U.S. patent application number 10/503664 was filed with the patent office on 2005-06-16 for process for producing 4-aminoquinazoline compound.
This patent application is currently assigned to Ube Industries, Ltd.. Invention is credited to Harada, Takashi, Hirotsu, Kenji, Nishino, Shigeyoshi, Oda, Hiroyuki, Shima, Hidetaka.
Application Number | 20050130995 10/503664 |
Document ID | / |
Family ID | 27739271 |
Filed Date | 2005-06-16 |
United States Patent
Application |
20050130995 |
Kind Code |
A1 |
Nishino, Shigeyoshi ; et
al. |
June 16, 2005 |
Process for producing 4-aminoquinazoline compound
Abstract
A 4-aminoquinazoline derivative can be obtained by the steps of
reacting quinazolin-4-one or its derivative with a chlorinating
agent in a first organic solvent in the presence of an organic
base, and subsequently reacting the reaction product with an amine
compound represented by the formula R.sup.5--NH--R.sup.6 (each of
R.sup.5 and R.sup.6 represents hydrogen or an optionally
substituted hydrocarbyl group) in the presence of a second organic
solvent.
Inventors: |
Nishino, Shigeyoshi;
(Yamaguchi, JP) ; Hirotsu, Kenji; (Yamaguchi,
JP) ; Shima, Hidetaka; (Yamaguchi, JP) ;
Harada, Takashi; (Yamaguchi, JP) ; Oda, Hiroyuki;
(Yamaguchi, JP) |
Correspondence
Address: |
Thomas W Cole
Nixon Peabody
Suite 800
8180 Greebsboro Drive
Mc Lean
VA
22102
US
|
Assignee: |
Ube Industries, Ltd.
Ube-shi, Yamaguchi
JP
755-8633
|
Family ID: |
27739271 |
Appl. No.: |
10/503664 |
Filed: |
August 6, 2004 |
PCT Filed: |
February 6, 2003 |
PCT NO: |
PCT/JP03/01254 |
Current U.S.
Class: |
514/266.4 ;
544/293 |
Current CPC
Class: |
C07D 239/94 20130101;
C07D 239/88 20130101 |
Class at
Publication: |
514/266.4 ;
544/293 |
International
Class: |
A61K 031/517; C07D
239/94 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 6, 2002 |
JP |
2002-29745 |
Aug 27, 2002 |
JP |
2002-246656 |
Sep 19, 2002 |
JP |
2002-272892 |
Sep 19, 2002 |
JP |
2002-272893 |
Claims
What is claimed is:
1. A process for preparing a 4-aminoquinazoline compound having the
formula (3): 6in which each of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 independently represents a group not participating the
below-mentioned reaction, or R.sup.1, R.sup.2, R.sup.3 and R.sup.4
are combined to form a ring, and each of R.sup.5 and R.sup.6
independently represents a hydrogen atom or a hydrocarbyl group
which can have a substituent, which comprises: a first step of
reacting a quinazolin-4-one compound having the formula (1): 7in
which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the same meaning
as above, with a chlorinating agent in a first organic solvent in
the presence of an organic base, and a second step for reacting a
reaction product of the first step with an amine compound having
the formula (2): R.sup.5--NH--R.sup.6 (2) in which R.sup.5 and
R.sup.6 have the same meaning as above, in the presence of a second
organic solvent.
2. The process of claim 1, wherein each of R.sup.1, R.sup.4 and
R.sup.6 is hydrogen, each of R.sup.2 and R.sup.3 is
2-methoxyethoxy, and R.sup.5 is 3-ethynylphenyl.
3. The process of claim 1, wherein each of R.sup.1, R.sup.4 and
R.sup.6 is hydrogen, R.sup.2 is methoxy, R.sup.3 is
3-morpholinopropoxy, and R.sup.5 is 3-chloro-4-fluorophenyl.
4. The process of claim 1, wherein the quinazolin-4-one compound of
formula (1) is 6-halogenoquinazolin-4-one of the following formula
(4), the amine compound of formula (2) is arylamine of the
following formula (5), and the 4-arylaminoquinazoline compound of
formula (3) is 6-halogeno-4-arylaminoquinazoline of the following
formula (6): 8in which X is a halogen atom, and Ar is an aryl group
which can have a substituent.
5. The process of claim 4, wherein X is iodine.
6. The process of claim 5, wherein Ar is
3-chloro-4-(3-fluorobenzyloxy)phe- nyl.
7. The process of claim 1, wherein the reaction of the first step
is performed by adding the organic base to a mixture of the
quinazolin-4-one compound, first organic solvent, and chlorinating
agent.
8. The process of claim 1, wherein the organic base is used in an
amount of 0.8 to 2.5 moles, based on one mole of the
quinazolin-4-one compound.
9. The process of claim 1, wherein the first organic solvent is an
aliphatic hydrocarbon, a halogenated aliphatic hydrocarbon, an
aromatic hydrocarbon, a halogenated aromatic hydrocarbon, ether, or
amide.
10. The process of claim 1, wherein the first organic solvent is an
aromatic hydrocarbon.
11. The process of claim 1, wherein the chlorinating agent is
phosphorus oxychloride.
12. The process of claim 1, wherein the chlorinating agent is used
in an amount of 1.0 to 2.5 moles, based on one mole of the
quinazolin-4-one compound.
13. The process of claim 1, wherein the second organic solvent is a
halogenated aliphatic hydrocarbon, a halogenated aromatic
hydrocarbon, nitrile, ketone, or ether.
14. The process of claim 1, wherein each of the reactions of the
first and second steps is performed at a temperature of 10 to
150.degree. C.
15. The process of claim 1, wherein the reaction product of the
first step is subjected to the second step without isolating the
reaction product from a reaction mixture of the first step.
16. A process for preparing 6-halogeno-4-chloroquinazoline having
the formula (7): 9in which X is a halogen atom, which comprises
reacting 6-halogenoquinazolin-4-one having the formula (4): 10in
which X has the same meaning as above, with a chlorinating agent in
an organic solvent in the presence of an organic base.
17. The process of claim 16, wherein X is iodine.
18. The process of claim 16, wherein the reaction is performed by
adding the organic base to a mixture of the quinazolin-4-one
compound, organic solvent, and chlorinating agent.
19. The process of claim 16, wherein the organic base is used in an
amount of 0.8 to 2.5 moles, based on one mole of the
quinazolin-4-one compound.
20. The process of claim 16, wherein the organic solvent is an
aliphatic hydrocarbon, a halogenated aliphatic hydrocarbon, an
aromatic hydrocarbon, a halogenated aromatic hydrocarbon, ether, or
amide.
21. The process of claim 16, wherein the first organic solvent is
an aromatic hydrocarbon.
22. The process of claim 16, wherein the chlorinating agent is
phosphorus oxychloride.
23. The process of claim 16, wherein the chlorinating agent is used
in an amount of 1.0 to 2.5 moles, based on one mole of the
quinazolin-4-one compound.
