TECHNICAL FIELD
[0001] The present invention relates to a novel method for producing a nitrogencontaining
heterocyclic N-oxide compound by N-oxidation reaction of a nitrogen-
10 containing heterocyclic compound, and a novel N-oxide compound.
BACKGROUND ART
[0002] (3R*34S*)-7-hydroxymethyl-2)2)9-ti-imethyl-4-(phenethylamino)-3,4-
15 dihydro-2H-pyrano[2,3-g]quinolin-3-ol (compound (3)) has an anti-arrhythmic action,
and its possible use as a pharmaceutical product has been known (e.g., see Patent
Document 1).
As a method for synthesizing the compound (3), a method is known in which
20 2J2,7,9~tetramethyI-2H~pyrano[2,3-g]quinolme (compound (1)) is reacted with mchloroperberizoic
acid, followed by a reaction with acetic anhydride to obtain (2,2,9-
trimethyl-2H-pyrano[2,3-g]quinoIin-7-yI)-methyI acetate (compound (6)), as shown in
the following reaction formula (I), and the compound (6) is transfeired to the compound
2
(3). In a reaction of the reaction formula (I), it is presumed that the compound (1) is
oxidized by m-chloroperbenzoic acid to produce 2,2,7,9-tetramethyl-2H-pyrano[2,3-
g]quinoline 6-oxide (compound (2)) in which the nitrogen atom in the quinoline ring is
N-oxidized. However, the details of the reaction were not clear.
5 In the production method through the reaction formula (I), m-chloroperbenzoic acid
is used as an oxidizing agent. m-Chloroperbenzoic acid is a hazardous reagent, which is
classified as Class 5.2 (organic peroxides) of the UN Recommendations on the Transport
of Dangerous Goods, and care is necessary in use on an industrial scale.
Therefore, in order to establish a method for industrially producing the compound
10 (3), the establishment of a method for producing the compound (2), in particular, a
method that enables safe, large-volume production without a hazardous reagent such as
m-chloroperbenzoic acid has been required.
Reaction Formula (I)
For synthesis of a N-oxide compound such as a pyridine ring and a quinoline ring
15 that are generally a nitrogen-containing heterocycle, an oxidation process using peracetic
acid (e.g., see Non-Patent Document 1), and an oxidation process using rare metal or
heavy metal as a catalyst and hydrogen peroxide (e.g., see Non-Patent Documents 2 and
3) are known. However, the processes have a problem in safety of an oxidizing agent.
As a safe oxidizing agent capable of causing an N-oxidation reaction, OXONE
20 (registered trademark by DuPont Co.) is known. OXONE is a white ciystal that is a
double salt of potassium hydrogen persulfate-potassium hydrogen sulfate-potassium
sulfate, and is an excellent oxidizing agent that is industrially handled with ease. As an
N-oxidation reaction using OXONE, a reaction method using only OXONE is known.
However, the yield in this reaction is very low (see, Non-Patent Document 4). As another
25 example of the N-oxidation reaction using OXONE, a method of improving the reactivity
3
by addition of a base is known. However, the details of this reaction are not clear, and in
particular, a method of using the base and an effect thereof are not established, for
example, the equivalent weight of base to be used is excessive or insufficient for OXONE
(e.g., see Non-Patent Documents 5 and 6). As further another example of the N-oxidation
5 reaction using OXONE, a method of improving the reactivity by further addition of
acetone is also known (e.g., see Non-Patent Document 7). However, dimethyl dioxirane
that is a hazardous peroxide is considered to be produced during this reaction, and
therefore this method has a problem of unsuitability as an industrial production method.
