TECHNICAL FIELD
The present invention relates to a method for producing a 2-pyridone compound5 .
BACKGROUND ART
The 2-pyridone compound (compound (2)) represented by the formula (2) is a
compound included in the claims in a compound patent (Patent Document 1) for a
10 therapeutic agent for diabetes, which claims a series of 2-pyridone compounds, and the
possibility for its use as pharmaceuticals has been known:
[Ka 1]
Accordingly, a specific method for producing the compound (2) has been desired.
15
PRIOR ART DOCUMENT
PATENT DOCUMENT
Patent Document 1: WO2011/068211
20 DISCLOSURE OF INVENTION
TECHNICAL PROBLEM
An object of the present invention is to provide a method for producing a 2-
pyridone compound.
25 SOLUTION TO PROBLEM
As a result of extensive studies to accomplish the above object, the present
inventors have established a synthetic route for a 6-benzoyl-2-pyridone compound
which is a key intermediate and found that a compound (1) can be obtained by using
the intermediate as a starting material.
30 [Ka 2]
In the production of the compound (1) from the 6-benzoyl-2-pyridone compound
as the starting material, the present inventors have tried applying the general synthetic
method described in Patent Document 1. As a result, they have found that in addition
35 to the desired compound (1) in the form of Z-isomer, a compound in the form of Eisomer
is formed as a by-product. The yield of the desired compound (1) deteriorates
due to the by-production of the compound in the form of E-isomer, and it is necessary to
purify the desired compound (1) by column chromatography. Thus, the method
2
described in Patent Document 1 is problematic as an industrial production method.
Accordingly, the present inventors have conducted extensive studies for the production
of the compound (1) and have found the method for selectively producing the
compound (1) in the form of Z-isomer.
[Ka 35 ]
Further, the present inventors have found for the first time that the compound (1)
obtained by the above production method is crystallized in the form of a sodium salt and
thus have developed a purification method which does not require column
10 chromatography.
Further, the present inventors have found a production method to be industrially
applied in which the compound (2) is formed from the compound (1) in the following
scheme. Thus, the present inventors have accomplished the present invention.
[Ka 4]
15
That is, the present invention has the following features.
(I) A method for producing a 2-pyridone compound represented by the formula (1),
which comprises reacting a 6-benzoyl-2-pyridone compound represented by the formula
(3) with a sulfone compound represented by the formula (4):
20 [Ka 5]
3
(II) The production method according to (I), wherein the reaction is carried out in
the presence of a urea derivative.
(III) The production method according to (II), wherein the urea derivative is 1,3-
dimethyl-2-imidazolidinone5 .
(IV) A compound represented by the formula (1):
[Ka 6]
(V) A compound represented by the formula (3):
10 [Ka 7]
(VI) A sodium salt of a compound represented by the formula (1):
[Ka 8]
15 (VII) A compound represented by the formula (6):
[Ka 9]
4
(VIII) A compound represented by the formula (7):
[Ka 10]
􀊢􀌓􀊣
(IX) A compound represented by the formula (8)5 :
[Ka 11]
(X) A compound represented by the formula (9):
[Ka 12]
10
(XI) A compound represented by the formula (10):
[Ka 13]
15 ADVANTAGEOUS EFFECTS OF INVENTION
According to the present invention, it has been made possible to provide a method
for producing a 2-pyridone compound which is useful as a pharmaceutical or its
intermediate.
20 BRIEF DESCRIPTION OF DRAWING
Fig. 1 shows a powder X-ray diffraction pattern of a crystal of the sodium (R, Z)-3-
cyclopropyl-6-{1-[4-(1,1-difluoroethyl)phenyl]-2-[5-oxopyrrolidin-2-yl]vinyl}pyridin-2-olate
of the present invention.
25 DESCRIPTION OF EMBODIMENTS
Now, the present invention will be described in detail.
In this invention, “n” means normal, “i” means iso, “s” and “sec” mean secondary,
“t” and “tert” mean tertiary, “c” means cyclo, “o” means ortho, “m” means meta, “p”
means para, “Boc” means t-butoxycarbonyl, “Me” means methyl. Further, “(E)” means
30 E-isomer, and “(Z)” means Z-isomer.
A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an
5
iodine atom.
A C1-4 alkyl group means a linear or branched alkyl group having from 1 to 4
carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an i-propyl
group, an n-butyl group, an i-butyl group, an s-butyl group or a t-butyl group.
Now, each production route of the present invention will be described in detail5 .
1. Method for producing the compound (3)
General processes for producing the compound (3) will be illustrated as schemes
1 to 3, however, they are examples of general production processes, and the production
process is by no means restricted thereto. The compound (3) can also be produced by
10 methods well known to those skilled in the art such that the order to carry out steps is
changed, a protecting group is added to a hydroxy group or the like, a reaction is carried
out, and then the protecting group is released in a post step, an additional step is added
in each step, etc.
In the production of the compound of the present invention, the method for
15 protecting or deprotecting functional groups contained in starting materials,
intermediates, etc. may be carried out in accordance with methods well known to those
skilled in the art, for example, the method described in Greene’s Protective Groups in
Organic Synthesis, published by John Wily and Sons, year 2006, etc.
Scheme 1: Method for producing the compound (3) from the compound (1-a)
20 [Ka 14]
In Scheme 1, G1 is a protecting group of hydroxy group in the hydroxy pyridyl
group.
The compound (1-a) and the compound (1-b) can be obtained by the methods
25 described in WO2008/103185 or methods based on it.
Step (1-1) and Step (1-2):
“Addition reaction” using the compound (1-a) and an anion such as a lithium
reagent e.g. heteroaryl lithium or a Grignard reagent e.g. heteroaryl magnesium
bromide, is carried out, and the obtained compound is treated with an acid such as
30 hydrochloric acid to obtain the compound (1-c).
The “addition reaction” may, for example, be a method of generating an anion by
using the compound (1-b) as a substrate and an organic metal reagent such as n-butyl
lithium, sec-butyl lithium, tert-butyl lithium or diisopropyl magnesium bromide, a metal
reagent such as magnesium or a base such as lithium bis(trimethylsilyl)amide or
35 potassium bis(trimethylsilyl)amide in an inert solvent at a temperature of from -78°C to
200°C, followed by reacting the anion with a nitrile compound of the compound (1-a).
Step (1-3):
The compound (3) can be produced by carrying out “deprotection reaction” of a
protecting group G1 in the compound (1-c).
6
The “deprotecting reaction” may, for example, be a deprotecting reaction such as
(i) in a case where the protecting group G1 is an alkyl group or an allyl group, a method
in which the protecting group G1 is removed by a hydrolytic reaction in the presence of
an acid or a strong acid in an inert solvent at a temperature of from 0°C to 200°C, a
method using trimethylsilyl iodide or the like or a method using aluminum chloride an5 d
an alkylthiol. Further, (ii) in a case where the protecting group G1 is a benzyl group, a
4-methoxybenzyl group, a 2,4-dimethoxybenzyl group, a benzyloxycarbonyl group, a
benzhydryl(diphenylmethyl) group or the like, the deprotecting reaction may, for
example, be a method in which the protecting group G1 is removed by a hydrogenolysis
10 reaction using an catalytic amount of palladium-activated carbon, rhodium-activated
carbon or the like in the presence of or the absence of an acid in an inert solvent at a
temperature of from 0°C to 80°C or a method using an oxidizing agent such as
ammonium cerium(IV) nitrate or 2,3-dichloro-5,6-dicyano-p-benzoquinone. Further, in
a case where the protecting group G1 is an alkyl group, G1 represents a C1-4 alkyl group,
15 preferably a methyl group or an ethyl group, more preferably a methyl group.
Scheme 2: Method for producing the compound (3) from the compound (2-a)
[Ka 15]
The compound (2-a) and the compound (2-b) are available as commercial
20 compounds.
Step (2-1) and Step (2-2):
“Addition reaction” using the compound (2-a) and an anion such as a lithium
reagent e.g. phenylaryl lithium or Grignard reagent e.g. phenylaryl magnesium bromide
is carried out, and the obtained compound is treated with an acid such as hydrochloric
25 acid to produce the compound (6).
