U.S. patent application number 10/565981 was filed with the patent office on 2006-12-07 for process for producing 6, 7-bis (2-methoxyethoxy)-quinazolin-4-one.
This patent application is currently assigned to UBE INDUSTRIES, LTD. Invention is credited to Kenji Hirotsu, Shigeyoshi Nishino, Hiroyuki Oda, Hidetaka Shima, Shinobu Suzuki.
Application Number | 20060276647 10/565981 |
Document ID | / |
Family ID | 34113782 |
Filed Date | 2006-12-07 |
United States Patent
Application |
20060276647 |
Kind Code |
A1 |
Nishino; Shigeyoshi ; et
al. |
December 7, 2006 |
Process for producing 6, 7-bis
(2-methoxyethoxy)-quinazolin-4-one
Abstract
A process comprising a reaction of ethyl
2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formic acid
compound in the presence of an ammonium carboxylate gives
6,7-bis(2-methoxyethoxy)quinazolin-4-one in a high yield.
Inventors: |
Nishino; Shigeyoshi;
(Yamaguchi, JP) ; Hirotsu; Kenji; (Yamaguchi,
JP) ; Shima; Hidetaka; (Yamaguchi, JP) ; Oda;
Hiroyuki; (Yamaguchi, JP) ; Suzuki; Shinobu;
(Yamaguchi, JP) |
Correspondence
Address: |
NIXON PEABODY, LLP
401 9TH STREET, NW
SUITE 900
WASHINGTON
DC
20004-2128
US
|
Assignee: |
UBE INDUSTRIES, LTD
1978-96, O-Aza Kogushi
Ube-shi, Yamaguchi
JP
755-8633
|
Family ID: |
34113782 |
Appl. No.: |
10/565981 |
Filed: |
July 30, 2004 |
PCT Filed: |
July 30, 2004 |
PCT NO: |
PCT/JP04/10965 |
371 Date: |
January 26, 2006 |
Current U.S.
Class: |
544/287 |
Current CPC
Class: |
C07C 67/31 20130101;
C07D 239/88 20130101; C07C 67/31 20130101; C07C 69/92 20130101 |
Class at
Publication: |
544/287 |
International
Class: |
C07D 239/80 20060101
C07D239/80 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 30, 2003 |
JP |
2003-282696 |
Claims
1. A process for preparation of
6,7-bis(2-methoxyethoxy)quinazolin-4-one, which comprises causing a
reaction of ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate with a
formic acid compound in the presence of an ammonium
carboxylate.
2. A process for preparation of
6,7-bis(2-methoxyethoxy)quinazolin-4-one, which comprises the steps
in order of: causing a reaction of ethyl
4,5-bis(2-methoxyethoxy)-2-nitrobenzoate with hydrogen in the
presence of a metallic catalyst to prepare ethyl
2-amino-4,5-bis(2-methoxyethoxy)benzoate; and causing a reaction of
the ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formic
acid compound in the presence of an ammonium carboxylate to prepare
6,7-bis(2-methoxyethoxy)-quinazolin-4-one.
3. A process for preparation of
6,7-bis(2-methoxyethoxy)quinazolin-4-one, which comprises the steps
in order of: causing a reaction of ethyl
3,4-bis(2-methoxyethoxy)benzoate with nitric acid in the presence
of sulfuric acid to prepare ethyl
4,5-bis(2-methoxyethoxy)-2-nitrobenzoate; causing a reaction of the
ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate with hydrogen in the
presence of a metallic catalyst to prepare ethyl
2-amino-4,5-bis(2-methoxyethoxy)benzoate; and causing a reaction of
the ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formic
acid compound in the presence of an ammonium carboxylate to prepare
6,7-bis(2-methoxyethoxy)-quinazolin-4-one.
4. A process for preparation of
6,7-bis(2-methoxyethoxy)quinazolin-4-one, which comprises the steps
in order of: causing a reaction of ethyl 3,4-dihydroxybenzoate with
2-chloroethyl methyl ether in an organic solvent in the presence of
a base to prepare ethyl 3,4-bis(2-methoxyethoxy)benzoate; causing a
reaction of the ethyl 3,4-bis(2-methoxyethoxy)benzoate with nitric
acid in the presence of sulfuric acid to prepare ethyl
4,5-bis(2-methoxyethoxy)-2-nitrobenzoate; causing a reaction of the
ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate with hydrogen in the
presence of a metallic catalyst to prepare ethyl
2-amino-4,5-bis(2-methoxyethoxy)benzoate; and causing a reaction of
the ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formic
acid compound in the presence of an ammonium carboxylate to prepare
6,7-bis(2-methoxyethoxy)quinazolin-4-one.
