JPH0313234B2 - - Google Patents

Description

[Detailed description of the invention]

Field of use of the invention The present invention provides a novel dialkoxypyridine, which
Manufacturing methods, uses and medicines containing it
Regarding. The compounds according to the invention can be used in the pharmaceutical industry.
It is used as an intermediate and in the manufacture of drugs. technical level European Patent Application No. 0005129 states that gastric acid
Substituted pyridyl sulfides that may exhibit secretion-blocking properties
Nylbenzimidazole is mentioned. -Yo
-Rotupa Patent Application No. 0074341 has the ability to inhibit gastric acid secretion.
Some benzimidazole derivatives have been described for
ing. British Patent Application No. 2082580 states that gastric acid
Tricyclics that block secretion and prevent the development of
Imidazole derivatives have been described. By the way, surprisingly, I will explain the details below.
Dialkoxypyridines have an important unexpected
This property shows that compounds known to be advantageous due to this property are
It was discovered that it can be distinguished from objects. Description of the invention The object of the present invention is the general formula (In the ceremony R1 is completely or mostly due to fluorine
Substituted 1-3C-alkyl group or chloro
difluoromethyl group and R1′ is a hydrogen atom, halogen, trifluoromethyl
1-3C-alkyl group or -optionally
completely or mostly replaced by fluorine
-1-3C-alkoxy group or R1 and R1′ together and the oxygen source to which R1 binds
including children, sometimes fully or partially
1-2C-alkylene substituted by fluorine
Dioxy group or chlorotrifluoroethylene di
Oxy group, R3 is a 1-3C-alkoxy group, One of the groups R2 and R4 is 1-3C-alkoxy
group, the other is a hydrogen atom or 1-3C-alkyl
kill group, n represents the number 0 or 1. ) A novel dialkoxypyridine represented by
It is a salt of a compound. "1~3C-" and 1~ in the above and below
2C-” indicates the number of C- atoms from 1 to 3 and C-
It means 1 to 2 atoms. completely or mostly replaced by fluorine
Examples of the 1-3C-alkyl group include 1,1,
2-trifluoroethyl group, perfluoropropyl group
perfluoroethyl group, especially 1,1,2,
2-tetrafluoroethyl group, trifluoromethyl group
group, 2,2,2-trifluoroethyl group and di-
Mention may be made of the fluoromethyl group. Halogen in the sense of the present invention includes bromine, chlorine and
Especially fluorine. 1-3C-alkyl group is propyl group, isopropyl group
The pyru group, the ethyl group and especially the methyl group. In addition to the oxygen atom, the 1-3C-alkoxy group
It includes the above-mentioned 1-3C-alkyl groups. Especially preferred
The latter is a methoxy group. completely or mostly replaced by fluorine
The 1-3C-alkoxy group is an oxygen atom as well as
The above is completely or mostly due to fluorine.
1-3C-alkyl groups substituted with example
1,1,2,2-tetrafluoroethoxy-,
Trifluoromethoxy-,2,2,2-triflu
Examples include oroethoxy and difluoromethoxy groups.
can be done. In some cases, it may be completely or partially fluorine-based.
1-2C-alkylenedioxy group substituted with
For example, 1,1-difluoroethylenedio
xy group (-O-CF₂−CH₂-O-), 1, 1, 2,
2-tetrafluoroethylenedioxy group (-O-
C.F.₂−CF₂-O-), 1,1,2-trifluoroe
Tylendioxy group (-O-CF₂-CHF-O-) and
and especially difluoromethylenedioxy group (-O-
C.F.₂-O-) as a group with a substituent, and
No ethylenedioxy group or methylenedioxy group left
It can be mentioned as a substituted group. Compounds of the formula where n means the number 0 (sulfuryl)
As a salt for (d), preferably all of the acid
Take into account salting. In particular, the Galen medical method
Inorganic acids and organic acids commonly used in (Galenik)
Pharmaceutically compatible salts of acids (Pharmakologisch
vertra¨glichen Salze).
For example, if the compounds according to the invention are produced on an industrial scale,
Pharmaceutically incompatible salts that may initially form during
shall be carried out by methods known to those skilled in the art.
It is then converted into a pharmaceutically acceptable salt. child
For example, water-soluble and water-insoluble
Acid addition salts such as hydrochloride, hydrobromide, iodide
Hydrogenates, phosphates, nitrates, sulfates, acetates,
Citrate, Gluconate, Benbrozoate, Hybe
Hibenzat: 2-(4-hydroxybenzat)
zoyl)-benzoate), fendizoate
(Fendizoat;o-[(2'-hydroxy-4-biphenate
(nilyl) carbonyl]-benzoate), butyre
t, sulfosalicylate, maleate, lauray
malate, fumarate, succinate,
Urate, tartrate, Amsonat;
4,4'-diaminostilbene-2,2'-disulfo
Embonat: 4,4′-method
tyrene-bis-(3-hydroxy-2-naphthoate)
Metembonat, Ste.
Alate, tosylate, 2-hydroxy-3-na
Phthoate, 3-hydroxy-2-naphthoate
Or Mesilat is suitable. Compounds of the formula in which n means the number 1 (sulfokyl
As a salt for (Sid), preferably a basic salt
Salts, especially inorganic bases commonly used in galenic medicine
and pharmaceutically compatible salts with organic bases.
take into consideration. An example of a basic salt is sodium
salt, potassium salt, calcium salt or aluminum
Mug salt can be mentioned. In an embodiment (aspect a) of the present invention, R1′ is hydrogen.
where R1, R2, R3, R4 and n have the above meanings.
These are compounds with the formula and salts thereof. Another embodiment (aspect b) of the present invention is that R1 and
R1′ together and including the oxygen atom to which R1 is bonded
represents a 1-2C-alkylenedioxy group and
Compounds of formulas in which R2, R3, R4 and n have the above meanings
and its salt. Another embodiment (aspect c) of the invention is that R1 and
R1′ together and including the oxygen atom to which R1 is attached
completely or partially replaced by fluorine
represents a 1-2C-alkylenedioxy group.
Then, R2, R3, R4 and n have the above meanings.
compounds and their salts. In preferred compounds of embodiment a, R1 is 1, 1, 2,
2-tetrafluoroethyl, trifluoromethyl
2,2,2-trifluoroethyl, difluoro
chloromethyl or chlorodifluoromethyl,
R1′ represents hydrogen, R3 represents methoxy, and between R2 and R4,
one for methoxy and the other for hydrogen or methoxy.
A compound of the formula where n represents the number 0 or 1
and a salt of the compound. Particularly preferred compounds of embodiment a are those in which R1 is 1,1,
2,2-tetrafluoroethyl, trifluoromethane
methyl, 2,2,2-trifluoroethyl or di
Fluoromethyl, R1′ is hydrogen, R3 is methoxy
, one of R2 and R4 is methoxy, and the other is
1 is hydrogen or methyl, n is the number 0 or 1
Compounds of the formula shown and salts of the compounds. Preferred compounds of embodiment b are those in which R1 and R1' are the same.
and methylene including the oxygen atom to which R1 is bonded.
- or represents an ethylene-dioxy group, R3
is a methoxy group, and one of R2 and R4 is a methoxy group.
one is hydrogen or methyl, where n is a number
Compounds of the formula representing 0 or 1 and the compounds
It's salt. Particularly preferred compounds of embodiment b are those in which R1 and R1' are
methyl together and including the oxygen atom to which R1 is bonded.
Represents a dioxy group, R3 is methoxy, R2
and R4, one contains methoxy and the other contains water.
element or methyl, n represents the number 0 or 1
and salts thereof. Preferred compounds of embodiment c are such that R1 and R1' together
and difluoro including the oxygen atom to which R1 is bonded.
