U.S. patent application number 10/627642 was filed with the patent office on 2004-02-05 for process for preparing butanetriol derivative.
This patent application is currently assigned to Daiso Co., Ltd.. Invention is credited to Furukawa, Yoshiro, Hirata, Makoto, Mikami, Masafumi.
Application Number | 20040024261 10/627642 |
Document ID | / |
Family ID | 11981732 |
Filed Date | 2004-02-05 |
United States Patent
Application |
20040024261 |
Kind Code |
A1 |
Hirata, Makoto ; et
al. |
February 5, 2004 |
Process for preparing butanetriol derivative
Abstract
A process for preparing a butanetriol derivative of the formula
(1) useful as intermediates of medicines 1 wherein R.sup.1 is the
same defined below, which comprises reacting a compound of the
formula (3) 2 wherein R.sup.1 and R.sup.2 are the different
protecting groups, and an ethylene glycol derivative in a basic
condition to prepare a compound of the formula (4) or (4a) 3
wherein R.sup.1 and R.sup.2 are the same defined above, and then
subjecting the compound (4) or (4a) to selective deprotection
reaction.
Inventors: |
Hirata, Makoto;
(Amagasaki-shi, JP) ; Mikami, Masafumi;
(Amagasaki-shi, JP) ; Furukawa, Yoshiro;
(Amagasaki-shi, JP) |
Correspondence
Address: |
JACOBSON HOLMAN PLLC
400 SEVENTH STREET N.W.
SUITE 600
WASHINGTON
DC
20004
US
|
Assignee: |
Daiso Co., Ltd.
Osaka-shi
JP
|
Family ID: |
11981732 |
Appl. No.: |
10/627642 |
Filed: |
July 28, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10627642 |
Jul 28, 2003 |
|
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|
09581086 |
Jun 9, 2000 |
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6620977 |
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09581086 |
Jun 9, 2000 |
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PCT/JP99/00355 |
Jan 28, 1999 |
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Current U.S.
Class: |
568/675 |
Current CPC
Class: |
Y02P 20/55 20151101;
C07C 303/28 20130101; C07C 303/30 20130101; C07C 303/28 20130101;
C07C 309/66 20130101; C07C 303/30 20130101; C07C 309/66
20130101 |
Class at
Publication: |
568/675 |
International
Class: |
C07C 043/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 30, 1998 |
JP |
018802/1998 |
Claims
1. A process for preparing a butanetriol derivative of the formula
(1) 23which comprises subjecting a compound of the following
formula (4) or (4a) to deprotection reaction 24wherein in the above
formulae, R.sup.1 and R.sup.2 are the different each other and are
protecting groups for alcohol and said protecting groups such that
only R.sup.2 is removed when the deprotection reaction is carried
out.
2. A process for preparing a butanetriol derivative of the formula
(1) 25wherein R.sup.1 is the same defined above, which comprises
reacting a compound of the formula (3) 26wherein R.sup.1 and
R.sup.2 are the same defined above, and a compound of the formula
(2) 27wherein X is halogen atom or sulfonyloxy group, and R.sup.2
is the same as defined above, in a basic condition to prepare a
compound of the formula (4) 28wherein R.sup.1 and R.sup.2 are the
same defined above, and then subjecting the compound (4) to
deprotection reaction.
3. A process for preparing a butanetriol derivative of the formula
(1) 29wherein R.sup.1 is the same defined above, which comprises
reacting a compound of the formula (3) 30wherein R.sup.1 and
R.sup.2 are the same defined above, and a compound of the following
formula (2a) 31wherein X is halogen atom or sulfonyloxy group, or
ethylene oxide in a basic condition to prepare a compound of the
formula (4a) 32wherein R.sup.1 and R.sup.2 are the same defined
above, and then subjecting the compound (4a) to deprotection
reaction.
4. A process for preparing a compound (1) which comprises
protecting primary hydroxy group for a compound of the formula (5)
33wherein R.sup.2 is the same as defined above, and then carrying
out the process of claim (2) or claim (3).
5. A process for preparing a compound (1) which comprises
protecting a compound of the formula (7) 34wherein R.sup.3 and
R.sup.4 are the same or different and are hydrogen, C.sub.1-C.sub.4
alkyl or phenyl, or may form a C.sub.3-C.sub.6 cycloalkyl with the
adjacent carbon atom, with a protecting agent of alcohol to prepare
a compound of the formula (6) 35wherein R.sup.2, R.sup.3 and
R.sup.4 are the same as defined above, and then treating the
compound (6) with an acid to prepare a compound (5) and then
carrying out the process of claim (4).
6. A process for preparing a compound (1) which comprises
protecting primary hydroxy group for a compound of the formula (8)
36wherein R.sup.1 is the same as defined above, to prepare a
compound (3) and then carrying out the process of claim (2) or
claim (3).
7. A process for preparing a compound (1) which comprises reducing
a compound of the formula (9) 37wherein R.sup.5 is C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl, phenyl, C.sub.1-C.sub.6 alkyl
substituted phenyl, aralkyl or 2-alkenyl, and R.sup.1 is the same
as defined above, with an aluminum-reducing agent or a
boron-reducing agent, to prepare a compound (8) and then carrying
out the process of claim (6).
8. A process for preparing a compound (1) which comprises
protecting primary hydroxy group for a compound of the formula (10)
38wherein R.sup.1 is the same as defined above, to prepare a
compound (9) and then carrying out the process of claim (7).
9. The process for preparing a compound (1) according to any of
claims 1 to 8, comprising using compound (3) and compound (4) or
(4a), wherein the protecting groups, R.sup.1 and R.sup.2 in
compounds (3) and (4) or (4a) are different each other and are
protecting groups selected from the group of silyl ether-protecting
groups, phenyl substituted methyl-protecting group and
acetal-protecting groups, and that only R.sup.2 is removed when the
deprotection is carried out.
10. The process for preparing a compound (1) according to claim 9,
wherein the protecting groups, R.sup.1 and R.sup.2 in compounds (3)
and (4) or (4a) are a silyl ether-protecting group and a phenyl
substituted methyl-protecting group, respectively.
11. The process for preparing a compound (1) according to claim 9,
wherein the protective groups, R.sup.1 and R.sup.2 in compounds (3)
and (4) or (4a) are a phenyl substituted methyl-protecting group
and a silyl ether-protecting group, respectively.
12. The process for preparing a compound (1) according to claim 9,
wherein the protecting groups, R.sup.1 and R.sup.2 in compounds (3)
and (4) or (4a) are a silyl ether-protecting group and an
acetal-protecting group, respectively.
13. The process for preparing a compound (1) according to claim 9,
wherein the protecting groups, R.sup.1 and R.sup.2 in compounds (3)
and (4) or (4a) are an acetal-protecting group and a silyl
ether-protecting group, respectively.
14. The process for preparing a compound (1) according to claim 9,
wherein the protecting groups, R.sup.1 and R.sup.2 in compounds (3)
and (4) or (4a) are a phenyl substituted methyl-protecting group
and an acetal-protecting group, respectively.
15. The process for preparing a compound (1) according to claim 9,
wherein the protecting groups, R.sup.1 and R.sup.2 in compounds (3)
and (4) or (4a) are an acetal-protecting group and a phenyl
substituted methyl-protecting group, respectively.
16. The process for preparing a compound (1) according to claim 9,
wherein the protecting groups, R.sup.1 and R.sup.2 in compounds (3)
and (4) or (4a) are trityl and benzyl, respectively.
17. The process for preparing a compound (1) according to any of
claims 2 to 16, comprising reacting compound (2), (2a) or ethylene
oxide with compound (3) in an aprotic solvent.
18. The process for preparing a compound (1) of claim 17, wherein
the aprotic solvent is N,N-dimethylformamide or dimethyl
sulfoxide.