5. The process according to one of the claims 1 to 4, wherein the
formic acid compound is an orthoformic ester.
6. The process according to one of the claims 1 to 4, wherein the
ammonium carbonate is ammonium acetate.
7. The process according to the claim 3 or 4, wherein the reaction
of ethyl 3,4-bis(2-methoxyethoxy)-benzoate with nitric acid in the
presence of sulfuric acid is conducted at a temperature in the
range of 45 to 75.degree. C. to prepare ethyl
4,5-bis(2-methoxyethoxy)-2-nitrobenzoate.
8. The process according to the claim 3 or 4, wherein the metallic
catalyst comprises 1 to 2.9 wt. % of platinum carried on a carbon
carrier.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a process for preparation
of 6,7-bis(2-methoxyethoxy)quinazolin-4-one.
BACKGROUND OF THE INVENTION
[0002] U.S. Pat. No. 5,747,498 discloses
6,7-bis(2-methoxyethoxy)quinazolin-4-one as an intermediate in
synthesis of
6,7-bis(2-methoxyethoxy)-4-(3-ethynylphenyl)-aminoquinazoline
hydrochloride, which can be used as an anti-cancer drug.
[0003] Japanese Patent Provisional Publication No. 2002-293773
discloses a process comprising a reaction of ethyl
2-amino-4,5-bis(2-methoxyethoxy)benzoate with ammonium formate to
prepare 6,7-bis(2-methoxyethoxy)quinazolin-4-one. The publication
reports that the yield of the reaction was 80.5%.
DISCLOSURE OF THE INVENTION
Problems to be Solved by the invention
[0004] A primary object of the present invention is to provide a
process for preparing 6,7-bis(2-methoxyethoxy)-quinazolin-4-one in
a high yield from ethyl
2-amino-4,5-bis(2-methoxyethoxy)benzoate.
[0005] Another object of the invention is to provide an
industrially advantageous process for preparing
6,7-bis(2-methoxyethoxy)quinazolin-4-one in a high yield using
ethyl 3,4-dihydroxybenzoate as a starting compound.
MEANS TO SOLVE THE PROBLEM
[0006] First, the present invention provides a process for
preparation of 6,7-bis(2-methoxyethoxy)quinazolin-4-one, which
comprises causing a reaction of ethyl
2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formic acid
compound in the presence of an ammonium carboxylate.
[0007] Second, the invention provides a process for preparation of
6,7-bis(2-methoxyethoxy)quinazolin-4-one, which comprises the steps
in order of: causing a reaction of ethyl
4,5-bis(2-methoxyethoxy)-2-nitrobenzoate with hydrogen in the
presence of a metallic catalyst to prepare ethyl
2-amino-4,5-bis(2-methoxyethoxy)benzoate; and causing a reaction of
the ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formic
acid compound in the presence of an ammonium carboxylate to prepare
6,7-bis(2-methoxyethoxy)quinazolin-4-one.
[0008] Third, the invention provides a process for preparation of
6,7-bis(2-methoxyethoxy)quinazolin-4-one, which comprises the steps
in order of: causing a reaction of ethyl
3,4-bis(2-methoxyethoxy)benzoate with nitric acid in the presence
of sulfuric acid to prepare ethyl
4,5-bis(2-methoxyethoxy)-2-nitrobenzoate; causing a reaction of the
ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate with hydrogen in the
presence of a metallic catalyst to prepare ethyl
2-amino-4,5-bis(2-methoxyethoxy)benzoate; and causing a reaction of
the ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formic
acid compound in the presence of an ammonium carboxylate to prepare
6,7-bis(2-methoxyethoxy)quinazolin-4-one.