Methylenedioxy group or 1,1,2-triful
represents an oleethylenedioxy group, and R3 is methoxy
One of R2 and R4 is methoxy, the other is
One is hydrogen or methyl, n is the number 0 or 1
These are compounds of the formula and salts of the compounds. Particularly preferred compounds of embodiment c are those in which R1 and R1' are
together and including the oxygen atom to which R1 is bonded.
Represents a fluoromethylenedioxy group, and R3 is meth
One of R2 and R4 is also methoxy.
The other is hydrogen or methyl, where n is the number 0 or
A compound of formula 1 and a salt of the compound
Ru. Due to the tautomerism of the imidazole ring, benzoyl
The substitution at the 5-position of midazole is the same as the substitution at the 6-position.
Ru. Correspondingly, R1 and R1′ together and R1 connected
Substituted ethylenedioxy group including the oxygen atom that combines
In the compound representing [1,4]-dioxyno
[2,3-f]The 6th position of the benzimidazole moiety is
Same as 7th place. Other objects of the invention are R, R1', R2,
Dial of the formula where R3, R4 and n have the above meanings
This is a method for producing coxypyridine and its salt. The method is (a) Eq. Mercaptobenzimidazole and the formula
with a picoline derivative represented by or (b) Eq. Benzimidazole and the formula with mercaptopicoline indicated by or (c) Eq. o-phenylenediamine represented by the formula and a formic acid derivative represented by react and optionally then (a), (b) or
is the formula obtained by (c) 2-benzimidazolyl-2-pyri represented by
oxidizes dimethyl-sulfide and/or
to turn into salt, or (d) Equation Benzimidazole and the formula or a pyridine derivative represented by (e) Formula XI Sulfinyl derivatives of formula XII and the 2-picoline derivative represented by react and optionally then convert into a salt.
(where Y, Z, Z′ and Z″ are appropriate leaving groups)
, M is an alkali metal atom (Li, Na,
or K), and M′ represents the equivalent metal atom.
eagle and R1, R1', R2, R3, R4 and n are
(having the meaning of the following) Manufacturing steps (a), (b) and (c) are performed using sulfur fluoride according to the present invention.
Steps (d) and (e) lead to the oxidation of the compound.
yields sulfoxides according to the invention. Which leaving group Y, Z, Z' or Z'' is suitable?
Well-known for their expertise among those in the field of technology
ing. Suitable leaving groups Y include, for example, those to which the group is attached.
The reactive sulfinyl group together with the
This is a group that forms a phyric acid derivative. appropriate departure
As the group Y, for example, an alkoxy group, dialkylami
or an alkylmercapto group.
can. As an appropriate leaving group Z, Z' or Z''
a halogen atom, especially a chlorine atom, or (e.g.
esterification (with p-toluenesulfonic acid)
Listing the hydroxyl group activated by
Can be done. The equivalent metal atom M′ is, for example, an alkali
Metal (Li.Na or K) or halogen atom
(e.g. Br, Grignard reagent)
alkaline earth metals (e.g. Mg), or the above
Reacts with substitution reactions of metal-organic compounds such as metals.
Something else, possibly placed, that is known to
It is a metal atom that has been replaced. The reaction with and can be carried out in a known manner using suitable
rotonic or neutral solvents (e.g. methanol, ionic
Sopropanol, dimethyl sulfoxide, acetate
dimethylformamide or acetonitrile
It is carried out with or without the addition of water.
The reaction is carried out, for example, in the presence of a proton acceptor.
Ru. Alkali metal hydroxides such as
For example, sodium hydroxide, alkali metal carbonate
e.g. potassium carbonate, or tertiary amines e.g.
zine, triethylamine or ethyl diisopropylene
Pyramine is suitable. Proton reaction with two alternatives
It can also be done without receptors, in which case -
Depending on the type of starting compound - optionally acidification first
The salt can be separated in particularly pure form. anti
The response temperature can be between 0°C and 150°C,
in the presence of proton acceptors between 20°C and 80°C
temperature, and without the proton acceptor it would be 60°C.
Temperatures between 120°C – especially the boiling point of the solvent used
Elevating temperatures are preferred. Reaction time is 0.5 hours and 24 hours
It is between. In the reaction with and carried out in a known manner,
Similar reaction conditions were used for the reaction with and
Ru. The reaction with is preferably polar in some cases.
in the presence of a strong acid, e.g. hydrochloric acid, in a water-containing solvent.
This is done at the boiling temperature of the solvent used. Sulfide oxidation is a known method.
For the oxidation of hydrogen to sulfoxide,
carried out under conditions familiar to those in the field.
[For example, see J. Drabowicz and
M.Mikolajczyk, Organic preparations and
procedures int.14 (1-2), 45-89 (1982) and
is E.Block in S.Patai, The Chemistry of
Functional Groups, Supplement E.Part1, Chapter
pp. 539-608, John Wiley and Sons
(Interscience Publication), 1980]. oxidation
As an agent, oxidation of sulfide to sulfoxide
All reagents normally used for
Ipohalogenites, especially peroxy acids, e.g.
peroxyacetic acid, trifluoroperoxyacetic acid,
3,5-dinitroperoxybenzoic acid, peroxybenzoic acid
cimalic acid or preferably m-chloroperiodic acid
Take into account xybenzoic acid. The reaction temperature (depending on the reactivity and dilution of the oxidant)
) between -70℃ and the boiling temperature of the solvent used, but
Preferably it is between -50°C and +20°C. purposeful purpose
halogen, typically carried out at temperatures between 0°C and 30°C
or by hypohyaline halogenites (e.g. aqueous hypohyde
Oxidation with sodium chlorate solution) is also preferred.
I understood. Oxidation is purposefully analogized to an inert solvent.
aromatic or chlorinated hydrocarbons, e.g.
toluene, dichloromethane or chloro
in form, or also with esters such as ethyl acetate.
or in isopropyl acetate or in ether.
performed in dioxane with or without water.
be exposed. The reaction with is preferably carried out using enolate iodine.
It is also commonly used for the reaction of carbon with alkylating agents.
It is carried out in an inert solvent such as For example, aroma
Group solvents such as benzene or toluene may be mentioned.
I can do that. The reaction temperature is (of the alkali metal atom M)
and depending on the type of leaving group Z) is generally 0°C.
120℃, especially when the boiling temperature of the solvent used is
preferable. For example, [M is Li (lithium) and Z
is Cl (chlorine) and the reaction takes place in benzene.
] The boiling temperature of benzene (80℃)
preferred. Compound XI is a reaction between compound XII and a metal organic compound.
well known to those in the technical field for
can be reacted by known methods such as Starting compounds which can optionally also be used in salt form
Depending on the type of
The compound according to the invention is obtained in its original form.
or obtained in salt form. Additionally, it may contain or contain the desired acid or base.
the desired acid or base - possibly precisely calculated.
in a stoichiometric amount - then added to a suitable solvent, e.g.
chlorinated hydrocarbons such as methylene chloride or chloride.
Roform, low molecular weight aliphatic alcohol (ethano)
alcohol, isopropanol), ether (diisopropanol),
(lopyl ether), ketone (acetone) or water
salt by dissolving the free compound in
obtain. The salt can be removed by filtration, reprecipitation or precipitation or
Obtained by evaporation of the solvent. The resulting salt can be used, for example, as aqueous sodium bicarbonate.
or with dilute hydrochloric acid.
or by acidification.
and the compound is converted back into a salt.
be able to. Purify the above compound in this way
or pharmaceutically unacceptable salts
can be converted into pharmaceutically acceptable salts.
Wear. The sulfoxide according to the invention is an optically active compound
It is. Therefore, the present invention relates to optical antipodes and optical
It includes mixtures of enantiomers and racemates.