10 Prior Art Documents
Patent Document
[0003] Patent Document 1: WO 2005/090357
Non-Patent Documents
[0004] Non-Patent Document 1: Org. Synth., Coll. Vol. 4, 828(1963), Vol. 33,
15 79(1953)
Non-Patent Document 2: Josepf F. P. et al., J. Org. Chem., 2005, 70,175-178
Non-Patent Document 3: JP 2005-255560 A
Non-Patent Document 4: Richard J. K, and Albert M. S., J., Org. Chem. I960, 25,
1901-1906
20 Non-Patent Document 5: Azami H. et al., Bioorg. Med. Chem., 2001, 9, 961-982
Non-Patent Document 6: Sylvie P. et al., J. Org. Chem., 2007,72, 9195-9202
Non-Patent Document 7: Murray R. W. et al., J. Org. Chem., 1985, 50, 2847-2853
SUMMARY OF THE INVENTION
25
Problem to be solved by the invention
[0005] It is an object of the present invention to provide a production method for
safely synthesizing a nitrogen-containing heterocyclic N-oxide compound in high yield.
Another object of the present invention is to provide a novel N-oxide compound.
4
Means for Solving Problem
[0006] The inventors of the present invention have intensively studied, and as a
result, found that a compound (2) is obtained by oxidation of a compound (1) using a
persulfate and this oxidation reaction is promoted by adding a basic compound to a
reaction system. Since the compound (1) has an olefin structure, an epoxidation reaction
of olefin is caused as a side reaction in addition to the N-oxidation reaction, and
compounds such as the following compounds (4) and (5) are produced as byproducts.
This epoxidation as the side reaction is an oxidation reaction that is the same as N-
10 oxidation as a major reaction. Therefore, selectivity may not be improved by merely
adjusting the strength of an oxidizing agent, The inventors have found that by adjusting
the pH of a reaction mixed solution, a reaction with little side reaction and high
selectivity of N-oxidation can be caused. Thus, the present invention has been
accomplished. Specifically, the present invention is characterized as follows:
15 (I)
Amethod for producing a quinoline N-oxide compound of Formula (B) by reacting
a quinoline compound of Formula (A) with a persulfate:
1 0
(In the formula, R and R are each independently a hydrogen atom, a Ci-6 alkyl
20 group, or a C7-12 aralkyl group; and X is a hydrogen atom, a halogen atom, a Cj-g alkyl
group, a C3.6 cycloalkyl group, a C6-io aryl group, a C7.12 aralkyl group, a Ci.6 alkoxy
5
group, a Cue acyloxy group, or a cyano group).
(H)
The method according to the item (I), wherein the quinoline compound of Formula
(A) is 2,2)7,9-tetramethyl-2H-pyrano[2)3-g]qumolme of Formula (1) and the quinoline N-
5 oxide compound of Formula (B) is 2)2,7,9-tetramethyl-2H-pyrano[2,3-g]quinoline Noxide
of Formula (2)
cm)
The method according to the item (I) or (II), comprising adding a base.
10 (IV)
The method according to the item (III), wherein the base added is a hydroxide of
alkali metal.
(V)
The method according to the item (IV), wherein the base added is potassium
15 hydroxide.
(VI)
The method according to any one of the items (III) to (V), wherein the base added is
an aqueous solution form of the base.
(VII)
20 The method according to any one of the items (I) to (VI), comprising adjusting the
pH of a reaction solution to 6 to 7.
(VIII)
The method according to any one of the items (I) to (VII), wherein the persulfate is
potassium hydrogen persulfate.
25 (IX)
6
The method according to any one of the items (I) to (VII), wherein the persulfate is a
double salt containing potassium hydrogen persulfate.
(X)
The method according to the item (IX), wherein the double salt containing
5 potassium hydrogen persulfate is a double salt of potassium hydrogen persulfate,
potassium hydrogen sulfate, and potassium sulfate.
(XI)
The method according to any one of the items (I) to (X), wherein the persulfate
added has an aqueous solution form.
10 (XII)
2J2,7,9-tetramethyl-2H-pyrano[2J3-g]quinoline 6-oxide of Formula (2)
MODES FOR CARRYING OUT THE INVENTION
15 [0007] As a compound usable in a production method of the present invention, a
compound of Formula (A) can be used in addition to the compound (1).