[0009] Fourth, the invention provides a process for preparation of
6,7-bis(2-methoxyethoxy)quinazolin-4-one, which comprises the steps
in order of: causing a reaction of ethyl 3,4-dihydroxybenzoate with
2-chloroethyl methyl ether in an organic solvent in the presence of
a base to prepare ethyl 3,4-bis(2-methoxyethoxy)benzoate; causing a
reaction of the ethyl 3,4-bis(2-methoxyethoxy)benzoate with nitric
acid in the presence of sulfuric acid to prepare ethyl
4,5-bis(2-methoxyethoxy)-2-nitrobenzoate; causing a reaction of the
ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate with hydrogen in the
presence of a metallic catalyst to prepare ethyl
2-amino-4,5-bis(2-methoxyethoxy)benzoate; and causing a reaction of
the ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formic
acid compound in the presence of an ammonium carboxylate to prepare
6,7-bis(2-methoxyethoxy)quinazolin-4-one.
[0010] The formulas of the compounds involved in the process of
starting from ethyl 3,4-dihydroxybenzoate and yielding
6,7-bis(2-methoxyethoxy)quinazolin-4-one are shown below.
[0011] Ethyl 3,4-dihydroxybenzoate is represented by the formula
(1): ##STR1##
[0012] Ethyl 3,4-bis(2-methoxyethoxy)benzoate is represented by the
formula (2): ##STR2##
[0013] Ethyl 4,5-bis (2-methoxyethoxy) -2-nitrobenzoate is
represented by the formula (3): ##STR3##
[0014] Ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate is
represented by the formula (4): ##STR4##
[0015] 6, 7-Bis(2-methoxyethoxy)quinazolin-4-one is represented by
the formula (5): ##STR5##
BEST MODE FOR CARRYING OUT THE INVENTION
[0016] The process for preparation of
6,7-bis(2-methoxyethoxy)quinazolin-4-one according to the present
invention is described below by referring to the steps in order
of:
[0017] causing a reaction of ethyl 3,4-dihydroxybenzoate with
2-chloroethyl methyl ether in an organic solvent in the presence of
a base to prepare ethyl 3,4-bis(2-methoxyethoxy)benzoate (first
step);
[0018] causing a reaction of the ethyl
3,4-bis(2-methoxyethoxy)benzoate with nitric acid in the presence
of sulfuric acid to prepare ethyl
4,5-bis(2-methoxyethoxy)-2-nitrobenzoate (second step);
[0019] causing a reaction of the ethyl
4,5-bis(2-methoxyethoxy)-2-nitrobenzoate with hydrogen in the
presence of a metallic catalyst to prepare ethyl
2-amino-4,5-bis(2-methoxyethoxy)benzoate (third step); and
[0020] causing a reaction of the ethyl
2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formic acid
compound in the presence of an ammonium carboxylate to prepare
6,7-bis(2-methoxyethoxy)quinazolin-4-one (fourth step).
[0021] (A) First Step
[0022] In the first step, ethyl 3,4-dihydroxybenzoate reacts with
2-chloroethyl methyl ether in an organic solvent in the presence of
a base to prepare ethyl 3,4-bis(2-methoxyethoxy)benzoate.
[0023] In the first step, the 2-chloroethyl methyl ether is used
preferably in an amount of 1.0 to 20 moles, more preferably in an
amount of 1.1 to 10 moles, and most preferably in an amount of 1.1
to 5.0 mole based on one mole of ethyl 3,4-dihydroxybenzoate.
[0024] Examples of the bases used in the first step include: alkali
metal hydroxides such as sodium hydroxide, potassium hydroxide;
alkali metal carbonates such as sodium carbonate and potassium
carbonate; alkali metal hydrogencarbonates such as sodium
hydrogencarbonate and potassium hydrogencarbonate; and alkali metal
alkoxides such as sodium methoxide and potassium methoxide. The
alkali metal hydroxides and the alkali metal carbonates are
preferred. The alkali metal carbonates are more preferred. Most
preferred is potassium carbonate. The base can be used alone or in
combination.
[0025] The base is used preferably in an amount of 1.0 to 20 moles,
more preferably in an amount of 1.1 to 10 moles, and most
preferably in an amount of 1.1 to 5.0 moles based on one mole of
ethyl 3,4-dihydroxybenzoate.