As the “addition reaction”, the substantially same reaction as the addition reaction
in the step (1-1) and the step (1-2) may be mentioned.
Step (2-3):
The compound (7) can be produced by subjecting the compound (6) to “oxidation
30 reaction” with an oxidizing agent.
The “oxidation reaction” may, for example, be a method in which the compound
(6) is reacted with an “oxidizing agent” in an inert solvent such as chloroform or water at
-20°C to 60°C to obtain the compound (7).
The “oxidizing agent” may, for example, be a peracid such as
7
metachloroperoxybenzoic acid. The peracid may also be generated by combining
hydrogen peroxide and an acid or an acid anhydride in the system and used.
Step (2-4):
The compound (3) can be produced by subjecting the compound (7) to
“transferring reaction” with an acid anhydride5 .
The “transferring reaction” may, for example, be a method in which the compound
(7) is reacted with an acid anhydride such as trifluoroacetic acid anhydride in an inert
solvent such as chloroform, tetrahydrofuran, 2-methyltetrahydrofuran or methyl t-butyl
ether at a temperature of from -20°C to 60°C to obtain the compound (3).
10 Scheme 3: Method for producing the compound (3) from the compound (3-a)
[Ka 16]
In the scheme 3, X is a halogen atom, and G1 is the same as defined above.
The compound (3-a) may be obtained by the method described in
15 WO2008/103185 or a method based on it.
Step (3-1):
The compound (3-b) can be produced by subjecting the compound (3-a) as a
substrate to “coupling reaction” with a cyclopropyl magnesium compound, a cyclopropyl
zinc compound or cyclopropyl boronic acid.
20 The “coupling reaction” may, for example, be a method of a reaction with a
cyclopropyl magnesium compound, a cyclopropyl zinc compound or a cyclopropyl
boronic acid in the presence of a palladium, nickel or iron catalyst in an inert solvent
such as 1,2-dimethoxyethane, methylene chloride, acetonitrile, toluene, tetrahydrofuran,
2-methyltetrahydrofuran, N-methylpyrrolidone or 1,4-dioxane at -20°C to 40°C.
25 The palladium catalyst used in the “coupling reaction” may, for example, be a
palladium catalyst well known for those skilled in the art, such as
tetrakistriphenylphosphine palladium(0), bis(dibenzylideneacetone) palladium(0),
bis(triphenylphosphine) palladium(II) dichloride, bis(triphenylphosphine) palladium(II)
acetate or [1,1’-bis(diphenylphosphine)ferocene] palladium(II) dichloride30
dichloromethane complex (1:1). Further, a palladium(0) catalyst can be formed in the
system by using palladium acetate (II) or palladium-activated carbon and
triphenylphosphine and used for the reaction.
The nickel catalyst used for the “coupling reaction” may, for example, be a nickel
catalyst well known for those skilled in the art, such as bis(triphenylphosphine) nickel(II)
35 dichloride. Further, a nickel catalyst may be formed in the system by using nickel
8
chloride(II) and triphenylphosphine and used for the reaction.
The iron catalyst used for the “coupling reaction” may, for example, be an iron
catalyst well known for those skilled in the art, such as tris(2,4-pentanedionate) iron(III).
Further, an iron catalyst may be formed in the system and used for the reaction.
Step (3-2) and Step (3-3)5 :
The compound (1-c) can be produced by carrying out “addition reaction” using a
compound (3-b) and an anion such a lithium reagent e.g. phenylaryl lithium or a
Grignard reagent e.g. phenylaryl magnesium bromide, followed by treating the obtained
compound with an acid such as hydrochloric acid.
10 As the “addition reaction”, the addition reactions described in step (1-1) and step
(1-2) in the above scheme 1 may be mentioned.
Step (3-4):
The compound (3) can be produced by carrying out the reaction of step (1-3) in
the above scheme 1.
15 2. Method for producing the compound (1)
The method for producing the compound (1) is illustrated in scheme 4.
Scheme 4: Method for producing the compound (1) from the compound (3)
[Ka 17]
20 Step (4-1):
The compound (1) can be produced by subjecting the compound (3) as a
substrate to “coupling reaction” with the compound (4) in the presence of a base.
The compound (4) used for the “coupling reaction” can be obtained by the method
described in WO2008/103185.
25 The compound (1) to be obtained by the “coupling reaction” is obtained as a
mixture containing E-isomer.
The base to be used for the “coupling reaction” is not particularly restricted, and a
base may be solely used, or a mixture containing plural bases may be used. The base
is preferably an organic base or an organic metal base, more preferably an alkali metal
30 base of an amine in which silyl groups are substituted by alkyls, allyls or both of them,
further preferably lithium bis(trimethylsilyl)amide.
The base is preferably used in a molar equivalent amount of from 1.0 to 20.0,
more preferably in a molar equivalent amount of from 3.0 to 10.0 to the compound (3).
The compound (4) is preferably used in a molar equivalent amount of from 1.0 to
35 10.0, more preferably in a molar equivalent amount of from 1.0 to 3.0 to the compound
(3).
The “coupling reaction” is preferably carried out in the presence of a solvent, and
the solvent to be used is not particularly restricted, so far as the reaction is not impaired.
As preferred examples of the solvent, an aliphatic hydrocarbon (such as hexane or
40 heptane), an aromatic hydrocarbon (such as benzene, toluene or xylene), an ether
(such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane or t-butyl methyl
9
ether), a halogenated aliphatic hydrocarbon (such as methylene chloride, chloroform or
dichloroethane), a nitrile (such as acetonitrile or propionitrile) or an amide (N,Ndimethylformamide
or N,N-dimethylacetoamide) may be mentioned. The solvent is
preferably an aliphatic hydrocarbon or an ether, more preferably hexane or
tetrahydrofuran, particularly preferably tetrahydrofuran5 .
The solvent may be used alone, or plural solvents may be used in combination.
Further, the amount of the solvent to be used is optionally adjusted depending on a type
of a substrate, since whether the substrate is crystal or not, whether the viscosity is high
or not, etc. influence in general. The amount of the solvent to be used may be a range
10 where a part of the substrate is dissolved, however, from the viewpoint of the influence
of the stirring efficiency and the volume efficiency, etc., the amount of the solvent to be
used is usually from 1 to 50 wt%, preferably from 2 to 20 wt%, more preferably from 3 to
10 wt%, as the substrate concentration of the compound (3).
The “coupling reaction” may be carried out at any of from -78°C to the boiling point
15 of a reaction medium, however, from the handling of the reaction and the industrial
viewpoint, the coupling reaction is usually carried out at -40°C to 60°C, preferably -30°C
to 50°C, more preferably -20°C to 40°C.
The “coupling reaction” may be carried out in the presence of an additive. The
additive is preferably a urea derivative (such as 1,3-dimethyl-2-imidazolidinone, 1,3-
20 dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone or tetramethylurea), more preferably
1,3-dimethyl-2-imidazolidinone. When the coupling reaction is carried out in the
presence of the urea derivative, the proportion of E-isomer and Z-isomer of a compound
to be formed changes, and the selectivity and the yield of the compound (1) which is Zisomer
improve.
25 In a case where the additive is used, the additive may be solely used, or plural
additives may be used in combination. The amount of the additive to be used may be
optionally adjusted depending on the type of the substrate, and the amount of the
additive to be used is from 0.1 to 100 times by weight, preferably from 1 to 20 times by
weight, more preferably from 2 to 6 times by weight, per the compound (3) as the
30 substrate.
After the termination of the “coupling reaction”, an acidic aqueous solution such as
sulfuric acid aqueous solution is added to a reaction solution, and the reaction solution
is stirred, whereby an organic metal compound is decomposed, and liquid-liquid
extraction is carried out to remove mainly components derived from bases. Then, an
35 alkaline solution such as a sodium carbonate aqueous solution is added, and liquidliquid
extraction is carried out to extract the desired product. The obtained organic
layer is purified by column chromatography, crystallization or the like to obtain the
desired product.
3. Method for producing a sodium salt of a compound represented by the formula (1)
40 Scheme 5 shows a method for producing a sodium salt (hereinafter referred to
also as “compound (5)”) of a compound represented by the formula (1).
