluorobutanesulfonic acid
anhydride, and o-nitrobenzenesulfonic acid anhydride.
[0107] The amount of the base for use is typically 1 to 10 moles,
and preferably 1 to 6 moles, per mole of compound (7).
[0108] The amount of the organic sulfonyl halide or organic
sulfonic acid anhydride for use is typically 1 to 5 moles, and
preferably 1 to 2 moles, per mole of compound (7).
[0109] The reaction temperature is not particularly limited, and
the reaction can be typically performed under any of the following
conditions: with cooling, at room temperature, or with heating. The
reaction is preferably performed at a temperature of about 0 to
60.degree. C. for 1 to 30 hours.
[0110] The reaction described above produces compound (8'), wherein
the leaving group represented by X.sup.4 is an organic
sulfonyloxy.
[0111] Compound (8''), wherein the leaving group represented by
X.sup.4 is halogen, can be produced by reacting compound (8') with
a halogenating agent in a solvent. When the leaving group
represented by X.sup.4 is halogen, the halogen includes fluorine,
chlorine, bromine, and iodine, with chlorine, bromine, and iodine
being preferable and chlorine being more preferable.
[0112] The solvent can be any solvent that does not adversely
affect the reaction. Examples of the solvent include ketone
solvents (e.g., acetone and methyl ethyl ketone), ether solvents
(e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane,
and diglyme), ester solvents (e.g., methyl acetate and ethyl
acetate), aprotic polar solvents (e.g., acetonitrile,
N,N-dimethylformamide, and dimethyl sulfoxide), halogenated
hydrocarbon solvents (e.g., methylene chloride and ethylene
chloride), and combinations of these solvents.
[0113] Examples of the halogenating agent include alkali metal
halides (e.g., lithium chloride, lithium bromide, and lithium
iodide), and quaternary ammonium halides (e.g., tetrabutylammonium
chloride and tetrabutylammonium bromide). The halogenating agent is
preferably an alkali metal halide (in particular, lithium
bromide).
[0114] The amount of the halogenating agent for use is typically 1
to 5 moles, and preferably 1 to 3 moles, per mole of compound
(8').
[0115] The reaction temperature is not particularly limited, and
the reaction can be typically performed under any of the following
conditions: with cooling, at room temperature, or with heating. The
reaction is preferably performed at a temperature about 0 to
60.degree. C. for 1 to 30 hours.
[0116] The step of producing compound (8') from compound (7) and
the step of producing compound (8'') from compound (8') are each
independently performed. Alternatively, both steps can be performed
in one pot.
[0117] The obtained compound (8) (including compounds (8') and
(8'')) is subjected to the following reaction step.
Compound (8).fwdarw.Compound (9)
[0118] Compound (9) can be produced by reacting compound (8) with a
compound represented by the following formula:
##STR00030##
wherein M.sup.2 represents an alkali metal (which may be
hereinafter referred to as "phthalimide M.sup.2 compound").
Examples of the alkali metal represented by M.sup.2 include
lithium, sodium, and potassium, with potassium being
preferable.
[0119] The reaction can be performed in a common solvent. The
solvent can be any solvent that does not adversely affect the
reaction. Examples of the solvent include ketone solvents (e.g.,
acetone and methyl ethyl ketone), ether solvents (e.g.,
tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, and
diglyme), ester solvents (e.g., methyl acetate and ethyl acetate),
aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide,
and dimethyl sulfoxide), halogenated hydrocarbon solvents (e.g.,
methylene chloride and ethylene chloride), and combinations of
these solvents. The solvent is more preferably
N,N-dimethylformamide.
[0120] The proportion of compound (8) and phthalimide M.sup.2
compound is typically at least 1 mole, and preferably about 1 to 5
moles of phthalimide M.sup.2 compound, per mole of compound
(8).
[0121] The reaction temperature is not particularly limited, and
the reaction can be typically performed under any of the following
conditions: with cooling, at room temperature, or with heating. The
reaction is performed at a temperature of about 0 to 100.degree. C.
for 1 to 30 hours.
Compound (9).fwdarw.Compound (10)
[0122] Compound (10) can be produced by reacting compound (9) with
methylamine.
[0123] The reaction can be performed in a common solvent. The
solvent can be any solvent that does not adversely affect the
reaction. Examples of the solvent include water, alcohol solvents
(e.g., methanol, ethanol, isopropanol, n-butanol, trifluoroethanol,
and ethylene glycol), ether solvents (e.g., tetrahydrofuran,
dioxane, diethyl ether, dimethoxyethane, and diglyme), aprotic
polar solvents (e.g., acetonitrile, N,N-dimethylformamide, and
dimethyl sulfoxide), and combinations of these solvents. The
solvent is preferably a combination solvent of water and an alcohol
solvent (in particular, methanol or ethanol).
[0124] Methylamine can be typically used in the form of a
methylamine aqueous solution.
[0125] The amount of methylamine for use is typically 1 to 10
moles, and preferably 1 to 5 moles, per mole of compound (9).
[0126] The reaction temperature is not particularly limited, and
the reaction can be typically performed under any of the following
conditions: with cooling, at room temperature, or with heating. The
reaction is preferably performed at a temperature within the range
of around room temperature to about 100.degree. C. for 10 minutes
to 30 hours.
[0127] Obtained compound (10) is a primary amine compound. Compound
(10) can optionally be converted into a salt formed with an acid
from the standpoint of handleability. The salt can be formed in
accordance with a known method. The acid can be selected from a
wide range of organic acids or inorganic acids. The organic acids
include organic carboxylic acids, such as formic acid, acetic acid,
lactic acid, tartaric acid, and succinic acid; and sulfonic acids,
such as methanesulfonic acid, toluenesulfonic acid, and
naphthalenesulfonic acid. Examples of the inorganic acids include
hydrochloric acid, sulfuric acid, nitric acid, and phosphoric
acid.
[0128] The solvent for use in forming the salt can be any solvent
that does not adversely affect the reaction. Examples of the
solvent include alcohol solvents (e.g., methanol, ethanol,
isopropanol, n-butanol, trifluoroethanol, and ethylene glycol),
ketone solvents (e.g., acetone and methyl ethyl ketone), ether
solvents (e.g., cyclopentyl methyl ether (CPME), tetrahydrofuran,
dioxane, diethyl ether, dimethoxyethane, and diglyme), ester
solvents (e.g., methyl acetate and ethyl acetate), aprotic polar
solvents (e.g., acetonitrile, N,N-dimethylformamide, and dimethyl
sulfoxide), and combinations of these solvents. The solvent is
preferably ether solvents (in particular, CPME).
Compound (10).fwdarw.Compound (11)
[0129] Compound (11) can be produced by subjecting compound (10) to
condensation reaction with 2-ethoxybenzoic acid.
[0130] The condensation reaction is typically performed in a
solvent in the presence of a condensation agent. When compound (10)
is a salt formed with an acid, compound (10) may be converted into
a free primary amine by removing the acid from the salt using a
base (e.g., inorganic bases, such as sodium hydroxide, potassium
hydroxide, sodium carbonate, and sodium hydrogen carbonate; and
organic bases, such as triethylamine and N,N-diisopropylethylamine)
before performing the reaction.
[0131] The solvent can be any solvent that does not adversely
affect the reaction. Examples of the solvent include halogenated
aliphatic hydrocarbon solvents (e.g., methylene chloride,
chloroform, and ethylene chloride), ketone solvents (e.g., acetone
and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran,
dioxane, diethyl ether, dimethoxyethane, and diglyme), ester
solvents (e.g., methyl acetate and ethyl acetate), aromatic
hydrocarbons (e.g., toluene and xylene), aprotic polar solvents
(e.g., acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone,
and dimethyl sulfoxide), and combinations of these solvents. The
solvent is preferably ketone solvents (in particular, acetone and
methyl ethyl ketone), ether solvents (in particular,
tetrahydrofuran, dioxane, diethyl ether, and dimethoxyethane), and
ester solvents (e.g., methyl acetate and ethyl acetate).
[0132] Examples of the condensation agent include 1,1'-carbonyl
diimidazole (CDI), dicyclohexyl carbodiimide (DCC), diisopropyl
carbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
hydrochloride (EDC or WSC), diphenylphosphoryl azide (DPPA),
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium salts (e.g.,
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate), and 2-chloro-4,6-dimethoxytriazine (CDMT).
The condensation agent is preferably CDI or WSC.
[0133] The amount of the condensation agent for use is typically at
least 0.5 moles, and preferably about 1 to 5 moles, per mole of
2-ethoxybenzoic acid.
[0134] Together with the condensation agent, an additive
(activator), such as 1-hydroxy benzotriazole (HOBt) or N-hydroxy
succinimide (HOSu), can optionally be used.
[0135] The amount of the additive for use is typically at least 1
mole, and preferably about 1 to 5 moles, per mole of the
condensation agent.
[0136] The reaction can be performed by optionally adding a base.
Examples of the base include tertiary amines, such as triethylamine
and N,N-diisopropylethylamine; and nitrogen-containing aromatic
compounds, such aspyridine and 4-dimethylaminopyridine.
[0137] When a base is used, the amount of the base may be typically
at least 0.5 moles, and preferably about 1 to 5 moles, per mole of
the condensation agent.
[0138] The proportion of compound (10) and 2-ethoxybenzoic acid is
typically at least 1 mole, and preferably about 1 to 2 moles of
2-ethoxybenzoic acid, per mole of compound (10).
[0139] The reaction temperature is not particularly limited, and
the reaction can be typically performed under any of the following
conditions: with cooling, at room temperature, or with heating. The
reaction is preferably performed at a temperature of about 0 to
100.degree. C. for 1 to 30 hours.
