U.S. patent application number 17/732804 was filed with the patent office on 2022-08-18 for method for preparing intermediate of 4-methoxypyrrole derivative.
The applicant listed for this patent is Daewoong Pharmaceutical Co., Ltd.. Invention is credited to Seung Chul Lee, Jeong-Taek Shin, Jeong-Hyun Son.
Application Number | 20220259146 17/732804 |
Document ID | / |
Family ID | |
Filed Date | 2022-08-18 |
United States Patent
Application |
20220259146 |
Kind Code |
A1 |
Shin; Jeong-Taek ; et
al. |
August 18, 2022 |
METHOD FOR PREPARING INTERMEDIATE OF 4-METHOXYPYRROLE
DERIVATIVE
Abstract
The present invention relates to a method for preparing
intermediates of 4-methoxypyrrole derivatives. The preparation
method according to the present invention has advantages that the
production cost can be lowered by using inexpensive starting
materials, a high-temperature reaction is not required as a whole,
inexpensive and non-explosive reagents are used instead of
(trimethylsilyl)diazomethane, and further an intermediate of
4-methoxypyrrole derivatives can be prepared as a whole at a high
yield.
Inventors: |
Shin; Jeong-Taek;
(Gyeonggi-do, KR) ; Son; Jeong-Hyun; (Gyeonggi-do,
KR) ; Lee; Seung Chul; (Gyeonggi-do, KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Daewoong Pharmaceutical Co., Ltd. |
Gyeonggi-do |
|
KR |
|
|
Appl. No.: |
17/732804 |
Filed: |
April 29, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16608924 |
Oct 28, 2019 |
11345660 |
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PCT/KR2018/006989 |
Jun 21, 2018 |
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17732804 |
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International
Class: |
C07D 207/36 20060101
C07D207/36 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 21, 2017 |
KR |
10-2017-0078745 |
Claims
1. A method for preparing a compound represented by the following
Chemical Formula 1, comprising the steps of: 1) reacting a compound
represented by the following Chemical Formula 1-1 with ammonium
chloride, and sodium cyanide, or potassium cyanide, followed by
reaction with an acid to prepare a compound represented by the
following Chemical Formula 1-2; 2) protecting a compound
represented by the following Chemical Formula 1-2 with an amine
protecting group (P) to prepare a compound represented by the
following Chemical Formula 1-3; 3) reacting a compound represented
by the following Chemical Formula 1-3 with (i) methylpotassium
malonate, or methylsodium malonate, (ii) carbonyldiimidazole, and
(iii) magnesium halide, followed by reaction with an acid to
prepare a compound represented by the following Chemical Formula
1-4; 4) reacting a compound represented by the following Chemical
Formula 1-4 with N,N-dimethylformamide dimethylacetal to prepare a
compound represented by the following Chemical Formula 1-5; 5)
reacting a compound represented by the following Chemical Formula
1-5 with dimethyl sulfate to prepare a compound represented by the
following Chemical Formula 1-6; and 6) reacting a compound
represented by the following Chemical Formula 1-6 with an acid to
prepare a compound represented by the following Chemical Formula 1:
##STR00007##
2. The method according to claim 1, wherein in the step 1, the
molar ratio of the compound represented by the Chemical Formula 1-1
to ammonium chloride is 10: 1 to 1:10, and the molar ratio of the
compound represented by the Chemical Formula 1-1 to sodium cyanide
or potassium cyanide is 10:1 to 1:10.
3. The method according to claim 1, wherein in the step 1, the
reaction with the compound represented by the Chemical Formula 1-1,
ammonium chloride, and sodium cyanide or potassium cyanide is
carried out at 0 to 40.degree. C., and the reaction with an acid is
carried out at 80 to 120.degree. C.
4. The method according to claim 1, wherein the acid in the step 1
is acetic acid or hydrochloric acid.
5. The method according to claim 1, wherein, the amine protecting
group (P) in the step 2 is tert-butoxycarbonyl (Boc),
fluorenylmethyloxycarbonyl (Fmoc), Tosyl, or Acyl.
6. The method according to claim 1, wherein the reaction of the
step 2 is carried out at 10 to 40.degree. C.
7. The method according to claim 1, wherein the magnesium halide in
the step 3 is magnesium chloride or magnesium bromide.
8. The method according to claim 1, wherein in the step 3, the
molar ratio of the compound represented by the Chemical Formula 1-3
to methylpotassium malonate or methylsodium malonate is 10:1 to
1:10, the molar ratio of the compound represented by the Chemical
Formula 1-3 to carbonyldiimidazole is 10:1 to 1:10, and the molar
ratio of the compound represented by the Chemical Formula 1-3 to
the magnesium halide is 10:1 to 1:10.
9. The method according to claim 1, wherein the acid in the step 3
is hydrochloric acid, nitric acid, sulfuric acid, or phosphoric
acid.
10. The method according to claim 1, wherein the reaction between
the compound represented by the Chemical. Formula 1-3 and (i)
methylpotassium malonate or methylsodium malonate, (ii)
carbonyldiimidazole, and (iii) magnesium halide in the step 3 is
carried out at 50 to 100.degree. C., and the reaction with the acid
is carried out at 0 to 40.degree. C.