Scheme 5: Method for producing the compound (5) from the compound (1)
[Ka 18]
10
Step (5-1):
The compound (1) as the substrate can be formed into a sodium salt with a
sodium alkoxide to produce the compound (5). By crystallizing the compound (5), the
compound (5) having a high purity can be formed. A solvent for salt formation o5 r
crystallization is preferably an alcohol solvent or an ester solvent. The sodium alkoxide
is preferably dissolved in an alcohol solvent for use, and the compound (1) is preferably
dissolved in an ester solvent for use.
The sodium alkoxide to be used is a C1-4 alkoxide such as sodium methoxide,
10 sodium ethoxide, sodium n-propoxide, sodium i-propoxide, sodium n-butopoxide,
sodium s-butopoxide or sodium t-butopoxide, preferably sodium methoxide.
The sodium alkoxide to be used is more preferably a solution of an alcohol
corresponding to an alkoxide.
Such a sodium alkoxide may be used as a mixture with other sodium alkoxide in
15 an optional proportion.
Further, such a sodium alkoxide is preferably used in a molar equivalent amount
of from 1.0 to 10.0, more preferably in a molar equivalent amount of from 1.0 to 3.0, per
the compound (1).
The alcohol solvent to be used is a C1-4 alcohol such as methanol, ethanol, n20
propanol, i-propanol, n-butanol, s-butanol or t-butanol, preferably methanol. An alcohol
may be added as a solution of the sodium alkoxide.
Such a solvent may be mixed with another solvent in an optional proportion for
use.
The alcohol solvent may be solely used, or plural solvents may be mixed for use.
25 Further, the amount of the solvent to be used may be optionally adjusted depending on
the type of the sodium alkoxide, since in a case where the sodium alkoxide is dissolved,
the solubility also influences. The amount of the solvent to be used may be a ranged
where a part of the sodium alkoxide can be dissolved, however, the amount of the
solvent to be used is usually from 1 to 90 wt%, preferably from 5 to 60 wt%, more
30 preferably from 10 to 40 wt%, as the concentration of the sodium alkoxide.
The ester solvent to be used is an ester of formic acid (methyl formate, ethyl
formate or n-propyl formate) or an ester of acetic acid (methyl acetate, ethyl acetate, npropryl
acetate, i-propyl acetate, n-butyl acetate, i-butyl acetate or t-butyl acetate),
preferably ethyl acetate.
35 Such a solvent may be mixed with another solvent in an optional proportion for
use.
The ester solvent may be solely used, or plural solvents may be mixed for use.
Further, the amount of the solvent to be used may be optionally adjusted depending on
the type of the substrate, since whether the substrate is crystal or not, whether the
40 viscosity is high or not, etc. influence in general. The amount of the solvent to be used
may be a ranged where a part of the substrate is dissolved, however, from the viewpoint
11
of the stirring efficiency, the influence of the volume efficiency, etc., the amount of the
solvent to be used is usually from 1 to 50 wt%, preferably from 2 to 20 wt%, more
preferably from 3 to 10 wt%, as the substrate concentration of the compound (1).
The compound (1) is crystallized by any one method of mixing with a sodium
alkoxide, mixing with a sodium alkoxide, followed by heating, cooling, concentrating o5 r
dissolving followed by adding a solvent (poor solvent) having a low solubility, or
crystallized by a method combining them.
Unless otherwise specified, the temperature of the crystallization is from -20°C to
80°C, preferably from -10°C to 50°C.
10 A seed crystal may be used for the crystallization. The seed crystal may be
obtained by a method known for those skilled in the art, such as scratching a wall of a
container in which a solution of the desired product is added by a spatula.
The compound (5) which is a sodium salt of the compound (1) is a salt formed
from the compound (1) and a sodium alkoxide and is a salt comprising an anion of the
15 compound (1) and a sodium cation. Further, the proportion of components of the salt
is anion of the compound (1) : sodium cation = 1:1.
Further, the structure of the compound (5) may be a compound represented by the
formula (5A), the formula (5B) or the formula (5C). In the present invention, the
compound (5) means one type of the compounds represented by the formula (5A), the
20 formula (5B) and the formula (5C) or a mixture of two or more of them.
[Ka 19]
The structure of the crystal can be analyzed by powder X-ray diffraction
measurement. The position of a peak (peak value) obtained by the powder X-ray
25 diffraction measurement is represented by 2. The peak value may vary depending on
measurement condition or the like in some cases. Further, the same or the difference
of the crystal form should be determined by comprehensively analyzing measurement
condition, a peak value, a diffraction pattern, etc.
The error of the powder X-ray diffraction peak is usually ±0.2, and taking the error
30 of the crystal described in Example 6 into the consideration, the peak value is usually 2
= 6.9 ± 0.2, 7.6 ± 0.2, 8.8 ± 0.2, 11.5 ± 0.2, 13.1 ± 0.2, 13.6 ± 0.2, 16.1 ± 0.2, 17.4 ± 0.2,
19.6 ± 0.2, 20.7 ± 0.2 or 23.6 ± 0.2.
4. Method for producing the compound (2)
The compound (2) can be derived from the compound (5) and the compound (1).
35 The general production method is shown in scheme 6, however, scheme 6 is an
example of a general production method, and the production method is by no means
restricted thereto. The compound (2) can be also produced by a method well known
for those skilled in the art, for example, changing the order of steps to be carried out,
adding a protective group to an amide group or the like followed by carrying out reaction
40 and deprotecting in a subsequent step, or adding a new step between the respective
steps.
In the synthesis of the compound (2), the method for appropriately protection or
deprotecting functional groups contained the starting materials, the intermediates, etc.
12
can be carried out in accordance with a method well known for those skilled in the art
similarly to the general production method of the compound (3).
Scheme 6: Method for producing the compound (2) from the compound (5)
[Ka 20]
5
In Scheme 6, G2 is a protective group for the nitrogen atom in the 2-pyridone
group. G3 is a protective group for the nitrogen atom in the pyrrolidinyl group
substituted by an oxo group.
Step (6-1):
The compound (1) can be obtained by subjecting the compound (5) to liquid-liqui10 d
extrqaction from an aqueous solution such as an acid or a salt in an organic solvent to
be separated from water.
Step (6-2):
The compound (1) is reacted with di-tert-butyl dicarbonate or the like to produce a
15 compound (6-a) having a protective group G2 and a protective group G3.
Step (6-3):
The compound (6-b) can be produced by reducing the compound (6-a) as a
substrate by “catalytic hydrogenation reaction” with a catalytic amount of palladiumactivated
carbon, rhodium-activated carbon, platinum-activated carbon or the like in an
20 inert solvent at -20°C to 80°C. In this production, as a case requires, an acid or a base
may be added.
Step (6-4):
The compound (2) can be produced by carrying out “deprotection reaction” of
protective groups G2 and G3 in the compound (6-b).
25 The “deprotection reaction” may be a method using an acid such as hydrochloric
acid or trifluoroacetic acid.
EXAMPLES
Now, the present invention will be described in detail with reference to Examples,
30 however, the present invention is by no means restricted thereto.
In the silica gel column chromatography, “silica gel 60” manufactured by KANTO
CHEMICAL CO., INC., “PSQ60B” manufactured by FUJI SILYSIA CHEMICAL LTD., or a
packed column (YAMAZEN Hi-FlashTM Column, MORITEX Purif Pack or Biotage
(registered trademark) SNAP KP-Sil Catridge) was used.
13
Abbreviations used in the present specification have the following means.
s: singlet
d: doublet
t: triplet
q: quarte5 t
dd: double doublet
m: multiplet
br: broad
J: coupling constant
10 Hz: Hertz
CDCl3: deuterated chloroform
V/V: volume/volume
In a case where 1H-NMR data are mentioned, the data represent chemical shift
(unit: ppm) (split pattern, integrated value) of signals wherein tetramethylsilane was
15 used as an internal standard substance. 1H-NMR (proton magnetic resonance
spectrum) was measured by the following Fourier transform type NMR.
300 MHz: JNM-ECP300 (JEOL), JNM-ECX300 (JEOL)
600 MHz: JNM-ECA600 (JEOL)
ACD/SpecManager ver. 12.01 (trade name) was used for analysis.