19. The process for preparing a compound (1) according to any of
claims 2 to 18, comprising using an alkali metal hydride, hydroxide
or carbonate as a base in reacting compound (2), (2a) or ethylene
oxide with compound (3).
20. The process for preparing an optically active compound (1)
according to any of claims 1 to 19, comprising using a optically
active starting material.
21. A process for preparing a compound of the following formula
(11) or its optically active compound 39wherein R.sup.6 is
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, phenyl,
C.sub.1-C.sub.6 alkyl, hologen-substituted phenyl or
nitro-substituted phenyl and R.sup.1 is the same as defined above,
which comprising preparing a compound (1) by the process of any of
claims 1 to 20 and then subjecting the compound to sulfonyl
esterification.
22. A compound of the following formula (3), (5) or (8) or its
optically active compound 40wherein R.sup.1 and R.sup.2 are the
same as defined above.
23. A compound of the following formula (4) or its optically active
compound 41wherein R.sup.1 and R.sup.2 are the same as defined
above.
24. A compound of the following formula (4a) or its optically
active compound 42wherein R.sup.1 and R.sup.2 are the same as
defined above.
Description
TECHNICAL FIELD
[0001] The present invention relates to a process for preparing a
butanetriol derivative, which is important as an intermediate in
making antidiabetics having protein kinase C inhibiting activity
and relates to a novel intermediate of the butanetriol
derivative.
BACKGROUND ART
[0002] Butanetriol derivatives are used as intermediates in making
antidiabetics having protein kinase C inhibiting activity. It is
known that butanetriol derivatives are prepared by reacting
glycidyl trityl ether and vinylmagnesium bromide, by
allyl-etherification and by ozonolysis of resulting olefin,
followed by treatment of resulting aldehyde with sodium borohydride
(U.S. Pat. No. 5,541,347).
[0003] Glycidyl trityl ether, however is expensive and the
reactions with vinylmagnesium bromide and by ozonolysis have to be
carried out at lower temperature, -20.degree. C. and -35 to
-50.degree. C., respectively. The procedures, therefore are
troublesome. Furthermore, ozone is harmful to human body and there
is a possibility of explosion. Thus, the known methods are not
satisfactory for application to industrially scaled production. The
superior method has been desired.
DISCLOSURE OF INVENTION
[0004] As a result of extensive investigation on an improved method
for preparing butanetriol derivatives, the present inventors have
found that butanetriol derivatives can be favorably prepared in
industrial scale by using the starting material which is easily
available.
[0005] The present invention relates to a novel process for
preparing a butanetriol derivative, which is important as an
intermediate in making antidiabetics having protein kinase C
inhibiting activity and relates to a novel intermediate
thereof.
[0006] The process for preparing a butanetriol derivative (1) of
the present invention is shown as the following reaction scheme.
4
[0007] In the above formulae, R.sup.1 and R.sup.2 are the different
each other and are a protecting group for alcohol and said
protecting group such that only R.sup.2 is removed when
deprotection reaction is carried out. R.sup.3 and R.sup.4 are the
same or different and are hydrogen, C.sub.1-C.sub.4 alkyl or
phenyl, or may form a C.sub.3-C.sub.6 cycloalkyl group together
with the adjacent carbon atom. X is halogen atom or sulfonyloxy
group.
[0008] Each step is explained below in detail.
[0009] Process for Preparing Compound (6)
[0010] Compound (6) is prepared from compound (7).
[0011] Introduction of the protecting group (R.sup.2) except
tetrahydropyranyl group is carried out by etherifying hydroxy group
for compound (7) in the presence of a base to give compound
(6).
[0012] Examples of the protecting group are silyl ether-protecting
groups, such as triethylsilyl, tert-butyldimethylsilyl or
tert-butyldiphenylsilyl- , benzyl-protecting groups, such as
benzyl, p-methoxybenzyl or trityl, and acetal-protecting groups
such as methoxymethyl etc.
[0013] Introduction of tetrahydropyranyl group is carried out by
reacting compound (7) and dihydropyrane in the presence of acid
catalyst, such as p-toluenesulfonic acid or pyridinium
p-toluenesulfonate.
[0014] Preferable protecting groups are tert-butyldimethyl-silyl,
tert-butyldiphenylsilyl, benzyl and p-methoxybenzyl, especially
tert-butyldimethylsilyl and benzyl.
[0015] Introduction of the protecting group except
tetrahydropyranyl group is carried out by reacting hydroxy group of
compound (7) with an alkylating agent in the presence of a
base.
[0016] Examples of the base used in this reaction are alkali metal
or alkaline earth metal hydroxides, such as sodium hydroxide or
potassium hydroxide, alkali metal or alkaline earth metal hydrogen
carbonates, such as sodium hydrogen carbonate or potassium hydrogen
carbonate, alkali metal or alkaline earth metal carbonates, such as
sodium carbonate or potassium carbonate, alkali metal or alkaline
earth metal hydrides, such as sodium hydride or potassium hydride,
organic alkali metal salts, such as dimsyl sodium, n-butyllithium,
sec-butyllithium or tert-butyllithium, and alkali metal amides,
such as lithium diisopropylamide, potassium diisopropylamide,
sodium hexamethyldisilazide, potassium hexamethyldisilazide or
lithium hexamethyl-disilazide.
[0017] Amount of the base is equimole or more than equimole to the
substrate, preferably 1.0 to 1.2 moles.
[0018] Regarding of silyl ether-protecting groups or
benzyl-protecting groups, examples of the reacting agent used for
protection are silyl halides, such as tert-butyldimethylsilyl
chloride, tert-butyldiphenylsilyl chloride, alkyl halides, such as
benzyl chloride or benzyl bromide and sulfonic acid esters such as
trifluoromethane-sulfonic acid tert-butyldimethylsilyl ester.
Regarding acetal-protecting groups, examples of the reacting agent
used for protection are alkoxymethyl halides such as methoxymethyl
chloride.
[0019] Amount of the reacting agent is equimole or more than
equimole to the substrate, preferably 1.0 to 1.2 moles.
[0020] Examples of a solvent used are aprotic solvents, such as
N,N-dimethylformamide, dimethyl sulfoxide or
hexamethylphosphoramide, hydrocarbons, such as benzene or toluene,
ethers, such as tetrahydrofuran, 1,4-dioxane, glyme, diglyme or
triglyme, or a mixture thereof, when as the base are used alkali
metal or alkaline earth metal hydrides, such as sodium hydride or
potassium hydride, organic alkali metal salts, such as dimsyl
sodium, dimsyl potassium, n-butyllithium, sec-butyllithium or
tert-butyllithium, or alkali metal amides, such as lithium
diisopropylamide, potassium diisopropylamide, sodium
hexamethyldisilazide, potassium hexamethyldisilazide or lithium
hexamethyldisilazide.
[0021] Examples of a solvent used are aprotic solvents, such as
N,N-dimethylformamide, dimethyl sulfoxide or
hexamethyl-phosphoramide, hydrocarbons, such as benzene or toluene,
ethers, such as tetrahydrofuran, 1,4-dioxane, glyme, diglyme or
triglyme, halogen compounds, such as dichloromethane, chloroform or
1,2-dichloroethane, water or a mixture with an organic solvent
thereof and water, preferably ethers, aprotic solvents or a mixture
of an aprotic solvent and water, especially preferably
N,N-dimethylformamide, dimethyl sulfoxide or a mixture of dimethyl
sulfoxide and water, when as the base are used alkali metal or
alkaline earth metal hydroxides, such as sodium hydroxide or
potassium hydroxide, alkali metal or alkaline earth metal hydrogen
carbonates, such as sodium hydrogen carbonate or potassium hydrogen
carbonate, alkali metal or alkaline earth metal carbonates, such as
sodium carbonate or potassium carbonate.
[0022] The reaction temperature is from -78.degree. C. to reflux
temperature of the solvent.