11. The method according to claim 1, wherein the molar ratio of the
compound represented by the Chemical Formula 1-4 to
N,N-dimethylformamide dimethylacetal in the step 4 is 1:1 to
1:10.
12. The method according to claim 1, wherein the reaction of the
step 4 is carried out at 20 to 70.degree. C.
13. The method according to claim 1, wherein the molar ratio of the
compound represented by the Chemical Formula 1-5 to dimethylsulfate
in the step 5 is 10:1 to 1:10.
14. The method according to claim 1, wherein the reaction of the
step 5 is carried out at 20 to 60.degree. C.
15. The method according to claim 1, wherein the molar ratio of the
compound represented by the Chemical Formula 1-6 to trifluoroacetic
acid in the step 6 is 1:1 to 1:30.
16. The method according to claim 1, wherein the reaction of the
step 6 is carried out at 10 to 40.degree. C.
17. The method according to claim 1, wherein the acid of the step 6
is trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric
acid, or phosphoric acid.
Description
TECHNICAL FIELD
[0001] The present invention relates to a method for preparing
intermediates used in the preparation of 4-methoxypyrrole
derivatives.
BACKGROUND OF ART
[0002] Gastrointestinal track ulcers, gastritis, and reflux
esophagitis occur while the balance between aggressive factors
(e.g., gastric acid, Helicobacter pylori pepsin, stress, alcohol
and tobacco) and protective factors (e.g., gastric mucosa,
bicarbonate, prostaglandins, the degree of blood supply, etc.) is
destroyed. Therefore, a therapeutic agent for gastrointestinal
damage such as gastrointestinal track ulcer, gastritis and reflux
esophagitis is divided into a drug for inhibiting the aggressive
factors and a drug for enhancing the protective factors.
[0003] Meanwhile, it is reported that gastrointestinal track
ulcers, gastritis and reflux esophagitis occur ulcers even without
an increase in secretion of gastric acid. Thus, as much as the
aggressive factor increases, a reduction in protective factors due
to a pathological change of the gastric mucosa is thought to play
an important role in the occurrence of gastric ulcers. Therefore,
in addition to drugs for inhibiting the aggressive factor, drugs
for enhancing the protective factors are used for the treatment of
gastrointestinal ulcer and gastritis. As the drugs for enhancing
protective factors, mucosal protective drugs which are attached to
the ulcer site to form a physicochemical membrane, drugs that
promote the synthesis and secretion of mucus have been known.
[0004] On the other hand, Helicobacter pylori (H. pylori), which is
a bacteria present in the stomach, has been known to cause chronic
gastritis, gastric ulcer, duodenal ulcer and the like, and a number
of patients with gastrointestinal damages are infected with H.
pylori. Therefore, these patients should take antibiotics such as
clarithromycin, amoxicillin, metronidazole and tetracycline,
together with anti-ulcer agents such as a proton pump inhibitor, or
a gastric pump antagonist. Consequently, various side effects have
been reported.
[0005] Therefore, there is a need to develop anti-ulcer drugs which
inhibit the secretion of gastric acid (e.g., proton pump inhibitory
activity) and enhance protective factors (e.g., an increase in
mucus secretion) and at the same time have disinfectant activity
against H pylori.
[0006] In this connection, Korean Patent No. 10-1613245 discloses
that a 4-methoxypyrrole derivative or a pharmaceutically acceptable
salt thereof has excellent anti-ulcer activity (i.e., proton pump
inhibitory activity, etc.) and disinfectant activity against H.
pylori, and thus can be effectively used for the prevention and
treatment of gastrointestinal damage due to gastrointestinal track
ulcer, gastritis, reflux esophagitis or Helicobacter pylori.
[0007] In the preparation of the 4-methoxypyrrole derivative
described in the above patent, the following compound is prepared
as an intermediate.
##STR00001##
[0008] According to the description of the above patent, the
intermediate is prepared from 2,4-difluorophenylglycine, and the
preparation method consists of four steps in total (Steps (8-1) to
(8-3) of Example 8 described in Korean Patent No. 10-1613245).
However, according to the preparation method of the above patent,
the total yield is as low as 9.0%, a high-temperature reaction is
required as a whole, and thus expensive equipment is required.
Especially, (trimethylsilyl)diazomethane is used as a reactant, but
this reagent is not only expensive but also explosive and thus is
not suitable for industrial mass production.
[0009] Given the above circumstances, the present inventors have
conducted intensive studies on a new preparation method capable of
preparing the above intermediate. As a result, the inventors have
found a preparation method in which a high-temperature reaction is
not required as a whole as in the preparation method described
later, and inexpensive, non-explosive reagent is used instead of
(trimethylsilyl)diazomethane, and further, the yield is improved as
a whole, thereby completing the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Technical Problem
[0010] It is an object of the present invention to provide a method
for preparing an intermediate which can be usefully used in the
preparation of 4-methoxypyrrole derivatives.