[0026] There are no specific limitations with respect to the
organic solvent used in the first step, unless the organic solvent
participates in the reaction. Examples of the organic solvents
include: alcohols such as methanol, ethanol, isopropanol and
t-butanol; ketones such as acetone, methyl ethyl ketone and methyl
isobutyl ketone; amides such as N,N-dimethylformamide and
N-methyl-pyrrolidone; ureas such as N,N'-dimethylimidazolidinone;
sulfoxides such as dimethyl sulfoxide; nitriles such as
acetonitrile and propionitrile; ethers such as diethyl ether,
diisopropyl ether, tetrahydrofuran and dioxane; and aromatic
hydrocarbons such as toluene and xylene. The ketones, nitrites and
amides are preferred. The organic solvent can be used alone or in
combination.
[0027] The amount of the organic solvent is adjusted in
consideration of homogeneity of the reaction solution and stirring
conditions. The organic solvent is used preferably in an amount of
1 to 100 g, and more preferably in an amount of 2 to 20 g based on
1 g of ethyl 3,4-dihydroxybenzoate.
[0028] The first step can be carried out, for example, by mixing
ethyl 3,4-dihydroxybenzoate, 2-chloroethyl methyl ether, a base and
an organic solvent under stirring in an inert gas atmosphere. The
reaction temperature is preferably in the range of 20 to
200.degree. C., and more preferably in the range of 40 to
120.degree. C. There are no specific limitations with respect to
the reaction pressure.
[0029] In the first step, ethyl 3,4-bis(2-methoxyethoxy)-benzoate
is obtained. After the reaction is complete, ethyl
3,4-bis(2-methoxyethoxy)benzoate can be isolated or purified for
the second step. The isolation or purification can be conducted
according to the conventional method such as filtration,
concentration, distillation, recrystallization, crystallization, or
column chromatography. Ethyl 3,4-bis(2-methoxyethoxy)benzoate can
also be used in the second step without conducting isolation or
purification. In the case that isolation or purification is not
conducted, the solvent can be replaced in the second step.
[0030] (B) Second Step
[0031] In the second step, ethyl 3,4-bis(2-methoxyethoxy)-benzoate
reacts with nitric acid in the presence of sulfuric acid to prepare
ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate.
[0032] In the second step, nitric acid is used preferably in an
amount of 1.0 to 50 moles, more preferably in an amount of 2.0 to
10 moles based on one mole of ethyl
3,4-bis(2-methoxyethoxy)benzoate. The nitric acid has a
concentration preferably in the range of 40 to 90 wt. %, and more
preferably in the range of 50 to 70 wt. %.
[0033] The second step is preferably carried out in the presence of
a solvent. There are no specific limitations with respect to the
solvent, unless the solvent participates in the reaction. Examples
of the solvents include carboxylic acids such as formic acid,
acetic acid, propionic acid and butyric acid. Acetic acid is
preferred. The solvent can be used alone or in combination.
[0034] The amount of the solvent is adjusted in consideration of
homogeneity of the reaction solution and stirring conditions. The
solvent is used preferably in an amount of 1 to 50 g, and more
preferably in an amount of 1.1 to 20 g based on 1 g of ethyl
3,4-bis(2-methoxyethoxy)benzoate.
[0035] The second step can be carried out, for example by mixing
ethyl 3,4-bis(2-methoxyethoxy)benzoate, nitric acid, sulfuric acid
and a solvent under stirring in an atmosphere of an inert gas. The
reaction temperature is preferably in the range of 20 to 90.degree.
C., more preferably in the range of 30 to 80.degree. C., and most
preferably in the range of 45 to 75.degree. C. There are no
specific limitations with respect to the reaction pressure.
[0036] In the second step, ethyl
4,5-bis(2-methoxyethoxy)-2-nitrobenzoate is obtained. After the
reaction is complete, ethyl
4,5-bis(2-methoxyethoxy)-2-nitrobenzoate can be isolated or
purified for the third step. The isolation or purification can be
conducted according to the conventional method such as filtration,
concentration, distillation, recrystallization, crystallization, or
column chromatography. Ethyl
4,5-bis(2-methoxyethoxy)-2-nitrobenzoate can also be used in the
third step without conducting isolation or purification. In the
case that isolation or purification is not conducted, the solvent
can be replaced in the third step.