[0023] The reaction proceeds without catalyst, but the reaction is
promoted in the presence of iodo compounds, such as cesium iodide,
potassium iodide or sodium iodide, bromo compounds, such as cesium
bromide, potassium bromide or sodium bromide, quaternaryammonium
phase transfer catalysts, such as tetrabutylammonium chloride or
trimethylbenzyl-ammonium bromide, Crown ethers such as 18-Crown-6,
4-N,N-dimethylaminopyridine, 2,6-lutidine or 4-methoxypyridine,
especially effective when a leaving group for the reacting agent
used for protection is chlorine atom.
[0024] As the reaction promoter, alkali metal bromides or iodides
are preferable, especially sodium bromide, potassium bromide,
sodium iodide and potassium iodide.
[0025] Amount of the reaction promoter is 0.5 to 1.1 moles to
compound (7). To use too small amount causes decrease of reaction
rate and is not practical.
[0026] When R.sup.2 is silyl ether-protecting groups, such as
triethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl,
phenyl-substituted methyl-protecting groups, such as benzyl or
trityl, or acetal-protecting groups such as methoxymethyl, the
protection reaction can be also carried out with halogeno silane
compounds, such as trityl chloride or tert-butyldimethylsilyl
chloride, alkyl halides, such as benzyl chloride or benzyl bromide,
sulfonic acid esters, such as tert-butyldimethylsilyl
trifluoromethanesulfonate, or alkoxymethyl halides such as
methoxymethyl chloride in the presence of a tertiary amine, such as
triethylamine or pyridine.
[0027] Amount of said reagent is equimole or more than equimole to
the substrate, preferably 1.0 to 1.2 moles.
[0028] Examples of a solvent used are aprotic solvents, such as
N,N-dimethylformamide, dimethyl sulfoxide or
hexamethyl-phosphoramide, ethers, such as tetrahydrofuran,
1,4-dioxane, glyme, diglyme or triglyme, hydrocarbons, such as
benzene or toluene, nitriles such as acetonitrile, halogen
compounds, such as dichloromethane, chloroform or
1,2-dichloroethane, or a mixture thereof, preferably aprotic
solvents or ethers, especially preferably N,N-dimethylformamide or
dimethyl sulfoxide. The reaction is promoted by adding a pyridine
derivative, such as 4-N,N-dimethylaminopyridine, 2,6-lutidine or
4-methoxypyridine, preferably 4-N,N-dimethylaminopyridine.
[0029] The reaction temperature is from 0.degree. C. to reflux
temperature of the solvent, preferably from room temperature to
around. 50.degree. C.
[0030] On the other hand, introduction of tetrahydropyranyl group
is carried out by reacting dihydropyrane in the presence of acid
catalyst, such as p-toluenesulfonic acid or pyridinium
p-toluenesulfonate.
[0031] Amount of dihydropyrane is 1 to 1.2 moles to the
substrate.
[0032] Examples of a solvent are aprotic solvents, such as
N,N-dimethylformamide, dimethyl sulfoxide or
hexamethyl-phosphoramide, hydrocarbons, such as benzene or toluene,
ethers, such as tetrahydrofuran, 1,4-dioxane, glyme, diglyme or
triglyme, halogen compounds, such as dichloromethane, chloroform or
1,2-dichloroethane, or a mixture thereof, preferably aprotic
solvents or ethers, especially preferably N,N-dimethylformamide or
tetrahydro-furan.
[0033] The reaction temperature is from -78.degree. C. to reflux
temperature of the solvent.
[0034] Process for Preparing Compound (5)
[0035] Diol compound (5) is prepared by reacting compound (6) with
an acid.
[0036] Examples of the acid are mineral acids, such as hydrochloric
acid or sulfuric acid, organic acid, such as p-toluenesulfonic
acid, benzenesulfonic acid, methanesulfonic acid or trifluoroacetic
acid, or Lewis acid, such as boron trifluoride etherate, aluminum
trichloride, tin tetrachloride or titanium tetrachloride.
[0037] Amount of the acid is equimole or more than equimole to the
substrate, preferably 1.0 to 1.2 moles.
[0038] The solvents, when the acid is a mineral acid or an organic
acid, are alcohols, such as methanol, ethanol or 2-propanol,
hydrocarbons, such as benzene or toluene, ethers, such as
tetrahydrofuran, 1,4-dioxane, glyme, diglyme or triglyme, or a
mixture thereof, preferably alcohols, especially methanol. When
Lewis acid is used, examples of the solvent are aprotic solvents,
such as N,N-dimethylformamide, dimethyl sulfoxide or
hexamethyl-phosphoramide, hydrocarbons, such as benzene or toluene,
ethers, such as tetrahydrofuran, 1,4-dioxane, glyme, diglyme or
triglyme, or a mixture thereof, preferably aprotic solvents or
ethers, especially N,N-dimethylformamide or tetrahydrofuran.
[0039] The reaction temperature is from 0.degree. C. to reflux
temperature of the solvent, preferably from room temperature to
around 50.degree. C.
[0040] Process for Preparing Compound (3)
[0041] Compound (3) is prepared by protecting a primary hydroxy
group for compound (5) with the protecting group (R.sup.1)
different from the protecting group (R.sup.2).
[0042] R.sup.1 is not limited as long as R.sup.1 and R.sup.2 can be
removed under different condition, and R.sup.1 is not removed when
R.sup.2 is deprotected.
[0043] The protecting groups (R.sup.1) are different from R.sup.2
and are silyl. ether-protecting groups, such as triethylsilyl,
tert-butyldimethylsilyl or tert-butyldiphenylsilyl,
phenyl-substituted methyl-protecting groups, such as benzyl,
p-methoxybenzyl or trityl, or acetal-protecting groups, such as
tetrahydropyranyl or methoxymethyl.
[0044] The combination of the protecting groups R.sup.1 and R.sup.2
is selected from silyl ether-protecting groups, phenyl-substituted
methyl-protecting groups and acetal-protecting groups. The
combination is different each other and is such the combination as
only R.sup.2 is removed, when deprotection reaction is carried
out.
[0045] For example, the following combinations are illustrated;
R.sup.1 is a silyl ether-protecting group and R.sup.2 is a
phenyl-substituted methyl-protecting group; R.sup.1 is a
phenyl-substituted methyl-protecting group and R.sup.2 is a silyl
ether-protecting group; R.sup.1 is a silyl ether-protecting group
and R.sup.2 is an acetal-protecting group; R.sup.1 is an
acetal-protecting group and R.sup.2 is a silyl ether-protecting
group; R.sup.1 is a phenyl-substituted methyl-protecting group and
R.sup.2 is an acetal-protecting group.
[0046] More concretely, when R.sup.2 is a phenyl-substituted
methyl-protecting group, such as benzyl or p-methoxybenzyl, R.sup.1
is tetrahydropyranyl, methoxymethyl, trityl, or a silyl
ether-protecting group, such as tert-butyldimethylsilyl or
tert-butyldiphenylsilyl. When R.sup.2 is tert-butyldimethylsilyl,
R.sup.1 is a phenyl-substituted methyl-protecting group, such as
benzyl, p-methoxybenzyl or trityl, an acetal-protecting group, such
as tetrahydropyranyl or methoxymethyl, or tert-butyldiphenylsilyl
more bulky than tert-butyldimethylsilyl.
[0047] When R.sup.2 is tert-butyldiphenylsilyl, R.sup.1 is a
phenyl-substituted methyl-protecting group, such as benzyl,
p-methoxybenzyl or trityl, an acetal-protecting group such as,
tetrahydropyranyl or methoxymethyl, or dimethylthexylsilyl. When
R.sup.2 is an acetal-protecting group, such as tetrahydropyranyl or
methoxymethyl, R.sup.1 is phenyl-substituted methyl-protecting
group, such as benzyl, p-methoxybenzyl except trityl, or a silyl
ether-protecting group, such as tert-butyldimethylsilyl or
tert-butyldiphenylsilyl. The preferable combination of R.sup.1 and
R.sup.2 is that R.sup.2 is tert-butyldimethylsilyl,
tert-butyldiphenylsilyl, benzyl or p-methoxybenzyl, and R.sup.1 is
dimethylthexylsilyl or trityl. The especially preferable
combination is one that R.sup.2 is benzyl and R.sup.1 is
trityl.