Optical enantiomers can be determined in a known manner (e.g. by
The production and resolution of astereomeric compounds
) can be separated. but optical
Enantiomers can also be obtained by asymmetric synthesis, such as optically active
Pure compound X or diastereomerically pure
By reacting pure compound XI with compound XII,
[For this,
K.K. Andersen, Tetrahedron Lett., 93 (1962)
(see ). The compounds according to the invention are preferably compound
and optionally then the resulting
Synthesized by oxidizing sulfide
Ru. Some of the compounds of the formula are known (German patent publication).
Application Publication No. 3132613) or a known model
Therefore, it can be manufactured in the same way. The compound is
For example, compounds can be dioxidized in the presence of alkali hydroxide.
React carbon sulfide or alkali-O-ethyl
by reacting with ludithiocarbonate
can get. The compound can be prepared according to the general formula described in the following reaction scheme A.
It can be synthesized according to the manufacturing method. Reaction formula A: Starting compounds A1-A3 can also be prepared by known methods.
is similar to this [e.g. J.Org.Chem,44,2097
~2910 (1979); J.Org.Chem.29, 1-11 (1964);
German Patent Application No. 2029556; Germany
Patent Application Publication No. 2848531; J.Fluorine
Chem.18, 281-91 (1981); Synthesis 1980, 727
~8] can be produced, in which case R1′ and R1−O
- isomer mixture in the case of substituents that are not the same as
can also occur. Compounds and XI are, for example,
Methods already known to those in the technical field
It can be manufactured in Compounds can be methylated, oxidized, etc.
and - e.g. alkali metal hydrides or
using alcoholates or ordinary metal-organic compounds.
- Produced by deprotonation. The compound is
Z. Talik, Roczniki Chem.35, 475 (1961).
Manufactured as a repository. The compounds are new and are the subject of the present invention.
Ru. The compounds can be prepared in different ways - depending on the type of substitution.
Can be manufactured with: 1 R2 and R3 are 1-3C-alkoxy
and R4 is hydrogen or 1-3C-alkyl
Compound. The compound can be prepared, for example, by known or known methods.
3-hydroxy- or 3-hydro which can be produced with
Starting from roxy-5-alkylpyridine,
(e.g. hydroxide in dimethyl sulfoxide)
of hydroxyl groups with lithium and benzyl chloride.
Benzylation, (e.g. with 30% hydrogen peroxide)
N-oxidation, nitro at position 4 (e.g. with mixed acids)
(e.g. reacted with alkali-alkoxides)
) nitro group and 1-3C-alco
exchange with xyl group, (e.g. palladium in acid medium)
reductive debenzylation (with hydrogen on charcoal) and
Simultaneous N-deoxygenation (e.g. alkaline forma
(by reacting with phosphorus solution) pyridine nitrogen
Introduction of the hydroxymethyl group to the o-position relative to the element
(e.g. 1-3C-a iodide in basic medium)
3-hydro) by alkylation with
Conversion of roxy group to 1-3C-alkoxy group and
(e.g. by reaction with thionyl chloride)
) produced by the introduction of a temporary group Z.
In a preferred alternative, the compound is known or
3-hydroxy-2-alk which can be produced by the method of
Kyl- or 3-hydroxy-2,5-dial
Starting from kyl-pyridine (e.g. dimethyridine)
Potassium hydroxide and iodine in Rusulfoxide
alkylation of hydroxy groups (by methyl chloride),
N-oxidation (e.g. with 30% hydrogen peroxide),
4-position nitration (e.g. with nitric acid), (e.g.
By reacting with alkali-alkoxide
) Interaction between a nitro group and a 1-3C-alkoxy group
(e.g. with hot acetic anhydride)
Conversion to dimethylpyridine, (e.g. dilute hydroxylation)
to the hydroxymethyl group (by sodium solution)
saponification and (e.g. reaction with thionyl chloride)
produced by the introduction of a temporary group Z′
will be built. 2 R3 and R4 are 1-3C-alkoxy
A compound in which R2 is hydrogen. The compound may be, for example, the known 5-hydroxy-2
- Starting from methylpyridine (e.g. dimethylpyridine)
Alkyl iodide and hydroxyl acid in Rusulfoxide
alkyl of hydroxy group (by potassium oxide)
oxidation, N-acid (e.g. with 30% hydrogen peroxide)
4-position nitration (e.g. with nitric acid), e.g.
For example, by reacting with an alkali-alkoxide.
) nitro group and 1-3C-alkoxy group
exchange of 2-acetic acid (e.g. with hot acetic anhydride)
Conversion to toxymethylpyridine, (e.g. dilute water
2-hydroxymethane (by sodium oxide solution)
Saponification to thyl groups (e.g. with thionyl chloride)
(by reaction) to introduce a temporary group Z′
It is manufactured by 3 R3 and R4 are 1-3C-alkoxy
and R2 is 1-3C-alkyl. The compound may be prepared, for example, in a known manner or in a known manner.
Manufacturable 2-methyl-3-alkyl-4-a
Lucoxypyridine (e.g. European patent application)
0080602), starting from (e.g. 30
% hydrogen peroxide), (e.g. with no
Hydroacetic acid and then sodium hydroxide solution
) Acetoxylation of the target 5th position and its next step
(e.g. iodine in dimethyl sulfoxide)
1-3C-alkyl uride and sodium hydroxide
alkylation of the 5-hydroxy group (by solution),
N-acid (e.g. with m-chloroperbenzoic acid)
(e.g. with hot acetic anhydride)
Conversion to dimethylpyridine, (e.g. dilute hydroxylation)
(by sodium solution) 2-hydroxymethyl
saponification to groups (e.g., reaction with thionyl chloride)
by introducing a temporary group Z′
Manufactured by What reaction conditions (temperature, reaction time, solvent, etc.)
Individually required for the production of compounds in the above synthetic route
Whether or not the
well known from knowledge. Individual representatives of compounds
The exact preparation of the material is described in the examples. other representatives
Quality manufacturing is carried out in a similar manner. Compounds, and XII starting from e.g.
methods known to those skilled in the art;
Manufactured in The present invention will be explained in more detail with reference to the above examples.
The invention is not limited to the examples only. name mentioned in example
Compounds of the formulas described above and salts of the compounds are
It is a preferred subject of the present invention. In the example, F stands for the melting point.
Zers stands for decomposition and Sdp stands for boiling point.
vinegar. example 1 2-[(4,5-dimethoxy-2-pyridyl)
Methylthio]-5-trifluoromethoxy-1H
-benzimidazole 40ml of ethanol and 1N sodium hydroxide solution
2-mercapto-5-trifluorome in 20 ml of solution
Solution of 1.64g of toxy-1H-benzimidazole
to, 2-chloromethyl-4,5-dimethoxypi
Add 1.57g of lysinium chloride and 2 hours at 20°C.
and then stirred for a further 1 h at 40°C and the ethanol
The oil was distilled off in a rotary evaporator (at 1kPa/40°C).
Then remove the colorless precipitate that precipitates with Nutsuchie.