Technical Solution
[0011] In order to achieve the above object, the present invention
provides a preparation method as shown in the following Reaction
Scheme 1, and more specifically, the preparation method comprises
the steps of:
[0012] 1) reacting a compound represented by the following Chemical
Formula 1-1 with ammonium chloride, sodium cyanide, or potassium
cyanide, followed by reaction with an acid to prepare a compound
represented by the following Chemical Formula 1-2;
[0013] 2) protecting a compound represented by the following
Chemical Formula 1-2 with an amine protecting group (P) to prepare
a compound represented by the following Chemical Formula 1-3;
[0014] 3) reacting a compound represented by the following Chemical
Formula 1-3 with (i) methylpotassium malonate or methylsodium
malonate, (ii) carbonyldiimidazole, and (iii) magnesium halide,
followed by reaction with an acid to prepare a compound represented
by the following Chemical Formula 1-4;
[0015] 4) reacting a compound represented by the following Chemical
Formula 1-4 with N,N-dimethylformamide dimethylacetal to prepare a
compound represented by the following Chemical Formula 1-5;
[0016] 5) reacting a compound represented by the following Chemical
Formula 1-5 with dimethyl sulfate to prepare a compound represented
by the following Chemical Formula 1-6; and 6) reacting a compound
represented by the following Chemical Formula 1-6 with an acid via
deprotection to prepare a compound represented by the following
Chemical Formula 1.
##STR00002##
[0017] Hereinafter, the present invention will be described in
detail for each step.
[0018] (Step 1)
[0019] The step 1 relates to Strecker amino acid synthesis, which
is a step of preparing an amino acid like a compound represented by
the Chemical Formula 1-2 from the Chemical Formula 1-1.
[0020] The reaction consists substantially of two reactions. First,
the first reaction is to react a compound represented by the
Chemical Formula 1-1 with ammonium chloride, and sodium cyanide, or
potassium cyanide.
[0021] Preferably, the molar ratio of the compound represented by
the Chemical Formula 1-1 to ammonium chloride is 10:1 to 1:10, more
preferably 5:1 to 1:5, and most preferably 3:1 to 1:3. Preferably,
the molar ratio of the compound represented by the Chemical Formula
1-1 to sodium cyanide or potassium cyanide is 10:1 to 1:10, more
preferably 5:1 to 1:5, and most preferably 3:1 to 1:3.
[0022] Preferably, as a solvent for the first reaction, an alcohol
having from 1 to 4 carbon atoms, and ammonium hydroxide or ammonium
carbonate are used. More preferably, the alcohol having 1 to 4
carbon atoms is methanol, ethanol, propanol, iso-propanol, butanol,
or tert-butanol.
[0023] Preferably, the first reaction is carried out at 0.degree.
C. to 40.degree. C. When the reaction temperature is less than
0.degree. C., there is a problem that the production yield is
lowered. When the reaction temperature exceeds 40.degree. C., the
production yield does not substantially increase.
[0024] Preferably, the first reaction is carried out for 1 to 48
hours. When the reaction time is less than 1 hour, there is a
problem that the reaction does not proceed sufficiently and thus
the production yield is lowered. When the reaction time exceeds 48
hours, the production yield does not substantially increase.
[0025] On the other hand, after the first reaction is completed, a
step of purifying the product may be included, if necessary.
Preferably, the purification is carried out by crystallizing a
cyanamide compound from the product of the reaction. As the
crystallization solvent, water and an alcohol having 1 to 4 carbon
atoms can be used. Preferably, the alcohol having 1 to 4 carbon
atoms is methanol, ethanol, propanol, iso-propanol, butanol, or
tert-butanol. Preferably, water is added to the reaction product
and cooled to 10 to 15.degree. C. Then, an alcohol having 1 to 4
carbon atoms is added thereto and stirred for 10 minutes to 2
hours.
[0026] After the first reaction is completed, a second reaction is
carried out in which the product of the first reaction is reacted
with an acid.
[0027] As the acid that can be used, acetic acid or hydrochloric
acid can be mentioned. Preferably, acetic acid and hydrochloric
acid are used together. The acid not only acts as a reactant in the
second reaction, but also acts as a solvent. Therefore, it is
preferable to use the acid in an amount sufficient to dissolve the
first product.
[0028] Preferably, the second reaction is carried out at 80 to
120.degree. C. When the reaction temperature is less than
80.degree. C., there is a problem that the production yield is
lowered. When the reaction temperature exceeds 120.degree. C., the
production yield does not substantially increase.
[0029] Preferably, the second reaction is carried out for 1 to 10
hours. When the reaction time is less than 1 hour, there is a
problem that the reaction does not proceed sufficiently and thus
the production yield is lowered. When the reaction time exceeds 10
hours, the production yield does not substantially increase.
[0030] On the other hand, after the second reaction is completed, a
step of purifying the product may be included, if necessary.