[0048] Introduction of these protecting groups is carried out in
accordance with the method of introduction of R.sup.2 for compound
(7) mentioned above.
[0049] Process for Preparing Compound (4)
[0050] Compound (4) is prepared by reacting compound (3) with
ethylene glycol derivative (2) after treating compound (3) with a
base.
[0051] Examples of leaving group (X) of ethylene glycol derivative
(2) are halogen, such as chlorine or bromine, sulfonic acid ester,
such as methanesulfonyloxy or p-toluenesulfonyloxy, and examples of
R.sup.2 of ethylene glycol derivative (2) are the same protecting
groups as the protective groups (R.sup.2) of compound (3) mentioned
above, such as benzyl, tert-butyldimethylsilyl,
tert-butyldiphenylsilyl, tetrahydropyranyl or methoxymethyl.
[0052] Examples of the base used in this reaction are alkali metal
or alkaline earth metal hydroxides, such as sodium hydroxide or
potassium hydroxide, alkali metal or alkaline earth metal hydrogen
carbonates, such as sodium hydrogen carbonate or potassium hydrogen
carbonate, alkali metal or alkaline earth metal carbonates, such as
sodium carbonate or potassium carbonate, alkali metal or alkaline
earth metal hydrides, such as sodium hydride or potassium hydride,
organic alkali metal salts, such as dimsyl sodium, n-butyllithium,
sec-butyllithium or tert-butyllithium, or alkali metal amides, such
as lithium diisopropylamide, potassium diisopropylamide, sodium
hexamethyldisilazide, potassium hexamethyldisilazide or lithium
hexamethyl-disilazide, preferably alkali metal hydride, alkali
metal hydroxide, alkali metal carbonate, especially sodium hydride,
sodium hydroxide or potassium hydroxide.
[0053] Amount of the base is 1.0-10 moles to the substrate,
preferably 1.0 to 2.0 moles.
[0054] Examples of a solvent are aprotic solvents such as
N,N-dimethylformamide, dimethyl sulfoxide or
hexamethyl-phosphoramide, hydrocarbons, such as benzene or toluene,
ethers, such as tetrahydrofuran, 1,4-dioxane, glyme, diglyme or
triglyme, or a mixture thereof, when as the base are used alkali
metal or alkaline earth metal hydrides, such as sodium hydride or
potassium hydride, organic alkali metal salts, such as dimsyl
sodium, dimsyl potassium, n-butyllithium, sec-butyllithium or
tert-butyllithium, or alkali metal amides, such as lithium
diisopropylamide, potassium diisopropylamide, sodium
hexamethyldisilazide, potassium hexamethyldisilazide or lithium
hexamethyl-disilazide.
[0055] Examples of a solvent are aprotic solvents such as
N,N-dimethylformamide, dimethyl sulfoxide or
hexamethyl-phosphoramide, hydrocarbons, such as benzene or toluene,
ethers, such as tetrahydrofuran, 1,4-dioxane, glyme, diglyme or
triglyme, halogen compounds, such as dichloromethane, chloroform or
1,2-dichloroethane, water or a mixture with an organic solvent
thereof and water, preferably ethers, aprotic solvents or a mixture
of an aprotic solvent and water, especially preferably
N,N-dimethylformamide, dimethyl sulfoxide or a mixture of dimethyl
sulfoxide and water, when as the base are used alkali metal or
alkaline earth metal hydroxides, such as sodium hydroxide or
potassium hydroxide, alkali metal or alkaline earth metal hydrogen
carbonates, such as sodium hydrogen carbonate or potassium hydrogen
carbonate, alkali metal or alkaline earth metal carbonates, such as
sodium carbonate or potassium carbonate.
[0056] The reaction proceeds without catalyst, but the reaction is
promoted in the presence of iodo compounds such as cesium iodide,
potassium iodide or sodium iodide, bromo compounds, such as cesium
bromide, potassium bromide or sodium bromide, quaternaryammonium
phase transfer catalysts, such as tetrabutylammonium chloride or
trimethylbenzyl-ammonium bromide, Crown ethers such as 18-Crown-6,
or pyridine derivatives, such as 4-N,N-dimethylaminopyridine,
2,6-rutidine or 4-methoxypyridine, especially effective when the
leaving group of a reactive substance used for protection is
chlorine atom.
[0057] As the reaction promoter, alkali metal bromides or iodides
are preferable, especially sodium bromide, potassium bromide,
sodium iodide or potassium iodide.
[0058] Amount of the reaction promoter is 0.05 to 1.1 moles to
compound (3). To use too small amount causes decrease of the
reaction rate and is not practical.
[0059] The reaction temperature is from -100.degree. C. to reflux
temperature of the solvent, preferably from 0.degree. C. to reflux
temperature of the solvent.
[0060] The preferable reaction is to react compound (3) with
benzyloxyethyl methanesulfonate as ethylene glycol derivative (2),
in N,N-dimethylformamide or dimethyl sulfoxide under sodium hydride
at 0.degree. C. to room temperature or to react compound (3) with
benzyloxyethyl methanesulfonate in N,N-dimethylformamide under
sodium hydroxide or potassium hydroxide.
[0061] Process for Preparing Compound (1)
[0062] Compound (1) is prepared by selectively removing a
protective group ( R.sup.2) of compound (4).
[0063] When R.sup.2 is a phenyl-substituted methyl-protecting
group, such as benzyl or p-methoxybenzyl, it is removed under
catalytic hydrogenation. Catalysts used in the hydrogenation are
heterogeneous catalysts, such as 5% Pt--C, 5%-10% Pd--C, Palladium
black or Raney nickel, or homogeneous catalysts such as Wilkinson's
complex.
[0064] Amount of the catalyst to a substrate is 1-100% by weight.
As hydrogen donor, hydrogen gas, cyclohexene, cyclohexadiene and
ammonium formate are illustrated. Solvents used are alcohols, such
as ethanol or 2-propanol, esters, such as methyl acetate or ethyl
acetate, ethers, such as tetrahydrofuran, 1,4-dioxane, glyme,
diglyme or triglyme, hydrocarbons, such as benzene or toluene, or a
mixture thereof, preferably alcohols or esters, especially
methanol, ethanol or ethyl acetate.
[0065] The reaction is carried out under ambient pressure. The
reaction temperature is from 0.degree. C. to reflux temperature,
preferably from room temperature to reflux temperature.
[0066] p-Methoxybenzyl group can be also removed by reacting
2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a solvent, such as
ethers, e.g. tetrahydrofuran, 1,4-dioxane, glyme, diglyme or
triglyme, or hydrocarbons, such as benzene or toluene.
[0067] Preferable deprotection method is subjecting to catalytic
reduction with 5% or 10% Pd--C under hydrogen gas in methanol or
ethyl acetate under ambient pressure at room temperature.
[0068] When R.sup.2 is a silyl ether-protecting group such as
tert-butyldimethylsilyl, it is deprotected by reacting fluoro
anion, such as hydrogen fluoride or tetrabutylammonium
fluoride.
[0069] Amount of the fluoro anion is 2.0-10 moles to the substrate.
Solvents used are ethers, such as tetrahydrofuran, 1,4-dioxane,
glyme, diglyme or triglyme, nitriles such as acetonitrile,
hydrocarbons, such as benzene or toluene, or a mixture thereof,
preferably ethers or nitrites, especially tetrahydrofuran.
[0070] The reaction temperature is from 0.degree. C. to reflux
temperature of the solvent, preferably from room temperature to
reflux temperature of the solvent.