(In the formula, R1 and R2 are each independently a hydrogen atom, a C\.^ alkyl
group, or a C7.12 aralkyi group; and X is a hydrogen atom, a halogen atom, a Ci-s alkyl
20 group, a C6.10 aryl group, a C7-i2 aralkyi group, a Ci-6 alkoxy group, a Ci.6 acyloxy group,
or a cyano group.)
7
[0008] A substituent in the present invention will be described.
A halogen atom refers to fluorine, chlorine, bromine, or iodine.
The concept of an alkyl group in the present invention includes a linear alkyl group
and a branched alkyl group.
A Cj-6 alkyl group refers to an alkyl group having a carbon atom number of 1 to 6.
Examples thereof include a methyl group, an ethyl group, a n-propyl group, an isopropyl
group, a n-butyl group, an isobutyl group, a sec-butyl group, a teit-butyl group, a n-pentyl
group, and a n-hexyl group.
The Ci_6 alkyl group in the present invention is preferably a C1.3 alkyl group, that is,
an alkyl group having a carbon atom number of 1 to 3, and more preferably a methyl
group.
A C3-6 cycloalkyl group refers to a cycloalkyl group having a carbon atom number
of 3 to 6. Examples thereof include a cyclopropyl group, a cyclobutyl group, and a
cyclohexyl group.
The C3.6 cycloalkyl group in the present invention is preferably a cyclopropyl group.
A C6.10 aiyl group refers to an aryl group having a carbon atom number of 6 to 10.
Examples thereof include a phenyl group and a naphthyl group.
The C^-io aryl group in the present invention is preferably a phenyl group.
A C7-12 aralkyl group refers to a group in which the C\.e alkyl group is substituted
with one phenyl group. The phenyl group may substitute on any position of the Cj-6 alkyl
group. Examples of the aralkyl group include a benzyl group, a phenylethyl group, a
phenylpropyl group, and a phenylbutyl group.
The C7.12 aralkyl group in the present invention is preferably a benzyl group.
A C[_6 alkoxy group refers to an oxy group substituted by the Cj_6 alkyl group.
Examples thereof include a methoxy group, an ethoxy group, an isopropoxy group, and a
tert-butoxy group.
The Ct-6 alkoxy group in the present invention is preferably a C1-3 alkoxy group,
that is, an oxy group substituted by a C1-3 alkyl group, and more preferably a methoxy
group.
8
A C|-6 acyloxy group refers to a carbonyloxy group substituted by the Ci.e alkyl
group. Examples thereof include an acetoxy group (CH3C(=0)0- group).
The Ci-6 acyloxy group in the present invention is preferably an acetoxy group.
[0009] As the compound of Formula (A) and the compound of Formula (1)
5 (hereinafter referred to as a reactant) that are used as a raw material in the method of the
present invention, a free form thereof may be used, or an acid salt or solvate thereof may
be used as long as it does not prevent reaction. Examples of the acid salt of the reactant
include a hydrohalogenie acid salt (e.g., hydrochloride, and hydrobromide), a sulfonate
(e.g., sulfate, methanesulfonate, and tosylate), a phosphate (e.g., phosphate), and a
10 carboxylate (e.g., acetate, benzoate, and maleate). Preferred examples of the acid salt
may include a carboxylate, and particularly preferably maleate.
[0010] In the method of present invention, the reactant may be dissolved or
suspended in a solvent.
[0011] A solvent usable in the method of present invention is not particularly
15 limited as long as it does not prevent this reaction. It is preferable that water, an alcohol
solvent (e.g., methanol, ethanol, and isopropanol), a halogen-containing hydrocarbon
solvent (e.g., methylene chloride), a carboxylic acid solvent (e.g., acetic acid, and
trifluoroacetic acid), a sulfonic acid solvent (e.g., methanesulfonic acid), a phosphoric
acid solvent (e.g., phosphoric acid), an aromatic hydrocarbon solvent (e.g., benzene,
20 toluene, and xylene), an aliphatic hydrocarbon solvent (e.g., hexane, and heptane), an
amide solvent (e.g., N,N-dimethylformamide, and N,N-dimethylacetamide), a nitrile
solvent (e.g., acetonitrile), a sulfone solvent (e.g., dimethyl sulfone), a sulfoxide solvent
(e.g., dimethyl sulfoxide), 1,4-dioxane, or cyclopentyl methyl ether be used since a
peroxide is unlikely to be produced in the presence of a persulfate.