Remove and wash with 1N sodium hydroxide solution and water.
and dry. 2.15g with melting point 92-93℃
(79% of theory) of the title compound is obtained. Similarly, 5-chlorodifluoromethoxy-2
-mercapto-1H-benzimidazole, 5
-difluoromethoxy-2-mercapto-1H
-benzimidazole, 5,6-bis(diflu
(olomethoxy)-2-mercapto-1H-benzo
imidazole, 5-difluoromethoxy-2-
Mercapto-6-methoxy-1H-benzimi
dazole and 5-difluoromethoxy-6-ph
Luolo-2-mercapto-1H-benzimida
Sol and 2-chloromethyl-4,5-dimethoxy
By reacting with cypyridinium chloride
Then, 5-chlorodifluoromethoxy-2-[(4,
5-dimethoxy-2-pyridyl)methylthio]
-1H-benzimidazole, 5-difluoromethoxy-2[(4,5-dimethoxy)
Toxy-2-pyridyl)methylthio]-1H-be
Nzimidazole (oil), 5,6-bis(difluoromethoxy)-2-
[(4,5-dimethoxy-2-pyridyl)methyl
[thio]-1H-benzimidazole, 5-difluoromethoxy-6-methoxy-2
-[(4,5-dimethoxy-2-pyridyl)methy
Lucio]-1H-benzimidazole (melting point 159
~160℃) and 5-difluoromethoxy-6-fluoro-2
-[(4,5-dimethoxy-2-pyridyl)methy
Lucio]-1H-benzimidazole is obtained. 2 2-[(4,5-dimethoxy-2-pyridyl)
Methylsulfinyl]-5-trifluorometho
xy-1H-benzimidazole 2-[4,5-dimethoxy] in 10 ml of methylene chloride
C-2-pyridyl)methylthio]-5-trif
Luolomethoxy-1H-benzimidazole
To a solution of 0.36 g m-chloride in methylene chloride at -50 °C
Drop 5.5ml of 0.2M solution of lorperoxybenzoic acid
Add and stir for an additional 30 minutes at the above temperature. 0.3ml
After adding triethylamine, cold reaction
Add the mixture to 10 ml of 5% sodium thiosulfate and 5%
Stir in a solution of 10 ml of % sodium carbonate;
After phase separation, extract three more times with 10 ml of methylene chloride.
The combined organic phases were diluted once with 5% sodium thiosulfate.
Wash with 5 ml of thorium solution, dry, and remove desiccant.
(magnesium sulfate) and concentrate. Residue
The residue was crystallized with diisopropyl ether and then
Reconcretion with methylene chloride/diisopropyl ether
crystallize Colorless solid with melting point 159-61℃ (decomposition)
0.27g (72% of theory) of the title compound as
can get. Similarly, the other sulfide of Example 1 is m-chlorper.
By oxidation with oxybenzoic acid, 5-chlorodifluoromethoxy-2-[(4,
5-dimethoxy-2-pyridyl)methylsulfur
[inyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(4,5-di
methoxy-2-pyridyl)methylsulfini
]-1H-benzimidazole [melting point 159℃
(Disassembly)〕, 5,6-bis(difluoromethoxy)-2-
[(4,5-dimethoxy-2-pyridyl)methyl
sulfinyl]-1H-benzimidazole, 5-difluoromethoxy-6-methoxy-2
-[(4,5-dimethoxy-2-pyridyl)methy
Rusulfinyl]-1H-benzimidazole and
Beauty 5-difluoromethoxy-6-fluoro-
2,2-[(4,5-dimethoxy-2-pyridi
) Methylsulfinyl]-1H-benzimida
Sol is obtained. 3 2-[(4,5-dimethoxy-2-pyridyl)
Methylthio]-5-(1,1,2,2-tetraph
(fluoroethoxy)-1H-benzimidazole Following the procedure described in Example 1, 2-mel
capto-5-(1,1,2,2-tetrafluoro
loethoxy)-1H-benzimidazole 1.07g
and 2-chloromethyl-4,5-dimethoxypyri
0.90g of zincium chloride in 15ml of ethanol
by adding 17 ml of 0.5N sodium hydroxide solution.
By reacting, 1.40 g of the title compound
is obtained as a yellow oil. Re-in petroleum ether
When crystallized, it is a colorless crystal with a melting point of 125-127℃.
The product is obtained in the form of Yield: 1.20g (theoretical amount)
72%). 4 2-[(4,5-dimethoxy-2-pyridyl)
Methylsulfinyl]-5-(1,1,2,2-
Tetrafluoroethoxy)-1H-benzimida
sol Following the procedure described in Example 2, 2-
[(4,5-dimethoxy-2-pyridol)methyl
Thio-5-(1,1,2,2-tetrafluoro
ethoxy)-1H-benzimidazole 0.76g
m-chloroperoxybenzene in 30 ml of methylene chloride
Oxidation with 19 ml of 0.1M solution of aromatic acid at −40°C
Solution of the product in methylene chloride after extraction by
is obtained. dried with magnesium sulfate
After that, remove the desiccant, concentrate, and dissolve the residue in methylene chloride.
crystallized from ethylene/diisopropyl ether
Ru. Colorless crystalline substance with a melting point of 160-162℃ (decomposition)
0.64 g (82% of theory) of the title compound was obtained in the form
It will be done. 5 2-[(4,5-dimethoxy-2-pyridyl)
Methylthio]-5-(2,2,2-trifluoro
ethoxy)-1H-benzimidazole 2-Mercapto-5-(2,2,2-trif
(fluoroethoxy)-1H-benzimidazole
1.0g to 15ml of ethanol and 1N sodium hydroxide
2-chloromethyl-
4,5-dimethoxypyridinium chloride
Add 0.90g and stir for 20 hours. Add 30ml of water
After that, extract with 30 ml of methylene chloride three times.
Then, add 0.1N sodium hydroxide to the methylene chloride phase once.
Wash the combined organic phases with a sulfuric acid mug solution.
After drying with nesium and removing the desiccant,
Concentrate completely. Amorphous solid residue with melting point of 55-57℃
1.51 g (94% of theory) of the title compound as residue
can get. 6 2-[(4,5-dimethoxy-2-pyridyl)
Methylsulfinyl]-5-(2,2,2-tri
Fluoroethoxy)-1H-benzimidazole 2-[(4,5-dimethoxy-2-pyridyl)
methylthio]-5-(2,2,2-trifluoro
ethoxy)-1H-benzimidazole (0.8 g)
15 ml of oxane and 2.5 ml of 1N sodium hydroxide solution
Dissolve in ml. 8% sodium hypochlorite in 2 hours
3ml of thorium solution and 1N sodium hydroxide solution
3.5 ml of the mixture at 0-5℃ with cooling.
Add dropwise. 5ml of 5% sodium thiosulfate solution
After adding, concentrate to dryness and pour the residue into water.
and adjust the pH to 7 with phosphate buffer. precipitation
The solid material was removed, dried, and treated with acetic acid ester.
Recrystallize from diisopropyl ether/diisopropyl ether. Melt
As a colorless crystal with a point of 142-143℃ (decomposition)
0.45 g (55% of theory) of the title compound was obtained.
Ru. 7 2-[(4,5-dimethoxy-3-methyl-2
-pyridyl)methylthio]-5-(1,1,2,
2-tetrafluoroethoxy)-1H-benzoy
midazole Following the procedure described in Example 1, 2-mel
capto-5-(1,1,2,2-tetrafluoro
loethoxy)-1H-benzimidazole 1.07g
and 2-chloromethyl-4,5-dimethoxy-3
-Methylpyridinium chloride 0.96g
0.5N sodium hydroxide solution in 12 ml of alcohol 17
By adding ml and reacting, the melting point
1.46 g (83% of theory) of the title compound at 127-128 °C
(colorless powder) is obtained. 8 2-[(4,5-dimethoxy-3-methyl-2
-pyridyl)methylsulfinyl]-5-(1,
1,2,2-tetrafluoroethoxy)-1H-
Benzimidazole Following the procedure described in Example 2, 2-
[(4,5-dimethoxy-3-methyl-2-pyri
zyl)methylthio]-5-(1,1,2,2-te
(trafluoroethoxy)-1H-benzimidazo
m-chlorpero in methylene chloride.
12 ml of a 0.2 M solution of xybenzoic acid at −40 °C and
By oxidizing with a reaction time of 1.5 hours,
0.8 g of pale yellow oil is obtained. Methylene chloride/
Recrystallize twice with diisopropyl ether
colorless crystals with a melting point of 125°C (decomposed)
0.30 g (34% of theory) of the title compound was obtained in the form of
It will be done. 9 5-difluoromethoxy-2-[(4,5-di
Methoxy-3-methyl-2-pyridyl)methyl
Thio]-1H-benzimidazole Following the procedure described in Example 1, 5-diphenyl
fluoromethoxy-2-mercapto-1H-ben
Zoimidazole 0.38g (2mMol) and 2-chloro
Methyl-4,5-dimethoxy-3-methylpyri
Zinium chloride 0.48g (2mMol) and ethano
Add 8.8 ml of 1N sodium hydroxide solution in 10 ml of water.