20 MS (mass spectrum) was measured by the following devices.
micromass ZQ (Waters)
LTQ XL (Thermo Fisher Scientific)
LCMS-2010EV (Shimadzu)
LCMS-IT-TOF (Shimadzu)
25 Agilent 6150 (Agilent)
LCQ Deca XP (Thermo Fisher Scientific)
As the iodination method, ESI (Electrospray Ionization) method or a dualionization
method of ESI and APCI (Atmospheric Pressure Chemical Ionization) method was
used.
30 The powder X-ray diffraction measurement was carried out by using “MiniFlex600”
(radiation source: Cu, wavelength: 1.54 (10-10 m)) manufactured by Rigaku Corporation
and “PertPRO” (radiation source: Cu, wavelength: 1.54 (10-10 m)) manufactured by
PANalytical were used.
The names of compounds were named by using ACD/Name ver. 12.01 (trade
35 name), etc.
Example 1
Method for producing the compound (3) (No. 1)
(1) (5-Cyclopropyl-6-methoxypyridin-2-yl)[4-(1,1-difluoroethyl)phenyl]methanone
[Ka 21]
N OMe
O
F
F
40
A 1.6M solution of n-butyl lithium in hexane (127 mL) was dropwise added to a
solution of 6-bromo-3-cyclopropyl-2-methoxypyridine (41.5 g) in tetrahydrofuran (273
mL) over 50 minutes at -78°C in a nitrogen atmosphere, followed by stirring at -78°C for
1 hour. Then, at -78°C as it was, a solution of 4-(1,1-difluoroethyl)benzonitrile (24.3 g)
14
in tetrahydrofuran (137 mL) was dropwise added to the reaction solution over 75
minutes, followed by stirring for 1 hour. The reaction solution was warmed to 0°C, and
then 1M hydrochloric acid (437 mL), tetrahydrofuran (365 mL) and 1M hydrochloric acid
(146 mL) were dropwise added in this order.
The reaction solution was separated into an organic layer and an aqueous layer5 ,
and then the aqueous layer was extracted with ethyl acetate (1,000 mL). The mixed
organic layer was dried over anhydrous magnesium sulfate, and the drying agent was
filtered off, and then the solvent was distilled off under reduced pressure. The resulting
residue was purified by silica gel column chromatography (hexane/ethyl acetate = 100/0
10 19/1, V/V) to obtain the title compound (34.0 g, yield 74%) as a colorless oil.
1H NMR (300 MHz, CDCl3) ppm 0.72-0.81 (m, 2H), 1.00-1.10 (m, 2H), 1.96 (t,
J=18.2 Hz, 3H), 2.10-2.25 (m, 1H), 3.95 (s, 3H), 7.24 (d, J=6.9 Hz, 1H), 7.59 (d, J=9.0
Hz, 2H), 7.67 (d, J=7.8 Hz, 1H), 8.21 (d, J=8.6 Hz, 2H).
MS (+): 318 [M+H]+
15 (2) Compound (3): 3-cyclopropyl-6-[4-(1,1-difluoroethyl)benzoyl]pyridin-2(1H)-one
Trimethylsilyl chloride (104.36 g) was dropwise added to a solution of (5-
cyclopropyl-6-methoxypyridin-2-yl)[4-(1,1-difluoroethyl)phenyl]methanone (76.31 g) and
potassium iodide (146.97 g) in acetonitrile (656.07 g) over 5 minutes at 23 to 24°C in a
nitrogen atmosphere, followed by heating to 64°C over 3 hours and 32 minutes and
20 stirring at 63 to 64°C for 5 hours and 14 minutes. The mixture was cooled to room
temperature and stirred for 14 hours, and then stirred for 1 hour and 30 minutes while
heating to 64°C. After cooling, an aqueous solution prepared by mixing sodium
carbonate (50.97 g) and water (201.34 g) was dropwise added thereto over 10 minutes
at 17 to 30°C, followed by adding water (102.93 g) and distilling the solvent off under
25 reduced pressure so as to be 669.38 g. Ethyl acetate (760.66 g) was added to the
resulting residue and mixed, followed by liquid-liquid extraction into an organic layer and
an aqueous layer. A 10% sodium thiosulfate aqueous solution (349.82 g) was added
to the organic layer and mixed, followed by liquid-liquid extraction into an organic layer
and an aqueous layer. A 10% sodium thiosulfate aqueous solution (350.40 g) was
30 added to the organic layer and mixed, followed by liquid-liquid extraction into an organic
layer and an aqueous layer. The organic layer was distilled to remove the solvent
under reduced pressure so as to be 116.9 g, followed by adding ethyl acetate (1,496.40
g) and heating to 33°C. A 10% sodium thiosulfate aqueous solution (353.05 g) and
saturated saline solution (107.24 g) were added thereto and mixed, followed by liquid35
liquid extraction into an organic layer and an aqueous layer.
The organic layer was distilled to remove the solvent under reduced pressure so
as to be 79.79 g. Then, ethyl acetate (383.57 g) was added to the organic layer, and
the mixture was heated to 40°C. Then, normal heptane (385.13 g) was dropwise
added to the mixture at 38 to 41°C over 11 minutes, followed by cooling to 15°C over 42
40 minutes and stirring for 15 minutes to obtain a suspension. The resulting solid was
filtered and washed with a mixed solution of cooled ethyl acetate (77.09 g) and normal
heptane (76.26 g), followed by drying under reduced pressure at 50°C for 3 hours to
obtain the title compound (67.95 g, yield 63.2%) as a yellow solid.
1H NMR (300 MHz, CDCl3) ppm 0.78-0.83 (m, 2H), 1.08-1.14 (m, 2H), 1.96 (t,
45 J=18.2 Hz, 3H), 2.25-2.35 (m, 1H), 6.68 (d, J=6.8 Hz,1H), 6.91 (d, J=7.2 Hz, 1H), 7.65
(d, J=8.2 Hz, 2H), 7.80 (d, J=8.2 Hz, 2H), 9.62 (s,1H).
MS (+): 304 [M+H]+
Example 2
15
Method for producing the compound (3) (No. 2)
(1) (5-Cyclopropylpyridin-2-yl)[4-(1,1-difluoroethyl)phenyl]methanone
[Ka 22]
N
O
F
F
A 1.6M solution of n-butyl lithium in hexane (13.9 mL) was dropwise added to 5 a
solution of 1-bromo-4-(1,1-difluoroethyl)benzene (5.54 g) in tetrahydrofuran (5.41 g)
over 24 minutes at -70°C or below in a nitrogen atmosphere, followed by washing with
tetrahydrofuran (2.71 g). After stirring at -70°C or below for 1 hour, a solution of 5-
cyclopropyl picolinonitrile (2.71 g) in tetrahydrofuran (4.20 g) was dropwise added over
10 15 minutes, followed by washing with tetrahydrofuran (2.74 g). After stirring for 4 hours
and 19 minutes, the mixture was warmed to room temperature. Concentrated
hydrochloric acid (4.48 g) and water (5.43 g) were added, followed by stirring for 8
minutes, and then the reaction solution was separated into an organic layer and an
aqueous layer. Ethyl acetate (11.08 g) was added to the obtained aqueous layer,
15 followed by stirring for 10 minutes, and then the mixture was subjected to liquid-liquid
extraction into an organic layer and an aqueous layer. The obtained organic layers
were mixed, and an aqueous solution prepared by mixing potassium hydrogen
carbonate (1.35 g) and water (8.43 g) was added thereto, followed by stirring for 6
minutes and liquid-liquid extraction into an organic layer and an aqueous layer. An
20 aqueous solution prepared by mixing sodium chloride (0.55 g) and water (8.43 g) was
added to the obtained organic layer, followed by stirring for 5 minutes and liquid-liquid
extraction into an organic layer and an aqueous layer. The obtained organic layer was
subjected to distillation under reduced pressure to remove the solvent. The resulting
residue was purified by silica gel column chromatography (hexane/ethyl acetate = 19/1,
25 V/V) to obtain an oily substance (5.87 g).
Hexane (10.19 g) and ethyl acetate (1.30 g) were added to the obtained oily
substance, and the mixture was heated to 50°C and then cooled. Then, ethyl acetate
(0.51 g) was added to the mixture at 36°C. Then, the mixture was cooled with ice,
followed by stirring for 4 minutes so as to be a suspension. The obtained solid was
30 filtered and washed with a mixed solution of ethyl acetate (0.75 g) and hexane (4.95 g),
followed by drying under reduced pressure at 40°C to obtain the title compound (3.98 g,
yield 72.1%) as a white solid.