[0071] The protective group can be removed by reacting a mineral
acid, such as hydrochloric acid or sulfuric acid, an organic acid,
such as p-toluenesulfonic acid, benzenesulfonic acid,
methanesulfonic acid or trifluoroacetic acid, or a Lewis acid, such
as boron trifluoride etherate, aluminum trichloride, tin
tetrachloride or titanium tetrachloride in an ether, such as
tetrahydrofuran, 1,4-dioxane, glyme, diglyme or triglyme, a
hydrocarbon, such as benzene or toluene, or a mixture thereof.
[0072] The reaction temperature is from 0.degree. C. to refluxing
temperature of the solvent, preferably 0.degree. C. to room
temperature. Preferable deprotection method is carried out by
reacting 2 moles or more than 2 moles, preferably 2.0-2.2 moles of
tetrabutylammonium fluoride to a substrate in tetrahydrofuran at
0.degree. C. to room temperature.
[0073] When R.sup.2 is an acetal-protecting group, such as
tetrahydropyranyl or methoxymethyl, it is removed by treating with
an acid. The acid used are mineral acids, such as hydrochloric acid
or sulfuric acid, organic acids such as p-toluenesulfonic acid,
benzenesulfonic acid, methanesulfonic acid or trifluoroacetic acid,
or Lewis acids, such as boron trifluoride etherate, aluminum
trichloride, tin tetrachloride or titanium tetrachloride.
[0074] The acid is used 0.1-10 moles to a substrate, preferably 2-4
moles.
[0075] Solvents used are alcohols, such as methanol, ethanol or
2-propanol, ethers, such as tetrahydrofuran, 1,4-dioxane, glyme,
diglyme or triglyme, nitriles such as acetonitrile, hydrocarbons,
such as benzene or toluene, or a mixture thereof, preferably ethers
or alcohols, especially methanol or ethanol.
[0076] The reaction temperature is from 0.degree. C. to reflux
temperature, preferably from 0.degree. C. to room temperature.
[0077] Preferable deprotection method is carried out by reacting 2
moles of p-toluenesulfonic acid to a substrate in tetrahydrofuran
or methanol at 0.degree. C. to room temperature.
[0078] Another Process for Preparing Compound (1)
[0079] As shown in the following reaction scheme, after reacting
compound (3) with a base, compound (4a) is prepared by reacting
compound (2a) or ethylene oxide (2b) therewith, and then, by
selectively removing the protecting group (R.sup.2) of the compound
to give compound (1). 5
[0080] wherein R.sup.1, R.sup.2 and X are the same as defined
above.
[0081] Process for Preparing Compound (4a)
[0082] Compound (4a) is prepared by reacting compound (2a) or
ethylene oxide (2b) with compound (3), after treating compound (3)
with a base.
[0083] The reaction of compound (3) with compound (2a) or ethylene
oxide (2b) is carried out in the almost same manner as the reaction
of compound (3) and compound (2) as mentioned above.
[0084] By deprotecting R.sup.2 for thus obtained compound (4a)
there is obtained butanetriol derivative (1).
[0085] The deprotection of R.sup.2 can be carried out in the same
manner as the method for preparing compound (1) by removing the
protecting group (R.sup.2) of compound (4) as mentioned above.
[0086] Another Process for Preparing Compound (3)
[0087] Compound (3) is prepared from compound (10) as shown in the
following reaction scheme. 6
[0088] wherein R.sup.1 and R.sup.2 are the same as defined above,
R.sup.5 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl,
phenyl or C.sub.1-C.sub.6 alkyl substituted phenyl, aralkyl or
2-alkenyl.
[0089] Process for Preparing Compound (9)
[0090] Compound (9) is prepared by protecting the primary hydroxy
group for compound (10) with the protecting group (R.sup.1)
different from the protecting group (R.sup.2) of compound (3),
which is prepared in the latter step.
[0091] R.sup.1 is not limited as long as R.sup.1 and R.sup.2 can be
removed by the different condition, and R.sup.1 is not removed when
R.sup.2 is deprotected. Examples of R.sup.1 and the combination of
R.sup.1 and R.sup.2 are the same described in the above section on
the process for preparing compound (3).
[0092] Introduction of the protecting group is also carried out in
the same manner as introduction of R.sup.2 to compound (7).
[0093] Process for Preparing Compound (8)
[0094] Compound (8) is prepared by reducing the ester group of
compound (8).
[0095] Reducing agents are aluminum-reducing agents, such as
lithium aluminum hydride or diisobutyl aluminum hydride, or
boron-reducing agents, such as sodium borohydride, lithium
borohydride, lithium tri-sec-butyl borohydride, potassium
tri-sec-butyl borohydride, boron tetrahydrofuran or boron
dimethylsulfide complex, preferably lithium aluminum hydride or
sodium borohydride.
[0096] The reduction is carried out in a solvent such as ethers,
e.g. tetrahydrofuran, 1,4-dioxane, glyme, diglyme or triglyme, or
hydrocarbons, e.g. benzene, toluene or a mixture thereof. When
sodium borohydride is used, an alcohol, such as methanol, ethanol
or propanol may be used as a solvent.
[0097] Amount of the reducing agent calculated in hydrido ion is
2.0-15 moles to the substrate.
[0098] The reaction temperature is from -100.degree. C. to reflux
temperature of the solvent, preferably -78.degree. C. to room
temperature.
[0099] Another Process for Preparing Compound (3)
[0100] Compound (3) is prepared by protecting primary hydroxy group
for compound (8) with the protecting group (R.sup.2) different from
R.sup.1.
[0101] R.sup.2 is not limited as long as R.sup.1 and R.sup.2 can be
deprotected by the different condition and R.sup.1 is not removed
when R.sup.2 is deprotected. Examples of R.sup.2 and the
combination of R.sup.1 and R.sup.2 are the same described in the
above section on processes for preparing compound (6) and compound
(3).
[0102] Introduction of the protecting group is also carried out in
the same manner as introduction of R.sup.2 to compound (7).
[0103] Process for Preparing Compound (11)
[0104] A compound of the following formula (11) is prepared by
bissulfonyl esterification of compound (1) in the presence of a
tertiary amine, such as triethylamine or pyridine. 7
[0105] wherein R.sup.6 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, substituted or non-substituted C.sub.1-C.sub.6 alkyl,
halogeno phenyl or nitro phenyl, and R.sup.1 is the same as defined
above.
[0106] By bissulfonyl esterification, crystallizabilty of the
product becomes good and therefore, it becomes easy to purify the
product by recrystallization.
[0107] Sulfonyl halides, such as methanesulfonyl chloride,
methanesulfonyl bromide, p-toluenesulfonyl chloride,
benzenesulfonyl chloride, or sulfonic acid anhydride such as
methanesulfonic acid anhydride are used in the sulfonyl
esterification.
[0108] Amount of the esterification agent is 2 moles or more than 2
moles to the substrate, preferably 2.0 to 2.2 moles.
[0109] Examples of a solvent are aprotic solvents, such as
N,N-dimethylformamide, dimethyl sulfoxide or
hexamethylphosphoramide, ethers, such as tetrahydrofuran,
1,4-dioxane, glyme, diglyme or triglyme, nitriles such as
acetonitrile, halogen compounds, such as dichloromethane,
chloroform or 1,2-dichloroethane, or a mixture thereof.
[0110] The reaction is promoted by addition of about 0.01 mole of
4-N,N-dimethylaminopyridine.
[0111] The reaction temperature is from -100.degree. C. to reflux
temperature of the solvent, preferably from 0.degree. C. to room
temperature.
[0112] When compounds (7) and (10) are optically active compounds,
optically active compound (1) and optically active intermediates
(3)-(6), (4a), (8)-(9) and (11) can be obtained. When natural
L-malic acid is used as an optically active starting material, (S)
formed compound is obtained. When unnatural D-malic acid is used as
an optically active starting material, (R) formed compound is
obtained.