25 The solvent may be used alone or in a mixture of two or more thereof.
In order to dissolve both the persulfate and the reactant, it is preferable that water
and a water-soluble organic solvent be used in combination. Herein, water-soluble means
that a substance can be completely dissolved in water at any ratio. The water-soluble
organic solvent is preferably a water-soluble alcohol solvent, a water-soluble amide
9
solvent, or a water-soluble carboxylic acid solvent, more preferably a water-soluble
alcohol solvent, and particularly preferably methanol.
[0012] The reaction can be caused using water in combination with a waterinsoluble
solvent in the presence of a phase transfer catalyst in a two-layer system.
5 Examples of a phase transfer catalyst used in the present invention include an ammonium
salt (e.g., tetrabutylammonium bromide), and a phosphonium salt (e.g.,
tetrabutylphosphonium bromide).
[0013] The amount of the solvent to be used is not particularly limited, and is
0.1 parts by mass to 1,000 parts by mass, preferably 1 part by mass to 100 parts by mass,
10 and more preferably 3 parts by mass to 20 parts by mass, relative to the mass of the
reactant.
[0014] Examples of the persulfate used in the method of the present invention
include an alkali metal persulfate (e.g., sodium persulfate, and potassium persulfate), an
ammonium persulfate, and a hydrogen persulfate (e.g., sodium hydrogen persulfate,
15 potassium hydrogen persulfate, and ammonium hydrogen persulfate).
The persulfate is preferably a hydrogen persulfate, more preferably an alkali metal
hydrogen persulfate, and further preferably potassium hydrogen persulfate.
[0015] As the persulfate used in the method of the present invention, a double
salt of the persulfate can be used, The double salt refers to a salt containing two or more
20 kinds of cations, two or more kinds of anions, or two or more kinds of cations and two or
more kinds of anions.
A double salt of the persulfate used in the method of the present invention is
preferably a double salt of hydrogen persulfate, more preferably a double salt of
potassium hydrogen persulfate, potassium hydrogen sulfate, and potassium sulfate, and
25 further preferably commercially available OXONE (registered trademark by DuPont Co.)
of 2KHS05-KHS04-K.2S04. Further, the persulfates may be prepared in a reaction system
using ammonium persulfate or persulfuric acid as a raw material and used.
[0016] The persulfate is used in an amount of 1 mol to 10 mol, preferably 1 mol
to 5 mol, and further preferably 1 mol to 3 mol, relative to 1 mol of the reaction substrate.
10
One mol of OXONE includes 2 mol of potassium hydrogen persulfate. The amount
by mol of OXONE in the following Examples is represented as a double salt with a
molecular weight of 614.76.
[0017] Since an aqueous solution of the persulfate is acidic, the pH can be
5 adjusted by adding a base as a solid or a solution thereof. A base usable in the reaction is
not particularly limited as long as it does not prevent this reaction. A hydroxide (e.g.,
sodium hydroxide, and potassium hydroxide), a bicarbonate (e.g., sodium bicarbonate,
and potassium bicarbonate), a carbonate (e.g., sodium carbonate, and potassium
carbonate), a phosphate (e.g., sodium phosphate, disodium hydrogen phosphate, sodium
10 dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, and
potassium dihydrogen phosphate), an acetate (e.g., sodium acetate, and potassium
acetate), an amine (e.g., a tertiary amine such as triethylamine), or aqueous ammonia can
be used. Due to the basic strength thereof and no generation of gas during neutralization,
a hydroxide is preferably used, a hydroxide of alkali metal is further preferably used, and
15 potassium hydroxide is particularly preferably used.