[0037] (C) Third Step
[0038] In the third step, ethyl
4,5-bis(2-methoxyethoxy)-2-nitrobenzoate reacts with hydrogen in
the presence of a metallic catalyst to prepare
2-amino-4,5-bis(2-methoxyethoxy)benzoate.
[0039] The metallic catalyst used in the third step can contain at
least one metal atom selected from the group consisting of
palladium, platinum and nickel. Examples of the metallic catalysts
include palladium/carbon, palladium/barium sulfate, palladium
hydroxide/carbon, platinum/carbon, platinum sulfide/carbon,
palladium-platinum/carbon, platinum oxide and Raney nickel.
Palladium/carbon, platinum/carbon, platinum sulfide/carbon and
Raney nickel are preferred. The platinum/carbon catalyst is
particularly preferred. The metallic catalyst can be used alone or
in combination.
[0040] In the third step, the metallic catalyst is used preferably
in an amount of 0.1 to 1,000 mg in terms of metal atom amount, and
more preferably in an amount of 0.5 to 500 mg based on 1 g of ethyl
4,5-bis(2-methoxyethoxy)-2-nitrobenzoate. When the metallic
catalyst comprises a metal carried on a carrier, the amount of the
metal on the carrier preferably is in the range of 1 to 2.9 wt. %
based on amount of the carrier.
[0041] In the third step, hydrogen is used preferably in an amount
of 3 to 50 moles, and more preferably in an amount of 3 to 10 moles
based on one mole of ethyl
4,5-bis(2-methoxyethoxy)-2-nitrobenzoate.
[0042] The reaction in the third step is preferably carried out in
the presence of a solvent. There are no specific limitations with
respect to the solvent, unless the solvent participates in the
reaction. Examples of the solvents include: water; alcohols such as
methanol, ethanol, isopropanol, n-butanol, and t-butanol;
carboxylic esters such as methyl acetate, ethyl acetate, and methyl
propionate; aromatic hydrocarbons such as benzene, toluene, xylene,
and mesitylene; and ethers such as diethyl ether, tetrahydrofuran,
and dioxane. The alcohols and carboxylic esters are preferred, and
methanol and ethanol are more preferred. The solvent can be used
alone or in combination.
[0043] The amount of the solvent is adjusted in consideration of
homogeneity of the reaction solution and stirring conditions. The
solvent is used preferably in an amount of 1 to 100 g, and more
preferably in an amount of 2 to 30 g based on 1 g of ethyl
4,5-bis(2-methoxyethoxy)-2-nitrobenzoate.
[0044] The reaction of the third step can be carried out, for
example by mixing ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate, a
metallic catalyst and a solvent under stirring in the presence of
hydrogen gas (which can be diluted with an inert gas). The reaction
temperature is preferably in the range of 0 to 300.degree. C., and
more preferably in the range of 20 to 200.degree. C. The reaction
pressure is preferably in the range of 0.1 to 10 MPa, and more
preferably in the range of 0.1 to 2 MPa.
[0045] After the reaction is complete, the final product, i.e.,
ethyl 2-amino-4,5-bis(methoxyethoxy)benzoate, can be isolated or
purified for the fourth step. The isolation or purification can be
conducted according to the conventional method such as filtration,
concentration, distillation, recrystallization, crystallization, or
column chromatography. Ethyl 2-amino-4,5-bis(methoxyethoxy)benzoate
can also be used in the fourth step without conducting the
isolation or purification. In the case that the isolation or
purification is not conducted, the solvent can be replaced in the
fourth step.
[0046] (D) Fourth Step
[0047] In the fourth step, ethyl
2-amino-4,5-bis(2-methoxyethoxy)benzoate reacts with a formic acid
compound in the presence of an ammonium carboxylate to prepare
6,7-bis(2-methoxyethoxy)quinazolin-4-one.
[0048] Examples of the formic acid compounds include: formic acid;
formic esters such as an ester of formic acid with a lower alcohol
having 1 to 6 carbon atoms (e.g., methyl formate and ethyl
formate); and orthoformic esters such as an ester of orthoformic
acid with a lower alcohol having 1 to 6 carbon atoms (e.g., methyl
orthoformate and ethyl orthoformate). Formic esters and orthoformic
esters are preferred. More preferred are orthoformic esters. Most
preferred are methyl orthoformate and ethyl orthoformate.