24. The process of claim 16, wherein the reaction is performed at a
temperature of 10 to 150.degree. C.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a process for preparing a
4-aminoquinazoline compound from a quinazolin-4-one compound. The
4-aminoquinazoline compound is useful as an intermediate or a
starting compound for preparing a pharmaceutically active compound
or an agricultural chemical.
[0002] The invention specifically relates to a process for
preparing 6-halogeno-4-arylaminoquinazoline from
6-halogenoquinazolin-4-one.
[0003] The invention further relates to a process for preparing
6-halogeno-4-chloroquinazoline from 6-halogenoquinazolin-4-one. The
6-halogeno-4-chloroquinazoline is employable as a starting compound
for preparing the 6-halogeno-4-arylaminoquinazoline.
BACKGROUND OF THE INVENTION
[0004] JP-A-10-152477 describes a process for preparing a
4-arylaminoquinazoline compound from a quinazolin-4-one, which
comprises the steps of chlorinating 4-iodoquinazolin-4-one using an
excessive amount of oxalyl chloride to produce
6-iodo-4-chloroquinazoline (intermediate compound), concentrating
the reaction product under reducing pressure to isolate the
resulting product; reacting the 6-iodo-4-chloroquinazoline with
5-aminoindole to give 6-iodo-4-(5-indolylamino)quinazoline.
Unfortunately, the yield is not high. Further, it should be noted
that the intermediate compound, i.e., 4-chloroquinazoline compound,
shows no satisfactory stability in the presence of water and no
satisfactory resistance to heat. Accordingly, the compound should
be handled carefully.
[0005] WO 96/09294 describes a process for preparing
6-halogeno-4-chloroquinazoline from 6-halogenoquinazolin-4-one
which comprises reacting the 6-halogenoquinazolin-4-one with an
excessive amount of phosphorus oxychloride. This process, however,
has problems in that a large amount of smelly phosphorus
oxychloride should be used, yield of the reaction product (i.e.,
6-halogeno-4-chloroquinazoline) is low, and a large amount of an
organic solvent is necessarily employed for recovering the reaction
product from an excessive amount of phosphorus oxychloride. Thus,
complicated post-treating procedures are required.
DISCLOSURE OF THE INVENTION
[0006] The present invention has an object to provide a simple
process for preparing a 4-aminoquinazoline compound from a
quinazolin-4-one compound.
[0007] The invention specifically has an object to provide a
process for preparing 6-halogeno-4-arylaminoquinazoline from
6-halogenoquinazolin-4-o- ne.
[0008] The invention further relates has an object to provide a
process for preparing 6-halogeno-4-chloroquinazoline from
6-halogenoquinazolin-4-- one. The 6-halogeno-4-chloroquinazoline is
employable as a starting compound for preparing the
6-halogeno-4-arylaminoquinazoline.
[0009] The present invention resides in a process for preparing a
4-aminoquinazoline compound having the formula (3): 1
[0010] in which each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4
independently represents a group not participating the
below-mentioned reaction, or R.sup.1, R.sup.2, R.sup.3 and R.sup.4
are combined to form a ring, and each of R.sup.5 and R.sup.6
independently represents a hydrogen atom or a hydrocarbyl group
which can have a substituent, which comprises:
[0011] a first step of reacting a quinazolin-4-one compound having
the formula (1): 2
[0012] in which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the same
meaning as above, with a chlorinating agent in a first organic
solvent in the presence of an organic base, and
[0013] a second step for reacting a reaction product of the first
step with an amine compound having the formula (2):
R.sup.5--NH--R.sup.6 (2)
[0014] in which R.sup.5 and R.sup.6 have the same meaning as above,
in the presence of a second organic solvent.
[0015] The invention further resides in the process wherein the
quinazolin-4-one compound of formula (1) is
6-halogenoquinazolin-4-one of the following formula (4), the amine
compound of formula (2) is arylamine of the following formula (5),
and the 4-arylaminoquinazoline compound of formula (3) is
6-halogeno-4-arylaminoquinazoline of the following formula (6):
3
[0016] in which X is a halogen atom, and Ar is an aryl group which
can have a substituent.
[0017] The invention furthermore resides in a process for preparing
6-halogeno-4-chloroquinazoline having the formula (7): 4
[0018] in which X is a halogen atom,
[0019] which comprises reacting 6-halogenoquinazolin-4-one having
the formula (4): 5
[0020] in which X has the same meaning as above,
[0021] with a chlorinating agent in an organic solvent in the
presence of an organic base.
DETAILED DESCRIPTION OF THE INVENTION
[0022] The quinazolin-4-one compound employed in the reaction of
the invention as the starting compound is represented by the
aforementioned formula (1). In formula (1), each of R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 a group that can have a substituent,
and does not participate in the reactions of the first and second
steps. For example, the group is a hydrogen atom, an alkyl group
having 1-12 carbon atoms, a cycloalkyl group having 1-12 carbon
atoms, an aralkyl group having 7-15 carbon atoms, an aryl group
having 6-14 carbon atoms, a halogen atom, an alkoxy group having
1-12 carbon atoms, an alkylthio group having 1-12 carbon atoms, an
arylthio group having 6-14 carbon atoms, nitro, cyano, amino,
carboxyl, ester groups, or amide. R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 can be combined with each other to form a ring.
[0023] Examples of the alkyl groups include methyl, ethyl, propyl,
butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. These groups
can be any of isomers.
[0024] Examples of the cycloalkyl groups include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl.
[0025] Examples of the aralkyl groups include benzyl, phenethyl,
and phenylpropyl. These groups can be any of isomers.
[0026] Examples of the aryl groups include phenyl, p-tolyl,
naphthyl, and anthryl. These groups can be any of isomers.
[0027] Examples of halogen atoms include fluorine, chlorine,
bromine, and iodine.
[0028] Examples of the alkoxy groups include methoxy, ethoxy, and
propoxy. These groups can be any of isomers.
[0029] Examples of the alkylthio groups include methylthio,
ethylthio, and propylthio. These groups can be any of isomers.
[0030] Examples of the arylthio groups include phenylthio,
p-tolylthio, naphthylthio, and anthrylthio. These groups can be any
of isomers.
[0031] Examples of the ester groups include methoxycarbonyl,
ethoxycarbonyl, and propoxycarbonyl. These groups can be any of
isomers.
[0032] The above-mentioned alkyl, cycloalkyl, aralkyl, aryl,
alkoxy, alkylthio, arylthio, and amino may have a substituent.
Examples of the substituents include a substituent bonded via a
carbon atom, a substituent bonded via an oxygen atom, a substituent
bonded via a nitrogen atom, a substituent bonded via a sulfur atom,
and a halogen atom.