[0018] In the present invention, a hydrogen ion concentration index is
represented as pH. The pH in the present invention is not restricted to the hydrogen ion
concentration index of an aqueous solution, and the concept includes the hydrogen ion
concentration index of a solvent other than water, a mixed solvent of water and the water-
20 soluble organic solvent, and a solution or suspension containing the solvents.
[0019] The base is used in an amount of 1 mol to 10 mol, preferably 1 mol to 5
mol, and further preferably 1 mol to 3 mol, relative to 1 mol of the reactant.
[0020] The persulfate used in the method of the present invention is watersoluble,
and the reactant is lipophilic. For this reason, a mixed solvent of water and the
25 water-soluble organic solvent may be used to dissolve both the reactant and the persulfate
and efficiently promote the reaction. At this time, the reactant and the persulfate partly
remain without dissolving in a state of suspension at the outset of the reaction, and then
are dissolved with progression of the reaction.
[0021] In the method of the present invention, a suspended persulfate may be
11
dissolved with progression of the reaction, to decrease the pH of the reaction solution in
the reaction. In this case, the pH of the reaction solution is adjusted by adding a base to
the reaction solution. Thus, the pH can be maintained at a constant range.
[0022] The pH of the reaction solution is preferably maintained at 4 to 8, more
5 preferably at 5 to 7, and further preferably at 6 to 7.
[0023] Examples of a method of adjusting the pH include a method A; of adding
the persulfate and the base to a reactor containing the reactant, a method B: of adding the
reactant and the base to a reactor containing the persulfate, and a method C: of adding the
reactant and the persulfate to a reactor containing the base. Since the persulfate can be
10 supplied while consumption thereof is always confirmed, the methods A and C are
preferred in terms of safety, and the method A is further preferred.
[0024] An order of adding the persulfate and the base to the reactant may be an
order of adding the whole amounts of the persulfate and the base in turn or an order of
adding the persulfate and the base together. The order of adding the persulfate and the
15 base together is preferred.
Alternatively, a portion of the persulfate or the base may be first added until the pH
reaches a target pH, and the rest may be then added together. It is desirable that the
persulfate and the base be gradually added while the progression of the reaction, the
generation of oxygen gas, and heat generation are controlled. When the persulfate and
20 the base are added together, it is preferable that the persulfate and the base be not mixed
using separate dropping devices or input ports before they reach the solution or
suspension of the reactant.
[0025] When the acid salt of the reactant is used, the base is added to the
solution of the reactant, and the persulfate and the base can be added together. When the
25 pH of the reaction solution decreases after completion of addition of the persulfate, the
base is gradually added to maintain the pH.
[0026] The time required for addition of the persulfate is not particularly
limited, and is a time sufficient to control the progression of the reaction, the generation
of oxygen gas, and heat generation, 0.5 hours to 8 hours, and preferably 2 hours to 4
12
hours.
[0027] The reaction temperature in the present invention is not particularly
limited, and preferably falls within a range of-10°C to 120°C, more preferably 0°C to
100°C, and further preferably 10°C to 40°C.
5 [0028] The reaction time in the present invention is not limited as long as it is
sufficient to consume the reaction substrate, and is preferably 10 minutes to 24 hours, and
more preferably 30 minutes to 6 hours.
[0029] The N-oxide compound obtained by the method of the present invention
may be isolated or used in a solution form as it is at the next production process. The
10 conditions of the solution, such as the content of the N-oxide compound in the solution,
can be quantitatively analyzed by an analysis method such as HPLC, and the yield in the
reaction can be measured by quantitative analysis.
Examples
15 [0030] Hereinafter, the present invention will be described specifically with
reference to Examples, but the scope of the present invention is not limited to these
Examples.
In Examples, NMR means nuclear magnetic resonance, and HPLC means high
performance liquid chromatography.
20 The purity of each compound by HPLC analysis is represented by an area
percentage method of expressing the ratio of a target peak area in the whole peak area in
percentage.
The pH of a reaction solution can be measured by a method familiar to those skilled
in the art. For example, a solution or mixed solution in a reaction is directly measured
25 with a pH meter or a small amount of the solution or mixed solution is sampled and
measured with a pH meter or a pH test paper.