[0049] In the fourth step, the formic acid compound is used
preferably in an amount of 1.0 to 30 moles, and more preferably in
an amount of 1.1 to 10 moles based on one mole of ethyl
2-amino-4,5-bis(2-methoxyethoxy)benzoate.
[0050] In the fourth step, an ammonium carboxylate is used.
Examples of the ammonium carboxylates include: ammonium aliphatic
carboxylates such as an ammonium aliphatic carboxylate having 1 to
6 carbon atoms (e.g., ammonium formate, ammonium acetate, and
ammonium propionate); and ammonium aromatic carboxylates such as an
ammonium aromatic carboxylate having 7 to 12 carbon atoms (e.g.,
ammonium benzoate and ammonium dichlorobenzoate). Ammonium
aliphatic carboxylates are preferred. More preferred are ammonium
formate and ammonium acetate. Most preferred is ammonium acetate.
The ammonium carboxylate can be used alone or in combination.
[0051] In the fourth step, the ammonium carboxylate is used
preferably in an amount of 1.0 to 30 moles, and more preferably in
an amount of 1.1 to 10 moles based on one mole of
2-amino-4,5-bis(2-methoxyethoxy)benzoate.
[0052] The reaction in the fourth step can be carried out in the
presence of a solvent. The reaction can also be carried out without
a solvent. There are no specific limitations with respect to the
solvent, unless the solvent participates in the reaction. Examples
of the solvents include alcohols such as methanol, ethanol,
isopropanol, n-butanol, and t-butanol; amides such as
N,N-dimethylformamide and N-methylpyrrolidone; ureas such as
N,N'-dimethylimidazolidinone; sulfoxides such as dimethyl
sulfoxide; aromatic hydrocarbons such as benzene, toluene, xylene,
and mesitylene; halogenated hydrocarbons such as methylene
chloride, chloroform, and dichloroethane; nitriles such as
acetonitrile, and propionitrile; and ethers such as diethyl ether,
tetrahydrofuran, and dioxane. The alcohols, amides and nitriles are
preferred. More preferred are methanol, ethanol,
N,N'-dimethylimidazolidinone and acetonitrile. The solvent can be
used alone or in combination.
[0053] The amount of the solvent is adjusted in consideration of
homogeneity of the reaction solution and stirring conditions. The
solvent is used preferably in an amount of 0 to 50 g, more
preferably in an amount of 0 to 20 g, and most preferably in an
amount of 0 to 5 g based on 1 g of ethyl
2-amino-4,5-bis(2-methoxyethoxy)benzoate.
[0054] The reaction in the fourth step can be carried out, for
example, by mixing an ammonium carboxylate, ethyl
2-amino-4,5-bis(2-methoxyethoxy)benzoate, a formic acid compound
and a solvent under stirring in an inert gas atmosphere. The
reaction temperature is preferably in the range of 40 to
200.degree. C., and more preferably in the range of 50 to
150.degree. C. There are no specific limitations with respect to
the reaction pressure.
[0055] After the reaction is complete, the final product, i.e.,
6,7-bis(2-methoxyethoxy)quinazolin-4-one, can be isolated or
purified. The isolation or purification can be conducted according
to the conventional method such as filtration, concentration,
distillation, recrystallization, crystallization, or column
chromatography.
[0056] The present invention is further described by referring to
the following examples.
EXAMPLES
Synthesis Example 1
Synthesis of ethyl 3,4-bis(2-methoxyethoxy)benzoate
[0057] In a 20 L-volume glass reaction vessel equipped with a
stirrer, a thermometer and a reflux condenser, 1,300 g (7.14 moles)
of ethyl 3,4-dihydroxybenzoate, 2,324 g (21.4 moles) of
2-chloroethyl methyl ether, 2,958 g (21.4 moles) of potassium
carbonate and 6,500 mL of N,N-dimethylformamide were placed. The
mixture was allowed to react with each other at 90 to 100.degree.
C. for 9 hours while stirring. After the reaction was complete, the
reaction solution was cooled to room temperature. The reaction
solution was then filtered, and washed with 6,500 mL of acetone.