[0140] In this specification, the term "comprising" includes
"consisting essentially of" and "consisting of." The present
invention covers all combinations of the elements described in this
specification.
EXAMPLES
[0141] The following describes the present invention in detail.
However, the present invention is not limited to the Examples.
Production Example 1: Production 1 of Compound (3)
[0142] Compound (3) was produced in accordance with the following
reaction scheme.
##STR00031##
[0143] 10.00 g (55.5 mmol) of compound (1a) and 9.20 g (66.6 mmol)
of potassium carbonate were added to 40 ml of N,N-dimethylformamide
and 6 ml of water, and the mixture was stirred until exotherm
subsided. 16.92 g (111 mmol) of sodium chlorodifluoroacetate was
added thereto, and the mixture was reacted at 95 to 110.degree. C.
for 3 hours. 80 ml of butyl acetate and 80 ml of water were added
to the reaction solution, and the solution was partitioned. 80 ml
of water was added again to the organic layer, followed by
partitioning. 3 ml of concentrated hydrochloric acid was added to
the organic layer, and the mixture was stirred at 60 to 70.degree.
C. for 30 minutes. 40 ml of water and 10 ml of a 25% sodium
hydroxide aqueous solution were added to the reaction solution, and
the mixture was partitioned. 5.93 g (61.1 mmol) of sulfamic acid
and 10 ml of water were added to the organic layer, and 22.08 g
(61.0 mmol) of a 25% sodium chlorite aqueous solution was added
dropwise thereto at a temperature of 20.degree. C. or below. The
mixture was reacted at 20.degree. C. or below for 15 minutes, and
10 ml of a 25% sodium hydroxide aqueous solution was added dropwise
thereto at a temperature of 20.degree. C. or below, followed by
pouring in 83.95 g (66.6 mmol) of a 10% sodium sulfite aqueous
solution. Additionally, 2 ml of concentrated hydrochloric acid was
added and the mixture was partitioned, followed by concentration of
the organic layer under reduced pressure. 40 ml of methanol, 80 ml
of water, and 10 ml of a 25% sodium hydroxide aqueous solution were
added to the concentrated residue to dissolve the residue, and 5 ml
of concentrated hydrochloric acid was added dropwise thereto to
precipitate crystals. The precipitated crystals were collected by
filtration and dried at 80.degree. C., thereby obtaining 11.81 g
(yield: 86.4%) of compound (3) as a white powder.
[0144] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.70 (2H, dd, J=6.4 Hz,
2.0 Hz), 7.22 (1H, d, J=9.2 Hz), 6.66 (1H, t, J=74.8 Hz), 4.66 (1H,
sept, J=6.0 Hz), 1.39 (6H, d, J=6.0 Hz).
Production Example 2: Production 2 of Compound (3)
[0145] Compound (3) was produced in accordance with the following
reaction scheme.
##STR00032##
[0146] 10.00 g (53.2 mmol) of compound (1b), 9.55 g (69.1 mmol) of
potassium carbonate, and 8.50 g (69.1 mmol) of isopropyl bromide
were added to 40 ml of N,N-dimethylformamide, and the mixture was
reacted at 75 to 85.degree. C. for 2 hours. 80 ml of butyl acetate
and 80 ml of water were added to the reaction solution, and the
mixture was partitioned. 5.68 g (58.5 mmol) of sulfamic acid and 10
ml of water were added to the organic layer, and 21.15 g (58.5
mmol) of a 25% sodium chlorite aqueous solution was added dropwise
thereto at 20.degree. C. or below, followed by reaction for 15
minutes. 10 ml of a 25% sodium hydroxide aqueous solution was added
thereto at 20.degree. C. or below, and subsequently 80.41 g (63.8
mmol) of a 10% sodium sulfite aqueous solution was poured in.
Additionally, 2 ml of concentrated hydrochloric acid was added, and
the mixture was partitioned, followed by concentration of the
organic layer under reduced pressure. 40 ml of methanol, 80 ml of
water, and 10 ml of a 25% sodium hydroxide aqueous solution were
added to the concentrated residue, and the residue was dissolved,
followed by dropwise addition of 5 ml of concentrated hydrochloric
acid to precipitate crystals. The precipitated crystals were
collected by filtration and dried at 80.degree. C., thereby
obtaining 12.09 g (yield: 92.4%) of compound (3) as a white
powder.
Production Example 3: Production of Compound (7)
[0147] Compound (7) was produced in accordance with the following
reaction scheme.
##STR00033##
Synthesis of Compound (4)
[0148] 10.00 g (40.6 mmol) of compound (3) was added to 25 ml of
acetonitrile at room temperature and stirred. 7.90 g (48.7 mmol) of
carbonyl diimidazole was gradually added, and the mixture was
reacted at room temperature for 1 hour. 10 ml (134 mmol) of 25%
ammonia water was added to 120 ml of water and cooled to 10.degree.
C. or below, followed by dropwise addition of the reaction solution
thereto. The precipitated crystals were collected by filtration and
dried at 80.degree. C., thereby obtaining 9.25 g (yield: 92.9%) of
compound (4) as a white powder.
[0149] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.54 (1H, d, J=1.6 Hz),
7.25 (1H, dd, J=8.4 Hz, 2.0 Hz), 7.17 (1H, d, J=8.0 Hz), 6.62 (1H,
t, J=75.0), 5.96 (2H, br-d, J=75.2 Hz), 4.66 (1H, sept, J=6.13 Hz),
1.36 (6H, d, J=6.0 Hz).
Synthesis of Compound (5)
[0150] 10.00 g (40.8 mmol) of compound (4) and 6.21 g (48.9 mmol)
of 1,3-dichloroacetone were added to 10 ml of toluene at room
temperature, and the mixture was reacted under reflux for 3 hours.
60 ml of toluene, 20 ml of water, and 2 ml of a 25% sodium
hydroxide aqueous solution were added to the reaction solution, and
the mixture was partitioned. The organic layer was concentrated
under reduced pressure, thereby obtaining compound (5) as a
brownish solid (after recrystallization: fine yellow powder).
[0151] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.69 (1H, d, J=0.8 Hz),
7.64 (1H, d, J=2.0 Hz), 7.58 (1H, dd, J=8.0 Hz, 1.6 Hz), 7.21 (1H,
d, J=8.0 Hz), 6.61 (1H, t, J=75.0 Hz), 4.69 (1H, sept, J=6.1 Hz),
4.56 (2H, s), 1.38 (6H, d, J=6.0 Hz).
Synthesis of Compound (7)
[0152] 20 ml of N,N-dimethylformamide and 4.80 g (48.9 mmol) of
potassium acetate were added to the crude product of compound (5)
obtained in the section above, and the mixture was reacted at 90 to
100.degree. C. for 3 hours. 20 ml of methanol, 20 ml of water, and
5 ml of a 25% sodium hydroxide aqueous solution were added to the
reaction solution, and reacted under reflux for 1 hour. 35 ml of
water was added to the reaction solution, and the precipitated
crystals were collected by filtration, followed by drying at
80.degree. C., thereby obtaining 10.33 g (yield: 84.6%) of compound
(7) as a pale brownish powder.
[0153] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.65-7.63 (2H, m), 7.57
(1H, dd, J=8.4 Hz, 2.0 Hz), 7.21 (1H, d, J=8.0 Hz), 6.61 (1H, t,
J=75.2 Hz), 4.70-4.66 (3H, m), 1.39 (6H, d, J=6.0 Hz).
Production Example 4: Production of Compound (11)
[0154] Compound (11) was produced in accordance with the following
reaction scheme.
##STR00034##
Synthesis of Compound (9)
[0155] 20.00 g (66.8 mmol) of compound (7) and 17.28 g (134 mmol)
of N,N-diisopropylethylamine were added to 300 ml of ethyl acetate,
and the mixture was cooled. 11.48 g (100 mmol) of methanesulfonyl
chloride was poured in and stirred at 10 to 30.degree. C. for 1
hour. 17.41 g (200 mmol) of lithium bromide was added thereto and
reacted at 20 to 35.degree. C. for 1 hour. 100 ml of water was
added to the reaction solution, and the mixture was partitioned,
followed by concentration of the organic layer under reduced
pressure. 300 ml of ethyl acetate was added to the concentrated
residue to dissolve the residue, and the solution was again
concentrated under reduced pressure. 200 ml of
N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium
phthalimide were added to the concentrated residue and reacted at
75 to 85.degree. C. for 1 hour. 200 ml of water was added to the
reaction solution to precipitate crystals. The precipitated
crystals were collected by filtration and dried at 80.degree. C.,
thereby obtaining 25.90 g (yield: 90.5%) of compound (9) as a white
powder.
[0156] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.22 (1H, s), 7.94-7.86
(4H, m), 7.58 (1H, d, J=2.0 Hz), 7.52 (1H, dd, J=8.8 Hz, 2.4 Hz),
7.30 (1H, d, J=8.4 Hz), 7.14 (1H, t, J=74.2 Hz), 4.78-4.69 (3H, m),
1.30 (6H, d, J=6.0 Hz).
Synthesis of Compound (10)
[0157] 15.00 g (35.0 mmol) of compound (9) was mixed with 30 ml of
a 40% methylamine aqueous solution, 30 ml of methanol, and 75 ml of
water, and reacted under reflux for 30 minutes. 150 ml of
cyclopentyl methyl ether (CPME) and 15 ml of a 25% sodium hydroxide
aqueous solution were added to the reaction solution, and the
temperature was adjusted to 65 to 75.degree. C., followed by
partitioning. A mixture of 150 ml of water and 7.50 g of sodium
chloride was added to the organic layer, and the temperature was
adjusted to 65 to 75.degree. C. again, followed by partitioning.