1H NMR (300 MHz, CDCl3) ppm 0.80-0.94 (m, 2H), 1.12-1.24 (m, 2H), 1.84-2.07
(m, 4H), 7.46 (dd, J=2.4, 8.2 Hz, 1H), 7.60 (d, J=8.6 Hz, 2H), 8.00 (d, J=8.2 Hz, 1H),
35 8.10 (d, J=8.2 Hz, 2H), 8.49 (d, J=2.0 Hz, 1H).
MS (+): 288 [M+H]+
(2) 5-Cyclopropyl-2-[4-(1,1-difluoroethyl)benzoyl]pyridin-1-oxide
[Ka 23]
N+
O
F F
O-
40 A m-chloroperoxybenzoic acid (30% water, 34.32 g) was added to a solution of (5-
16
cyclopropylpyridin-2-yl)[4-(1,1-difluoroethyl)phenyl]methanone (20.00 g) in chloroform
(100.00 g) in a nitrogen atmosphere, followed by washing with chloroform (10.02 g), and
then stirring for 4 hours at 25°C. A chloroform, an aqueous solution prepared by
mixing sodium thiosulfate (14.31 g) and water (60.01 g) and a 5% sodium hydrogen
carbonate aqueous solution (60.01 g) were added to the reaction solution and mixed5 ,
followed by liquid-liquid extraction into an organic layer and an aqueous layer. A 5%
sodium hydrogen carbonate aqueous solution (60.00 g) was added to the organic layer
and mixed, followed by liquid-liquid extraction into an organic layer and an aqueous
layer. A 5% sodium hydrogen carbonate aqueous solution (120.01 g) was added to the
10 organic layer and mixed, followed by liquid-liquid extraction into an organic layer and an
aqueous layer. A 5% sodium hydrogen carbonate aqueous solution (120.00 g) was
added to the organic layer and mixed, followed by liquid-liquid extraction into an organic
layer and an aqueous layer. Water (60.02 g) was added to the organic layer and
mixed, followed by liquid-liquid extraction into an organic layer and an aqueous layer.
15 The obtained organic layer was distilled under reduced pressure to remove the solvent,
and a pale yellow solid (25.33 g) was obtained. The obtained solid was purified by
silica gel column chromatography (hexane/ethyl acetate = 1/1, V/V) to obtain the title
compound (18.05 g, yield 85.5%) as a pale yellow solid.
1H NMR (300 MHz, CDCl3) ppm 0.81-0.92 (m, 2H), 1.14-1.28 (m, 2H), 1.91 (t,
20 J=18.2 Hz, 3H), 1.87-2.04 (m, 1H), 7.07 (dd, J=1.7, 8.3 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H),
7.59 (d, J=8.3 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H), 7.99 (d, J=1.4 Hz, 1H).
MS (+): 304[M+H]+
(3) Compound (3): 3-cyclopropyl-6-[4-(1,1-difluoroethyl)benzoyl]pyridin-2(1H)-one
Anhydrous trifluoroacetic acid (59.82 g) was added to a solution of 5-cyclopropyl-
25 2-[4-(1,1-difluoroethyl)benzoyl]pyridin-1-oxide (12.00 g) in 2-methyltetrahydrofuran
(120.02 g) in a nitrogen atmosphere, followed by stirring for 7 hours at 23 to 26°C. An
aqueous solution prepared by mixing sodium hydroxide (22.15 g) and water (36.00 g)
was dropwise added to the reaction solution and then mixed with an aqueous solution
prepared by mixing potassium hydrogen carbonate (11.88 g) and water (108.00 g), and
30 chloroform (72.08 g) was added thereto and mixed, followed by liquid-liquid extraction
into an organic layer and an aqueous layer. Chloroform (60.00 g) was added to the
obtained aqueous layer, followed by stirring and liquid-liquid extraction into an organic
layer and an aqueous layer. The obtained organic layers were mixed, and water
(60.00 g) was added thereto, followed by stirring and liquid-liquid extraction into an
35 organic layer and an aqueous layer. The obtained organic layer was distilled under
reduced pressure to remove the solvent, followed by drying under reduced pressure at
room temperature to obtain a pale yellow solid (11.77 g).
Ethyl acetate (47.08 g) was added to the obtained solid, and the mixture was
stirred in the state of suspension for 30 minutes at 50 to 51°C. The mixture was cooled
40 and stirred for 30 minutes at 1°C. The obtained solid was filtered, washed with ethyl
acetate (17.67 g) and dried under reduced pressure for 2 hours at 50°C to obtain the
title compound (9.07 g, yield 75.6%) as a pale yellow solid.
MS (+): 304 [M+H]+
Example 3
45 Method for producing the compound (3) (No. 3)
(1) 5-Cyclopropyl-6-methoxypicolinonitrile
[Ka 24]
17
NC N OMe
Tris(2,4-pentanedionate) iron(III) (0.05 g) was added to a solution of 5-chloro-6-
methoxypicolinonitrile (0.50 g) in tetrahydrofuran (2.51 g) and N-methylpyrrolidone (2.50
g) at 6 to 7°C in a nitrogen atmosphere, followed by adding a 0.7 M solution of
5 cyclopropyl magnesium bromide in tetrahydrofuran (5.93 mL) and stirring for one hour
and 15 minutes at 4 to 7°C. Water (5.00 g) and ethyl acetate (5.00 g) were added to
the reaction solution and mixed, followed by liquid-liquid extraction into an organic layer
and an aqueous layer. Ethyl acetate (5.02 g) was added to the obtained aqueous layer
and mixed, followed by liquid-liquid extraction into an organic layer and an aqueous
10 layer. Ethyl acetate (5.01 g) was added to the obtained aqueous layer and mixed,
followed by liquid-liquid extraction into an organic layer and an aqueous layer. The
obtained organic layers were mixed, and saturated saline solution (5.00 g) was added
thereto and mixed, followed by liquid-liquid extraction into an organic layer and an
aqueous layer. The obtained organic layer was dried over anhydrous magnesium
15 sulfate, and the drying agent was filtered off, followed by distillation under reduced
pressure to remove the solvent. The resulting residue was purified by silica gel column
chromatography (hexane and ethyl acetate) to obtain the title compound (0.29 g, yield
55.8%) as a pale yellow solid.
1H NMR (600 MHz, CDCl3) ppm 0.69-0.75 (m, 2H), 1.02-1.09 (m, 2H), 2.10-2.16
20 (m, 1H), 4.00 (s, 3H), 7.10 (d, J=7.4 Hz, 1H), 7.20 (d, J=7.4 Hz, 1H).
MS (+): 175 [M+H]+
(2) (5-Cyclopropyl-6-methoxypyridin-2-yl)[4-(1,1-difluoroethyl)phenyl]methanone
[Ka 25]
25 A 1.6 M solution of n-butyl lithium in hexane (0.4 mL) was dropwise added to a
solution of 1-bromo-4-(1,1-difluoroethyl)benzene (0.17 g) in tetrahydrofuran (0.61 g) at -
60°C or below, followed by stirring for 1 hour, and a solution of 5-cyclopropyl-6-
methoxypicolinonitrile (0.10 g) in tetrahydrofuran (0.30 g) was dropwise added over 4
minutes. After stirring for 2 hours and 2 minutes, the mixture was warmed to room
30 temperature. A 5% hydrochloric acid aqueous solution (0.93 g) was added thereto,
followed by stirring, and then water and ethyl acetate were added thereto and mixed,
followed by liquid-liquid extraction into an organic layer and an aqueous layer. Ethyl
acetate (4 mL) was added to the obtained aqueous layer and mixed, followed by liquidliquid
extraction into an organic layer and an aqueous layer. Both the organic layers
35 were mixed, and a 5% sodium hydrogen carbonate aqueous solution was added thereto
and mixed, followed by liquid-liquid extraction into an organic layer and an aqueous
layer. Ethyl acetate (2 mL) was added to the obtained aqueous layer and mixed,
followed by liquid-liquid extraction into an organic layer and an aqueous layer. Both
the organic layers were mixed, and water was added thereto and mixed, followed by
40 liquid-liquid extraction into an organic layer and an aqueous layer. Ethyl acetate (2 mL)
was added to the obtained aqueous layer and mixed, followed by liquid-liquid extraction
18
into an organic layer and an aqueous layer. Both the organic layers were mixed, and
sodium sulfate was added thereto and dried. Then, the mixture was filtered to remove
the drying agent, followed by distillation under reduced pressure to remove the solvent.