50℃ after 2 hours by adding and reacting.
and 0.64g (84% of theoretical amount) with a melting point of 100-102℃
The title compound (colorless crystalline powder) is obtained. 10 2-[(3,4-dimethoxy-2-pyridyl)
Methylthio]-5-(1,1,2,2-tetraph
(fluoroethoxy)-1H-benzimidazole 10ml ethanol, 10ml water and 2N sodium hydroxide
2-mercapto-5-(1,
1,2,2-tetrafluoroethoxy)-1H-
Solution of benzimidazole 0.46g (1.7mMol)
to, 2-chloromethyl-3,4-dimethoxy-
Added 0.38g (1.7mMol) of pyridinium chloride
After stirring at 20℃ for 1 hour, add 10ml of water again.
Add dropwise; then stir again for 4 hours at 20°C. Analysis
Take out the solid material and add 0.01N sodium hydroxide.
solution and then water until neutral.
and dry until it reaches a constant weight. Melting point is 98~
0.63g (theoretical amount) as colorless crystalline powder at 102℃
90%) of the title compound is obtained. Similarly, 5-difluoromethoxy-2-mer
capto-1H-benzimidazole and 5-di
Fluoromethoxy-6-methoxy-2-merca
pt-1H-benzimidazole and 2-chloro
Methyl-3,4-dimethoxypyridinium chloro
5-diflu
Oromethoxy-2-[(3,4-dimethoxy-2
-pyridyl)methylthio]-1H-benzimida
sol (melting point 104-108°C) and 5-difluoro
Methoxy-6-methoxy-2-[(3,4-dime
Toxy-2-pyridyl)methyl]-1H-benzo
Imidazole (melting point 137-138°C) is obtained. 11 2-[(4,5-dimethoxy-3-methyl-2
-pyridyl)methylthio]-5-trifluoro
Ethoxy-1H-benzimidazole Following the procedure described in Example 1, 2-mel
capto-5-trifluoromethoxy-1H-be
1.15g of ndzimidazole and 2-chloromethyl-
4,5-dimethoxy-3-methylpyridinium
1.20g of chloride in 20ml of isopropanol
Add 20.5ml of 0.5N sodium hydroxide solution and incubate.
1.40g (70% of the theoretical amount)
The title compound is obtained. diisopropyl ether
melted by recrystallization in petroleum/petroleum ether.
A product with a point of 94-97°C is obtained. Similarly, 2-mercapto-5-(2,2,2
-trifluoroethoxy)-1H-benzimida
sol, 5-chlorodifluoromethoxy-2-
Mercapto-1H-benzimidazole, 5,
6-bis(difluoromethoxy)-2-merca
pt-1H-benzimidazole, 5-diflu
Oromethoxy-2-mercapto-6-methoxy
-1H-benzimidazole and 5-difluoro
lomethoxy-6-fluoro-2-mercapto-
1H-benzimidazole and 2-chloromethyl
-4,5-dimethoxy-3-methyl-pyridiny
By reacting with umchloride, 2-[(4,5-dimethoxy-3-methyl-2
-pyridyl)methylthio]-5-(2,2,2-
trifluoroethoxy)-1H-benzimidazo
rule, 5-chlorodifluoromethoxy-2-[(4,
5-dimethoxy-3-methyl-2-pyridyl)
methylthio]-1H-benzimidazole, 5,6-bis(difluoromethoxy)-2-
[4,5-dimethoxy-3-methyl-2-pyri
methylthio]-1H-benzimidazole
le, 5-difluoromethoxy-6-methoxy-2
-[(4,5-dimethoxy-3-methyl-2-pi
lysyl)methylthio]-1H-benzimidazole
le and 5-difluoromethoxy-6-fluoro-2
-[(4,5-dimethoxy-3-methyl-2-pi
lysyl)methylthio]-1H-benzimidazole
le is obtained. 12 2-[(4,5-dimethoxy-3-methyl-2
-pyridyl)methylsulfinyl]-5-tri
Fluoromethoxy-1H-benzimidazole Following the procedure described in Example 2, 2-
[(4,5-dimethoxy-3-methyl-2-pyri
methylthio]-5-trifluoromethoxy
0.24 g of C-1H-benzimidazole was added to methyl chloride.
0.2M of m-chloroperoxybenzoic acid in
Oxidize and methylene chloride at −50 °C in 3.3 ml of solution.
Recrystallize with diisopropyl ether
0.19 g (76% of theory) of the title compound was obtained by
Obtained as a colorless powder;
Solution. Similarly, the sulfides of Examples 9 to 11 above were
by oxidation with loroperoxybenzoic acid.
hand, 2-[(4,5-dimethoxy-3-methyl-2
-pyridyl)methylsulfinyl]-5-(2,
2,2-trifluoroethoxy)-1H-benzo
imidazole, 5-chlorodifluoromethoxy-2-[(4,
5-dimethoxy-3-methyl-2-pyridyl)
Methylsulfinyl]-1H-benzimidazole
le, 5-difluoromethoxy-2-[(4,5-di
Methoxy-3-methyl-2-pyridyl)methyl
Sulfinyl]-1H-benzimidazole
Point 133-135℃ (decomposition)], 5,6-bis(difluoromethoxy)-2-
[(4,5-dimethoxy-3-methyl-2-pyri
methylsulfinyl]-1H-benzimi
Dazol, 5-difluoromethoxy-6-methoxy-2
-[(4,5-dimethoxy-3-methyl-2-pi
lysyl)methylsulfinyl]-1H-benzoy
midazole, 5-difluoromethoxy-6-fluoro-2
-[(4,5-dimethoxy-3-methyl-2-pi
lysyl)methylsulfinyl]-1H-benzoy
midazole, 2-[(3,4-dimethoxy-2-pyridyl)
Methylsulfinyl]-5-(1,1,2,2-
Tetrafluoroethoxy)-1H-benzimida
Sol [melting point 117-119℃ (decomposition)] and 5-difluoromethoxy-2-[(3,4-di
methoxy-2-pyridyl)methylsulfini
]-1H-benzimidazole [melting point 136℃
(Disassembly)〕 is obtained. 13 2,2-difluoro-6-[(4,5-dimeth
xy-3-methyl-2-pyridyl)methylthi
O]-5H-[1,3]-dioxolo[4,5-
f] Benzimidazole 10ml of ethanol and 1N sodium hydroxide solution
2,2-difluoro-5H-[1,3] in 10ml of solution
-Dioxolo[4,5-f]benzimidazole
2-Chloromethane into a solution of 0.92 g of Ru-6-thiol
Chyl-4,5-dimethoxy-3-methylpyridi
Add 0.96g of nium chloride. yellow reaction
Stir the mixture for 1 hour at 20°C and add 10ml of water again.
During addition, a colorless solid substance precipitates out, and further
Stir for 5 hours, filter, and add 1N sodium hydroxide.
Wash with solution and water and dry to constant weight.