[0113] These compounds are led to compound (10) by two steps and to
compound (7) by 3 steps.
[0114] It is also possible to use
.beta.-hydroxy-.gamma.-butyrolactone as an optically active
starting material. .beta.-Hydroxy-.gamma.-butyrolacto- ne is
prepared by the method described in Japanese Patent Publication A
9-47296, and the compound can be led to compound (10) by the method
described in Japanese Patent Publication A 4-149151.
[0115] Significant racemization does not occur during synthesis of
these optically active compounds and. therefore, there is
obtainable compound (1) with highly optical purity.
[0116] Starting compounds (2), (7) and (10) are prepared as
follows.
[0117] Compound (7) is prepared by acetalization of the adjacent
hydroxy groups of 1,2,4-butanetriol in the presence of acid
catalyst.
[0118] Examples of acetalization agents are ketones, such as
acetone, diethyl ketone, benzophenone, cyclohexanone, aldehydes,
such as acetoaldehyde or benzaldehyde, dialkoxyacetals of ketone,
such as 2,2-dimethoxypropane or 3,3-dimethoxypentane, or enol
ethers of ketone such as 2-methoxypropene.
[0119] Examples of the acid catalysts are mineral acids, such as
hydrochloric acid or sulfuric acid, organic acids, such as
p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid
or trifluoroacetic acid, or Lewis acids, such as boron trifluoride
etherate, aluminum trichloride, tin tetrachloride, or titanium
tetrachloride.
[0120] Amount of the acid catalyst is 0.05-0.1 mole to the
substrate.
[0121] Examples of the solvents are aprotic solvents, such as
N,N-dimethylformamide, dimethyl sulfoxide or
hexamethylphosphoramide, ethers, such as tetrahydrofuran,
1,4-dioxane, glyme, diglyme or triglyme, halogen compounds, such as
dichloromethane, chloroform or 1,2-dichloroethane, or acetalization
agents themselves, preferably aprotic solvents or acetalization
agents themselves, especially preferably N,N-dimethylformamide or
acetone.
[0122] For example, a compound, wherein R.sup.3 and R.sup.4 are
methyl, is prepared by a method described in the literature (J.
Org. Chem., 53, 4495 (1988), that is, by reacting
2,2-dimethoxypropane in the presence of catalytic amount of
p-toluenesulfonic acid in N,N-dimethylformamide.
[0123] Ethylene glycol derivative (2) is prepared by a method
described in the literature (J. Am. Chem. Soc., 60, 1472-1473
(1938). For example, a compound (2), wherein R.sup.2 is benzyl, is
prepared by reacting 0.25 moles of benzyl bromide or benzyl
chloride with 5 moles of ethylene glycol in which 0.25 mole of
potassium hydroxide was dissolved. Furthermore, by halogenation of
another hydroxy group with thionyl chloride or carbon
tetrachloride, or sulfonyl esterification of another hydroxy group
with methanesulfonyl chloride or p-toluenesulfonyl chloride, there
is obtainable a compound (2), wherein X is a leaving group. A
compound, wherein R.sup.2 is another protective group, is prepared
by using tert-butyldimethylsilyl chloride or methoxymethyl chloride
in stead of benzyl halide.
[0124] Compound (10) is prepare by reducing malic acid ester, such
as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl
ester, cyclohexyl ester, phenyl ester, 4-methylphenyl ester, benzyl
ester or allyl ester in a method described in the literature (Chem.
Lett., 1984, 1389-1392), namely by selectively reducing one of
ester groups with boron dimethylsulfide or sodium borohydride in
tetrahydrofuran at room temperature.
[0125] On the other hand, compound (10) is prepared by reacting
.beta.-hydroxy-.gamma.-butyrolactone with alcohol in acidic
condition or by subjecting it to ring opening reaction with
alkoxide, such as sodium methoxide or sodium ethoxide.
BEST MODE FOR CARRYING OUT THE INVENTION
[0126] The present invention is explained by following examples,
but scope of the invention should not be limited by these
examples.
EXAMPLE 1
[0127] (1) Preparation of
(S)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolan- e (12) 8
[0128] To a solution of (s)-1,2,4-butanetriol (0.842 g, 7.9 mmol)
dissolved in acetone (12 ml) was added p-toluenesulfonic acid
hydrate (20 mg) and the mixture was stirred for 21 hours at room
temperature. Sodium carbonate (20 mg) was added to the mixture.
After stirring for 1 hour, the mixture was filtered and condensed
in vacuo to give (S)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane
(1.023 g, yield 88%).
[0129] (2) Preparation of
(S)-4-(2-benzyloxyethyl)-2,2-dimethyl-1,3-dioxol- ane (13) 9
[0130] Sodium hydride (1.33 g, 33.3 mmol, 60% in oil) was loaded
under argon circumstance in three-necked flask and hexane (20 ml)
was added thereto. After stirring for a while, it was allowed to
stand and the supernatant was removed by syringe. By repeating this
procedure three times, the oil of sodium hydride was removed. After
drying in vacuo, anhydrous N,N-dimethylformamide (DMF) (5 ml) was
added and the mixture was cooled at 0.degree. C.
(S)-4-(2-Hydroxyethyl)-2,2-dimethyl-1,3-dioxol- ane (4.42 g, 30.25
mmol) in DMF (8 ml) was dropped to the mixture over a one hour
period by taking care of the temperature and then the mixture was
stirred for 1 hour. Benzyl chloride (3.83 ml, 33.3 mmol) in DMF (3
ml) was dropped to the solution over a one hour period in the range
of 0.degree. C. and 5.degree. C. and then the solution was stirred
for 4 hours. After stirring water (20 ml) was added to the solution
and the solution was extracted with ethyl acetate. The extract was
washed with water (40 ml) twice and with saturated brine once,
dried on sodium sulfate, filtered and condensed in vacuo. The
residue was subjected to silica gel chromatography to give
(S)-4-(2-benzyloxyethyl)-2,2-dimethyl-1- ,3-dioxolane (6.32 g,
yield 88%).
[0131] (3) Preparation of (S)-4-benzyloxy-1,2-butandiol (14) 10
[0132] In methanol (50 ml) were dissolved
(S)-4-(2-benzyloxyethyl)-2,2-dim- ethyl-1,3-dioxolane (2.06 g, 8.73
mmol) and p-toluenesulfonic acid hydrate (1.68 g, 8.8 mmol), and
the solution was stirred at room temperature for 24 hours. After
removal of methanol in vacuo, aqueous saturated sodium hydrogen
carbonate was added to neutralize the solution. The solution was
extracted with ethyl acetete and the extract was washed with
saturated brine, dried on sodium sulfate, filtered, and condensed
in vacuo. The residue was subjected to silica gel chromatography to
give (S)-4-benzyloxy-1,2-butanediol (1.70 g, yield 99%).
[0133] (4) Preparation of (S)-4-benzyloxy-1-trityloxy-2-butanol
(15) 11
[0134] In toluene (100 ml) were dissolved
(S)-4-benzyloxy-1,2-butanediol (25.8 g, 0.132 mol), triethylamine
(20.2 ml, 0.145 mol) and 4-N,N-dimethylaminopyridine (DMAP) (0.80
g, 6.58 mmol). After cooling in ice bath, trityl chloride (36.69 g,
0.1316 mol) was added to the solution and the mixture was stirred
at room temperature for 10 hours. The mixture was condensed in
vacuo, diluted with ethyl acetate, washed with water and then
saturated brine, dried on sodium sulfate, filtered and condensed in
vacuo to give (S)-4-benzyloxy-1-trityloxy-2-butanol quantitatively
(55.89, yield 100%).