The resulting residue was purified by silica gel column chromatography (hexane/ethyl
acetate = 49/1, V/V) to obtain the title compound (0.14 g, yield 75.1%) as a pale yello5 w
oil.
MS (+): 318 [M+H]+
(3) Compound (3): 3-cyclopropyl-6-[4-(1,1-difluoroethyl)benzoyl]pyridin-2(1H)-one
A compound was prepared by the same method as in Example 1-(2).
10 Reference Example 1 (the production method described in Patent Document 1 was
applied)
Preparation of (5R)-5-{(Z)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-[4-(1,1-
difluoroethyl)phenyl]ethenyl}pyrrolidin-2-one (Reference Example 1a) and (5R)-5-{(E)-2-
(5-cyclopropyl-6-methoxypyridin-2-yl)-2-[4-(1,1-difluoroethyl)phenyl]ethenyl}pyrrolidin-2-
15 one (Reference Example 1b)
[Ka 26]
A 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (22.0 mL) was
dropwise added to a solution of (5-cyclopropyl-6-methoxypyridin-2-yl)[4-(1,1-
20 difluoroethyl)phenyl]methanone (1.00 g) and (R)-5-[(benzothiazol-2-yl
sulfonyl)methyl]pyrrolidin-2-one (1.90 g) in tetrahydrofuran (6.00 g) and 1,3-dimethyl-2-
imidazolidinone (4.02 g) over 30 minutes at -17 to -12°C in a nitrogen atmosphere,
followed by stirring for 1 hour and 50 minutes at -17 to -10°C. The mixture was
warmed to 22°C, and water (10.10 g) was added thereto, followed by stirring for 1 hour
25 and 4 minutes. Then, a 50% sulfuric acid aqueous solution (4.78 g) was added
thereto, followed by distillation under reduced pressure to remove the solvent. Ethyl
acetate (20.00 g) and water (20.00 g) were added to the resulting residue and mixed,
followed by liquid-liquid extraction into an organic layer and an aqueous layer. A
saturated sodium hydrogen carbonate aqueous solution (20.00 g) was added to the
30 obtained organic layer and mixed, followed by liquid-liquid extraction into an organic
layer and an aqueous layer. A saline solution was added to the obtained organic layer
and mixed, followed by liquid-liquid extraction into an organic layer and an aqueous
layer. The obtained organic layer was distilled under reduced pressure to remove the
solvent, and the resulting residue was purified by silica gel column chromatography
35 (hexane and ethyl acetate) to obtain a mixture (1.10 g) containing the title compound as
an brown amorphous substance. Based on calculation of the proportion of the area
ratio of the characteristic peaks in 1H NMR data, the yield of (5R)-5-{(Z)-2-(5-
cyclopropyl-6-methoxypyridin-2-yl)-2-[4-(1,1-difluoroethyl)phenyl]ethenyl}pyrrolidin-2-
one was 49.3%, and the yield of (5R)-5-{(E)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-
19
[4-(1,1-difluoroethyl)phenyl]ethenyl}pyrrolidin-2-one was 38.0%.
(5R)-5-{(Z)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-[4-(1,1-
difluoroethyl)phenyl]ethenyl}pyrrolidin-2-one (Reference Example 1a)
1H NMR (300 MHz, CDCl3) ppm 0.65-0.71 (m, 2H), 0.96-1.02 (m, 2H), 1.86-2.16
(m, 5H), 2.28-2.49 (m, 3H), 4.00 (s, 3H), 4.65-4.72 (m, 1H), 5.91 (d, J=8.9 Hz, 1H), 5.95 6
(br, 1H), 6.54 (d, J=7.7 Hz, 1H), 7.05 (d, J=7.0 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.44 (d,
J=8.6 Hz, 2H).
MS (+): 399 [M+H]+
(5R)-5-{(E)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-[4-(1,1-
10 difluoroethyl)phenyl]ethenyl}pyrrolidin-2-one (Reference Example 1b)
1H NMR (600 MHz, CDCl3) ppm 0.56-0.64 (m, 2H), 0.90-0.97 (m, 2H), 1.93-2.09
(m, 5H), 2.20-2.34 (m, 2H), 2.37-2.45 (m, 1H), 4.04 (s, 3H), 4.07-4.16 (m, 1H), 5.73-
5.75 (br. s., 1H), 6.23 (d, J=7.4 Hz, 1H), 6.90 (d, J=9.9 Hz, 1H), 6.92 (d, J=7.8 Hz, 1H),
7.24 (d, J=8.3 Hz, 2H), 7.57 (d, J=7.8 Hz, 2H).
15 MS (+): 399 [M+H]+
In Examples 4 and 5, the reaction yield was calculated by a quantitative analysis
method using HPLC, (R, Z)-3-cyclopropyl-6-{1-[4-(1,1-difluoroethyl)phenyl]-2-[5-
oxopyrrolidin-2-yl]vinyl}pyridin-2(1H)-one and (R, E)-3-cyclopropyl-6-{1-[4-(1,1-
difluoroethyl)phenyl]-2-[5-oxopyrrolidin-2-yl]vinyl}pyridin-2(1H)-one which were purified
20 by silica gel column chromatography or the like as standard substances and phthalic
acid di(2-ethyl hexyl) ester as an internal standard substance.
Column: L-Column ODS (3.0 × 150 mm, 3 m) (manufactured by Chemical
Evaluation and Research Institute, Japan)
Column oven temperature: 40°C
25 Elute: Acetonitrile-0.01 M ammonium acetate aqueous solution, 22:78 (0-15 min),
22:78-40:60 (15-20 min), 40:60 (20-30 min), 40:60-95:5 (30-40 min), 95:5 (40-55 min),
V/V
Elute rate: 0.4 mL/min
Detection wavelength: 240 nm
30 Example 4
Preparation of (R, Z)-3-cyclopropyl-6-{1-[4-(1,1-difluoroethyl)phenyl]-2-[5-
oxopyrrolidin-2-yl]vinyl}pyridin-2(1H)-one (Example 4a) and (R, E)-3-cyclopropyl-6-{1-[4-
(1,1-difluoroethyl)phenyl]-2-[5-oxopyrrolidin-2-yl]vinyl}pyridin-2(1H)-one (Example 4b)
[Ka 27]
35
A 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (23.0 mL) was
dropwise added to a solution of 3-cyclopropyl-6-[4-(1,1-difluoroethyl)benzoyl]pyridin-
2(1H)-one (1.00 g) and (5R)-5-[(1,3-benzothiazol-2-yl-sulfonyl)methyl]pyrrolidin-2-one
(1.95 g) in tetrahydrofuran (6.03 g) and 1,3-dimethyl-2-imidazolidinone (4.02 g) over 30
40 minutes at -12 to -10°C in a nitrogen atmosphere, followed by stirring at -11 to -10°C for
20
1 hour and 30 minutes. The reaction solution was warmed to room temperature and
subjected to quantitative determination. As a result, the quantitative yield of (R, Z)-3-
cyclopropyl-6-{1-[4-(1,1-difluoroethyl)phenyl]-2-[5-oxopyrrolidin-2-yl]vinyl}pyridin-2(1H)-
one as the main component (desired compound) was 77.7%, and the quantitative yield
of (R, E)-3-cyclopropyl-6-{1-[4-(1,1-difluoroethyl)phenyl]-2-[5-oxopyrrolidin-5 2-
yl]vinyl}pyridin-2(1H)-one as a by-product was 9.2%.