3.75 ml of concentrated hydrochloric acid was added to the organic
layer to precipitate crystals. The precipitated crystals were
collected by filtration and dried at 60.degree. C., thereby
obtaining 11.95 g (yield: quant.) of compound (10) as a white
powder.
[0158] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.51 (3H, br-s), 8.29
(1H, s), 7.64 (1H, d, J=2 Hz), 7.59 (1H, dd, J=8.0 Hz, 1.6 Hz),
7.37 (1H, d, J=8.4 Hz), 7.18 (1H, t, J=74.0 Hz), 4.72 (1H, sept,
J=6.1 Hz), 4.03 (2H, s), 1.33 (6H, d, J=6.4 Hz).
Synthesis of Compound (11)
[0159] 13.30 g (39.7 mmol) of compound (10) was mixed with 3.83 g
(37.8 mmol) of triethylamine and 108 ml of ethyl acetate, and
stirred at 20 to 30.degree. C. for 1 hour. 9.78 g (58.9 mmol) of
2-ethoxybenzoic acid and 11.28 g (58.8 mmol) of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC)
were added to the reaction solution, and reacted at 20 to
30.degree. C. for 1 hour. 54 ml of water and 5.4 ml of concentrated
hydrochloric acid were added to the reaction solution, and the
temperature was adjusted to 40 to 50.degree. C., followed by
partitioning. 54 ml of water and 5.4 ml of a 25% sodium hydroxide
aqueous solution were added to the organic layer, and the
temperature was adjusted to 40 to 50.degree. C. again. The mixture
was partitioned, and the organic layer was concentrated under
reduced pressure. 45 ml of ethanol, 18 ml of water, 5.4 ml of a 25%
sodium hydroxide aqueous solution, and 0.54 g of activated carbon
were added to the concentrated residue, and the mixture was
refluxed for 30 minutes. The activated carbon was removed by
filtration, and the filtrate was washed with 11 ml of ethanol. The
filtrate was cooled, and a seed crystal was added thereto to
precipitate crystals. The precipitated crystals were collected by
filtration and dried at 35.degree. C., thereby obtaining 12.88 g
(72.6%) of compound (11) as a white powder.
[0160] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.56 (1H, br-s), 8.23 (1H,
dd, J=7.6 Hz, 1.6 Hz), 7.66 (1H, s), 7.63 (1H, d, J=2.0 Hz), 7.58
(1H, dd, J=8.4 Hz, 2.0 Hz), 7.44-7.39 (1H, m), 7.21 (1H, d, J=8.0
Hz), 7.08-7.04 (1H, mH), 6.94 (1H, d, J=8.0 Hz), 6.61 (1H, t,
J=75.2 Hz), 4.68 (1H, sept, J=6.0 Hz), 4.62 (2H, d, J=6.0 Hz), 4.17
(2H, q, J=6.93), 1.48 (3H, t, J=7.2 Hz), 1.39 (6H, d, J=5.6
Hz).
Production Example 5: Production of Compounds (i) to (ix)
[0161] The compounds shown in the following Table 2 were produced
as described below. The .sup.1H-NMR of the produced compounds is
also shown below. Compound (ii) is the same as compound (9).
TABLE-US-00002 TABLE 2 Formula Number Structural Formula i
##STR00035## ii ##STR00036## iii ##STR00037## iv ##STR00038## v
##STR00039## vi ##STR00040## vii ##STR00041## viii ##STR00042## ix
##STR00043##
Synthesis of Compound (i)
[0162] 13.1 g of
2-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]isoindoline-1-
,3-dione(2-((2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)oxazol-4-yl)methyl-
)isoindoline-1,3-dione) synthesized in accordance with the
synthesis procedure described in PTL 2 (WO2014/034958 pamphlet) was
dissolved in a mixture of 260 ml of ethanol and 140 ml of DMF, and
1.3 g of a 10% palladium carbon powder was added thereto, followed
by stirring in a hydrogen atmosphere at 40.degree. C. for 1 hour.
100 ml of methylene chloride was added to the reaction solution and
stirred, followed by removal of the catalyst by filtration. The
crude crystals obtained by concentrating the filtrate were
recrystallized from ethyl acetate, thereby obtaining 8.8 g of
2-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-ylmethyl]isoindoline-1,3-
-dione
(2-((2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazol-4-yl)methyl)isoi-
ndoline-1,3-dione: compound (i)) as a white powder.
[0163] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.18 (1H, br-s) 7.85-8.17
(5H, m) 6.89-7.51 (4H, m) 4.74 (2H, s).
Synthesis of Compound (ii)
[0164] 2 g of compound (i) and 3.9 ml of
1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) were dissolved in 20 ml of
ethanol, and 3.18 g of isopropyl bromide was added thereto,
followed by heating under reflux overnight. Subsequently, 1 ml of a
10% sodium hydroxide aqueous solution was added to the reaction
solution, and the mixture was heated under reflux for 30 minutes.
Ice water was added to the reaction solution, followed by
extraction with ethyl acetate. The organic layer was washed with
water twice, and concentrated under reduced pressure, thereby
obtaining
[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]isoindoline-1,-
3-dione
(2-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-
isoindoline-1,3-dione: compound (ii)).
[0165] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.85-7.92 (2H, m)
7.71-7.77 (2H, m) 7.68 (1H, s) 7.61 (1H, d, J=2.1 Hz) 7.55 (1H, dd,
J=8.4 Hz, 2.1 Hz) 7.18 (1H, d, J=8.4 Hz) 6.60 (1H, t, J=75 Hz) 4.86
(2H, d, J=1.2 Hz) 4.68 (1H, sept, J=6.0 Hz) 1.38 (6H, d, J=6.0
Hz).
Synthesis of Compound (iii)
[0166] 1.58 g of compound (ii) was dissolved in 16 ml of methanol,
and 3.2 ml of a methylamine aqueous solution (40%) was added
thereto, followed by heating under reflux for 1 hour. The reaction
solution was concentrated, and the reaction product was dissolved
in ethyl acetate, followed by washing of the organic layer with a
10% sodium hydroxide aqueous solution and water. The organic layer
was separated and concentrated under reduced pressure, thereby
obtaining 1.17 g of
[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-yl]methylamine
((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methanamine:
compound (iii)) as a brownish solid.
[0167] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.65 (1H, d, J=1.8 Hz)
7.58 (1H, d, J=8.4 Hz, 1.8 Hz) 7.55 (1H, s) 7.22 (1H, d, J=8.4 Hz)
6.62 (1H, t, J=75 Hz) 4.70 (1H, sept, J=6.3 Hz) 3.85 (2H, s) 1.40
(6H, d, J=6.3 Hz).
Synthesis of Compound (iv)
[0168] 0.24 g of 5-benzyloxy-2-ethoxybenzoic acid and 0.44 g of
compound (iii) were suspended in 20 ml of acetone, and 0.27 g of
1-hydroxy benzotriazole (HOBt) and 0.38 g of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC)
were added thereto, followed by heating under reflux for 1 hour.
The reaction solution was cooled, and acetone was evaporated under
reduced pressure, followed by addition of water to the residue and
extraction with ethyl acetate. The organic layer was washed with
water twice and concentrated under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(n-hexane:ethyl acetate=3:1). The obtained crude crystals were
recrystallized from n-hexane:ethyl acetate, thereby obtaining 0.28
g of
N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-5-benzyloxy-
-2-ethoxybenzamide
(5-(benzyloxy)-N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)-
methyl)-2-ethoxybenzamide: compound (iv)) as a white powder.
[0169] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.68 (1H, br-s), 7.76 (1H,
d, J=3 Hz), 7.66-7.57 (3H, m), 7.38-7.20 (6H, m), 6.97 (1H, dd,
J=3.3, 8.7 Hz), 6.62 (1H, t, J=75 Hz), 4.71-4.61 (4H, m), 4.05 (2H,
q, J=6.9 Hz), 1.57-1.37 (9H, m).
Synthesis of Compound (v)
[0170] 5.5 g of
[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]methylamine(2-(3-(ben-
zyloxy)-4-(difluoromethoxy)phenyl)oxazol-4-yl)methanamine
(MAP-15211) synthesized in accordance with the synthesis procedure
described in PTL 2 (WO2014/034958 pamphlet) and 3.4 g of
acetylsalicylic acid were suspended in 150 ml of acetone. 3.4 g of
1-hydroxy benzotriazole (HOBt) and 4.8 g of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC)
were added thereto, followed by heating under reflux for 1 hour.
Subsequently, 10 ml of a 10% sodium hydroxide aqueous solution was
added thereto, and the mixture was heated under reflux for 30
minutes. The reaction solution was then cooled, and acetone was
evaporated under reduced pressure. Water was added to the residue
and extraction was performed with ethyl acetate. The organic layer
was washed with water twice and concentrated under reduced
pressure, thereby obtaining 3.1 g of
N-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-hydroxyben-
zamide
(N-((2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)oxazol-4-yl)methyl)-
-2-hydroxybenzamide: compound (v)) as a white powder.
[0171] .sup.1H-NMR (CDCl.sub.3) .delta.: 12.19 (1H, s) 7.70-7.72
(2H, m), 7.63 (1H, dd, J=8.4, 1.8 Hz), 7.28-7.51 (7H, m), 7.22-7.26
(2H, m), 6.98-7.01 (1H, m), 6.82-6.88 (2H, m), 6.63 (1H, t, J=74.7
Hz), 5.22 (2H, s), 4.60 (2H, dd, J=5.4, 0.9 Hz).