[0031] (Step 2)
[0032] The step 2 is a step of protecting a compound represented by
the Chemical Formula 1-2 with an amine protecting group (P), which
is a step of preparing a compound represented by the Chemical
Formula 1-3 by reacting a compound represented by the Chemical
Formula 1-2 with a compound capable of introducing an amine
protecting group (P).
[0033] Preferably, the amine protecting group (P) is
tert-butoxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc),
Tosyl, or Acyl. In addition, the compound capable of introducing an
amine protecting group (P) refers to various compounds used in the
art for introducing the protecting group. For example, when the
amine protecting group (P) is a tert-butoxycarbonyl (Boc), the
compound capable of introducing the amine protecting group includes
di-tert-butyl dicarbonate.
[0034] Preferably, the molar ratio of the compound represented by
the Chemical Formula 1-2 to the compound capable of introducing the
amine protecting group (P) is 10:1 to 1:10, and more preferably 3:1
to 1:5.
[0035] Preferably, the reaction is carried out in the presence of a
base. As the base, triethylamine, diisopropylamine,
diisopropylethylamine, potassium carbonate, potassium
hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate,
sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium
methylate, potassium butyrate, or cesium carbonate can be used, and
preferably, sodium hydrogencarbonate is used. Preferably, the molar
ratio of the compound represented by the Chemical Formula 1-2 to
the base is 1:1 to 1:10, and more preferably 1:1 to 1:5.
[0036] Preferably, as a solvent for the above reaction, water,
tetrahydrofuran, dioxane, methylene chloride, butyl alcohol,
tetrahydrofuran, or a mixture thereof may be used. Preferably,
water and tetrahydrofuran are used together.
[0037] Preferably, the reaction is carried out at 10 to 40.degree.
C. When the reaction temperature is less than 10.degree. C., there
is a problem that the production yield is lowered. When the
reaction temperature exceeds 40.degree. C., the production yield
does not substantially increase. More preferably, the reaction is
carried out at 20 to 30.degree. C.
[0038] Preferably, the above reaction is carried out for 1 to 48
hours. When the reaction time is less than 1 hour, there is a
problem that the reaction does not proceed sufficiently and thus
the production yield is lowered. When the reaction time exceeds 48
hours, the production yield does not substantially increase. More
preferably, the reaction is carried out for 6 to 24 hours.
[0039] On the other hand, after the reaction is completed, a step
of purifying the product may be included, if necessary.
[0040] (Step 3)
[0041] The step 3 is a reaction for substituting a carboxyl group
of the compound represented by the Chemical Formula 1-3, wherein
the reaction consists substantially of two reactions.
[0042] First, the first reaction is a reaction for preparing a
compound of the following Chemical Formula, which is a magnesium
salt of the compound represented by the
[0043] Chemical Formula 1-4 to be prepared. The second reaction is
a reaction for preparing the magnesium salt of the compound
represented by the Chemical Formula 1-4 by dissociating the
magnesium salt of the compound represented by the Chemical Formula
1-4
##STR00003##
[0044] The compound represented by the Chemical Formula 1-4 is
difficult to crystallize. Therefore, in the present invention, it
is prepared by first preparing a magnesium salt thereof and then
purifying it through crystallization.
[0045] First, the first reaction is a reaction of reacting a
compound represented by the Chemical Formula 1-3 with (i)
methylpotassium malonate or methylsodium malonate, (ii)
carbonyldiimidazole, and (iii) magnesium halide. Preferably, as the
magnesium halide, magnesium chloride or magnesium bromide may be
used, and more preferably, magnesium chloride is used.
[0046] Preferably, the molar ratio of the compound represented by
the Chemical Formula 1-3 to methylpotassium malonate or
methylsodium malonate is 10:1 to 1:10, more preferably from 5:1 to
1:5, most preferably 3:1 to 1:3. Preferably, the molar ratio of the
compound represented by the Chemical Formula 1-3 to
carbonyldiimidazole is 10:1 to 1:10, more preferably 5:1 to 1:5,
and most preferably 3:1 to 1:3. Preferably, the molar ratio of the
compound represented by the Chemical Formula 1-3 to magnesium
halide is 10:1 to 1:10, more preferably 5:1 to 1:5, and most
preferably 3:1 to 1:3.
[0047] Preferably, the first reaction is carried out in the
presence of triethylamine. Preferably, the molar ratio of the
compound represented by the Chemical Formula 1-3 to triethylamine
is 10:1 to 1:10, more preferably 5:1 to 1:5 and most preferably 3:1
to 1:3.
[0048] Preferably, as a solvent for the first reaction,
acetonitrile or tetrahydrofuran is used, and more preferably,
acetonitrile is used.
[0049] Preferably, the first reaction is carried out at 50 to
100.degree. C. When the reaction temperature is less than
50.degree. C., there is a problem that the production yield is
lowered. When the reaction temperature exceeds 100.degree. C., a
side reaction occurs, which is not preferable.
[0050] Preferably, the first reaction is carried out for 10 minutes
to 10 hours. When the reaction time is less than 10 minutes, there
is a problem that the reaction does not proceed sufficiently and
thus the production yield is lowered. When the reaction time
exceeds 10 hours, a side reaction occurs, which is not preferable.