[0033] Examples of the substituents bonded via a carbon atom
include alkyl groups such as methyl, ethyl, propyl, butyl, pentyl,
and hexyl; cycloalkyl groups such as cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl; alkenyl groups such as vinyl, allyl,
propenyl, cyclopropenyl, cyclobutenyl, and cyclopentenyl;
heterocyclic alkenyl groups such as pyrrolidyl, pyrrolyl, furyl,
and thienyl; aryl groups such as phenyl, tolyl, xylyl, biphenylyl,
naphthyl, anthryl, and phenanthryl; acyl groups (possibly be
acetallized) such as formyl, acetyl, propionyl, acryloyl, pivaloyl,
cyclohexylcarbonyl, benzoyl, naphthoyl, and toluoyl; carboxyl
groups; alkoxycarbonyl groups such as methoxycarbonyl and
ethoxycarbonyl; aryloxycarbonyl groups such as phenoxycarbonyl;
halogenated alkyl groups such as trifluoromethyl; and cyano. These
groups can be any of isomers.
[0034] Examples of the substituents bonded via an oxygen atom
include hydroxyl; alkoxy groups such as methoxy, ethoxy, propoxy,
butoxy, pentyloxy, hexyloxy, heptyloxy, benzyloxy, piperidyloxy,
and pyranyloxy; and aryloxy groups such as phenoxy, toluyloxy, and
naphthyloxy. These groups can be any of isomers.
[0035] Examples of the substituents bonded via a nitrogen atom
include primary amino groups such as methylamino, ethylamino,
butylamino, cyclohexylamino, phenylamino, and naphthylamino;
secondary amino groups such as dimethylamino, diethylamino,
dibutylamino, methylethylamino, methylbutylamino, and
diphenylamino; heterocyclic amino groups such as morpholino,
piperidino, piperazinyl, pyrazolidinyl, pyrrolidino, and indolyl;
and imino. These groups can be any of isomers.
[0036] Examples of the substituents bonded via a sulfur atom
include mercapto; thioalkoxy groups such as thiomethoxy,
thioethoxy, and thiopropoxy; and thioaryloxy groups such as
thiophenoxy, thiotoluyloxy, and thionaphthyloxy. These groups can
be any of isomers.
[0037] Examples of the halogen atoms include fluorine, chlorine,
bromine, and iodine.
[0038] R.sup.5 is a hydrogen atom or a hydrocarbyl group which can
have a substituent. Examples of the hydrocarbyl groups include
alkyl groups having 1-12 carbon atoms such as methyl, ethyl,
propyl, butyl, pentyl, and hexyl; cycloalkyl groups such having
1-12 carbon atoms as cyclopropyl, cyclobutyl, cyclopentyl, and
cyclohexyl; aralkyl groups having 7-13 carbon atoms such as benzyl,
phenethyl, and phenylpropyl; and aryl groups having 7-13 carbon
atoms such as phenyl, tolyl, naphthyl, and anthryl. These groups
can be any of isomers.
[0039] The above-mentioned hydrocarbyl group can have a
substituent. Examples of the substituents are those described for
R.sup.1, R.sup.2, R.sup.3 and R.sup.4.
[0040] The organic base used in the reaction of the first step can
be an aliphatic amine such as trimethylamine, triethylamine,
ethyldiisopropylamine, or tributylamine; an aromatic amine such as
dimethylaniline or diethylaniline; or a heterocyclic amine such as
pyridine, quinoline, pyrimidine, or 4-dimethylaminopyridine.
Preferred is an aliphatic amine. More preferred is triethylamine.
The organic base can be used singly or in combination.
[0041] The organic base can be employed preferably in an amount of
0.8 to 2.5 moles, more preferably 1.0 to 1.5 moles, per one mole of
the quinazolin-4-one compound.
[0042] There are no specific limitations with respect to the
organic solvent employed in the reaction of the first step, so far
as the solvent does not participate in the reaction. Examples are
aliphatic hydrocarbons such as hexane, cyclohexane, and heptane;
halogenated hydrocarbons such as chloroform and dichloroethane;
aromatic hydrocarbons such as toluene, xylene, and mesitylene;
halogenated aromatic hydrocarbons such as chlorobenzene; ethers
such as diethyl ether, tetrahydrofuran, and dimethoxyethane; and
amides such as N,N-dimethylformamide and
1,3-dimethylimidazolindione. Preferred are aromatic hydrocarbons.
More preferred is toluene. The organic solvents can be employed
singly or in combination. Further, the organic solvent can be
placed in the reaction mixture while the reaction proceeds, if
necessary.
[0043] The amount of the organic solvent employed in the reaction
depends on the homogeneity and stirring condition of the reaction
mixture. It is preferred that the solvent is employed in an amount
of 0.5 to 30 g (more preferably 1 to 10 g, most preferably 1 to 5
g) per one gram of the quinazolin-4-one compound.
[0044] The chlorinating agent used in the reaction of the first
step can be phosphorus oxychloride, phosphorus trichloride,
phosphorus pentachloride, thionyl chloride, sulfuryl chloride,
nitrosyl chloride, and chlorine molecule. Preferred is phosphorus
oxychloride. The chlorinating agent can be used singly or in
combination.
[0045] The chlorinating agent is preferably employed in an amount
of 0.9 to 7.0 moles, more preferably 1.0 to 5.0 moles, most
preferably 1.0 to 2.5 moles per one mole of the quinazolin-4-one
compound.
[0046] There are no specific limitations with respect to the
organic solvent employed in the reaction of the second step, so far
as the solvent does not participate in the reaction. Examples of
the organic solvents include halogenated aliphatic hydrocarbons
such as methylene chloride and chloroform; halogenated aromatic
hydrocarbons such as chlorobenzene; nitrites such as acetonitrile
and propionitrile; ketones such as acetone, methyl ethyl ketone,
methyl isopropyl ketone, and methyl isobutyl ketone; and ethers
such as diethyl ether, tetrahydrofuran, and dimethoxyethane.
Preferred are ketones. More preferred is methyl ethyl ketone. The
organic solvent can be used singly or in combination.
[0047] The amount of the organic solvent employed in the reaction
depends on the homogeneity and stirring condition of the reaction
mixture. It is preferred that the solvent is employed in an amount
of 0.1 to 10 mL (more preferably 0.5 to 5 mL) per one gram of the
quinazolin-4-one compound.
[0048] The amine compound used in the reaction of the second step
of the invention is represented by the aforementioned formula
(2).
[0049] The reactions of the process of the invention can be
performed, for instance, by a first step in which a
quinazolin-4-one compound, an organic base, a chlorinating agent,
and an organic solvent are mixed and stirred in an inert gas
atmosphere, and a second step in which the resulting reaction
liquid is further stirred after addition of an organic solvent and
an amine compound. These reactions are preferably carried out at a
temperature in the range of 10 to 150.degree. C., more preferably
50 to 120.degree. C., most preferably 40 to 100.degree. C. There
are no specific limitations with respect to the reaction
pressure.
[0050] The combination of the first and second steps can give the
main product, i.e., hydrochloride of a 4-aminoquinazoline compound,
which can be neutralized with a base (e.g., aqueous alkali metal
hydroxide) to give a free 4-aminoquinazoline compound.