Synthesis of Compound (vi)
[0172] 3.1 g of compound (v) was dissolved in 45 ml of
N,N-dimethylformamide, and 1.7 g of 2-bromoethyl acetate and 1.8 g
of potassium carbonate were added thereto, followed by heating with
stirring at 80.degree. C. for 1 hour. Ice water was added to the
reaction solution, and extraction was performed with ethyl acetate.
The organic layer was washed with water twice and concentrated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (ethyl acetate:n-hexane=1:1), thereby
obtaining 3.6 g of
N-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-[(2-acetox-
y)ethoxy]benzamide
(2-(2-((2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)oxazol-4-yl)methylcarb-
amoyl)phenoxy)ethyl acetate: compound (vi)) as a white powder.
[0173] 1H-NMR (CDCl.sub.3) .delta.: 8.43 (1H, br-s) 8.25 (1H, d,
J=8.4 Hz), 7.73 (1H, d, J=1.8 Hz), 7.68 (1H, s), 7.62 (1H, dd,
J=5.4, 1.8 Hz), 7.34-7.49 (6H, m), 7.24-7.26 (1H, m), 7.09-7.15
(1H, m), 6.93 (1H, d, J=7.8 Hz), 6.63 (1H, t, J=74.4 Hz), 5.22 (2H,
s), 4.65 (2H, d, J=5.7 Hz), 4.50-4.53 (2H, m), 4.27-4.32 (2H, m),
2.03 (3H, s).
Synthesis of Compound (vii)
[0174] 3.5 g of compound (vi) was suspended in 100 ml of ethanol,
and 0.4 g of a 10% palladium carbon powder was added thereto,
followed by stirring in a hydrogen atmosphere at room temperature
for 4 hours. The catalyst was removed by filtration, and the crude
crystals obtained by concentrating the filtrate were recrystallized
from ethanol-n-hexane, thereby obtaining 2.1 g of
N-[2-(3-hydroxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-[(2-acetoxy)-
ethoxy]benzamide
(2-(2-((2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazol-4-yl)methylcarbamoy-
l)phenoxy)ethyl acetate: compound (vii)) as a white powder.
[0175] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.45 (1H, br-s), 8.25 (1H,
d, J=8.4 Hz), 7.76 (1H, s), 7.66 (1H, s), 7.42-7.53 (2H, m),
7.09-7.26 (3H, m), 6.95 (1H, d, J=7.8 Hz), 6.78 (1H, br-s), 6.64
(1H, t, J=74.1 Hz), 4.58-4.65 (4H, m), 4.31-4.34 (2H, m), 2.11 (2H,
s).
Synthesis of Compound (viii)
[0176] 5.1 g of methyl pyruvate and 0.8 ml of bromine were
dissolved in 15 ml of 1,2-dimethoxyethane, and the solution was
heated with stirring at 50.degree. C. for 1 hour. The reaction
solution was concentrated, and the residue was dissolved in 45 ml
of 2-methoxy ethanol. 3 g of 3-benzyloxy-4-difluoromethoxybenzamide
(3-(benzyloxy)-4-(difluoromethoxy)benzamide) synthesized in
accordance with the synthesis procedure described in PTL 1
(WO2007/058338 pamphlet) was added thereto and heated under reflux
for 4 hours. 25 ml of water was added to the reaction solution and
stirred at room temperature overnight. The precipitated crystals
were collected by filtration and dried under reduced pressure at
room temperature, thereby obtaining 0.73 g of methyl
2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazole-4-carboxylate
(methyl
2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxylate:
compound (viii)) as white crystals.
[0177] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.29 (1H, s) 7.84 (1H, d,
J=2.1 Hz) 7.71 (1H, dd, J=8.4 Hz, 1.8 Hz) 7.35-7.48 (6H, m) 6.64
(1H, t, J=75 Hz) 5.22 (2H, s) 3.97 (3H, s).
Synthesis of Compound (ix)
[0178] 0.28 g of compound (viii) was dissolved in 5 ml of ethanol,
1 ml of tetrahydrofuran, and 0.5 ml of N,N-dimethylformamide, and
0.03 g of a 10% palladium carbon powder was added thereto, followed
by stirring in a hydrogen atmosphere at room temperature for 2
hours. The catalyst was removed by filtration, and the filtrate was
concentrated under reduced pressure. Water was added to the
residue, and extraction was performed with ethyl acetate. The
organic layer was washed with a saturated sodium chloride solution
one time and concentrated under reduced pressure, thereby obtaining
0.18 g of methyl
2-(3-hydroxy-4-difluoromethoxyphenyl)oxazole-4-carboxylate (methyl
2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazole-4-carboxylate:
compound (ix)) as white crystals.
[0179] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.28 (1H, s), 7.77 (1H, d,
J=1.8 Hz), 7.68 (1H, dd, J=8.4, 1.8 Hz), 7.21 (1H, d, J=8.4 Hz),
6.61 (1H, t, J=72.9 Hz), 5.57 (1H, s), 3.96 (3H, s).
Production Example 6: Production of Compounds (11a) to (11s)
[0180] The compounds shown in the following Table 3 were produced
as described below. The .sup.1H-NMR of the produced compounds is
also shown below.
TABLE-US-00003 TABLE 3 Formula Number Structural Formula 11a
##STR00044## 11b ##STR00045## 11c ##STR00046## 11d ##STR00047## 11e
##STR00048## 11f ##STR00049## 11g ##STR00050## 11h ##STR00051## 11i
##STR00052## 11j ##STR00053## 11k ##STR00054## 11l ##STR00055## 11m
##STR00056## 11n ##STR00057## 11o ##STR00058## 11p ##STR00059## 11q
##STR00060## 11r ##STR00061## 11s ##STR00062##
Synthesis of Compound (11a)
[0181] 3 g of compound (iii) and 1.5 g of salicylic acid were
suspended in 60 ml of acetone, and 1.8 g of 1-hydroxy benzotriazole
(HOBt) and 2.6 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (WSC) were added thereto, followed by heating under
reflux for 1 hour. The reaction solution was cooled, and acetone
was evaporated under reduced pressure. Water was added to the
residue, and extraction was performed with ethyl acetate. The
organic layer was washed with water twice and concentrated under
reduced pressure. The obtained crude crystals were recrystallized
from ethyl acetate-n-hexane, thereby obtaining 1.47 g of
N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-hydroxybe-
nzamide
(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-
-2-hydroxybenzamide: compound (11a)) as a white powder.
[0182] .sup.1H-NMR (CDCl.sub.3) .delta.: 12.19 (1H, s), 7.70 (1H,
s), 7.50-7.64 (2H, m), 7.37-7.42 (2H, m), 7.23 (1H, d, J=8.4 Hz),
6.81-7.01 (3H, m), 6.63 (1H, t, J=75.0 Hz), 4.69 (1H, sept., J=6.0
Hz), 4.59 (2H, d, J=5.4 Hz), 1.40 (6H, d, J=6.0 Hz).
Synthesis of Compound (11b)
[0183] The procedure in "Synthesis of Compound (11a)" above was
repeated using 0.44 g of compound (iii) and 0.24 g of
2-ethoxy-3-hydroxy benzoic acid, thereby obtaining 0.28 g of
N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy-3--
hydroxybenzamide
(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-etho-
xy-3-hydroxybenzamide: compound (11b)) as a white powder.
[0184] .sup.1H-NMR (CDCl.sub.3) .delta.: 7.97 (1H, br-t, J=5.1 Hz),
7.70 (1H, s), 7.64 (1H, d, J=1.8 Hz), 7.52-7.60 (3H, m), 7.23 (1H,
d, J=8.4 Hz), 7.10 (1H, d, J=2.4 Hz), 7.09 (1H, s), 6.63 (1H, t,
J=75.0 Hz), 4.64-4.72 (1H, m), 4.61 (2H, d, J=5.1 Hz), 4.00 (2H, q,
J=6.9 Hz), 1.38 (3H, t, J=6.9 Hz).
Synthesis of Compound (11c)
[0185] The procedure in "Synthesis of Compound (11a)" above was
repeated using compound (iv), thereby obtaining 5 mg of
N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy-5--
hydroxybenzamide
(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-etho-
xy-5-hydroxybenzamide: compound (11c)) as a white powder.
[0186] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.83 (1H, br), 8.04 (1H,
d, J=3.3 Hz), 7.69 (1H, s), 7.64 (1H, d, J=1.8 Hz), 7.58 (1H, dd,
J=1.8, 8.4 Hz), 7.21 (1H, d, J=5.1 Hz), 6.87-6.99 (3H, m), 6.62
(1H, t, J=75 Hz), 4.61-4.72 (3H, m), 4.12 (2H, q, J=6.9 Hz),
1.38-1.47 (9H, m)
Synthesis of Compound (11d)
[0187] 0.1 g of compound (11a) was dissolved in 3 ml of
N,N-dimethylformamide, and 0.12 g of 2-bromoethyl acetate and 0.14
g of potassium carbonate were added thereto, followed by heating
with stirring at 80.degree. C. for 2 hours. Subsequently, 1 ml of
methanol and 0.3 ml of a 25% sodium hydroxide aqueous solution were
added to the reaction solution, and the mixture was heated under
reflux for 1 hour. Ice water was added to the reaction solution,
and extraction was performed with ethyl acetate. The organic layer
was washed with water twice and concentrated under reduced
pressure. The obtained residue was recrystallized from ethyl
acetate-n-hexane, thereby obtaining 70 mg of
N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-(2-hydrox-
yethoxy) benzamide
(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-(2-h-
ydroxyethoxy)benzamide: compound (11d)) as a white powder.