[0135] [.alpha.].sub.D.sup.25 2.29.degree. (C=1.072,
CHCl.sub.3)
[0136] .sup.1H-NMR (270 MHz, CDCl.sub.3).delta.:1.74-1.82(2H, m),
2.82(1H, d, J=2.7 Hz), 3.13(2H, d, J=5.4 Hz), 3.54-3.67(2H, m),
4.00(1H, br.s), 4.46(2H, s), 7.19-7.36(12H, m), 7.40-7.45(8H,
m).
[0137] .sup.13C-NMR (67.8 MHz, CDCl.sub.3).delta.:33.90, 67.41,
67.97, 69.91, 73.19, 86.54, 127.00, 127.69, 127.79, 127.89, 128.37,
128.58, 138.09, 143.91.
[0138] (5) Preparation of
(S)-4-benzyloxy-2-(2-benzyloxyethoxy)-1-tritylox- ybutane (16)
12
[0139] Sodium hydride (6.32 g, 0.158 mmol, 60% in oil) was loaded
under argon circumstance in three-necked flask and hexane (100 ml)
was added thereto. After stirring for a while, it was allowed to
stand and the supernatant was removed by syringe. By repeating this
procedure three times, the oil of sodium hydride was removed. After
drying in vacuo anhydrous dimethyl sulfoxide (DMSO) (30 ml) was
added and the solution was stirred at 60.degree. C. for 1 hour.
After cooling to room temperature,
(S)-4-benzyloxy-1-trityloxy-2-butanol (55.89 g, 0.132 mol) in DMSO
(40 ml) was gradually dropped at room temperature to the solution
and then the solution was stirred for 30 minutes. To the solution
was gradually dropped 2-benzyloxyethyl methanesulfonate (33.4 g,
0.145 mol) in DMSO (40 ml) at room temperature and then the
solution was stirred for 12 hours. To the reaction mixture was
added water (120 ml) and the solution was extracted with ethyl
acetate. The extract was washed with water (150 ml) twice and with
saturated brine once, dried on sodium sulfate, filtered and
condensed in vacuo. The residue was subjected to silica gel
chromatography to give (S)-4-benzyloxy-2-(2-benzyloxyethoxy)-1-
-trityloxybutane (55.0 g, yield 75%).
[0140] [.alpha.].sub.D.sup.25-13.77.degree. (C=1.032,
CHCl.sub.3).
[0141] .sup.1H-NMR (270 MHz, CDCl.sub.3).delta.:1.75-1.87(2H, m),
3.12-3.16(2H, m), 3.19-3.68(6H, m), 3.81-3.89(1H, m), 4.41(2H, s),
4.53(2H, s), 7.19-7.34(19H, m), 7.44-7.47(6H, m).
[0142] .sup.3C-NMR (67.8 MHz, CDCl.sub.3).delta.:32.53, 66.11,
66.75, 69.76, 69.94, 72.87, 73.01, 76.65, 86.51, 126.85, 127.44,
127.62, 127.70, 128.28, 128.36, 128.44, 128.64, 128.71, 138.40,
138.54, 144.10.
[0143] (5') Preparation of
(S)-4-benzyloxy-2-(2-benzyloxyethoxy)-1-tritylo- xybutane (16)
13
[0144] Sodium hydride (6.32 g, 0.158 mmol, 60% in oil) was loaded
under argon circumstance in three-necked flask and hexane (100 ml)
was added thereto. After stirring for a while, it was allowed to
stand and the supernatant was removed by syringe. By repeating this
procedure three times, the oil of sodium hydride was removed. After
drying in vacuo anhydrous dimethyl sulfoxide (DMSO) (30 ml) was
added and the solution was stirred at 60.degree. C. for 1 hour.
After cooling to room temperature,
(S)-4-benzyloxy-1-trityloxy-2-butanol (55.89 g, 0.132 mol) in DMSO
(40 ml) was gradually dropped at room temperature to the solution
and then the solution was stirred for 30 minutes. To the solution
was gradually dropped 2-benzyloxyethyl methanesulfonate (33.4 g,
0.145mol) in DMSO (40 ml) at room temperature and then the solution
was stirred for 12 hours. To the reaction mixture was added water
(120 ml) and the solution was extracted with ethyl acetate. The
extract was washed with water (150 ml) twice and with saturated
brine once, dried on sodium sulfate, filtered and condensed in
vacuo. The residue was subjected to silica gel chromatography to
give (S)-4-benzyloxy-2-(2-benzyloxyethoxy)-1-trityloxyb- utane
(70.8 g, yield 97%).
[0145] (6) Preparation of
(S)-3-(2-hydroxyethoxy)-4-trityloxy-butanol (17) 14
[0146] (S)-4-Benzyloxy-2-(2-benzyloxyethoxy)-1-trityloxy-butane (51
mg, 0.092 mmol) was dissolved in ethyl acetate (3 ml). To the
solution was added 5% Pd--C (5.0 mg) and the mixture was stirred
under an atmosphere of hydrogen for 15 hours at 50.degree. C. After
filtering off catalyst, the filtrate was condensed in vacuo, and
the residue was subjected to silica gel chromatography to give
(S)-3-(2-hydoxyethoxy)-4-trityloxybutan- ol (28 mg, yield 78%).
EXAMPLE 2
[0147] (1) Preparation of (S)-ethyl 3-hydroxy-4-trityloxybutanoate
(18) 15
[0148] To (S)-ethyl 3,4-dihydroxybutanoate (1.40 g, 9.45 mmol) in
methylene chloride (20 ml) were added triethylamine (1.15 g, 11.36
mmol) and DMAP (17 mg, 0.139 mmol) and the solution was cooled in
ice bath. Trityl chloride (2.90 g, 10.4 mol) in methylene chloride
(15 ml) was dropped to the solution under stirring and then stirred
at room temperature over night. The reaction mixture was washed
with saturated ammonium chloride and then saturated brine, dried on
magnesium sulfate, filtered and condensed in vacuo. The residue was
subjected to silica gel chromatography to give (S)-ethyl
3-hydroxy-4-trityloxybutanoate (1.11 g, yield 31%).
[0149] m.p. 98.8-101.1.degree. C.
[0150] [.alpha.].sub.D.sup.25 -13.1.degree. (C=1.0, EtOAc)
[0151] .sup.1H-NMR (270 MHz, CDCl.sub.3).delta.:1.23(3H, t, J=8.1
Hz), 2.54(2H, q, J=2.7 Hz), 2.94(1H, d, J=2.7 Hz), 3.17(2H, d,
J=5.4 Hz), 4.13(2H, q, J=8.1 Hz), 4.22(1H, m), 7.21-7.32(9H, m),
7.40-7.45(6H, m).
[0152] .sup.13C-NMR (67.8 MHz, CDCl.sub.3).delta.:14.10, 38.51,
60.63, 66.52, 67.55, 86.68, 127.05, 127.81, 128.59, 143.70,
172.21.
[0153] (2) Preparation of (S)-1-trityloxy-2,4-butandiol (19) 16
[0154] In ethanol (10 ml) was dissolved (S)-ethyl
3-hydroxy-4-trityloxybut- anoate (0.37 g, 0.975 mmol). Sodium
borohydride (0.238 g, 6.29 mmol) was added to the solution and the
solution was stirred at room temperature over night. Acetic acid
was added to neutralize the solution. The solution was diluted with
water (100 ml) and extracted with ethyl acetate. The extract was
washed with saturated brine, dried on magnesium sulfate, filtered,
and condensed in vacuo. The residue was subjected to silica gel
chromatography to give (S)-1-trityloxy-2,4-butanediol (0.28 g,
yield 82%).
[0155] m.p. 68.8-70.9.degree. C.
[0156] [.alpha.].sub.D.sup.25 5.20.degree. (C=0.607,
CHCl.sub.3)
[0157] .sup.1H-NMR (270 MHz, CDCl.sub.3).delta.:1.64(2H, q, J=5.4
Hz), 2.94(2H, br.s), 3.10(1H, d, J=2.7 Hz), 3.12(1H, d, J=2.7 Hz),
3.73(2H, m), 4.00(1H, m), 7.21-7.31(9H, m), 7.38-7.45(3H, m)
[0158] .sup.3C-NMR (67.8 MHz, CDCl.sub.3).delta.:34.97. 61.10,
67.56, 70.83, 86.74, 127.13, 127.87, 128.61, 143.72.