[0051] The 4-aminoquinazoline compound produced in the second step
can be isolated and purified by the conventional procedures such as
filtration, extraction, concentration, distillation,
recrystallization, and column chromatography.
[0052] As described above, 6-halogeno-4-arylaminoquinazoline of
formula (6) can be obtained by employing 6-halogenoquinazolin-4-one
of formula (4) as the quinazolin-4-one compound and arylamine of
formula (5) as the amine compound.
[0053] In formulas (4) and (6), X is a halogen atom (fluorine,
chlorine, bromine, or iodine). Preferred is iodine. Ar in formulas
(5) and (6) is an aryl group that can have a substituent. Examples
of the aryl groups are carbon ring aromatic groups having 6-14
carbon atoms and heterocyclic aromatic groups such as phenyl,
biphenylyl, naphthyl, anthryl, phenanthryl, pyridyl, quinolyl,
pyrrolidyl, pyrrolyl, furyl, and thienyl.
[0054] Examples of the substituents are substituents bonded via
carbon atom, substituents bonded via oxygen atom, substituents
bonded via nitrogen atom, substituents bonded via sulfur atom, and
halogen atoms. There are no limitations with respect to number and
position of the substituent.
[0055] When the compound of formula (4) and the compound of formula
(6) are employed as the starting compounds,
6-halogeno-4-arylaminoquinazoline hydrochloride is produced as a
main product after the second step. This product can be converted
to free 6-halogeno-4-arylaminoquinazoline by neutralization with a
base (e.g., aqueous alkali metal hydroxide). Thus obtained
6-halogeno-4-arylaminoquinazoline can be isolated and purified by
the conventional procedures such as filtration, extraction,
concentration, distillation, recrystallization, and column
chromatography.
[0056] When 6-halogenoquinazolin-4-one of formula (4) is employed
as the starting compound in the first step, the main reaction
product, i.e., 6-halogeno-4-chloroquinazoline can be isolated
before it is processed in the second step.
[0057] 6-Halogeno-4-chloroquinazoline can be recovered as a
crystalline product, for instance, by cooling the reaction liquid.
However, it is preferred that the reaction liquid is stirred
preferably at -10-70.degree. C., more preferably at 0-30.degree.
C., after addition of an organic solvent, whereby a crystalline
product precipitates.
[0058] The organic solvent can be halogenated aliphatic hydrocarbon
such as methylene chloride or chloroform; halogenated aromatic
hydrocarbon such as chlorobenzene; nitrites such as acetonitrile or
propionitrile, ketone such as acetone, methyl ethyl ketone, methyl
isopropyl ketone, or methyl isobutyl ketone; or ether such as
diethyl ether, tetrahydrofuran, or dimethoxyethane. Preferred is
ketone. More preferred is methyl ethyl ketone. The organic solvent
can be used singly or in combination.
[0059] The amount of the organic solvent depends on the homogeneity
and stirring condition of the reaction mixture. It is preferred
that the organic solvent is employed in an amount of 0.1 to 10 mL
(more preferably 0.5 to 5 mL) per one gram of the
6-halogenoquinazolin-4-one.
[0060] The crystalline product of 6-halogeno-4-chloroquinazoline
can be further purified by stirring the product in aqueous alkali
metal hydroxide to remove impurities (e.g., organic base
hydrochloride).
EXAMPLE I-1
Preparation of 4-(3-chloro-4-fluoro)anilinoquinazoline
[0061] In a 20 mL-volume glass vessel equipped with a stirrer, a
thermometer and a reflux condenser were placed 0.80 g (5.5 mmol) of
quinazolin-4-one, 1.00 g (6.6 mmol) of phosphorus oxychloride, and
10 mL of toluene in a nitrogen atmosphere. While the mixture was
stirred at room temperature, 0.66 g (6.6 mmol) of triethylamine was
slowly added. The resulting mixture was heated to 75.degree. C. and
then reaction was carried out for 2 hours. Subsequently, the
mixture was cooled to room temperature, and 1.6 mL of methyl
isobutyl ketone and 0.96 g (6.6 mmol) of 3-chloro-4-fluoroaniline
were added. The resulting mixture was again heated to 75.degree.
C., and then reaction was carried out under stirring for one hour.
After the reaction was complete, the reaction mixture was cooled to
room temperature, and thus precipitated crystalline product was
collected by filtration. Subsequently, the crystal-line product was
placed in 30 mL of aqueous sodium hydroxide (1 mol/L), and the
aqueous mixture was stirred for 30 minutes at room temperature. The
crystalline product was collected by filtration, washed with 30 mL
of water, and dried under reduced pressure, to give 1.35 g
(isolated yield: 89%, purity 99% in terms of area percentage
determined by high performance liquid chromatography) of
4-(3-chloro-4-fluoro)anilinoquinazoline as a yellowish crystalline
product.
[0062] 4-(3-Chloro-4-fluoro)anilinoquinazoline had the following
physical properties.
[0063] .sup.1H-NMR (DMSO-d.sub.6, .delta. (ppm)): 7.46 (1H, t,
J=9.0 Hz), 7.64-7.70 (1H, m), 7.81-7.92 (3H, m), 8.23 (1H, dd,
J=6.6, 2.4 Hz), 8.53 (1H, d, J=8.1 Hz), 8.66 (1H, s), 9.90 (1H,
s)
[0064] CI-MS (m/e): 274 (M+1)
EXAMPLE I-2
Preparation of
6-methyl-4-(3-chloro-4-methoxy)anilinoquinazoline
[0065] In a 20 mL-volume glass vessel equipped with a stirrer, a
thermometer and a reflux condenser were placed 0.80 g (5.0 mmol) of
6-methylquinazolin-4-one, 0.92 g (6.0 mmol) of phosphorus
oxychloride, and 5 mL of toluene in a nitrogen atmosphere. While
the mixture was stirred at room temperature, 0.61 g (6.0 mmol) of
triethylamine was slowly added. The resulting mixture was heated to
75.degree. C., and then reaction was carried out for 2 hours.
Subsequently, the mixture was cooled to room temperature, and 1.6
mL of methyl isobutyl ketone and 0.94 g (6.0 mmol) of
3-chloro-4-methoxyaniline were added. The resulting mixture was
again heated to 75.degree. C. and then reaction was carried out
under stirring for one hour. After the reaction was complete, the
reaction mixture was cooled to room temperature, and thus
precipitated crystalline product was collected by filtration.
Subsequently, the crystalline product was placed in 30 mL of
aqueous sodium hydroxide (1 mol/L), and the aqueous mixture was
stirred for 30 minutes at room temperature. The crystalline product
was collected by filtration, washed with 30 mL of water, and dried
under reduced pressure, to give 1.36 g (isolated yield: 91%, purity
99% in terms of area percentage determined by high performance
liquid chromatography) of 6-methyl-4-(3-chloro-4-meth-
oxy)anilinoquinazoline as a yellowish crystalline product.