(R, Z)-3-cyclopropyl-6-{1-[4-(1,1-difluoroethyl)phenyl]-2-[5-oxopyrrolidin-2-
yl]vinyl}pyridin-2(1H)-one (Example 4a)
1H NMR (300 MHz, CDCl3) ppm 0.61-0.71 (m, 2H), 0.90-1.03 (m, 1H), 1.14-1.30
10 (m, 1H), 1.92 (t, J=18.4 Hz, 3H), 1.87-2.00 (m, 1H), 2.09-2.18 (m, 1H), 2.28-2.50 (m,
3H), 4.33-4.41 (m, 1H), 6.05 (d, J=7.4 Hz, 1H), 6.16 (d, J=10.2 Hz, 1H), 7.03 (d, J=7.0
Hz, 1H), 7.35 (d, J=8.6 Hz, 2H), 7.46 (d, J=8.6 Hz, 1H), 7.81 (br, 1H), 13.17 (br, 1H).
MS (+): 385 [M+H]+
(R, E)-3-cyclopropyl-6-{1-[4-(1,1-difluoroethyl)phenyl]-2-[5-oxopyrrolidin-2-
15 yl]vinyl}pyridin-2(1H)-one (Example 4b)
1H NMR (300 MHz, CDCl3) ppm 0.50-0.65 (m, 2H), 0.90-1.03 (m, 2H), 1.91-2.46
(m, 8H), 4.07-4.15 (m, 1H), 5.63 (d, J=7.4 Hz, 1H), 6.63 (d, J=9.2 Hz, 1H), 6.80 (dd,
J=0.7, 7.4 Hz, 1H), 7.15 (s, 1H), 7.25 (d, J=9.2 Hz, 2H), 7.56 (d, J=8.5 Hz, 2H), 12.46
(br, 1H).
20 MS (+): 385 [M+H]+
Example 5
Preparation of (R, Z)-3-cyclopropyl-6-{1-[4-(1,1-difluoroethyl)phenyl]-2-[5-
oxopyrrolidin-2-yl]vinyl}pyridin-2(1H)-one (Example 5a) and (R, E)-3-cyclopropyl-6-{1-[4-
(1,1-difluoroethyl)phenyl]-2-[5-oxopyrrolidin-2-yl]vinyl}pyridin-2(1H)-one (Example 5b)
25 [Ka 28]
A 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (23.0 mL) was
dropwise added to a solution of 3-cyclopropyl-6-[4-(1,1-difluoroethyl)benzoyl]pyridin-
2(1H)-one (1.00 g) and (5R)-5-[(1,3-benzothiazol-2-ylsulfonyl)methyl]pyrrolidin-2-one
30 (1.95 g) in tetrahydrofuran (10.00 g) over 30 minutes at -11 to -9°C under a nitrogen
atmosphere, followed by stirring at -11 to -9°C for 3 hours and 35 minutes. The
reaction solution was warmed to room temperature and subjected to quantitative
determination. As a result, the quantitative yield of (R, Z)-3-cyclopropyl-6-{1-[4-(1,1-
difluoroethyl)phenyl]-2-[5-oxopyrrolidin-2-yl]vinyl}pyridin-2(1H)-one as the main
35 component (desired compound) was 66.2%, and the quantitative yield of (R, E)-3-
cyclopropyl-6-{1-[4-(1,1-difluoroethyl)phenyl]-2-[5-oxopyrrolidin-2-yl]vinyl}pyridin-2(1H)-
one as a by-product was 11.5%.
(R, Z)-3-cyclopropyl-6-{1-[4-(1,1-difluoroethyl)phenyl]-2-[5-oxopyrrolidin-2-
yl]vinyl}pyridin-2(1H)-one (Example 5a)
40 MS (+): 385 [M+H]+
(R, E)-3-cyclopropyl-6-{1-[4-(1,1-difluoroethyl)phenyl]-2-[5-oxopyrrolidin-2-
21
yl]vinyl}pyridin-2(1H)-one (Example 5b)
MS (+): 385 [M+H]+
Results of Reference Example 1, Example 4 and Example 5 are shown in Table 1
below. In the table, the additive is 1,3-dimethyl-2-imidazolidinone.
[Table 15 ]
Comparing Reference Example 1 with Example 4, it is evident that the selectivity
and the yield of the compound in the form of Z isomer improved in Example 4. Further,
10 comparing Example 4 with Example 5, it is evident that by adding 1,3-dimethyl-2-
imidazolidinone, the selectivity and the yield of the compound in the form of Z isomer
more improved.
Example 6
Preparation of sodium (R, Z)-3-cyclopropyl-6-{1-[4-(1,1-difluoroethyl)phenyl]-2-[5-
15 oxopyrrolidin-2-yl]vinyl}pyridin-2-olate
A solution of 3-cyclopropyl-6-[4-(1,1-difluoroethyl)benzoyl]pyridin-2(1H)-one (40.00
g) and (5R)-5-[(1,3-benzothiazol-2-yl sulfonyl)methyl]pyrrolidin-2-one (78.20 g) in
tetrahydrofuran (160.12 g) and 1,3-dimethyl-2-imidazolidinone (160.10 g) and a 1 M
solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran solution (930 mL) were
20 simultaneously dropwise added to tetrahydrofuran (80.1 g) at -15 to -13°C under a
nitrogen atmosphere over 1 hour and 50 minutes, followed by washing with
tetrahydrofuran (80.06 g). The mixture was stirred at -17 to 15°C for 1 hour and
warmed to 12°C, followed by adding water (400.19 g) thereto and stirring at 13 to 15°C
for 2 hours and 5 minutes. Then, a 50% sulfuric acid aqueous solution (199.30 g) was
25 added, followed by distillation under reduced pressure to remove the solvent so as to be
857.01 g. Ethyl acetate (400.81 g) and water (600.22 g) were added to the resulting
residue, followed by stirring and liquid-liquid extraction into an organic layer and an
aqueous layer. An aqueous solution prepared by mixing sodium carbonate (30.02 g)
and water (570.00 g) were added to the obtained organic layer and mixed, followed by
30 liquid-liquid extraction into an organic layer and an aqueous layer. An aqueous
22
solution prepared by mixing sodium chloride (30.00 g) and water (570.01 g) were added
to the obtained organic layer and mixed, followed by liquid-liquid extraction into an
organic layer and an aqueous layer. The obtained organic layer was distilled under
reduced pressure to remove the solvent, followed by adding ethyl acetate so as to be
800.12 g. While stirring, the obtained solution was cooled to -1°C, and then 5 a
methanol solution (43.26 g) of 28% sodium methoxide was dropwise added thereto over
1 hour, followed by stirring at -4 to -2°C for 1 hour to obtain a suspension. The
obtained solid was filtered and washed with ethyl acetate (160.00 g), followed by drying
under reduced pressure at 60°C to obtain the title compound (34.36 g, yield 67.8%) as a
10 white solid.
The solid obtained in Example 6 was subjected to powder X-ray diffraction
measurement, as a result the following characteristic peaks were measured.
(Characteristic peaks)
2 = 6.8, 7.5, 8.6, 11.4, 13.1, 13.5, 16.0, 17.3, 19.5, 20.6, 23.5
15 Further, the powder X-ray diffraction pattern obtained by the measurement is
shown in Fig. 1.
Example 7
Preparation of 3-cyclopropyl-6-{(1R)-1-[4-(1,1-difluoroethyl)phenyl]-2-[(2R)-5-
oxopyrrolidin-2-yl]ethyl}pyridin-2(1H)-one
20 [Ka 29]
(1) (R, Z)-tert-butyl-6-{2-[1-(tert-butoxycarbonyl)-5-oxopyrrolidin-2-yl]-1-[4-(1,1-
difluoroethyl)phenyl]vinyl}-3-cyclopropyl-2-oxopyridin-1(2H)-carboxylate
[Ka 30]
25
A 10% ammonium chloride aqueous solution (100 g) and ethyl acetate (100 g)
were added to sodium (R, Z)-3-cyclopropyl-6-{1-[4-(1,1-difluoroethyl)phenyl]-2-[5-
oxopyrrolidin-2-yl]vinyl}pyridin-2-olate (10.00 g), followed by stirring and then liquidliquid
extraction into an organic layer and an aqueous layer.