More preferably, the reaction is carried out for 10 minutes to 5
hours.
[0051] After the first reaction is completed, a second reaction is
performed in which the product of the first reaction is reacted
with an acid.
[0052] As the acid that can be used, there may be mentioned
hydrochloric acid, nitric acid, sulfuric acid, or phosphoric acid,
preferably hydrochloric acid.
[0053] As the solvent for the second reaction, ethyl acetate,
water, methylene chloride, or a mixture thereof may be used.
Preferably, ethyl acetate and water are used together.
[0054] The second reaction is adjusted to pH 4 to 8 with an acid at
0 to 40.degree. C. When the reaction temperature is less than
0.degree. C. or higher than 40.degree. C., there is a problem that
the production yield is lowered. Preferably it is adjusted to pH 6
to 8. When the pH is 8 or more, the magnesium salt is not
completely dissociated, and the production yield is lowered.
[0055] On the other hand, after the second reaction is completed, a
step of purifying the product can be included, if necessary.
[0056] (Step 4)
[0057] The step 4 is a step of preparing a pyrrole derivative from
a compound represented by the Chemical Formula 1-4, which is a step
of reacting a compound represented by the Chemical. Formula 1-4
with N,N-dimethylformamide dimethylacetal to prepare a compound
represented by the Chemical Formula 1-5.
[0058] Preferably, the molar ratio of the compound represented by
the Chemical Formula 1-4 to N,N-dimethylformamide dimethylacetal is
1:1 to 1:10, and more preferably 1:1 to 1:5.
[0059] Preferably, as a solvent for the reaction, toluene or xylene
may be used, and more preferably, toluene is used.
[0060] Preferably, the reaction is carried out at 20 to 70.degree.
C. When the reaction temperature is less than 20.degree. C., there
is a problem that the production yield is lowered. When the
reaction temperature exceeds 70.degree. C., the production yield
does not substantially increase.
[0061] Preferably, the reaction is carried out for 30 minutes to 12
hours. When the reaction time is less than 30 minutes, there is a
problem that the reaction does not proceed sufficiently and thus
the production yield is lowered. When the reaction time exceeds 12
hours, the production yield does not substantially increase.
[0062] On the other hand, since the compound represented by the
Chemical Formula 1-5, which is a product of the reaction, is
chemically unstable, it is preferable to continuously perform the
subsequent reaction of step 5 without further purification.
[0063] (Step 5)
[0064] The step 5 is a reaction of substituting a hydroxy group of
the compound represented by the Chemical Formula 1-5 with methoxy,
which is a step of reacting a compound represented by the Chemical
Formula 1-5 with dimethyl sulfate to prepare a compound represented
by the Chemical Formula 1-6.
[0065] Preferably, the molar ratio of the compound represented by
the Chemical Formula 1-5 to dimethyl sulfate is 10:1 to 1:10, more
preferably from 5:1 to 1:5, most preferably from 3:1 to 1:3.
[0066] Further, the reaction is preferably carried out in the
presence of a base. As the base, triethylamine, diisopropylamine,
diisopropylethylamine, potassium carbonate, potassium
hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate,
sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium
methylate, potassium butyrate, or cesium carbonate can be used, and
preferably, potassium carbonate is used. In addition, the reaction
can be carried out using methyl iodide in the presence of a base.
Preferably, the molar ratio of the compound represented by the
Chemical Formula 1-5 to the base is 1:1 to 1:5, and more preferably
1:1 to 1:3.
[0067] Preferably, as the solvent for the reaction, an alcohol
having 1 to 4 carbon atoms or a ketone having 3 to 6 carbon atoms
is used. More preferably, the solvent for the reaction is methanol,
ethanol, propanol, butanol, tert-butanol, acetone, methyl ethyl
ketone, or isobutyl ketone.
[0068] Preferably, the reaction is carried out at 20. to 60.degree.
C. When the reaction temperature is less than 20.degree. C., there
is a problem that the production yield is lowered. When the
reaction temperature exceeds 60.degree. C., a side reaction occurs,
which is not preferable.
[0069] Preferably, the reaction is carried out for 1 to 24 hours.
If the reaction time is less than 1 hour, there is a problem that
the reaction does not proceed sufficiently and thus the production
yield is lowered. When the reaction time exceeds 24 hours, a side
reaction occurs, which is not preferable.
[0070] On the other hand, after the reaction is completed, a step
of purifying the product may be included, if necessary.
[0071] (Step 6)
[0072] The step 6 is a step of removing a protecting group of the
compound represented by the Chemical Formula 1-6, which is a step
of reacting the compound represented by the Chemical Formula 1-6
with an acid to prepare a compound represented by the Chemical
Formula 1.
[0073] As the acid that can be used, there may be mentioned
trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric
acid, or phosphoric acid, preferably trifluoroacetic acid.
[0074] Preferably, the molar ratio of the compound represented by
the Chemical Formula 1-6 to the acid is 1:1 to 1:30, and more
preferably 1:5 to 1:20.