[0066] 6-Methyl-4-(3-chloro-4-methoxy)anilinoquinazoline had the
following physical properties.
[0067] .sup.1H-NMR (DMSO-d.sub.6, .delta. (ppm)): 3.87 (3H, d,
J=9.0 Hz) 7.47 (1H, dd, J=8.7, 1.8 Hz), 7.58 (1H, s), 7.75 (1H, dd,
J=9.0, 2.4 Hz), 8.03 (1H, d, J=2.7 Hz), 8.40 (1H, d, J=8.4 Hz),
8.55 (1H, s), 9.68 (1H, s)
[0068] CI-MS (m/e): 300 (M+1)
EXAMPLE I-3
Preparation of 6-iodo-4-benzylaminoquinazoline
[0069] In a 20 mL-volume glass vessel equipped with a stirrer, a
thermometer and a reflux condenser were placed 2.0 g (7.4 mmol) of
6-iodoquinazolin-4-one, 1.35 g (8.8 mmol) of phosphorus
oxychloride, and 10 mL of toluene in a nitrogen atmosphere. While
the mixture was stirred at room temperature, 0.66 g (6.6 mmol) of
triethylamine was slowly added. The resulting mixture was heated to
75.degree. C., and then reaction was carried out for 2 hours.
Subsequently, the mixture was cooled to room temperature, and 3 mL
of methyl isobutyl ketone and 3.15 g (29.4 mmol) of benzylamine
were added. The resulting mixture was again heated to 75.degree.
C., and then reaction was carried out under stirring for one hour.
After the reaction was complete, the reaction mixture was cooled to
room temperature. Thus precipitated crystalline product was
collected by filtration. Subsequently, the crystalline product was
placed in 30 mL of aqueous sodium hydroxide (1 mol/L), and the
aqueous mixture was stirred for 30 minutes at room temperature. The
crystalline product was collected by filtration, washed with 30 mL
of water, and dried under reduced pressure, to give 2.26 g
(isolated yield: 84%, purity 99% in terms of area percentage
determined by high performance liquid chromatography) of
6-iodo-4-benzylaminoquinazoline as a yellowish crystalline
product.
[0070] 6-Iodo-4-benzylaminoquinazoline had the following physical
properties.
[0071] .sup.1H-NMR (DMSO-d.sub.6, .delta. (ppm)): 4.77 (2H, d,
J=5.7 Hz), 7.22-7.39 (5H, m), 7.47 (1H, d, J=8.7 Hz), 8.03 (1H, dd,
J=9.0, 1.8 Hz), 8.48 (1H, s), 8.80 (1H, d, J=1.5 Hz), 8.99 (1H, t,
J=5.4 Hz)
[0072] CI-MS (m/e): 362 (M+1)
EXAMPLE I-4
Preparation of 6-iodo-4-piperidinoquinazoline
[0073] The procedures of Example I-3 were repeated except for
replacing benzylamine with 1.13 g (13.3 mmol) of piperidine, to
give 2.26 g (isolated yield: 79%, purity 87% in terms of area
percentage determined by high performance liquid chromatography) of
6-iodo-4-piperidinoquinazol- ine as a yellowish crystalline
product.
[0074] 6-Iodo-4-piperidinoquinazoline had the following physical
properties.
[0075] .sup.1H-NMR (DMSO-d.sub.6, .delta. (ppm)): 1.6-1.7 (6H, m),
3.6-3.7 (4H, m), 7.56 (1H, d, J=8.7 Hz), 8.04 (1H, dd, J=8.7, 1.8
Hz), 8.21 (1H, d, J=1.8 Hz), 8.60 (1H, s)
[0076] CI-MS (m/e): 340 (M+1)
EXAMPLE II-1
Preparation of 6-iodo-4-anilinoquinazoline
[0077] In a 20 mL-volume glass vessel equipped with a stirrer, a
thermometer and a reflux condenser were placed 2.00 g (7.35 mmol)
of 6-iodoquinazolin-4-one, 1.35 g (8.8 mmol) of phosphorus
oxychloride, and 6 mL of toluene in a nitrogen atmosphere. While
the mixture was stirred at room temperature, 0.89 g (8.8 mmol) of
triethylamine was slowly added. The resulting mixture was heated to
75.degree. C., and then reaction was carried out for 2 hours.
Subsequently, the mixture was cooled to room temperature, and 3 mL
of acetone and 821 mg (8.8 mmol) of aniline were added. The
resulting mixture was again heated to 75.degree. C., and then
reaction was carried out under stirring for one hour. After the
reaction was complete, the reaction mixture was cooled to room
temperature, and thus precipitated crystalline product was
collected by filtration. Subsequently, the crystalline product was
placed in 30 mL of aqueous sodium hydroxide (1 mol/L), and the
aqueous mixture was stirred for 30 minutes at room temperature. The
crystalline product was collected by filtration, washed with 30 mL
of water, and dried under reduced pressure, to give 1.91 g
(isolated yield: 73%, purity 97% in terms of area percentage
determined by high performance liquid chromatography) of
6-iodo-4-anilinoquinazoline as a yellowish crystalline product.
[0078] 6-Iodo-4-anilinoquinazoline had the following physical
properties.
[0079] .sup.1H-NMR (DMSO-d.sub.6, .delta. (ppm)): 7.12-7.18 (1H,
m), 7.37-7.44 (2H, m), 7.56 (1H, d, J=8.7 Hz), 7.82-7.88 (2H, m),
8.12 (1H, dd, J=2.1, 8.7 Hz), 8.61 (1H, s), 9.01 (1H, d, J=1.8 Hz),
9.87 (1H, s)
[0080] CI-MS (m/e): 348 (M+1)
EXAMPLE II-2
Preparation of 6-iodo-4-anilinoquinazoline
[0081] The procedures of Example II-1 were repeated except that
acetone was replaced with methyl isobutyl ketone and that 753 mg
(8.1 mmol) of aniline was used, to give 1.90 g (isolated yield:
74%, purity 99% in terms of area percentage determined by high
performance liquid chromatography) of
6-iodo-4-anilinoquinazoline.
EXAMPLE II-3
Preparation of 6-iodo-4-(3-chloro-4-methoxy)anilinoquinazoline
[0082] The procedures of Example II-1 were repeated except for
replacing aniline with 1.39 g (8.8 mmol) of
3-chloro-4-methoxyaniline, to give 2.92 g (isolated yield: 96%,
purity 96% in terms of area percentage determined by high
performance liquid chromatography) of 6-iodo-4-(3-chloro-4-methox-
y)anilinoquinazoline as a yellowish crystalline product.
[0083] 6-Iodo-4-(3-chloro-4-methoxy)anilinoquinazoline had the
following physical properties.