30 Water (50 g) was added to the organic layer, followed by stirring and then liquidliquid
extraction into an organic layer and an aqueous layer. The obtained organic
layer was distilled under reduced pressure to remove the solvent, and ethyl acetate (50
g) was added to the resulting residue, followed by distillation under reduced pressure to
remove the solvent. Acetonitrile (50 g) was added to the resulting residue, followed by
35 distillation under reduced pressure to remove the solvent. The resulting residue was
mixed with acetonitrile (70 g), triethylamine (8.73 g) and N,N-dimethyl-4-aminopyridine
23
(0.609 g), followed by dropwise adding a solution prepared by mixing di-tert-butyl
dicarbonate (16.12 g) and acetonitrile (30 g) thereto over 6 minutes at 24°C. The
mixture was heated to 40°C and stirred for 1 hour and 35 minutes, followed by
distillation under reduced pressure to remove the solvent. A 10% ammonium chloride
aqueous solution (100 g) and ethyl acetate (100 g) were added to the resulting residu5 e
and mixed, followed by liquid-liquid extraction into an organic layer and an aqueous
layer. Water (50 g) was added to the organic layer and mixed, followed by liquid-liquid
extraction into an organic layer and an aqueous layer. Ethyl acetate (50 g) was added
to the obtained aqueous layer and mixed, followed by liquid-liquid extraction into an
10 organic layer and an aqueous layer. The obtained organic layers were mixed, followed
by distillation under reduced pressure to remove the solvent. Toluene (30 g) was
added to the resulting residue, followed by distillation under reduced pressure to
remove the solvent. The resulting residue was purified by silica gel column
chromatography (hexane/ethyl acetate = 77/23 73/27, V/V) to obtain the title
15 compound (12.10 g, yield 84.1%) as a pale yellow amorphous substance.
1H NMR (300 MHz, CDCl3) ppm 0.70-0.75 (m, 2H), 1.01-1.07 (m, 2H), 1.40 (s,
9H), 1.58 (s, 9H), 1.93 (t, J=18.0 Hz, 3H), 1.96-2.08 (m, 2H), 2.44-2.62 (m, 3H), 5.06-
5.14 (m, 1H), 6.04 (d, J=9.0 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 7.26 (d, J=7.3 Hz, 1H),
7.28 (d, J=7.0 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H).
20 MS (+): 585 [M+H]+
(2) tert-butyl-6-{(R)-2-[(R)-1-(tert-butoxycarbonyl)-5-oxopyrrolidin-2-yl]-1-[4-(1,1-
difluoroethyl)phenyl]ethyl}-3-cyclopropyl-2-oxopyridine-1(2H)-carboxylate
[Ka 31]
25 (R, Z)-tert-butyl-6-{2-[1-(tert-butoxycarbonyl)-5-oxopyrrolidin-2-yl]-1-[4-(1,1-
difluoroethyl)phenyl]vinyl}-3-cyclopropyl-2-oxopyridine-1(2H)-carboxylate (7.00 g) was
mixed with ethyl acetate (35 g) and 5%palladium-activated carbon (1.40 g, wetted with
49.81% water), followed by strirring at 22 to 23°C for 3 hours under a hydrogen
atmosphere. The reaction solution was filtered, the resulting residue was washed with
30 ethyl acetate (70 g), and the filtrate was added to the residue, followed by distillation to
remove the solvent. Then, toluene (20 g) was added thereto, followed by distillation
under reduced pressure to remove the solvent.
The resulting residue was purified by silica gel column chromatography
(hexane/ethyl acetate = 71/29 65/35, V/V) to obtain the title compound (5.55 g, yield
35 79.1%) as a white amorphous substance.
1H NMR (300 MHz, CDCl3) ppm 0.61-0.66 (m, 2H), 0.91-0.98 (m, 2H), 1.47-1.65
(m, 1H), 1.48 (s, 9H), 1.56 (s, 9H), 1.69-1.77 (m, 1H), 1.86-2.17 (m, 2H), 1.88 (t, J=18.2
Hz, 3H), 2.30-2.54 (m, 2H), 2.79-2.87 (m, 1H), 4.07-4.16 (m, 2H), 7.00 (d, J=7.8 Hz,
1H), 7.24 (d, J=7.0 Hz, 1H), 7.36 (d, J=8.6 Hz, 2H), 7.42 (d, J=8.6 Hz, 2H).
40 MS (+): 587 [M+H]+
(3) 3-Cyclopropyl-6-{(1R)-1-[4-(1,1-difluoroethyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-
yl]ethyl}pyridin-2(1H)-one
24
[Ka 32]
35% hydrochloric acid (30.78 g) was dropwise added to an ethyl acetate solution
(376.48 g) containing tert-butyl 6-{(R)-2-[(R)-1-(tert-butoxycarbonyl)-5-oxopyrrolidin-2-
yl]-1-[4-(1,1-difluoroethyl)phenyl]ethyl}-3-cyclopropyl-2-oxopyrrolidine-1 (2H)5 -
carboxylate (39.95 g) at 32 to 34°C over 30 minutes, followed by stirring at 32 to 34°C
for 4 hours. An aqueous solution prepared by mixing sodium hydroxide (38.40 g) and
water (150.10 g) was dropwise added thereto, followed by stirring at 33 to 35°C and
then liquid-liquid extraction into an organic layer and an aqueous layer. An aqueous
10 solution prepared by mixing potassium hydrogen carbonate (29.88 g) and water (150.00
g) was added to the obtained organic layer and mixed, followed by liquid-liquid
extraction into an organic layer and an aqueous layer. The obtained organic layer was
distilled under reduced pressure to remove the solvent, and then ethanol (300.07 g) was
added to the resulting residue, followed by distillation under reduced pressure to
15 remove the solvent. Ethanol (300.00 g) was added to the resulting residue, followed
by distillation under reduced pressure to remove the solvent.
Ethanol was added to the resulting residue so as to be 210.02 g, followed by
stirring at 18 to 20°C for 1 hour to be a suspension, and then the suspension was
heated to 56°C over 3 hours and stirred for 1 hour. Then, the suspension was cooled
20 to -2°C and then stirred for 103 hours. The resulting solid was filtered, washed wish
ethanol (120.00 g) and dried under reduced pressure at 60°C to obtain the title
compound (22.22 g, yield 84.5%) as a white solid.
1H NMR (300 MHz, CDCl3) ppm 0.56-0.67 (m, 2H), 0.91-0.98 (m, 2H), 1.66-1.78
(m, 1H), 1.89 (t, J=18.1 Hz, 3H), 2.07-2.42 (m, 6H), 3.44-3.53 (m, 1H), 4.08 (dd, J=6.0,
25 9.6 Hz, 1H), 5.97 (d, J=7.4 Hz, 1H), 6.91 (d, J=7.0 Hz, 1H), 7.44 (s, 4H), 7.49 (br, 1H),
12.36 (br, 1H).
MS (+): 387 [M+H]+
INDUSTRIAL APPLICABILITY
30 The present invention is useful, since the 2-pyridone compound which is useful as
a pharmaceutical or an intermediate for a pharmaceutical can be produced at a high
yield from a 6-benzoyl-2-pyridone compound.
The entire disclosure of Japanese Patent Application No. 2014-099755 filed on
35 May 13, 2014 including specification, claims, drawings and summary is incorporated
herein by reference in its entirety.

CLAIMS
1. A method for producing a 2-pyridone compound represented by the formula (1),
which comprises reacting a 6-benzoyl-2-pyridone compound represented by the formula
(3) with a sulfone compound represented by the formula (4):
[Ka 15 ]
2. The production method according to Claim 1, wherein the reaction is carried out in
the presence of a urea derivative.
3. The production method according to Claim 2, wherein the urea derivative is 1,3-
10 dimethyl-2-imidazolidinone.
4. A compound represented by the formula (1):
[Ka 2]
5. A compound represented by the formula (3):
15 [Ka 3]
6. A sodium salt of a compound represented by the formula (1):
7. A compound represented by the formula (6):
8. A compound represented by the formula (7):
9. A compound represented by the formula (8):
TKa 71
10. A compound represented by the formula (9):
[Ka8]
11. A compound represented by the formula (10):
[Ka 9]