In Examples, ECP300 manufactured by JEOL Ltd. was used for NMR analysis, and
B-545 manufactured by SIBATA SCIENTIFIC TECHNOLOGY LTD. was used for
measurement of melting point.
13
HPLC analysis was performed using LC-lOAvp manufactured by Shimadzu
Corporation under the following conditions.
Column: L-coIumn ODS (available from Chemicals Evaluation and Research Institute,
Japan, 4.6 mm in diameter x 250 mm in length, particle diameter: 5 pm)
5 Eluent: 450mLof acetonitrile and 550 mL of 0.01 M acetic acid buffer (pH: 3.8) were
mixed and 1.4 g of sodium dodecylsulfate was dissolved in the mixture. As the 0.01 M
acetic acid buffer, a mixture of 800 mL of 0.01 M acetic acid aqueous solution and 100
mL of 0.01 M sodium acetate solution was used.
Flow rate: l.OmL/min
10 Column Temperature: 40°C
Wavelength of ultraviolet-visible spectroscopy: 254 nm
[0031] Reference Synthesis Example 1
Production of 2,2,7,9-tetramethyl-2H-pyrano[2,3-g]quinolinemaIeate
N-(2>2,-dimethyl-2H-chromen-6-yl)acetamide (199.38 g, 0.918 mol), 1-propanol
15 (800 g), and hydrochloric acid (288 g) were mixed and heated to reflux at 90°C to 95°C
for 5 hours. The mixture was cooled to room temperature, iron chloride (anhydrous) (400
g, 2.49 mol) was added, and the mixture was heated to 90°C. To the mixture, 3-penten-2-
one (140 g, 1.66 mol) was added dropwise and the mixture was heated for 2 hours. The
mixture was cooled to room temperature, toluene (1,100 g) and water (1,399 g) were
20 added, and the mixture was separated. To the obtained organic phase, a 16% sodium
carbonate aqueous solution (2,200 g) and water (901 g) were added, and the mixture was
separated. To the obtained organic phase, activated carbon (10 g) was added, and the
mixture was stirred and filtrated. From the filtrate, the solvent was evaporated, and the
residue was dried and solidified. The residue was dissolved in ethyl acetate (801 g) and
25 toluene (108 g), and the mixture was heated to 50°C. To the mixture, a solution of maleic
acid (85.5 g, 0.737 mol) dissolved in methanol (200 g) was added dropwise. The mixture
was cooled to 20°C, and the precipitated crystal was collected by filtration, washed with
ethyl acetate (201 g), and dried under reduced pressure at 50°C to obtain 204.77 g (yield:
62.8%) of 2,2,7,9-tetramethyl-2H-pyrano[2,3~g]quinoline maleate as a yellow solid.
14
Appearance: yellow solid
'H-NMR (CDCI3, TMS)
8 (ppm): 1,53 (6H, s), 2.76 (3H, s), 2.91 (3H, s), 6.09 (1H, d, J = 9.9 Hz), 6.40 (2H, s),
6.63 (1H, d, J - 9.9 Hz), 7.30 (2H, s), 8.09 (1H, s)
5 Melting Point: 175°C
[0032] Example 1
Production of 2,2,7,9-tetramethyl-2H-pyrano[2,3-g]quinoline 6-oxide
Methanol (25.0 g) and a 50% potassium hydroxide aqueous solution (1.52 g, 13.5
mmol) were added to 2,2,7)9-tetramethyl-2H-pyrano[2,3-g]quinoline maleate (5.01 g,
10 purity: 96%, 13.5 mmol), and the mixture was stirred at 21 °C for 20 minutes. A solution
of OXONE (9.55 g, 15.5 mmol) in water (30 g) was added dropwise over 30 minutes, and
at the same time, a 50% potassium hydroxide aqueous sohition was added dropwise while
being adjusted so that the temperature and the pH of the reaction solution were
maintained at 21°C to 27°C and 6 to 7, respectively. After completion of dropwise
15 addition of the OXONE aqueous solution, the mixture was stirred for 3 hours while the
pH was maintained at 6 to 7 by dropwise addition of 50% potassium hydroxide aqueous
solution.