[0084] .sup.1H-NMR (DMSO-d.sub.6, .delta. (ppm)): 3.88 (3H, s),
7.20 (1H, d, J=9.3 Hz), 7.55 (1H, d, J=8.7 Hz), 7.75 (1H, dd,
J=2.7, 9.0 Hz), 8.00 (1H, d, J=2.7 Hz), 8.10 (1H, dd, J=2.1, 8.7
Hz), 8.61 (1H, s), 8.96 (1H, d, J=1.8 Hz), 9.83 (1H, s)
[0085] CI-MS (m/e): 412 (M+1)
EXAMPLE II-4
Preparation of 6-iodo-4-(3-chloro-4-methoxy)anilinoquinazoline
[0086] In a 500 mL-volume glass vessel equipped with a stirrer, a
thermometer and a reflux condenser were placed 51.7 g (190 mmol) of
6-iodoquinazolin-4-one, 35.0 g (228 mmol) of phosphorus
oxychloride, and 153 mL of toluene in a nitrogen atmosphere. While
the mixture was stirred at room temperature, 23.1 g (228 mmol) of
triethylamine was slowly added. The resulting mixture was heated to
75.degree. C., and then reaction was carried out for 2 hours.
Subsequently, the mixture was cooled to room temperature, and 51 mL
of methyl ethyl ketone was added. The resulting mixture was stirred
for 10 minutes. Then, the mixture was again heated to 75.degree.
C., while 40.0 g (228 mmol) of 3-chloro-4-methoxyaniline was slowly
added. The resulting mixture was stirred for 2 hours at the same
temperature after addition of 250 mL of toluene and 150 mL of
methyl ethyl ketone. After the reaction was complete, the reaction
mixture was cooled to room temperature, and thus precipitated
crystalline product was collected by filtration. Subsequently, the
crystalline product was placed in 300 mL of aqueous sodium
hydroxide (1 mol/L), and the aqueous mixture was stirred for 30
minutes at room temperature. The crystalline product was collected
by filtration, washed with 500 mL of water, and dried under reduced
pressure, to give 73.4 g (isolated yield: 94%, purity 99.5% in
terms of area percentage determined by high performance liquid
chromatography) of 6-iodo-4-(3-chloro-4-methoxy)anilinoquinazoline
as a yellowish crystalline product.
EXAMPLE II-5
Preparation of 6-iodo-4-(3-chloro-4-methoxy)anilinoquinazoline
[0087] The procedures of Example II-3 were repeated except that
acetone was replaced with methyl isobutyl ketone and that 1.28 g
(8.1 mmol) of 3-chloro-4-methoxyaniline was used, to give 2.55 g
(isolated yield: 84%, purity 99% in terms of area percentage
determined by high performance liquid chromatography) of
6-iodo-4-(3-chloro-4-methoxy)anilinoquinazoline- .
EXAMPLE II-6
Preparation of 6-iodo-4-(3-chloro-4-fluoro)anilinoquinazoline
[0088] The procedures of Example II-1 were repeated except that
acetone was replaced with methyl isobutyl ketone and that aniline
was replaced with 1.18 g (8.1 mmol) of 3-chloro-4-fluoroaniline, to
give 2.45 g (isolated yield: 83%, purity 99% in terms of area
percentage determined by high performance liquid chromatography) of
6-iodo-4-(3-chloro-4-fluoro- )anilinoquinazoline as a pale yellow
crystalline product.
[0089] 6-Iodo-4-(3-chloro-4-fluoro)anilinoquinazoline had the
following physical properties.
[0090] .sup.1H-NMR (DMSO-d.sub.6, .delta. (ppm)): 7.46 (1H, t,
J=9.0 Hz), 7.59 (1H, d, J=8.7 Hz), 7.82-7.87 (1H, m), 8.12-8.21
(2H, m), 8.66 (1H, s), 8.96 (1H, d, J=2.1 Hz), 9.95 (1H, s)
[0091] CI-MS (m/e): 400 (M+1)
EXAMPLE III-1
Preparation of
6-iodo-4-[3-chloro-4-(3-fluorobenzyloxy)anilino]quinazoline
[0092] In a 200 mL-volume glass vessel equipped with a stirrer, a
thermometer and a reflux condenser were placed 9.80 g (36 mmol) of
6-iodoquinazolin-4-one, 6.63 g (43 mmol) of phosphorus oxychloride,
and 30 mL of toluene in a nitrogen atmosphere. While the mixture
was stirred at room temperature, 4.41 g (8.8 mmol) of triethylamine
was slowly added. The resulting mixture was heated to 75.degree.
C., and then reaction was carried out at 70-80.degree. C. for 3
hours. Subsequently, the mixture was cooled to room temperature,
and 40 mL of acetonitrile and 11.8 mg (43 mmol) of
3-chloro-4-(3-fluorobenzyloxy)aniline were added. The resulting
mixture was stirred at 70-80.degree. C. for 2 hours. After the
reaction was complete, the reaction mixture was cooled to room
temperature, and thus precipitated crystalline product was
collected by filtration and washed with 20 mL of acetonitrile.
Subsequently, the crystalline product was placed in 80 mL of
aqueous sodium hydroxide (1 mol/L), and the aqueous mixture was
stirred for 2 hours at room temperature. The crystalline product
was collected by filtration, washed with 500 mL of water and 20 mL
of acetonitrile, and dried under reduced pressure, to give 18.0 g
(isolated yield: 98%, purity 100% in terms of area percentage
determined by high performance liquid chromatography) of
6-iodo-4-[3-chloro-4-(3-fluorobenzyloxy)anilino]quinazoline as a
yellowish crystalline product.
[0093] 6-Iodo-4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-quinazoline
had the following physical properties.
[0094] .sup.1H-NMR (DMSO-d.sub.6, .delta. (ppm)): 5.26 (2H, s),
7.16-7.22 (1H, m), 7.26-7.35 (3H, m), 7.44-7.51 (1H, m), 7.56 (1H,
d, J=8.8 Hz), 7.75 (1H, dd, J=9.0, 2.4 Hz), 8.03 (1H, s), 8.12 (1H,
d, J=8.8 Hz), 8.61 (1H, s), 8.96 (1H, s), 9.85 (1H, s)
[0095] CI-MS (m/e): 506 (M+1)
EXAMPLE III-2
Preparation of
6,7-bis(2-methoxyethoxy)-4-(3-ethynylanilino)quinazoline
hydrochloride
[0096] In a 50 mL-volume glass vessel equipped with a stirrer, a
thermometer and a reflux condenser were placed 4.08 g (13.9 mmol)
of 6,7-bis(2-methoxy)quinazolin-4-one, 2.55 g (16.7 mmol) of
phosphorus oxychloride, 3.37 g (33.4 mmol) of triethylamine and 12
mL of toluene in a nitrogen atmosphere. The resulting mixture was
heated at 70-80.degree. C. for 3 hours. Subsequently the mixture
was cooled to room temperature, and 1.94 g (16.7 mmol) of
3-ethynylaniline was added. The resulting mixture was then stirred
at 70-80.degree. C. for 2 hours. Subsequently, the mixture was
stirred at room temperature after addition of 16 mL of
acetonitrile. After the reaction was complete, the precipitated
crystalline product was collected by filtration, washed with 8 mL
of cooled acetonitrile, and dried under reduced pressure, to give
6.75 g (isolated yield: 88%, purity 78.1% in terms of area
percentage determined by high performance liquid chromatography) of
6,7-bis(2-methoxyethoxy)-4-- (3-ethynylanilino)quinazoline
hydrochloride as yellow solid.