[0188] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.67 (1H, br-s) 8.16 (1H,
dd, J=7.8, 1.8 Hz), 7.70-7.74 (2H, m), 7.62 (1H, dd, J=8.4, 1.8
Hz), 7.40-7.46 (1H, m), 7.24-7.26 (1H, m), 7.06-7.12 (1H, m),
6.94-6.97 (1H, m), 6.65 (1H, t, J=75.0 Hz), 5.43 (1H, t, J=6.6 Hz),
4.69-4.77 (1H, m), 4.62 (2H, d, J=5.4 Hz), 4.18-4.21 (2H, m),
3.94-3.99 (2H, m), 1.42 (6H, d, J=6.3 Hz).
Synthesis of Compound (11e)
[0189] 0.3 g of compound (vii) and 0.3 ml of
1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) were dissolved in 4 ml of
ethanol, and 0.31 g of ethyl iodide was added thereto, followed by
heating under reflux overnight. Subsequently, 1 ml of a 10% sodium
hydroxide aqueous solution was added to the reaction solution, and
heated under reflux for 30 minutes. Thereafter, ice water was added
to the reaction solution, and extraction was performed with ethyl
acetate. The organic layer was washed with water twice and
concentrated under reduced pressure. The obtained crude crystals
were recrystallized from ethanol-n-hexane, thereby obtaining 95 mg
of
N-[2-(3-ethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-(2-hydroxyeth-
oxy)benzamide
N-((2-(4-(difluoromethoxy)-3-ethoxyphenyl)oxazol-4-yl)methyl)-2-(2-hydrox-
yethoxy)benzamide (OPA-15566) as a white powder.
[0190] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.86 (1H, br-s) 8.15 (1H,
dd, J=8.1, 1.8 Hz), 7.74 (1H, d, J=2.1 Hz), 7.70 (1H, s), 7.63 (1H,
dd, J=8.1, 2.1 Hz), 7.40-7.46 (2H, m), 7.06-7.09 (1H, m), 6.90-6.96
(1H, m), 6.66 (1H, t, J=74.7 Hz), 5.45 (1H, brs), 4.62 (2H, d,
J=5.4 Hz), 4.22 (2H, q, J=6.9 Hz), 4.19 (2H, dd, J=4.5, 4.2 Hz),
3.97 (2H, dd, J=4.5, 4.2 Hz), 1.50 (3H, t, J=6.9 Hz)
Synthesis of Compound (11f)
[0191] 0.3 g of compound (vii) and 0.3 ml of
1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) were dissolved in ethanol,
and 0.27 g of (bromomethyl)cyclopropane was added thereto, followed
by heating under reflux overnight. Subsequently, 1 ml of a 10%
sodium hydroxide aqueous solution was added to the reaction
solution, and heated under reflux for 30 minutes. Ice water was
then added to the reaction solution, and extraction was performed
with ethyl acetate. The organic layer was washed with water twice
and concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (methylene chloride).
The obtained crude crystals were recrystallized from ethyl
acetate-n-hexane, thereby obtaining 0.26 g of N-[2-(3-cyclopropyl
methoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-(2-hydroxyethoxy)ben-
zamide
(N-((2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-4-y-
l)methyl)-2-(2-hydroxyethoxy)benzamide: compound (11f)) as a white
powder.
[0192] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.85 (1H, br-s) 8.16 (1H,
dd, J=7.5, 1.8 Hz), 7.61-7.73 (2H, m), 7.40-7.46 (1H, m), 7.24-7.27
(1H, m), 7.06-7.12 (1H, m), 6.72 (1H, t, J=74.7 Hz), 5.37-5.42 (1H,
m), 4.18-4.21 (2H, m), 3.94-4.01 (4H, m), 1.32-1.37 (1H, m),
0.65-0.71 (2H, m), 0.37-042 (2H, m).
Synthesis of Compound (11g)
[0193] 0.3 g of compound (vii) and 0.3 ml of
1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) were dissolved in ethanol,
and 0.28 g of isobutyl bromide was added thereto, followed by
heating under reflux overnight. Subsequently, 1 ml of a 10% sodium
hydroxide aqueous solution was added to the reaction solution and
heated under reflux for 30 minutes. Ice water was then added to the
reaction solution, and extraction was performed with ethyl acetate.
The organic layer was washed with water twice and concentrated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (methylene chloride). The obtained crude
crystals were recrystallized from ethyl acetate-n-hexane, thereby
obtaining 0.15 g of
N-[2-(3-isobutoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-(2-hydroxy-
ethoxy) benzamide
(N-((2-(4-(difluoromethoxy)-3-isobutoxyphenyl)oxazol-4-yl)methyl)-2-(2-hy-
droxyethoxy)benzamide: compound (11g)) as a white powder.
[0194] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.86 (1H, br-s) 8.16 (1H,
dd, J=7.8, 1.8 Hz), 7.70-7.74 (2H, m), 7.61-7.64 (1H, m), 7.40-7.46
(1H, m), 7.24-7.26 (1H, m), 6.97-6.90 (1H, m), 6.64 (1H, t, J=75.0
Hz), 5.40 (1H, t, J=6.6 Hz), 4.62 (2H, d, J=5.4 Hz), 4.18-4.22 (2H,
m), 3.90-4.00 (4H, m), 2.11-2.25 (1H, m), 1.08 (6H, d, J=6.9
Hz).
Synthesis of Compound (11h)
[0195] 0.3 g of compound (vii) and 0.3 ml of
1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) were dissolved in ethanol,
and 0.3 g of (bromomethyl)cyclobutane was added thereto, followed
by heating under reflux overnight. Subsequently, 1 ml of a 10%
sodium hydroxide aqueous solution was added to the reaction
solution and heated under reflux for 30 minutes. Ice water was then
added to the reaction solution, and extraction was performed with
ethyl acetate. The organic layer was washed with water twice and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (methylene chloride).
The obtained crude crystals were recrystallized from ethyl
acetate-n-hexane, thereby obtaining 0.24 g of
N-[2-(3-cyclobutylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-(2-
-hydroxyethoxy) benzamide
(N-((2-(3-(cyclobutylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-4-yl)methy-
l)-2-(2-hydroxyethoxy) benzamide: compound (11h)) as a white
powder.
[0196] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.86 (1H, br-s) 8.16 (1H,
dd, J=7.8, 1.8 Hz), 7.63 (1H, dd, J=8.4, 2.1 Hz), 7.70-7.74 (2H,
m), 7.40-7.46 (1H, m), 7.23-7.26 (1H, m), 7.07-7.12 (1H, m), 6.95
(1H, d, J=7.8 Hz), 6.65 (1H, t, J=75.3 Hz), 5.41 (1H, t, J=6.6 Hz),
4.62 (2H, d, J=5.4 Hz), 4.20 (2H, dd, J=4.5, 4.2 Hz), 4.11 (2H, d,
J=6.6 Hz), 3.96-4.01 (2H, m), 2.80-2.90 (1H, m), 2.13-2.20 (2H, m),
1.88-2.02 (4H, m).
Synthesis of Compound (11i)
[0197] 0.28 g of compound (iii) and 0.17 g of 2,3-dihydroxy benzoic
acid were suspended in 3 ml of acetone, and 0.17 g of 1-hydroxy
benzotriazole (HOBt) and 0.23 g of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC)
were added thereto, followed by heating under reflux for 3 hours.
The reaction solution was cooled, and acetone was evaporated under
reduced pressure. Water was added to the residue, and extraction
was performed with ethyl acetate. The organic layer was washed with
water twice and concentrated under reduced pressure. The obtained
residue was partially purified by silica gel column chromatography
(dichloromethane:methanol=50:1). The obtained crude crystals were
recrystallized from n-hexane-acetone, thereby obtaining 0.2 g of
N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2,3-dihydro-
xybenzamide
(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2,3-di-
hydroxybenzamide: compound (11i)) as a white powder.
[0198] .sup.1H-NMR (DMSO) .delta.: 12.54 (1H, s), 9.30 (1H, br-t,
J=5.4 Hz), 9.23 (1H, s), 8.12 (1H, s), 7.61 (1H, d, J=1.8 Hz), 7.55
(1H, dd, J=8.4, 1.8 Hz), 7.38-7.28 (2H, m), 7.15 (1H, t, J=74.1
Hz), 6.95-6.89 (1H, m), 6.69 (1H, t, J=8.1 Hz), 4.74 (1H, sept.,
J=6.0 Hz), 4.45 (2H, d, J=5.4 Hz), 1.32 (6H, d, J=6.0 Hz).
Synthesis of Compound (11j)
[0199] The procedure in "Synthesis of Compound (11i)" above was
repeated using 0.28 g of compound (iii) and 0.17 g of
2,4-dihydroxybenzoic acid, thereby obtaining 0.17 g of
N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2,4-dihydro-
xybenzamide
(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2,4-di-
hydroxybenzamide: compound (11j)) as a white powder.
[0200] .sup.1H-NMR (DMSO) .delta.: 12.75 (1H, s), 10.11 (1H, s),
9.05 (1H, br-t, J=5.4 Hz), 8.10 (1H, s), 7.74 (1H, d, J=8.7 Hz),
7.61 (1H, d, J=1.8 Hz), 7.55 (1H, dd, J=8.4, 1.8 Hz), 7.32 (1H, d,
J=8.4 Hz), 7.16 (1H, t, J=74.1 Hz), 6.29 (1H, dd, J=8.7 Hz, 2.4
Hz), 6.24 (1H, d, J=2.4 Hz), 4.74 (1H, sept., J=6.0 Hz), 4.42 (2H,
d, J=5.7 Hz), 1.32 (6H, d, J=6.0 Hz).