[0075] Preferably, as a solvent for the reaction, methylene
chloride, ethyl acetate, methanol, toluene, diethyl ether,
tetrahydrofuran, or water may be used, and preferably, methylene
chloride is used.
[0076] Preferably, the reaction is carried out at 10 to 40.degree.
C. If the reaction temperature is less than 10.degree. C., there is
a problem that the production yield is lowered. If the reaction
temperature exceeds 40.degree. C., a side reaction occurs, which is
not preferable.
[0077] Preferably, the reaction is carried out for 1 to 24 hours.
When the reaction time is less than 1 hour, there is a problem that
the reaction does not proceed sufficiently and thus the production
yield is lowered. When the reaction time exceeds 24 hours, the
production yield does not substantially increase.
[0078] On the other hand, after the reaction is completed, a step
of purifying the product may be included, if necessary.
Advantageous Effects
[0079] As described above, the preparation method according to the
present invention has advantages that the production cost can be
lowered by using inexpensive starting materials, a high-temperature
reaction is not required as a whole, inexpensive and non-explosive
reagents are used instead of (trimethylsilyl)diazomethane, and
further an intermediate of 4-methoxypyrrole derivatives can be
prepared as a whole at a high yield.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0080] Hereinafter, the present invention will be described in more
detail with reference to the following examples. However, the
following examples are for illustrative purposes only and are not
intended to limit the scope of the present invention thereto. On
the other hand, in the example and comparative example, the
compounds prepared in each step are used in the next steps, and
each step can produce more products than those described below for
the next step.
Example
##STR00004## ##STR00005##
[0082] (Step 1)
[0083] 35.8 g of ammonium chloride and 26.9 g of sodium cyanide
were added to a flask, and 716.0 mL of ammonium hydroxide (25 to
28%) was added and then stirred for 10 minutes. The mixture was
cooled to 0 to 5.degree. C., stirred for 10 minutes, then heated to
room temperature, and stirred for 15 minutes. After cooling to 0 to
5.degree. C., 100.0 g of the prepared 2,4-difluorobenzaldehyde
(Chemical Formula 1-1) and 770.0 mL of methanol-containing solution
was slowly added to another flask for 15 to 20 minutes. The
temperature was raised to room temperature, and the mixture was
stirred for 22 hours to complete the first reaction. After
concentration under reduced pressure at 50.degree. C., 983.0 mL of
acetic acid and 983.0 mL of conc.HCl were added, and refluxed at
100 to 105.degree. C. (internal temperature) for 5 hours to
complete the second reaction. It was concentrated under reduced
pressure at 75.degree. C., and the solvent was removed until a
solid was precipitated. After purified water was added, the
crystals were precipitated by stirring. The pH was adjusted to 6.5
using 5M-NaOH solution at internal temperature of 25.degree. C. or
less. Ethanol was added thereto and stirred at 10 to 15.degree. C.
for 1 hour. After filtration under reduced pressure, the filtrate
was washed with ethanol. The resulting solid was dried under
reduced pressure to obtain 78.4 g of the compound represented by
the Chemical Formula 1-2 (yield: 59.5%).
[0084] (Step 2)
[0085] 100.0 g of the compound represented by the Chemical Formula
1-2 prepared in step 1, 1.5 L of THF and 1.5 L of purified water
were added to a flask, and then stirred at room temperature for 10
minutes. The internal temperature was cooled to 0 to 5.degree. C.,
and 134.6 g of sodium hydrogencarbonate and 139.5 g of
di-tert-butyl dicarbonate were added thereto. The mixture was
stirred at an internal temperature of 20 to 30.degree. C. for 12
hours to complete the reaction, followed by concentration under
reduced pressure at 45.degree. C. After ethyl acetate was added,
the internal temperature was cooled to 10.degree. C. or lower. The
pH was adjusted to 2.5 using 6N--HCl. The organic layer was
separated, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure at 45.degree. C. to obtain 151.2 g of the
compound represented by the Chemical Formula 1-3 (yield:
98.5%).
[0086] .sup.1H-NMR (500 MHz, CDCl.sub.3): 8.13-8.14; (d, 1H),
7.37-7.42; (m, 1H), 6.82-6.89; (m, 2H), 5.46-5.47; (d, 1H), 1.23;
(s, 9H)
[0087] (Step 3)
[0088] 100.0 g of the compound represented by the Chemical. Formula
1-3 prepared in step 2, 61.9 g of carbonyldiimidazole and 1.0 L of
acetonitrile were added to a flask, and then stirred at room
temperature for 1 hour. 59.8 g of methyl potassium malonate, 36.4 g
of anhydrous magnesium chloride, 1.0 L of acetonitrile and 38.8 g
of triethylamine were added to another flask and then stirred at 20
to 30.degree. C. for 1 hour. The reactants of the two flasks were
mixed and refluxed at an external temperature of 80.degree. C. for
1 hour to complete the reaction. After cooling to room temperature,
purified water was added. After cooling the internal temperature to
5 to 10.degree. C., stirring was carried out for 1 hour. The
obtained solid was filtered under reduced pressure and washed with
purified water. Since the obtained crystal is a magnesium salt, the
following salt dissociation process was carried out.