Ru. Amorphous powder in methylene chloride/diisopropylene
Recrystallize with pill ether. Melting point is 160~61℃
1.5 g (93% of theory) in the form of colorless crystals of
The title compound is obtained. Similarly, 6,6,7-trifluoro-6,7
-dihydro-1H-[1,4]-dioxino[2,
3-f] benzimidazole-2-thiol, 6-chloro-6,7,7-trifluoro-
6,7-dihydro-1H-[1,4]-dioxy
[2,3-f]benzimidazole-2-thi
ol or 6,7-dihydro-1H-[1,
4]-Dioxyno[2,3-f]benzimida
Sol-2-thiol and 2-chloromethyl-
4,5-dimethoxy-3-methylpyridinium
By reacting with chloride, 6,6,7-trifluoro-6,7-dihyde
rho-2-[(4,5-dimethoxy-3-methyl-
2-pyridyl)methylthio]-1H-[1,4]-
Dioxyno[2,3-f]benzimidazole
le, 6-chloro-6,7,7-trifluoro-
6,7-dihydro-2-[(4,5-dimethoxy
-3-methyl-2-pyridyl)methylthio]-
1H-[1,4]-dioxino[2,3-f]be
nzoimidazole and 6,7-dihydro-2-[(4,5-dimethoxy)
C-3-methyl-2-pyridyl)methylthio]
-1H-[1,4]-dioxino[2,3-f]
Benzimidazole is obtained. 14 2,2-difluoro-6-[(4,5-dimeth
xy-3-methyl-2-pyridyl)methylsul
finyl]-5H-[1,3]-dioxolo[4,
5-f] Benzimidazole 2,2-difluoro- in 10 ml of methylene chloride
6-[(4,5-dimethoxy-3-methyl-2-
pyridyl)methylthio]-5H-[1,3]-dio
Xiso[4,5-f]benzimidazole
0.80 g of salt in a suspension cooled to −40°C in 10 minutes.
of m-chloroperoxybenzoic acid in methylene chloride
Add 21 ml of 0.1M solution dropwise. Stir for another 20 minutes,
At that time, the temperature was raised to -20℃, and the triethyl acetate
Add 0.5 ml of minol and in each case 5 ml of the reaction mixture.
% sodium thiosulfate and 5% sodium carbonate
Pour into 40 ml of solution of Rium. After separation of layers
Next, extract the aqueous phase twice with 20 ml of methylene chloride each time.
Remove; each of the combined organic phases contains 5 ml of thiochloride.
From solutions of sodium sulfate and sodium carbonate
Wash, dry and concentrate the mixture. Residue
The residue was dissolved in methylene chloride/diisopropyl ether.
recrystallize. 0.62g (75% of theory) of the title compound
Decomposition point: 189-90°C. Similarly, the other sulfides listed in Example 13 can be
by oxidation with loperoxybenzoic acid.
hand, 6,6,7-trifluoro-6,7-dihyde
rho-2-[(4,5-dimethoxy-3-methyl-
2-pyridyl)methylsulfinyl]-1H-
[1,4]-Dioxyno[2,3-f]benzoy
midazole, 6-chloro-6,7,7-trifluoro-
6,7-dihydro-2-[(4,5-dimethoxy
-3-methyl-2-pyridyl)methylsulfuryl
]-1H-[1,4]-dioxino[2,3-
f] benzimidazole and 6,7-dihydro-2-[(4,5-dimethoxy)
C-3-methyl-2-pyridyl)methylsulfur
[ynyl]-1H-[1,4]-dioxino[2,3
-f] Benzimidazole is obtained. 15 6-[(4,5-dimethoxy-2-pyridyl)
Methylthio-5H-[1,3]-dioxolo[4,
5-f]-benzimidazole 5H-[1,
3]-Dioxolo[4,5-f]-benzimida
0.85g of sol-6-thiol and 2-chloromethy
-4,5-dimethoxypyridinium chloride
0.98g and 1N water in 10ml ethanol and 10ml water
Add 8.5 ml of sodium oxide solution and react
and after 20 hours reaction time by
After concentrating the solvent under reduced pressure to a volume of 10 ml,
A colored solid substance is obtained. Salt the crude product
Dissolve in 30 ml of methylene chloride, add white clay (e.g.
Tonsil ), concentrate, diisopropyl
ether and crystallized out, now a pale yellow color.
Boil the solid material thoroughly in 5 ml of methanol. Melt
0.90g as a colorless solid substance with a point of 198-200℃
(60% of theory) of the title compound is obtained. 16 6-[(4,5-dimethoxy-2-pyridyl)
Methylsulfinyl]-5H-[1,3]-dioxy
Solo[4,5-f]benzimidazole Following the procedure described in Example 14, 6-[4,
5-dimethoxy-2-pyridyl)methylthio]
-5H-[1,3]-dioxolo-(4,5-f)
0.7g of benzimidazole to m-chloroperoxy
Oxidized with 23ml of 0.1M solution of cybenzoic acid
Therefore, after recrystallizing with diethyl ether,
0.27 g in the form of colorless crystals with a melting point of 199 °C (decomposition)
The title compound is obtained. 17 2,2-difluoro-6-[(3,4-dimeth
xy-2-pyridyl)methylthio]-5H-[1,
3]-Dioxolo-[4,5-f]benzimida
sol Following the procedure described in Example 13, 2,2-
Difluoro-5H-[1,3)-dioxolo[4,
5-f]-benzimidazole-6-thiol
0.69g (3mMol) and 2-chloromethyl-3,4
-Dimethoxypyridinium chloride 0.67g
(3mMol) is mixed with 10ml of ethanol and 10ml of water.
Add 3.3 ml of 2N sodium hydroxide solution in the mixture
10 hours reaction time by reacting with
Microcrystalline colorless powder with melting point 185-187℃ after
As a final product, 1.05g (92% of theory) of the title compound was obtained.
can get. Similarly, 5H-[1,3]-dioxolo[4,
5-f] benzimidazole-6-thiol and
2-chloromethyl-3,4-dimethoxypyridi
By reacting with nium chloride,
6-[(3,4-dimethoxy-2-pyridyl)methane
tilthio]-5H-[1,3]-dioxolo[4,
5-f] Benzimidazole (melting point 155-157
°C) is obtained. 18 6-[(4,5-dimethoxy-3-methyl-2
-pyridyl)methylthio]-5H-[1,3]-di
Oxolo-[4,5-f]benzimidazole 5H-[1,3]-dioxolo[4,5-f]
Benzimidazole-6-thiol 0.78g
(4mMol) in 2-chloromethyl-4,5-dimethyl
Toxy-3-methylpyridinium chloride
Isopropanol 30 with 0.95g (4mMol)
ml and heat to boiling under stirring. precipitated
Take the solid substance and combine with isopropanol
Stir thoroughly, take again, and dry until constant weight.
Let dry. Colorless solid with a melting point of 206°C (decomposed)
1.0g of the dihydrochloride of the title compound as a substance (theoretical)
59% of the amount) obtained. 19 2,2-difluoro-6-[(4,5-dimeth
xy-2-pyridyl)methylthio]-5H-[1,
3]-Dioxolo[4,5-f]benzimida
sol 2,2-diflu in 9 ml ethanol and 4 ml water
Oro-5H-[1,3]-dioxolo[4,5-
f] Benzimidazole-6-thiol 0.69g
and 2-chloromethyl-4,5-dimethoxypi
A solution of 0.67g of lysinium chloride heated to 50℃
6.3ml of 1N sodium hydroxide solution in 1 minute
Add dropwise. Cool the clear reaction mixture to 20 °C.
A colorless precipitate separates out after a short time. 5 more
Stir at 20℃ for an hour, suction off with Nutsuchie, 1N
Wash with sodium hydroxide solution and water to constant weight
Dry until dry. raw colored solid substance
Dissolve in 10ml of methylene chloride to remove insoluble components.