After the reaction, an insoluble substance was filtered and washed with chloroform
(15.0 g) twice. To the resulting filtrate, a 50% potassium hydroxide aqueous solution
20 (0.76 g, 6.8 mmol) was added, and the mixture was separated to obtain a solution of
2,2,7,9-tetramethyl-2H-pyrano[2,3-g]quinoIine 6-oxide in chloroform. This solution was
quantitatively analyzed by HPLC to calculate the yield. The yield was 89.6%. The peak
areas (%) of the compounds (1), (2), (4), and (5) in the solution are shown in Table 1.
15
Table 1
This solution was purified by silica gel chromatography to obtain target 2,2,7,9-
tetramethyI-2H-pyrano[2,3-g]quinoline 6-oxide.
5 Appearance: yellow solid
'H-NMR (CDC13, TMS)
5 (ppm): 1.50 (6H, s), 2.51 (3H, s), 2.63 (3H, s), 5.93 (1H, d, J = 9.9 Hz), 6.61 (IH, d, J =
9.9 Hz), 7.02 (IH, s), 7.16 (IH, s), 8.42 (IH, s)
Melting Point: 187°C
10 [0033] Example 2
Methanol (25.1 g) and a 50% potassium hydroxide aqueous solution (1.52 g, 13.5
rmnol) were added to 2,2,7,9-tetramethyl-2H-pyrano[2,3-g]quinoline maleate (5.00 g,
purity: 96%, 13.5 rnmol), and the mixture was stirred at 21°C to 22°C for 30 minutes. A
solution of OXONE (9.56 g, 15.5 mmol) in water (30.6 g) was added dropwise over 30
15 minutes, and at the same time, a 50% potassium hydroxide aqueous solution was added
dropwise while being adjusted so that the temperature and the pH were maintained at
22°C to 23 °C and 5 to 6, respectively. After completion of dropwise addition of the
OXONE aqueous solution, the mixture was stirred for 6 hours whiie the pH was
maintained at 5 to 6 by dropwise addition of 50% potassium hydroxide aqueous solution.
20 After the reaction, an insoluble substance was filtered and washed with chloroform
(15.0 g) twice. To the resulting filtrate, a 50% potassium hydroxide aqueous solution
(0.76 g, 6.8 mmol) was added, and the mixture was separated to obtain a solution of
2,2,7,9-tetramethyl-2H-pyrano[2,3~g]quinoline 6-oxide in chloroform. This solution was
16
quantitatively analyzed by HPLC to calculate the yield. The yield was 75.2%. The peak
areas (%) of the compounds (1), (2), (4), and (5) in the solution are shown in Table 2.
The raw materials are almost consumed and the target favorably increases. However, the
production amount of the compound (5) as an impurity is larger as compared with
5 Example 1.
Table 2
1 hour
of
reaction
2 hours
of
reaction
3 hours
of
reaction
4 hours
of
reaction
5 hours
of
reaction
6 hours
of
reaction
CHj
11.377
5.596
4.057
3.101
2.362
2.079
9
X X X J ^
^ (2)
78.017
80.705
79.952
78.743
77.823
76.418
XXXMCH*
(4)
0.268
0.175
0.147
0.148
0.125
0.139
XXXXCH*
^ (B)
5.123
8.114
10.195
11.972
13.470
14.625
[0034] Example 3
Methanol (25.0 g) and a 50% potassium hydroxide aqueous solution (1.52 g, 13.5
10 mmol) were added to 2,2,7,9-tetramethyl-2H-pyrano[2,3-g]qumoline maleate (5.00 g,
purity: 96%, 13.5 mmol), and the mixture was stirred at 21°C for 30 minutes. A solution
of OXONE (9.55 g, 15.5 mmol) in water (30.6 g) was added dropwise over 20 minutes,
and at the same time, a 50% potassium hydroxide aqueous solution was added dropwise
while being adjusted so that the temperature and the pH were maintained at 22°C to 28°C
15 and 7 to 8, respectively. After completion of dropwise addition of the OXONE aqueous
solution, the mixture was stirred at 24°C to 26°C for 7 hours.