[0097] 6,7-Bis(2-methoxyethoxy)-4-(3-ethynylanilino)quinazoline
hydrochloride had the following physical properties.
[0098] .sup.1H-NMR (DMSO-d.sub.6, .delta. (ppm)): 3.63 (2H, s),
3.78-3.80 (4H, m), 4.28 (1H, s), 4.33-4.41 (4H, m), 7.39-7.52 (3H,
m), 7.80 (1H, d, J=8.1 Hz), 7.89 (1H, s), 8.46 (1H, s), 8.85 (1H,
brs), 11.60 (1H, s), 14.9 (1H, brs)
[0099] CI-MS (m/e): 394 (M+1)
EXAMPLE III-3
Preparation of
4-(3-chloro-4-fluoroanilino)-6-methoxy-7-(3-morpholinopropo-
xy)quinazoline
[0100] In a 50 mL-volume glass vessel equipped with a stirrer, a
thermometer and a reflux condenser were placed 2.00 g (6.3 mmol) of
6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-one, 1.19 g (7.6
mmol) of phosphorus oxychloride, 0.76 g (6.3 mmol) of
triethylamine, and 8 mL of toluene in a nitrogen atmosphere. The
mixture was then stirred at 70-80.degree. C. for 3 hours.
Subsequently, the mixture was cooled to room temperature, and 1.09
g (6.3 mmol) of 3-chloro-4-fluoroaniline and 6 mL of toluene were
added. The resulting mixture was stirred at 110.degree. C. for 10
hours. Further, the mixture was stirred at room temperature after
addition of 8 mL of acetonitrile. After the reaction was complete,
the precipitated crystalline product was collected by filtration,
and washed with 5 mL of cooled acetonitrile. Subsequently, the
crystalline product was placed in 16 mL of aqueous sodium hydroxide
(1 mol/L), and the aqueous mixture was stirred for 4 hours at room
temperature. The crystalline product was collected by filtration,
washed with 50 mL of water and 5 mL of acetonitrile, and dried
under reduced pressure, to give 2.28 g (isolated yield: 71%, purity
89% in terms of area percentage determined by high performance
liquid chromatography) of
4-(3-chloro-4-fluoroanilino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline
as a sallowish crystalline product.
[0101]
4-(3-Chloro-4-fluoroanilino)-6-methoxy-7-(3-morpholinopropoxy)quina-
zoline had the following physical properties.
[0102] .sup.1H-NMR (DMSO-d.sub.6, .delta. (ppm)): 1.93-2.00 (2H,
m), 2.36-2.51 (6H, m), 3.57-3.60 (4H, m), 3.97 (3H, s), 4.19-4.21
(2H, m), 7.20 (1H, s), 7.42-7.48 (1H, m), 7.78-7.84 (2H, m), 8.13
(1H, dd, J=6.8, 2.7 Hz), 8.50 (1H, s), 9.56 (1H, s)
[0103] CI-MS (m/e): 447 (M+1)
EXAMPLE IV-1
Preparation of 6-iodo-4-chloroquinazoline
[0104] In a 100 mL-volume glass vessel equipped with a stirrer, a
thermometer and a reflux condenser were placed 20.0 g (73.5 mmol)
of 6-iodoquinazolin-4-one, 13.5 g (88.2 mmol) of phosphorus
oxychloride, and 60 mL of toluene in a nitrogen atmosphere. While
the mixture was stirred at room temperature, 8.92 g (88.2 mmol) of
triethylamine was slowly added. The resulting mixture was heated to
75.degree. C., and the reaction was carried out for 2 hours. After
the reaction was complete, the reaction mixture was cooled to
0.degree. C. and stirred for one hour. Thus precipitated pale
yellow crystalline product of 6-iodo-4-chloroquinazoline was
collected by filtration. Subsequently, the crystalline product was
placed in 100 mL of aqueous sodium hydroxide (1 mol/L), and the
aqueous mixture was stirred for 30 minutes at room temperature. The
crystalline product was collected by filtration, washed with 120 mL
of water, and dried under reduced pressure, to give 19.3 g
(isolated yield: 90%, purity 99.3% in terms of area percentage
determined by high performance liquid chromatography) of
6-iodo-4-chloroquinazoline as a yellowish crystalline product.
[0105] The analysis of 6-halogeno-4-chloroquinazoline in the
reaction mixture was performed by the following procedures: After
the reaction was complete, 6-halogeno-4-chloroquinazoline was
reacted with methanol to give 6-halogeno-4-methoxyquinazoline
quantitatively, which was then analyzed by high performance liquid
chromatography.
[0106] 6-Iodo-4-chloroquinazoline had the following physical
properties.
[0107] .sup.1H-NMR (CDCl.sub.3, .delta. (ppm)): 7.80 (1H, d, J=7.8
Hz), 8.20 (1H, dd, J=2.1, 9.0 Hz), 8.65 (1H, d, J=2.1 Hz), 9.06
(1H, s)
[0108] CI-MS (m/e): 291 (M+1)
EXAMPLE IV-2
Preparation of 6-iodo-4-chloroquinazoline
[0109] In a 20 mL-volume glass vessel equipped with a stirrer, a
thermometer and a reflux condenser were placed 2.00 g (7.35 mmol)
of 6-iodoquinazolin-4-one, 1.24 g (8.09 mmol) of phosphorus
oxychloride, and 10 mL of toluene in a nitrogen atmosphere. While
the mixture was stirred at room temperature, 0.82 g (8.09 mmol) of
triethylamine was slowly added. The resulting mixture was heated to
75.degree. C., and the reaction was carried out for 2 hours. After
the reaction was complete, the reaction mixture was cooled to room
temperature, and 100 mL of methanol was added. The mixture was
stirred for 15 minutes at the same temperature, to give
6-iodo-4-methoxyquinazoline. Analysis of the reaction mixture by
high performance liquid chromatography indicated that 2.11 g
(reaction yield: 99%) of 6-iodo-4-chloroquinazoline was
produced.
EXAMPLE IV-3
Preparation of 6-iodo-4-chloroquinazoline
[0110] The procedures of Example IV-2 were repeated except that
1.80 g (11.8 mmol) of phosphorus oxychloride was used and that 1.19
g (11.8 mmol) of triethylamine was used. There was produced 2.11 g
(reaction yield: 99%) of 6-iodo-4-chloroquinazoline.
EXAMPLE IV-4
Preparation of 6-iodo-4-chloroquinazoline
[0111] The procedures of Example IV-2 were repeated except that
2.48 g (16.2 mmol) of phosphorus oxychloride was used and that 1.64
g (16.2 mmol) of triethylamine was used. There was produced 2.14 g
(reaction yield: 100%) of 6-iodo-4-chloroquinazoline.