Separate, concentrate the liquid, and diisopropyl ether
crystallize by adding and cooling
Ru. 1.02g (90% of theory) with melting point 189-91℃
The title compound is obtained. Similarly, 6,6,7-trifluoro-6,7
-dihydro-1H-[1,4]-dioxino[2,
3-f] benzimidazole-2-thiol,
6-chloro-6,7,7-trifluoro-6,
7-dihydro-1H-[1,4]-dioxino
[2,3-f]benzimidazole-2-thio
or 6,7-dihydro-1H-[1,
4]-Dioxyno[2,3-f]benzimida
Sol-2-thiol and 2-chloromethyl-
4,5-dimethoxy-pyridinium chloride and
By reacting 6,6,7-trifluoro-6,7-dihyde
rho-2-[(4,5-dimethoxy-2-pyridi
) methylthio]-1H-[1,4]-dioxino
[2,3-f]benzimidazole, 6-chloro-6,7,7-trifluoro-
6,7-dihydro-2-[(4,5-dimethoxy
-2-pyridyl)methylthio]-1H-[1,4]
-Dioxyno[2,3-f]benzimidazole
and, 6,7-dihydro-2-[(4,5-dimethoxy)
C-2-pyridyl)methylthio]-1H-[1,
4]-Dioxyno[2,3-f]benzimida
Sol is obtained. 20 2,2-difluoro-6-[(4,5-dimeth
xy-2-pyridyl)methylsulfinyl]-
5H-[1,3]-dioxolo[4,5-f]be
Nzimidazole 2,2-difluoro-6-[(4,5-dimeth
C-2-pyridyl)methylthio]-5H-[1,
3]-Dioxolo[4,5-f]benzimida
Add 0.76g of Sol to 10ml of dioxane and 1N sodium hydroxide.
Dissolve in 2 ml of thorium solution. Ice cold
First, 1 mole of hydroxide per -1 equimolar amount
Sodium solution added - titrated hypochlorous acid
Add sodium aqueous solution and add 1 portion again after 1 hour.
amount and after 3 hours half the equimolar amount of hypochlorite
acid sodium such that a complete reaction is achieved
Added. After 4 hours reaction time 5% thio
5 ml of sodium sulfate solution and an additional 25 ml of dioxicate
Add dioxane and separate the upper dioxane phase.
Wash twice with 5 ml of sodium thiosulfate solution and wash twice with 5 ml of sodium thiosulfate solution.
Concentrate in a converter. Dissolve the oily residue in 20ml of water and
Dissolved in 10 ml of ethyl acetate and buffered to pH 6.8.
Adjust the pH to 7 with approximately 100ml of liquid. The precipitated solid substance
Aspirate with Nutsuchie, wash with water, and acetate at 0℃.
Stir thoroughly and dry. colorless
0.7 g (87% of theory) of the title compound in the form of crystals of
Decomposes at 211-213℃. Similarly, the other sulfides listed in Examples 17 to 19
by oxidation with sodium hypochlorite solution.
Tsute 2,2-difluoro-6-[(3,6-dimetho
xy-2-pyridyl)methylsulfinyl]-
5H-[1,3]-dioxolo-[4,5-f]-
Benzimidazole [melting point 177-178℃ (min.
solution)], 6-[(4,5-dimethoxy-3-methyl-2
-pyridyl)methylsulfinyl]-5H-[1,
3]-Dioxolo-[4,5-f]-benzimi
Dazol, 6,6,7-trifluoro-6,7-dihyde
rho-2-[(4,5-dimethoxy-2-pyridi
) methylsulfinyl]-1H-[1,4]-di
oxino[2,3-f]benzimidazole, 6-[(3,4-dimethoxy-2-pyridyl)
Methylsulfinyl]-5H-[1,3]-dioxy
Solo[4,5-f]benzimidazole [melting point
170-171℃ (decomposition)], 6-chloro-6,7,7-trifluoro-
6,7-dihydro-2-[(4,5-dimethoxy
-2-pyridyl)methylsulfinyl]-1H-
[1,4]-Dioxyno[2,3-f]benzoy
midazole and 6,7-dihydro-2-[(4,5-dimethoxy)
C-2-pyridyl)methylsulfinyl]-1H
-[1,4]-Dioxyno[2,3-f]benzo
imidazole is obtained. 21 2-Mercapto-5-(1,1,2,2-te
(trafluoroethoxy)-1H-benzimidazo
rule (a) 1-nitro-4-(1,1,2,2-tet
(fluoroethoxy)benzene 55g to ethano
0.5 g of 10% palladium on charcoal in 300 ml of water.
Atmospheric pressure and 20 to 45℃ for 1 hour using hydrogen conversion equipment.
Hydrogenate, separate the catalyst and reduce the solution at 40°C.
Concentrate under pressure. 4-(1,1,2,2-tet
(fluoroethoxy) aniline to glacial acetic acid 100
ml, add 23 ml of acetic anhydride dropwise at room temperature,
After 30 minutes, add 2 ml of water and after a short time add 50 ml of the solution.
Concentrate under reduced pressure at °C and add 500 ml of ice water. Melt
56 g (97%) of N-[4-
(1,1,2,2-tetrafluoroethoxy)
phenyl]acetamide is obtained. (b) 55g of the above compound in 380ml of dichloromethane
Dissolve in 55ml of 100% nitric acid for 10 minutes.
at room temperature and stirred for an additional 6 hours. next
Wash the organic solution with aqueous sodium carbonate solution and water.
dried with magnesium sulfate and concentrated.
Ru. (from cyclohexane) Melting point is 80-81℃
65g (100%) of N-[2-nitro-4-
(1,1,2,2-tetrafluoroethoxy)
phenyl]-acetamide is obtained. (c) Dissolve 63g of the above compound in 450ml of methanol.
Dissolve in 6M sodium hydroxide solution 106 at room temperature.
ml, cooled in an ice bath, and added 900 ml of water dropwise.
53g (98%) of 2-nitro
-4-(1,1,2,2-tetrafluoroe
Toxy)-precipitates aniline (melting point 85~
86℃). (d) 33 g of the above compound in isopropanol
Rotating hydrogen with 1g of 10% palladium on charcoal in 600ml
Hydrogenation is carried out at room temperature without pressurization in an addition device.
Aspirate catalyst and chloride in 4M ether
34 g (89
%) of 4-(1,1,2,2-tetrafluoro
loethoxy)-1,2-phenylenediamine
- Precipitate dihydrochloride. (e) Add 330 ml of ethanol and water to 33 g of the above compound.
60ml, 8.9g of sodium hydroxide and (isopropylene)
(recrystallized from panol) potassium-O-ethyl
Add 23g of ludithiocarbonate and leave for 15 hours.
Heat under running water and bring to a boil. Add 1.2 liters of ice water
E, adjust the pH to 13-14 with sodium hydroxide solution,
Clarify with activated carbon and precipitate with dilute hydrochloric acid to pH 3.5.
let (from isopropanol) melting point 316 ~
27 g (91%) of the title compound are obtained at 319°C. 22 2-Mercapto-5-trifluoromethoxy
-1H-benzimidazole Similar to Example 21(e), 4-trifluoromethoxy
-1,2-phenylenediamine-dihydrochloro
Lido (C.A.55, 23408d, 1961) and Kali
Um-O-ethylthiocarbonate and hydroxide
React with sodium solution in ethanol
Possibly 75% yield with melting point of 305-307°C
The title compound is obtained (from decomposition, toluene). 23 2-Mercapto-5-(2,2,2-trif
(fluoroethoxy)-1H-benzimidazole (a) 50 g of 1-(2,2,2-trifluoroethylene
Toxy)-4-nitrobenzene
(Synthesis 1980, p. 727) as in Example 21(a)
hydrogenated and acetylated. 50g (95g)
of N-[4-(2,2,2-trifluoroeth
xy)phenyl]acetamide (melting point 140~
141℃). (b) 42 g of the above compound together with 9.7 ml of 100% nitric acid.
Stir in 290 ml of glacial acetic acid for 18 hours at room temperature, then add water.