Synthesis of Compound (11k)
[0201] The procedure in "Synthesis of Compound (11i)" above was
repeated using 0.28 g of compound (iii) and 0.17 g of
2,5-dihydroxybenzoic acid, thereby obtaining 0.16 g of
N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2,5-dihydro-
xybenzamide
(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2,5-di-
hydroxybenzamide: compound (11k)) as a white powder.
[0202] .sup.1H-NMR (DMSO) .delta.: 11.47 (1H, s), 9.14 (1H, br-t,
J=5.4 Hz), 8.98 (1H, s), 8.08 (1H, s), 7.61 (1H, d, J=1.8 Hz), 7.55
(1H, dd, J=8.4, 1.8 Hz), 7.31 (1H, d, J=8.4 Hz), 7.29 (1H, d, J=3.0
Hz), 7.14 (1H, t, J=74.1 Hz), 6.86 (1H, dd, J=8.7 Hz), 6.74 (1H, d,
J=8.7 Hz), 4.74 (1H, sept., J=6.0 Hz), 4.44 (2H, d, J=5.1 Hz), 1.31
(6H, d, J=6.0 Hz).
Synthesis of Compound (11l)
[0203] The procedure in "Synthesis of Compound (11i)" above was
repeated using 0.28 g of compound (iii) and 0.17 g of
2,6-dihydroxybenzoic acid, thereby obtaining 0.2 g of
N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2,6-dihydro-
xybenzamide
(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2,6-di-
hydroxybenzamide: compound (11l)) as a white powder.
[0204] .sup.1H-NMR (DMSO) .delta.: 12.51 (1H, s), 9.32 (1H, br-t,
J=5.4 Hz), 8.11 (1H, s), 7.62 (1H, d, J=1.8 Hz), 7.56 (1H, dd,
J=8.4, 1.8 Hz), 7.32 (1H, d, J=8.4 Hz), 7.18 (1H, t, J=8.1 Hz),
7.14 (1H, t, J=74.1 Hz), 6.37 (2H, d, J=8.1 Hz), 4.74 (1H, sept.,
J=6.0 Hz), 4.52 (2H, d, J=5.4 Hz), 1.32 (6H, d, J=6.0 Hz).
Synthesis of Compound (11m)
[0205] 0.2 g of compound (11a) was dissolved in 2 ml of
acetonitrile. 0.23 g of sodium iodide, 0.27 g of potassium
carbonate, and 98 mg of 3-chloropropyl acetate were added thereto,
followed by heating under reflux overnight. 2 ml of a 10% sodium
hydroxide aqueous solution was further added thereto, and the
mixture was heated under reflux until the reaction was completed.
After cooling, water was added to the reaction solution, and
extraction was performed with ethyl acetate. The organic layer was
washed with water twice and concentrated under reduced pressure.
The obtained residue was purified by silica gel column
chromatography (n-hexane:ethyl acetate=3:1), and the obtained crude
crystals were recrystallized from ethanol-n-hexane, thereby
obtaining 0.15 g of
N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-
-(3-hydroxypropoxyy)benzamide
(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-(3-h-
ydroxypropoxy)benzamide: compound (11m)) as a white powder.
[0206] .sup.1H-NMR (CDCl.sub.3) .delta.: 9.11 (1H, br-t, J=6.0 Hz),
8.21 (1H, dd, J=8.4, 1.8 Hz), 7.72 (1H, s), 7.61 (1H, d, J=1.8 Hz),
7.57 (1H, dd, J=8.4, 1.8 Hz), 7.38-7.44 (1H, m), 7.26-7.23 (1H, m),
7.03-7.08 (1H, m), 6.96 (1H, d, J=8.4 Hz), 6.63 (1H, t, J=75.0 Hz),
4.69 (1H, sept., J=6.0 Hz), 4.59 (2H, d, J=6.0 Hz), 4.29 (2H, t,
J=5.4 Hz), 3.89-3.94 (2H, m), 2.07-2.13 (2H, m), 1.41 (6H, d, J=6.0
Hz).
Synthesis of Compound (11n)
[0207] 0.18 g of compound (ix) was dissolved in 2 ml of
N,N-dimethylformamide, and 0.18 g of potassium carbonate and 0.12
ml of isopropyl bromide were added thereto, followed by stirring at
room temperature for 16 hours and at 45.degree. C. for 4 hours.
Water was added thereto with ice cooling, and extraction was
performed with ethyl acetate. The organic layer was washed with a
saturated sodium chloride solution one time and concentrated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=2:1), thereby
obtaining 0.16 g of methyl
2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazole-4-carboxylate
(methyl
2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazole-4-carboxylate:
compound (11n)) as a white powder.
[0208] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.28 (1H, s), 7.74 (1H, d,
J=1.8 Hz), 7.66 (1H, dd, J=8.4, 1.8 Hz), 7.25 (1H, d, J=8.4 Hz),
6.63 (1H, t, J=74.7 Hz), 4.71 (1H, sept., J=6.0 Hz), 3.96 (3H, s),
1.39 (6H, d, J=6.0 Hz).
Synthesis of Compound (11o)
[0209] 0.7 g of compound (11n) was dissolved in 7 ml of methanol,
and 1.4 ml of a 25% sodium hydroxide aqueous solution was added
thereto, followed by heating under reflux at room temperature for
30 minutes. The reaction solution was stirred with ice cooling, and
concentrated hydrochloric acid was added thereto to give a pH of 3,
followed by collection of the precipitated crystals by filtration.
The obtained crystals were dried under reduced pressure, thereby
obtaining
2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazole-4-carboxylic acid
(2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazole-4-carboxylic
acid: compound (11o)).
[0210] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.38 (1H, s), 7.74 (1H, d,
J=1.8 Hz), 7.66 (1H, dd, J=8.1 Hz, 1.8 Hz), 7.25 (1H, d, J=8.1 Hz),
6.64 (1H, t, J=75 Hz), 4.72 (1H, sept, J=6.3 Hz), 1.40 (6H, d,
J=6.3 Hz).
Synthesis of Compound (11p)
[0211] The procedure in "Synthesis of Compound (11i)" above was
repeated using compound (iii) and 2-ethoxy-6-hydroxy benzoic acid,
thereby obtaining
N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-
-ethoxy-6-hydroxybenzamide
(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-etho-
xy-6-hydroxybenzamide: compound (11p)).
[0212] .sup.1H-NMR (CDCl.sub.3) .delta.: 13.81 (1H, s), 9.00 (1H,
brs), 7.68-7.62 (2H, m), 7.60 (1H, dd, J=8.4 Hz, 2.1 Hz), 7.30-7.18
(2H, m), 6.63 (1H, t, J=75 Hz), 6.61 (1H, d, J=8.4 Hz), 6.37 (1H,
d, J=8.1 Hz), 4.69 (1H, sept, J=6.0 Hz), 4.60 (2H, dd, J=5.1 Hz,
0.9 Hz), 4.15 (2H, dd, J=14.1 Hz, 6.9 Hz), 1.48 (3H, t, J=6.9 Hz),
1.40 (6H, d, J=6.3 Hz).
Synthesis of Compound (11q)
[0213] The procedure in "Synthesis of Compound (11i)" above was
repeated using compound (iii) and 2-ethoxy-3,4-dihydroxybenzoic
acid, thereby obtaining
N-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-
-ethoxy-3,4-dihydroxybenzamide
(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-etho-
xy-3,4-dihydroxybenzamide: compound (11q)).
[0214] .sup.1H-NMR (d6-DMSO) .delta.: 9.83 (1H, brs), 8.65 (1H,
brs), 8.54 (1H, t, J=5.4 Hz), 8.10 (1H, s), 7.63 (1H, d, J=1.8 Hz),
7.56 (1H, dd, J=8.4 Hz, 1.8 Hz), 7.33 (1H, d, J=8.4 Hz), 7.21 (1H,
d, J=8.7 Hz), 7.15 (1H, t, J=74 Hz), 6.62 (1H, d, J=8.4 Hz), 4.73
(1H, sept, J=6.0 Hz), 4.45 (2H, d, J=5.4 Hz), 4.03 (2H, dd, J=14.1
Hz, 7.2 Hz), 1.32 (6H, d, J=6.0 Hz), 1.25 (3H, t, J=7.2 Hz).
Synthesis of Compound (11r)
[0215] A typical synthesis procedure was performed using 0.1 g of
compound (11a) and chlorosulfuric acid, thereby obtaining
N-[(2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-yl)methylcarbamoyl]--
2-phenyl ammonium sulfate (ammonium
2-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methylcarbamoyl-
)phenyl sulfate (compound (11r)) as a white powder. The melting
point was 162.0.degree. C.
Synthesis of Compound (11s)
[0216] A typical synthesis procedure was performed using 0.1 g of
compound (11a), 1-bromo-2,3,4-tri-O-acetyl-.alpha.-D-glucuronic
acid methyl, and silver oxide, thereby obtaining
(2S,3S,4S,5R,6S)-6-(2-((2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4--
yl)methylcarbamoyl)phenyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxyli-
c acid
((2S,3S,4S,5R,6S)-6-(2-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)-
oxazol-4-yl)methylcarbamoyl)
phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid:
compound (11s)) as a white powder. The melting point was
163.6.degree. C.