[0089] The magnesium salt prepared above, 1.5 L of ethyl acetate
and 1.0 L of purified water were added to a flask and stirred for
10 minutes. The pH was adjusted to 7.0 using 6N--HCl. The organic
layer was extracted, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure at 45.degree. C. to prepare
97.3 g of the compound represented by the Chemical Formula 1-4
(yield: 81.4%).
[0090] .sup.1H-NMR (500 MHz, CDCl.sub.3): 7.26-7.30; (m, 1H),
6.85-6.92; (m, 2H), 5.83; (s, 1H), 5.64-5.65; (d, 1H), 3.67; (s,
3H), 3.38-3.52; (dd, 2H), 1.41; (s, 9H)
[0091] (Step 4)
[0092] 100.0 g of the compound represented by the Chemical Formula
1-4 prepared in step 3, and 2.0 L of toluene were added to a flask,
and then stirred at room temperature for 10 minutes. 104.1 g of
N,N-dimethylformamide dimethylacetal was added and stirred at
40.degree. C. for 4 hours to complete the reaction. After
concentration under reduced pressure at 45.degree. C., ethyl
acetate and purified water were added to the concentrated residue,
and then stirred for 10 minutes. The pH was adjusted to 7.0 using
1N--HCl. The organic layer was extracted, dried over anhydrous
magnesium sulfate, and then concentrated under reduced pressure at
45.degree. C. to produce 79.2 g of the compound represented by the
Chemical Formula 1-5 (yield: 77.0%). On the other hand, the
compound represented by the Chemical Formula 1-5 was unstable
(aerial oxidation occurred), the following step 5 was continuously
carried out by an in-situ process.
[0093] .sup.1H-NMR (500 MHz, CDCl.sub.3): 7.73 (s, 1H), 7.48; (s,
1H), 7.38-7.43; (q, 1H), 6.83-6.95; (tt, 2H), 3.90; (s, 3H), 1.39;
(s, 9H)
[0094] (Step 5)
[0095] 100.0 g of the compound represented by the Chemical Formula
1-5 prepared in step 4, and 1.5 L of acetone were added to a flask,
and then stirred at room temperature for 10 minutes. 78.2 g of
potassium carbonate, and 42.9 g of dimethyl sulfate were added
thereto, and then stirred at 40.degree. C. for 6 hours to complete
the reaction. After cooling to room temperature, purified water and
ethyl acetate were added and stirred for 10 minutes. The pH was
adjusted to 7.0 using 6N-HCl. The organic layer was extracted,
dried over anhydrous magnesium sulfate, and then concentrated under
reduced pressure at 45.degree. C. to obtain 90.6 g of the compound
represented by the Chemical Formula 1-6 (yield: 87.1%). Then, the
following step 6 was carried out by an in-situ process without
further purification.
[0096] .sup.1H-NMR (500 MHz, CDCl.sub.3): 7.87; (s, 1H), 7.31-7.36;
(q, 1H), 6.84-6.95; (tt, 2H), 3.86; (s, 3H), 3.68; (s, 311), 1.38;
(s, 91-1)
[0097] (Step 6)
[0098] 100.0 g of the compound represented by the Chemical Formula
1-6 prepared in step 5, and 500.0 mL of methylene chloride were
added to a flask, and then stirred at room temperature for 10
minutes. 310.4 g of trifluoroacetic acid was added and stirred at
room temperature for 6 hours to complete the reaction. After
cooling to 0 to 5.degree. C., purified water was slowly added at
15.degree. C. or lower. The pH was adjusted to 7.0 using a 50.0%
NaOH solution at 15.degree. C. or lower. Ethyl acetate was added
and stirred for 10 minutes. The organic layer was extracted and
dried over anhydrous magnesium sulfate. The celite washed with
ethyl acetate was placed on a filter, and the organic layer was
filtered under reduced pressure and then concentrated under reduced
pressure at 45.degree. C. Ethyl acetate was added to the
concentrated residue and suspended by stirring. n-Hexane was added
thereto, the internal temperature was cooled to 0 to 5.degree. C.,
and the mixture was stirred for 1 hour. The obtained solid was
filtered under reduced pressure. The filtrate was washed with
n-hexane, and then dried under reduced pressure to obtain 65.5 g of
the compound represented by the Chemical Formula 1 (yield:
90.0%).
[0099] .sup.1H-NMR (500 MHz, CDCl.sub.3): 8.78; (s, 1H), 8.12; (m,
1H), 7.30; (d, 1H), 6.95; (t, 1H), 6.88; (t, 1H), 3.87; (s, 3H),
3.85; (s, 3H)
Comparative Example
##STR00006##
[0101] The preparation method was carried out as follows in the
same manner as in steps 8-1 to 8-3 of Example 8 of Korean. Patent
No. 10-1613245.