17
The peak areas (%) of the compounds (1), (2), (4), and (5) in the reaction solution
are shown in Table 3. The side reaction is suppressed and the target favorably increases.
However, the amount of remained compound (1) as the raw material is larger as
compared with Example 1.
[0035] Example 4
Methanol (25.0 g) and a 50% potassium hydroxide aqueous solution (3.05 g, 27.2
mmol) were added to 2)2,7,9-tetramethyl-2H-pyrano[2,3-g]quinoline maleate (5.00 g,
10 purity: 96%, 13.5 mmol), and the mixture was stirred at 25°C to 29°C for 30 minutes. A
solution of OXONE (7.89 g} 12.8 mmol) in water (27.5 g) was added dropwise at 27 to
30°C over 2 hours. The mixture was stirred at 28 to 30°C for 27 hours. During the
reaction, the pH changed between 2 to 3.
After the reaction, an insoluble substance was filtered and washed with 15.0 g of
15 chloroform twice. The mixture was separated to obtain a solution of 2,2,7,9-tetramethyl-
2H-pyrano[2,3-g]quinoline 6-oxide in chloroform. This solution was quantitatively
10
18
analyzed by HPLC to calculate the yield. The yield was 12,1%.
The peak areas (%) of the compounds (1), (2), (4), and (5) in the reaction solution
are shown in Table 4. The amount of remained compound (1) as the raw material is large,
and the decomposition of product is confirmed with time. It is found that a target is
obtained even by a reaction at a pH of 2 to 3. However, the relative ratio of the impurity
increases, and the yield of the target tends to decrease.
1VCIWHJJ.L
INDUSTRIAL APPLICABILITY
[0036] According to the present invention, a nitrogen-containing heterocyclic Noxide
compound useful as a raw material for a pharmaceutical product can be safely
produced in high yield.

CLAIMS
1. A method for producing a quinoline N-oxide compound of Formula (B) by
reacting a quinoline compound of Formula (A) with a persulfate:
?•
(In the formula, R1 and R2 are each independently a hydrogen atom, a Q.e alkyl group, or
a C7-12 aralkyl group; and X is a hydrogen atom, a halogen atom, a C[.6 alkyl group, a C3.6
cycloalkyl group, a C6-io aryl group, a C7.J2 aralkyl group, a C\.6 alkoxy group, a Cj.6
acyloxy group, or a cyano group).
2, The method according to claim 1, wherein the quinoline compound of Formula
(A) is 2,2>7,9-tetramethyl-2H-pyrano[2,3-g]quinoline of Formula (1) and the quinoline Noxide
compound of Formula (B) is 2,2,7,9-tetramethyl-2H-pyrano[2,3-g]quinoIine Noxide
of Formula (2)
rv
3. The method according to claim 1 or 2, comprising adding a base.
4. The method according to claim 3, wherein the base added is a hydroxide of alkali
metal.
5. The method according to claim 4, wherein the base added is potassium
20
hydroxide.
6. The method according to any one of claims 3 to 5, wherein the base added is an
aqueous solution form of the base.
5
7. The method according to any one of claims 1 to 6, comprising adjusting the pH of
a reaction solution to 6 to 7.
8. The method according to any one of claims 1 to 7, wherein the persulfate is
10 potassium hydrogen persulfate.
9. The method according to any one of claims 1 to 7, wherein the persulfate is a
double salt containing potassium hydrogen persulfate.
15 10. The niethod according to claim 9, wherein the double salt containing potassium
hydrogen persulfate is a double salt of potassium hydrogen persulfate, potassium
hydrogen sulfate, and potassium sulfate.
11. The method according to any one of claims 1 to 10, wherein the persulfate
20 added has an aqueous solution form.
12. 2,2,7,9-tetramethyl-2H-pyrano[2,3-g]quinoline 6-oxide of Formula (2)