[0159] (3) Preparation of
(S)-4-tert-butyldimethylsilyloxy-1-trityloxy-2-b- utanol (20)
17
[0160] (S)-1-Trityloxy-2,4-butanediol (1.64 g, 4.7 mmol) and
imidazole (0.321 g, 4.715 mmol) were dissolved in DMF (20 ml) and
the solution was cooled to 0.degree. C. To the solution was dropped
tert-butyldimethylsilyl chloride. (0.5 ml, 1.44 mmol, 50% in
toluene). After stirring for 1 hour, again to the solution was
dropped tert-butyldimethylsilyl chloride (0.5 ml, 1.44 mmol) and
the solution was stirred for 1 hour. Further
tert-butyldimethylsilyl chloride (0.6 ml, 1.73 mmol) was added to
the solution and the solution was stirred over night at room
temperature. After dilution with toluene (100 ml), the solution was
washed with water (100 ml) twice and saturated brine once, dried on
magnesium sulfate, filtered and condensed in vacuo. The residue was
subjected to silica gel chromatography to give
(S)-4-tert-butyldimethylsilyloxy-1-trityloxy-2-butanol (1.80 g,
yield 82.6%).
[0161] [.alpha.].sub.D.sup.25 0.30.degree. (C=1.075,
CHCl.sub.3)
[0162] .sup.1H-NMR (270 MHz, CDCl.sub.3).delta.:-0.03(3H, s),
-0.01(3H, s), 0.85(9H, s), 1.64-1.73(2H, m), 3.04-3.15(2H, m),
3.99(1H, br.s), 7.17-7.30(9H, s), 7.39-7.43(6H, m)
[0163] .sup.13C-NMR (67.8 MHz, CDCl.sub.3).delta.:-5.53, 18.14,
25.86, 35.70, 61.31, 67.41, 70.03, 86.50, 126.98, 127.88, 128.67,
144.00.
[0164] (4) Preparation of
(S)-4-tert-butyldimethylsilyloxy-2-(2-tert-butyl-
dimethylsilyloxyethoxy)-1-trityloxybutane (21) 18
[0165] Sodium hydride (2.11 g, 52.7 mmol, 60% in oil) was loaded
under argon circumstance in three-necked flask and hexane (30 ml)
was added thereto. After stirring for a while, it was allowed to
stand and the supernatant was removed by syringe. By repeating this
procedure three times, the oil of sodium hydride was removed. After
drying in vacuo anhydrous dimethyl sulfoxide (DMSO) (10 ml) was
added and the solution was stirred at 60.degree. C. for 1 hour.
After cooling to room temperature,
(S)-4-tert-butyldimethylsilyloxy-1-trityloxy-2-butanol (20.36 g,
44.0 mol) in DMSO (12 ml) was gradually dropped at room temperature
to the solution and then the solution was stirred for 30 minutes.
To the solution was gradually dropped 2-tert-butyldimethylsilylo-
xyethyl methanesulfonate (12.28 g, 48.3 mol) in DMSO (12 ml) at
room temperature and then the solution was stirred for 12 hours. To
the reaction mixture was added water (40 ml) and the solution was
extracted with ethyl acetate. The extract was washed with water (50
ml) twice and with saturated brine once, dried on sodium sulfate,
filtered and condensed in vacuo. The residue was subjected to
silica gel chromatography to give
(S)-4-tert-butyldimethylsilyloxy-2-(2-tert-butyldi-
methylsilyloxyethoxy)-1-trityloxybutane (11.2 g, yield 55%).
[0166] (5) Preparation of
(S)-3-(2-hydroxyethoxy)-4-trityloxy-butanol (17) 19
[0167]
(S)-4-tert-butyldimethylsilyloxy-2-(2-tert-butyldimethylsilyloxyeth-
oxy)-1-trityloxybutane (32 mg, 0.053 mmol) in dried tetrahydrofuran
(THF) (2 ml) was added tetrabutylammonium fluoride (0.10 ml, 0.11
mmol, 1.1M in THF) and the mixture was stirred for 1.5 hours at
room temperature. A small amount of saturated ammonium chloride was
added to the reaction mixture. The solution was dried on sodium
sulfate, filtered and condensed in vacuo. The residue was subjected
to silica gel chromatography to give
(S)-3-(2-hydroxyethoxy)-4-trityloxybutanol (16 mg, yield 75%).
EXAMPLE 3
[0168] (1) Preparation of (S)-4-benzyloxy-l-trityloxy-2-butanol
(15) 20
[0169] Sodium hydride (74 mg, 1.85 mmol, 60% in oil) was loaded
under argon circumstance in three necked flask and hexane (2 ml)
was added thereto. After stirring for a while, it was allowed to
stand and the supernatant was removed by syringe. By repeating this
procedure three times, the oil of sodium hydride was removed. After
drying in vacuo anhydrous dimethyl sulfoxide (DMSO) (2 ml) was
added and the solution was cooled to 0.degree. C.
(S)-1-Trityloxy-2,4-butandiol (0.62 g, 1.68 mmol) prepared by
Example 2-(2) in DMSO (3 ml) was dropped by taking care of the
temperature over a one hour period at room temperature to the
solution. Then the solution was stirred for 1 hour. To the solution
was dropped benzyl chloride (0.213 ml, 1.85 mol) in DMSO (3 ml)
over a one hour period at the range of 0.degree. C. to 5.degree. C.
and then the solution was stirred for 4 hours. To the reaction
mixture was added water (5 ml) and the solution was extracted with
ethyl acetate. The extract was washed with water (8 ml) twice and
with saturated brine once, dried on sodium sulfate, filtered and
condensed in vacuo. The residue was subjected to silica gel
chromatography to (S)-4-benzyloxy-1-trityloxy-2-b- utanol (0.32 g,
yield 45%).
[0170] (2) Preparation of
(S)-3-(2-hydroxyethoxy)-4-trityloxy-butanol (17) 21
[0171] By using (S)-4-benzyloxy-1-trityloxy-2-butanol(0.25 g, 0.59
mmol), compound (15) prepared by Example 3-(1), and in the same
manner of Examples 1-(5) and (6),
(S)-3-(2-hydroxyethoxy)-4-trityloxybutanol (0.166 g, 0.42 mmol,
yield 72%) was prepared by two steps from compound (15).
EXAMPLE 4
[0172] Preparation of
(S)-3-[(2-methylsulfonyloxy)ethoxy]-4-trityloxybutyl
methanesulfonate (22) 22
[0173] In toluene (120 ml) were dissolved crude
(S)-3-(2-benzyloxyethoxy)-- 4-trityloxybutanol (29.4 g) without
silica gel chromatography prepared in the same method as Example 1,
and triethylamine (23 ml, 0.165 mol). To the solution was added
portionwise methanesulfonyl chloride (12.2 ml, 0.1575 mol) under
ice cooling at the range of 0.degree. C. to 5.degree. C. Then, the
solution was stirred at the same temperature for 3 hours. The
solution was condensed in vacuo, diluted with ethyl acetate, washed
with water and saturated brine, dried on sodium sulfate, filtered
and condensed in vacuo to give crude
(S)-3-[(2-methylsulfonyloxy)ethoxy]-4-tr- ityloxybutyl
methanesulfonate (38.64 g). The crude product was recrystallized
twice from a mixture of ethyl acetate and heptane to give purified
product (18.15 g, yield 44%).
[0174] m.p. 97.2-99.5.degree. C.
[0175] [.alpha.].sub.D.sup.25 -15.78 (C=1.0, CHCl.sub.3)
* * * * *