EXAMPLE IV-5
Preparation of 6-iodo-4-chloroquinazoline
[0112] The procedures of Example IV-2 were repeated except that the
reaction temperature was changed to 55.degree. C. There was
produced 2.05 g (reaction yield: 96%) of
6-iodo-4-chloroquinazoline.
EXAMPLE IV-6
Preparation of 6-iodo-4-chloroquinazoline
[0113] The procedures of Example IV-2 were repeated except that the
reaction temperature was changed to 95.degree. C. There was
produced 2.09 g (reaction yield: 98%) of
6-iodo-4-chloroquinazoline.
EXAMPLE IV-7
Preparation of 6-iodo-4-chloroquinazoline
[0114] The procedures of Example IV-4 were repeated except for
replacing triethylamine with 1.96 g (16.2 mmol) of
N,N-dimethylaniline. There was produced 1.92 g (reaction yield:
90%) of 6-iodo-4-chloroquinazoline.
EXAMPLE IV-8
Preparation of 6-iodo-4-chloroquinazoline
[0115] The procedures of Example IV-4 were repeated except for
replacing triethylamine with 1.28 g (16.2 mmol) of pyridine. There
was produced 1.96 g (reaction yield: 92%) of
6-iodo-4-chloroquinazoline.
EXAMPLE IV-9
Preparation of 6-iodo-4-chloroquinazoline
[0116] In a 500 mL-volume glass vessel equipped with a stirrer, a
thermometer and a reflux condenser were placed 50.0 g (184 mmol) of
6-iodoquinazolin-4-one, 33.8 g (221 mmol) of phosphorus
oxychloride, and 300 mL of toluene in a nitrogen atmosphere. While
the mixture was stirred at room temperature, 22.3 g (221 mmol) of
triethylamine was slowly added. The resulting mixture was heated at
60.degree. C. for 30 minutes and then heated at 75.degree. C. for 2
hours, for carrying out reaction. After the reaction was complete,
the reaction mixture was cooled to room temperature, and 50 mL of
acetone was added. The mixture was then cooled to 0.degree. C. and
stirred for 30 minutes. Thus precipitated pale yellow crystalline
product of 6-iodo-4-chloroquinazoline was collected by filtration.
Subsequently, the crystalline product was placed in 200 mL of
water, and 9 mL of aqueous sodium hydroxide (1 mol/L) was added.
The aqueous mixture (pH 10-11) was stirred for 30 minutes at room
temperature. The crystalline product was collected by filtration,
washed successively with 100 mL of acetone, 200 mL of water and 100
mL of acetone, and dried at 60.degree. C. under reduced pressure,
to give 47.4 g (isolated yield: 89%, purity 99% in terms of area
percentage determined by high performance liquid chromatography) of
6-iodo-4-chloroquinazoline as a yellowish crystalline product.
EXAMPLE IV-10
Preparation of 6-iodo-4-chloroquinazoline
[0117] The procedures of Example IV-9 were repeated except for
replacing acetone with methyl ethyl ketone. There was produced 44.9
g (isolated yield: 84%) of 6-iodo-4-chloroquinazoline.
EXAMPLE IV-11
Preparation of 6-iodo-4-chloroquinazoline
[0118] The procedures of Example IV-9 were repeated except for
replacing acetone with methyl isopropyl ketone. There was produced
48.6 g (isolated yield: 91%) of 6-iodo-4-chloroquinazoline.
EXAMPLE IV-12
Preparation of 6-iodo-4-chloroquinazoline
[0119] The procedures of Example IV-9 were repeated except for
replacing acetone with acetonitrile. There was produced 48.1 g
(isolated yield: 90%) of 6-iodo-4-chloroquinazoline.
EXAMPLE IV-13
Preparation of 6-iodo-4-chloroquinazoline
[0120] The procedures of Example IV-9 were repeated except for
replacing acetone with chloroform. There was produced 48.1 g
(isolated yield: 90%) of 6-iodo-4-chloroquinazoline.
EXAMPLE IV-14
Preparation of 6-iodo-4-chloroquinazoline
[0121] The procedures of Example IV-9 were repeated except for
replacing acetone with tetrahydrofuran. There was produced 47.6 g
(isolated yield: 89%) of 6-iodo-4-chloroquinazoline.
EXAMPLE IV-15
Preparation of 6-iodo-4-chloroquinazoline
[0122] The procedures of Example IV-1 were repeated except for
replacing toluene with chlorobenzene. There was produced 48.1 g
(isolated yield: 90%) of 6-iodo-4-chloroquinazoline.
EXAMPLE IV-16
Preparation of 6-iodo-4-chloroquinazoline
[0123] The procedures of Example IV-1 were repeated except that the
stirring temperature after completion of the reaction was changed
from 0.degree. C. to 25.degree. C. There was produced 45.4 g
(isolated yield: 85%) of 6-iodo-4-chloroquinazoline.
EXAMPLE IV-17
Preparation of 6-iodo-4-chloroquinazoline
[0124] The procedures of Example IV-10 were repeated except that
the stirring temperature after completion of the reaction was
changed from 0.degree. C. to 25.degree. C. There was produced 44.9
g (isolated yield: 84%) of 6-iodo-4-chloroquinazoline.
EXAMPLE IV-18
Preparation of 6-iodo-4-chloroquinazoline
[0125] The procedures of Example IV-9 were repeated except that
acetone was replaced with methyl isopropyl ketone and that the
stirring temperature after completion of reaction was changed from
0.degree. C. to 25.degree. C. There was produced 47.0 g (isolated
yield: 88%) of 6-iodo-4-chloroquinazoline.
EXAMPLE IV-19
Preparation of 6-iodo-4-chloroquinazoline
[0126] The procedures of Example IV-9 were repeated except that
acetone was replaced with methyl isobutyl ketone and that the
stirring temperature after completion of reaction was changed from
0.degree. C. to 25.degree. C. There was produced 44.9 g (isolated
yield: 84%) of 6-iodo-4-chloroquinazoline.
UTILIZATION IN INDUSTRY
[0127] According to the invention, 4-aminoquinazoline compounds can
be produced from quinazolin-4-one compounds by simple procedures.
Further, 6-halogeno-4-arylaminoquinazoline can be produced from
6-halogenoquinazolin-4-one by simple procedures. Furthermore, the
invention provides processes for producing
6-iodo-4-[3-chloro-4-(3-fluoro- benzyloxy)anilino]quinazoline,
6,7-bis(2-methoxyethoxy)-4-(3-ethynylanilin- o)quinazoline, and
4-(3-chloro-4-fluoroanilino)-6-methoxy-7-(3-morpholinop-
ropoxy)quinazoline. These compounds are of value as intermediate
compounds for preparing pharmaceuticals showing excellent
pharmacological functions.
* * * * *