Production Example 7: Production of Formulations
Study of Solvent
[0217] To select a solvent for dissolving compound (11) in
preparing an ointment containing compound (11), the solubility of
compound (11) in various solvents was studied. Even a solvent
having a high solubility of compound (11) exhibits reduced
solubility of compound (11) if it has compatibility with a base
material (ointment base), such as petrolatum or paraffin, and is
mixed with the base material. Such a case may result in
precipitation of compound (11). Thus, a solvent that has a high
solubility of compound (11) but that has no or low miscibility
(compatibility) with petrolatum or paraffin is relatively
preferable for use. Table 4 shows the results of the study.
TABLE-US-00004 TABLE 4 Miscibility of Compound (11) Solubility
Solvent Solvent Solution with Petrolatum (W/W %) Triacetine
Immiscible 32.5 Propylene carbonate Immiscible 56.9 Diethyl
sebacate Miscible 42.6 Diisopropyl adipate Miscible 40.3 Isostearic
acid Miscible 19.8 Olive oil Miscible 6.1 Isopropyl myristate
Miscible 6.0 Hexyldodecanol Miscible 5.4 Isostearyl alcohol
Miscible 5.1 Decyl oleate Miscible 2.6 Liquid Paraffin Miscible
0.1
[0218] Table 4 indicates that triacetin and propylene carbonate
have low miscibility with petrolatum, and also indicates that
triacetin and propylene carbonate have a relatively high solubility
of compound (11).
Formulation of Ointment
[0219] Ointments (Examples 1 to 10 and Comparative Examples 1 to 8)
were prepared as described below. As noted above, solvents that
dissolve compound (11) were found. Thus, the present invention
encompasses all of the ointments prepared by dissolving compound
(11) in a solvent. However, of these, the following describes
particularly preferable examples as Examples, and others as
Comparative Examples for convenience. The particle size of droplets
is measured by placing a suitable amount of a prepared ointment on
a glass slide and observing the droplet size with a polarizing
microscope.
Example 1
[0220] 73.0 g of white petrolatum, 10.0 g of liquid paraffin, 3.0 g
of paraffin, and 1.0 g of beeswax (non-chemically bleached beeswax)
were heated and dissolved at 70.degree. C. in an agi-homomixer.
Thereafter, a solution of 3.0 g of compound (11) in 10.0 g of
propylene carbonate was further added thereto, and the mixture was
stirred with a homomixer at 5000 rpm and with a paddle at 30 rpm.
The homomixer was then turned off at 45.degree. C., and the paddle
and cooling were turned off at 40.degree. C. to give a droplet size
of 20 .mu.m or less. Thereafter, the resulting product was inserted
into aluminum tubes, 5 g in each tube, with a YS-7 filling machine,
and the tubes were sealed, thereby obtaining ointments.
Example 2
[0221] The procedure of Example 1 was repeated except that 72.0 g
of white petrolatum and 2.0 g of beeswax were used, thereby
obtaining ointments.
Example 3
[0222] The procedure of Example 1 was repeated except that 70.5 g
of white petrolatum and 3.5 g of beeswax were used, thereby
obtaining ointments.
Example 4
[0223] The procedure of Example 1 was repeated except that 81.0 g
of white petrolatum, 1.0 g of compound (11), and 4.0 g of propylene
carbonate were used, thereby obtaining ointments.
Example 5
[0224] The procedure of Example 4 was repeated except that 80.0 g
of white petrolatum and 2.0 g of beeswax were used, thereby
obtaining ointments.
Example 6
[0225] The procedure of Example 4 was repeated except that 78.5 g
of white petrolatum and 3.5 g of beeswax were used, thereby
obtaining ointments.
Example 7
[0226] The procedure of Example 6 was repeated except that 79.2 g
of white petrolatum and 0.3 g of compound (11) were used, thereby
obtaining ointments.
Example 8
[0227] The procedure of Example 6 was repeated except that 79.4 g
of white petrolatum and 0.1 g of compound (11) were used, thereby
obtaining ointments.
Example 9
[0228] 70.5 g of white petrolatum, 10.0 g of liquid paraffin, 3.0 g
of paraffin, and 3.5 g of beeswax (chemically bleached beeswax)
were heated and dissolved at 70.degree. C. in an agi-homomixer.
Thereafter, a solution of 3.0 g of compound (11) in 10.0 g of
propylene carbonate was further added thereto, and the mixture was
stirred with a homomixer at 5000 rpm and with a paddle at 30 rpm.
The homomixer was then turned off at 45.degree. C., and the paddle
and cooling were turned off at 40.degree. C. to give a droplet size
of 20 .mu.m or less. Thereafter, resulting product was inserted
into aluminum tubes, 5 g in each tube, with a YS-7 filling machine,
and the tubes were sealed, thereby obtaining ointments.
Example 10
[0229] The procedure of Example 3 was repeated except that 73.5 g
of white petrolatum and 7.0 g of propylene carbonate were used,
thereby obtaining ointments.
Comparative Example 1
[0230] The procedure of Example 4 was repeated except that 82.0 g
of white petrolatum was used, and that beeswax was not added,
thereby obtaining ointments.
Comparative Example 2
[0231] 58.5 g of white petrolatum, 6.0 g of paraffin, 6.0 g of
beeswax, and 5.0 g of diethyl sebacate were heated and dissolved at
70.degree. C. by hand stirring in a 200-mL beaker. After cooling to
50.degree. C., 17 g of liquid paraffin was added thereto, and the
mixture was heated to 50.degree. C. 13 g of a paste containing 10 g
of liquid paraffin and 3 g of micronized compound (11) was added
thereto and mixed well by hand stirring, with the temperature
maintained at 50.degree. C. The mixture was cooled to room
temperature with ice water. Thereafter, the mixture was inserted
into aluminum tubes, 5 g in each tube, with a YS-7 filling machine,
thereby obtaining ointments.
[0232] Micronized compound (11) was obtained by adding compound
(11) to liquid paraffin and pulverizing the mixture with a
DYNO-MILL (bead mill). Thus-obtained paste was used in the
operation above.
Comparative Example 3
[0233] The procedure of Example 3 was repeated except that 75.5 g
of white petrolatum and 5.0 g of propylene carbonate were used,
thereby obtaining ointments.
Comparative Example 4
[0234] The procedure of Example 6 was repeated except that 80.5 g
of white petrolatum and 2.0 g of propylene carbonate were used,
thereby obtaining ointments.
Comparative Example 5
[0235] The procedure of Example 6 was repeated except that 79.5 g
of white petrolatum was used, and that compound (11) was not added,
thereby obtaining ointments.
Comparative Example 6
[0236] The procedure of Example 3 was repeated except that the
mixture was stirred with a homomixer at 1500 rpm and with a paddle
at 15 rpm, thereby preparing an ointment having a droplet size of
about 50 .mu.m.
Comparative Example 7
[0237] The procedure of Example 6 was repeated except that the
mixture was stirred with a homomixer at 1500 rpm and with a paddle
at 15 rpm, thereby preparing an ointment having a droplet size of
about 50 .mu.m.
Comparative Example 8
[0238] The procedure of Example 7 was repeated except that the
mixture was stirred with a homomixer at 1500 rpm and with a paddle
at 15 rpm, thereby preparing an ointment having a droplet size of
about 50 .mu.m.
[0239] Table 5 shows the compositions of formulations described
above.
TABLE-US-00005 TABLE 5 Component and Amount of Component (w/w %)
White Liquid Propylene Diethyl State of Droplet Size Formulation
Compound(11) Petrolatum Paraffin Paraffin Beeswax Carbonate
Sebacate Formulation (Particle Size) Example 1 3 73 10 3 1 10 --
Homogeneous droplet- 20 .mu.m or less dispersion ointment Example 2
3 72 10 3 2 10 -- Homogeneous droplet- 20 .mu.m or less dispersion
ointment Example 3 3 70.5 10 3 3.5 10 -- Homogeneous droplet- 20
.mu.m or less dispersion ointment Example 4 1 81 10 3 1 4 --
Homogeneous droplet- 20 .mu.m or loss dispersion ointment Example 5
1 80 10 3 2 4 -- Homogeneous droplet- 20 .mu.m or less dispersion
ointment Example 6 1 78.5 10 3 3.5 4 -- Homogeneous droplet- 20
.mu.m or less dispersion ointment Example 7 0.3 79.2 10 3 3.5 4 --
Homogeneous droplet- 20 .mu.m or less dispersion ointment Example 8
0.1 79.4 10 3 3.5 4 -- Homogeneous droplet- 20 .mu.m or less
dispersion ointment Example 9 3 70.5 10 3 3.5 10 -- Homogeneous
droplet- 20 .mu.m or less dispersion ointment Example 10 3 73.5 10
3 3.5 7 -- Homogeneous droplet- 20 .mu.m or less dispersion
ointment Comparative 1 82 10 3 -- 4 -- Homogeneous droplet- 20
.mu.m or less Example 1 dispersion ointment Comparative 3 58.5 27 6
5 -- 5 Homogenous ointment 20 .mu.m or less Example 2 in which
crystals are (crystalline dispersed particle size) Comparative 3
75.5 10 3 3.5 5 -- Homogeneous ointment -- Example 3 Comparative 1
80.5 10 3 3.5 2 -- Homogeneous ointment -- Example 4 Comparative --
79.5 10 3 3.5 4 -- Homogeneous droplet- -- Example 5 dispersion
ointment Comparative 3 70.5 10 3 3.5 10 -- Inhomogeneous More than
Example 6 droplet-dispersion 50 .mu.m ointment Comparative 1 78.5
10 3 3.5 4 -- Inhomogeneous More than Example 7 droplet-dispersion
50 .mu.m ointment Comparative 0.3 79.2 10 3 3.5 4 -- Inhomogeneous
More than Example 8 droplet-dispersion 50 .mu.m ointment
Study into Formulation Stability 1
[0240] The ointments prepared in Comparative Example 1 and Examples
4, 5, and 6 were allowed to stand at 40.degree. C. for 2 months.