The filtrate was concentrated, 3,900 mL of ethyl acetate and 3,900
mL of a saturated aqueous sodium carbonate solution were added to
the concentrate. The separated organic layer (ethyl acetate layer)
was washed twice with 3,900 mL of a saturated aqueous sodium
chloride solution to obtain a solution mixture containing ethyl
3,4-bis(2-methoxyethoxy)benzoate. The solution mixture was analyzed
(according to an absolute quantitative method) by a high
performance liquid chromatography. It was confirmed that 2,023 g of
ethyl 3,4-bis(2-methoxyethoxy)benzoate was produced (reaction
yield: 95%). After 3,939 mL of acetic acid was added to the
solution mixture, the mixture was concentrated under reduced
pressure to distill ethyl acetate off. Thus, an acetic acid
solution of ethyl 3,4-bis(2-methoxyethoxy)benzoate was
obtained.
Synthesis Example 2
Synthesis of ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate
[0058] In a 20 L-volume glass reaction vessel equipped with a
stirrer, a thermometer and a reflux condenser, the acetic acid
solution containing 2,023 g (6.78 moles) of ethyl
3,4-bis(2-methoxyethoxy)benzoate prepared in the Synthesis Example
1 was placed. To the solution, 318 g (3.18 moles) of concentrated
sulfuric acid was gently added while stirring the solution at room
temperature. The mixture was heated to 60 to 70.degree. C. To the
mixture, 1,857 g (20.34 moles) of 69 wt. % nitric acid was gently
added while stirring the mixture. The resulting mixture was allowed
to react for 2 hours while maintaining the temperature. After the
reaction was complete, the reaction solution was cooled to room
temperature. To the reaction solution, 5,200 mL of a 20 wt. %
aqueous sodium chloride solution and 5,200 mL of toluene were
added. The separated organic layer (toluene layer) was washed twice
with 7,800 mL of a 1 mole per L aqueous sodium hydroxide solution,
and further washed twice with 7,800 mL of a 20 wt. % aqueous sodium
chloride solution. The organic layer was concentrated under reduced
pressure to obtain 2,328 g of ethyl
4,5-bis(2-methoxyethoxy)-2-nitrobenzoate as an orange liquid
(isolation yield: 100%).
Synthesis Example 3
Synthesis of ethyl 2-amino-4,5-bis(2-methoxyethoxy)-benzoate
[0059] In a 20 L-volume glass reaction vessel equipped with a
stirrer, a thermometer and a reflux condenser, 2,328 g (6.78 moles)
of the ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate prepared in
the Synthesis Example 2, 2 wt. % platinum per 118 g of carbon (50
wt.% product, N. E. Chemcat Corporation, 6.0 mmoles in terms of
platinum metallic atom) and 9,440 mL of methanol were placed. The
mixture was allowed to react at 50 to 60.degree. C. for 6 hours in
an atmosphere of hydrogen while stirring. After the reaction was
complete, the reaction solution was cooled to room temperature, and
filtered. The filtrate was concentrated under reduced pressure to
obtain 1,960 g of ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate as
an orange liquid (isolation yield: 92%).
Synthesis Example 4
Synthesis of 6,7-bis(2-methoxyethoxy)quinazolin-4-one
[0060] In a 20 L-volume glass reaction vessel equipped with a
stirrer, a thermometer and a reflux condenser, 1,600 g (5.11 moles)
of the ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate prepared in
the Synthesis Example 3, 1,626 g (15.3 moles) of methyl
orthoformate, 1,181 g (15.3 moles) of ammonium acetate and 4,800 mL
of methanol were placed. The mixture was allowed to react under
refluxing conditions (60 to 70.degree. C.) for 7 hours while
stirring. After the reaction was complete, the reaction solution
was cooled to 60.degree. C. To the reaction solution, 4,800 mL of
methanol was added. The mixture was stirred for 30 minutes while
maintaining the temperature, cooled to 0 to 5.degree. C., and
further stirred for 1 hour. The resulting mixture was filtered to
obtain 1,373 g of 6,7-bis(2-methoxyethoxy)quinazolin-4-one as white
crystals (isolation yield: 91%).
[0061] The total yield based on ethyl 3,4-dihydroxybenzoate was
80%.
* * * * *