[0102] (Step 1)
[0103] 2,4-Difluorophenylglycine (Chemical Formula 2-1, 150.0 g,
801.5 mmol), dimethyl 2-(methoxymethylene)malonate (Chemical
Formula 2-2, 126.9 g, 728.6 mmol), and sodium acetate (65.8 g,
801.5 mmol) were added to methanol (800.0 ml), and then refluxed at
60.degree. C. for 4 hours. The reaction mixture was cooled to room
temperature, and concentrated under reduced pressure to remove
about 70% of methanol, and then filtered. The resulting solid was
dried under reduced pressure to produce 190.0 g of the compound
represented by the Chemical Formula 2-3 (yield:
[0104] 79.2%).
[0105] .sup.1H-NMR (500 MHz, CDCl3): 8.02-7.99; (m, 1H), 7.45-7.40;
(m, 1H), 7.00-6.95; (m, 2H), 5.16; (s, 1H), 3.74; (s, 3H), 3.76;
(s, 3H)
[0106] (Step 2)
[0107] Acetic anhydride (1731.2 ml) and triethylamine (577.1 ml)
were added to the compound represented by the Chemical Formula 2-3
(190.0 g, 577.1 mmol) prepared in step 1. The reaction mixture was
refluxed at 140.degree. C. for 30 minutes and then cooled to
0.degree. C. To the reaction mixture, ice water (577.1 ml) was
added at 0.degree. C., stirred at room temperature for 1 hour and
then extracted with ethyl acetate. The obtained extract was dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The resulting compound was filtered using a
silica gel to remove a solid, and then concentrated under reduced
pressure to prepare the compound represented by the Chemical
Formula 2-4, which was then used in the following step 3.
[0108] (Step 3)
[0109] Tetrahydrofuran (140.0 ml) and water (120.0 ml) were added
to the resulting residue, cooled to 0.degree. C., followed by
addition of sodium hydroxide (46.17 g, 1154.2 mmol). The reaction
mixture was stirred at 0.degree. C. for 30 minutes, neutralized
using IN hydrochloric acid aqueous solution and then extracted with
ethyl acetate. The obtained extract was dried over anhydrous
magnesium sulfate, and then concentrated under reduced pressure.
The resulting residue was purified by silica gel column
chromatography (ethyl acetate: n-hexane =1:4 (v/v)) to produce 22.0
g of the compound represented by the Chemical Formula 2-5 (yield:
15.1%) (including steps 2 and 3).
[0110] .sup.1H-NMR (500 MHz, CDCl.sub.3): 8.80; (s, 1H), 8.17-8.12;
(m, 2H), 7.13; (d, 1H), 6.95; (t, 1H), 6.86-6.83; (m, 1H), 3.88;
(s, 3H)
[0111] (Step 4)
[0112] The compound represented by the Chemical Formula 2-5 (22.0
g, 86.9 mmol) prepared in step 3 was dissolved in tetrahydrofuran
(434.5 ml) and methanol (173.9 ml). (Trimethylsilyl)diazomethane
(2.0M diethyl ether solution, 173.8 ml) was added to the reaction
mixture and then stirred at room temperature for 48 hours. Water
was added to the reaction mixture, and extracted with ethyl
acetate. The obtained extract was dried over anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The
resulting residue was purified by silica gel column chromatography
(ethyl acetate: n-hexane=1:4 (v/v)) to produce 18.1 g of the
compound represented by the Chemical Formula 1 (yield: 75.3%).
[0113] .sup.1H-NMR (500 MHz, CDCl.sub.3): 8.78; (s, 1H), 8.12; (m,
1H), 7.30; (d, 1H), 6.95; (t, 1H), 6.88; (t, 1H), 3.87; (s, 3H),
3.85; (s, 3H)
Comparison of Examples and Comparative Examples
[0114] The yields of the preparation methods of the Example and
Comparative Example are shown in Table 1 below.
TABLE-US-00001 TABLE 1 Example Comparative Example Total yield
28.8% 9.0% Total yield from 2,4-ditluoroph- 48.4% 9.0% enylglycine
to Chemical Formula I
[0115] As shown Table 1, it was confirmed that the Example
according to the present invention could not only reduce the
production cost by using inexpensive aldehyde as a starting
material but also improve the yield by about 5.4 times as compared
with the Comparative Example.
[0116] In particular, both step 2 of Example according to the
present invention and step 1 of Comparative Example used
2,4-difluorophenylglycine as a starting material. Comparing the
methods for preparing the compound represented by the Chemical
Formula 1 from the above step, Example according to the present
invention showed a yield of about 50%, whereas Comparative Example
showed a yield of 9%, thereby confirming that the yield according
to the present invention was remarkably improved.
[0117] In addition, in Example according to the present invention,
the relatively low temperature was applied in the entire steps,
whereas in step 2 of Comparative Example, the reaction temperature
of about 140.degree. C. was applied. Thus, the preparation method
according to the present invention has an advantage that a
relatively low reaction temperature can be applied. Furthermore,
step 4 of Comparative Example used (trimethylsilyl)diazomethane
which is an explosive reaction material, whereas Example according
to the present invention has the advantage that such a reactant was
not used.
* * * * *