Thereafter, the dispersion state of the propylene carbonate
solution in each formulation was examined. Table 6 shows the
results. Table 6 reveals that beeswax maintains the homogeneous
dispersion state, and thus improves stability.
TABLE-US-00006 TABLE 6 Formulation Amount of Beeswax Dispersion
State Comparative 0 The particle size Example 1 was increased.
Example 4 1.0 Excellent Example 5 2.0 Excellent Example 6 3.5
Excellent
Study into Formulation Stability 2
[0241] The ointments prepared in Comparative Example 1 and Examples
1 to 6 are different in the amount of beeswax added. These
formulations were subjected to a stability test at 50.degree. C.
for 2 weeks, 4 weeks, or 6 weeks. To examine the degree of
decomposition of compound (11), the amount of generated
3-(2-propoxy 3-difluoromethoxy)benzamide, which is one of the
decomposed matters, was measured by high-performance liquid
chromatography. Table 7 shows the results. The values in Table 7
indicate the concentration (wt %) of compound (11), beeswax, and
the decomposed matter in each formulation. While Comparative
Example 1, to which beeswax was not added, generated about 1% of
the decomposed matter, the formulations made by adding beeswax
exhibited reduced generation of the decomposed matter.
TABLE-US-00007 TABLE 7 Concentration Amount of of Compound Beeswax
After 2 After 4 After 6 Formulation (11) (%) Added (%) weeks weeks
weeks Comparative 1.0 0 0.90 0.99 0.97 Example 1 Example 4 1.0 1.0
0.00 <0.05 <0.05 Example 5 1.0 2.0 0.00 0.00 0.00 Example 6
1.0 3.5 0.00 <0.05 <0.05 Example 1 3.0 1.0 <0.05 0.23 0.18
Example 2 3.0 2.0 0.00 0.00 <0.05 Example 3 3.0 3.5 0.00 0.00
<0.05
Study into Formulation Stability 3
[0242] The formulation of the formulation of Example 3 was prepared
using beeswax that was not bleached (unbleached beeswax), beeswax
bleached by non-chemical purification (non-chemically bleached
beeswax), or beeswax that was chemically bleached (chemically
bleached beeswax) as beeswax, and the formulation was inserted into
aluminum tubes, and sealed, followed by storage at 50.degree. C.
for 2 weeks, 4 weeks, or 8 weeks. In the same manner as above, with
the generated decomposed matter of compound (11) (3-(2-propoxy
3-difluoromethoxy)benzamide) as an index, the stability of compound
(11) was examined. Table 8 shows the results. While the use of
chemically bleached beeswax generated a high amount of the
decomposed matter, the use of non-chemically bleached beeswax and
unbleached beeswax exhibited reduced generation of the decomposed
matter.
TABLE-US-00008 TABLE 8 After 2 After 4 After 8 Type of Beeswax
Weeks weeks weeks Chemically Bleached Beeswax Produced by 0.19 0.20
0.16 Company A Non-Chemically Bleached Beeswax 0.00 0.00 0.00
Produced by Company A Unbleached Beeswax Produced by Company 0.00
0.00 0.00 A Non-Chemically Bleached Beeswax 0.00 0.00 0.00 Produced
by Company C Chemically Bleached Beeswax Produced by 0.18 0.16 0.25
Company D
Study into Formulation Stability 4
[0243] Ointments containing compound (11) and different amounts of
beeswax were prepared. A predetermined amount of each ointment was
placed on a glass slide, and the droplet size of each ointment was
confirmed with a polarizing microscope to search for the amount of
beeswax necessary to obtain an ointment in which droplets are
excellently dispersed. The ointments (Examples 11 to 19 and
Comparative Examples 9 to 11) were prepared as described below. The
present invention encompasses all of the ointments containing
beeswax. However, of these, the following describes particularly
preferable examples as Examples, and others as Comparative Examples
for convenience.
Example 11
[0244] 141.0 g of white petrolatum, 20.0 g of liquid paraffin, 6.0
g of paraffin, and 7.0 g of beeswax (non-chemically bleached
beeswax) were heated and dissolved at 70.degree. C. in an
agi-homomixer. Thereafter, a solution of 6.0 g of compound (11) in
20.0 g of propylene carbonate was further added thereto, and the
mixture was stirred with a homomixer at 5000 rpm and with a paddle
at 30 rpm, followed by cooling. The homomixer was turned off at
45.degree. C. and the paddle and cooling were turned off at
40.degree. C. The resulting product was inserted into aluminum
tubes, 5 g in each tube, with a YS-7 filling machine, and the tubes
were sealed, thereby obtaining ointments.
Example 12
[0245] The procedure of Example 11 was repeated except that 146.0 g
of white petrolatum and 2.0 g of beeswax were used, thereby
obtaining ointments.
Example 13
[0246] The procedure of Example 11 was repeated except that 146.4 g
of white petrolatum and 1.6 g of beeswax were used, thereby
obtaining ointments.
Example 14
[0247] The procedure of Example 11 was repeated except that 146.8 g
of white petrolatum and 1.2 g of beeswax were used, thereby
obtaining ointments.
Comparative Example 9
[0248] The procedure of Example 11 was repeated except that 147.2 g
of white petrolatum and 0.8 g of beeswax were used, thereby
obtaining ointments.
Comparative Example 10
[0249] The procedure of Example 11 was repeated except that 147.6 g
of white petrolatum and 0.4 g of beeswax were used, thereby
obtaining ointments.
Example 15
[0250] 157.0 g of white petrolatum, 20.0 g of liquid paraffin, 6.0
g of paraffin, and 7.0 g of beeswax (non-chemically bleached
beeswax) were heated and dissolved at 70.degree. C. in an
agi-homomixer. Thereafter, a solution of 2.0 g of compound (11) in
8.0 g of propylene carbonate was further added thereto, and the
mixture was stirred with a homomixer at 5000 rpm and with a paddle
at 30 rpm, followed by cooling. The homomixer was turned off at
45.degree. C., and the paddle and cooling were turned off at
40.degree. C. The resulting product was inserted into aluminum
tubes, 5 g in each tube, with a YS-7 filling machine, and the tubes
were sealed, thereby obtaining ointments.
Example 16
[0251] The procedure of Example 15 was repeated except that 162.0 g
of white petrolatum and 2.0 g of beeswax were used, thereby
obtaining ointments.
Example 17
[0252] The procedure of Example 15 was repeated except that 162.4 g
of white petrolatum and 1.6 g of beeswax were used, thereby
obtaining ointments.
Example 18
[0253] The procedure of Example 15 was repeated except that 162.8 g
of white petrolatum and 1.2 g of beeswax were used, thereby
obtaining ointments.
Example 19
[0254] The procedure of Example 15 was repeated except that 163.2 g
of white petrolatum and 0.8 g of beeswax were used, thereby
obtaining ointments.
Comparative Example 11
[0255] The procedure of Example 15 was repeated except that 163.6 g
of white petrolatum and 0.4 g of beeswax were used, thereby
obtaining ointments.
[0256] Table 9 shows the formulations and the state of the
dispersion of droplets of the ointments. The unit is wt %. Table 9
reveals that when an ointment containing 3 parts by weight of
component (11) contains 0.6 parts by weight or more of beeswax, the
ointment exhibits particularly excellent dispersion of the
droplets, and that when an ointment containing 1 part by weight of
compound (11) contains 0.4 parts by weight or more of beeswax, the
ointment exhibits particularly excellent dispersion of the
droplets.
TABLE-US-00009 TABLE 9 Component and Amount of Component (w/w %)
White Liquid Propylene State of Formulation Compound(11) Petrolatum
Paraffin Paraffin Beeswax Carbonate Formulation Example 11 3.0 70.5
10.0 3.0 3.5 10.0 Droplet-dispersion ointment having a particle
size of 20 .mu.m or less Example 12 3.0 73.0 10.0 3.0 1.0 10.0
Droplet-dispersion ointment having a particle size of 20 .mu.m or
less Example 13 3.0 73.2 10.0 3.0 0.8 10.0 Droplet-dispersion
ointment having a particle size of 20 .mu.m or less Example 14 3.0
73.4 10.0 3.0 0.6 10.0 Droplet-dispersion ointment having a
particle size of 20 .mu.m or less Comparative 3.0 73.6 10.0 3.0 0.4
10.0 Droplet-dispersion Example 9 ointment having a particle size
of more than 20 .mu.m Comparative 3.0 73.8 10.0 3.0 0.2 10.0
Droplet-dispersion Example 10 ointment having a particle size of
more than 50 .mu.m Example 15 1.0 78.5 10.0 3.0 3.5 4.0
Droplet-dispersion ointment having a particle size of 20 .mu.m or
less Example 16 1.0 81.0 10.0 3.0 1.0 4.0 Droplet-dispersion
ointment having a particle size of 20 .mu.m or less Example 17 1.0
81.2 10.0 3.0 0.8 4.0 Droplet-dispersion ointment having a particle
size of 20 .mu.m or less Example 18 1.0 81.4 10.0 3.0 0.6 4.0
Droplet-dispersion ointment having a particle size of 20 .mu.m or
less Example 19 1.0 81.6 10.0 3.0 0.4 4.0 Droplet-dispersion
ointment having a particle size of 20 .mu.m or less Comparative 1.0
81.8 10.0 3.0 0.2 4.0 Droplet-dispersion Example 11 ointment having
a particle size of more than 20 .mu.m
* * * * *