Precipitate with 47g (94%) of N-[2-nito
rho-4-(2,2,2-trifluoroethoxy
c) Phenyl]acetamide (melting point 117-118
°C]. (c) 47 g of the above compound was hydrogenated as in Example 21(c).
and 38.7 g (97%) of 2-nitro-4-(2,
2,2-trifluoroethoxy)-aniline
(melting point 84-85°C) is obtained. (d) 37 g of the above compound was hydrogenated as in Example 21(d).
41 g (94
%) of 4-(2,2,2-trifluoroethane)
xy)-1,2-phenylenediamine-dihy
Obtain Dolochloride. (e) Similar to Example 21(e), from 36 g of the above compound
30g (94%) of the title compound (melting point 288-290°C)
get. 24 5-chlorodifluoromethoxy-2-merca
-1H-benzimidazole (a) 10.0 g of N[4-(chlorodifluoromethochloride)
c) Phenyl]-acetamide (melting point 101~
103℃, 4-chlorodifluoromethoxyani
from phosphorus and acetic anhydride) and 100% nitric acid 12.3
ml in 80 ml of dichloromethane for 4 hours at 20°C.
Stir. Neutralize with potassium hydrogen carbonate aqueous solution,
The organic layer was concentrated and 11.4 g (96%) of N-(4-
Chlorodifluoromethoxy-2-nitrophe
)-acetamide (melting point 89-91℃) was obtained.
Ru. (b) The above compound in 200 ml of methanol at 5°C.
Sodium methylate in methanol to 10.5g
Add dropwise 8.6 ml of 30% solution of
Stir and add ice water to adjust the pH to 8.7g (97g).
%) of 4-chlorodifluoromethoxy-2-
Nitroaniline (melting point 40-42 °C) is obtained. (c) 8.5g of the above compound mixed with 0.8g of 10% palladium charcoal
Hydrogenation in 200ml of methanol without pressurization
Add concentrated hydrochloric acid, filter, concentrate, diiso
Stir with propyl ether. 8.5g
(97%) of 4-chlorodifluoromethoxy-
1,2-phenylenediamine-dihydrochloro
Get Lido. (d) From 8.5 g of the above compound, analogously to Example 21(e),
6.3g (72%) with melting point 268-270℃ (decomposition)
The title compound is obtained. 25 5-difluoromethoxy-2-mercapto-
1H-benzimidazole (a) 11.8 g of N-(4-difluoromethoxyphene)
Nyl)-acetamide [L.M. Jagupol'skii et al.
J.General Chemistry (USSR)39,190
(1969)] in 200 ml of dichloromethane.
Stir with 12.1 ml of acid for 1.5 hours at room temperature.
21(b), 13.3 g (92%) of N-[(4-di
Fluoromethoxy-2-nitro)phenyl]
- Acetamide (melting point 71-73°C) is obtained. (b) 4- from it in 96% yield as in Example 24b.
Difluoromethoxy-2-nitroaniline
(melting point 68-70°C). (c) 4-difluoride with 94% yield as in Example 24c.
Lomethoxy-1,2-phenylenediamine-di
Obtain hydrochloride. (d) Similar to Example 21e with a yield of 78% and a melting point of ~250
Title compound at 252℃ (from isopropanol)
get something 26 5,6-dis(difluoromethoxy)-2-
Mercapto-1H-benzimidazole (a) Bränzka in 500 ml of water and 400 ml of dioxane
100g of Tekin, 220g of sodium hydroxide and
50-55 into a solution of 60 g of sodium dithionate
Evaporate 275 g of chlorodifluoromethane at °C.
L.N. Sedova et al., Zh.
Org.Khim6, 568 (1970).
Ru. Distilled at 61-62℃/1.0-1.1kPa 1,
2-bis(difluoromethoxy)benzene and
Mixing with 2-difluoromethoxyphenol
obtained, and mixed it with cyclohexane/ethyl acetate.
Chromatography on silica gel (4:1)
Separate by roughy. (b) 1,2-bis(dichloromethane) in 150 ml of dichloromethane.
Fluoromethoxy)benzene 15g and 100%
A solution of 15 ml of nitric acid is stirred at room temperature for 7 hours.
Neutralize with potassium bicarbonate solution and separate the organic layer.
and cyclohexane/ethyl acetate (4:
1) Chromatography on silica gel
- to do. 1,2-bis(difluoromethoxy)
c)-4-nitrobenzene is obtained. Example 21a and
Similarly, this was hydrogenated, acetylated, and N
-[3,4-bis(difluoromethoxy)fluorocarbon
enyl] acetamide (melting point 81-83℃)
Ru. Similarly to Example 21, further N-[4,5-bisN
-[4,5-bis(difluoromethoxy)-2
-Nitrophenyl]acetamide (melting point 65~
67℃), N-[4,5-bis(difluorometho)
xy)-2-nitro]aniline (melting point 107~
109℃), 4,5-bis(difluoromethoxy)
c)-1,2-phenylenediamine-dihyde
Lochloride and melting point 285-287℃ (decomposition;
from sopropanol) to obtain the title compound. 27 5-difluoromethoxy-2-mercapto-
6-methoxy-1H-benzimidazole (a) Guayako in 300 ml of water and 300 ml of dioxane
in a solution of 55.5 g of chlorine and 130 g of sodium hydroxide.
Approximately 58 g of chlorodifluoromethane was introduced at 60℃ into
Enter. Filter the mixture at 10°C and separate the organic layer.
Remove, dry over anhydrous potassium carbonate, and distill
do. 56g (73%) with a boiling point of 75-76℃/0.9kPa
1-difluoromethoxy-2-methoxybe
get zen. (b) 47 g of the above compound in 230 ml dichloromethane.
100 in dichloromethane 90 ml at 0-5 °C to solution
Add dropwise a solution of 33.8 ml of % nitric acid, and add ice water after 30 minutes.
Add 250ml and neutralize with potassium bicarbonate.
Concentrate the dried organic phase under reduced pressure and sift the residue.
Recrystallize with chlorhexane. 53g (90%)
1-difluoromethoxy-2-methoxy-5
- Obtain nitrobenzene (melting point 48-49°C).
This was hydrogenated as in Example 21a and acetyl
become N-(3-difluoro
methoxy-4-methoxyphenyl)acetoa
Mido (melting point 129-130°C) is obtained. (c) Dichloromethane of 46 g of the above compound with 33 ml of 100% nitric acid.
Nitrate in the same manner as the above formulation in Rumethane.
Ru. N-(5-difluorometho) in 99% yield
xy-4-methoxy-2-nitrophenyl)
Acetamide (melting point 116-117°C) is obtained. (d) 54% of the above compound in 810 ml of methanol
Time 30% Methanolic Sodium Methyl
Stir with 44.8 ml of solution at room temperature. Decompression
Concentrate with water, add ice water and glacial acetic acid until pH 8,
5-difluoromethoxy-5- in 99% yield
Methoxy-2-nitroaniline (melting point 144~
145℃). (e) 25 g of the above compound in 300 ml of methanol
1.25 g of 10% palladium on charcoal in water according to Example 21d
Add element. Melting point is 218-220℃ (decomposition)
26g (88%) of 3-difluoromethoxy-4
-methoxy-1,2-phenylenediamine di
Obtain hydrochloride. (f) 25 g of the above compound and 19 g of potassium-O-
with ethyl dithiocarbonate according to Example 21e.
and react. Melting point: 280-282℃ (decomposition;
20g (89%) of title (from sopropanol)
Obtain the compound. 28 5-difluoromethoxy-6-fluoro-2
-Mercapto-1H-benzimidazole (a) 2-fluorophenol and
and chlorodifluoromethane to 1-difluoro
lomethoxy-2-fluorobenzene (boiling point 76
℃／10kpa；n²⁰ _D= 1.4340) is obtained. (b) 30 g of the above compound in 300 ml dichloromethane
Add 38.4 ml of 100% nitric acid dropwise at -10℃ to
Stir at −10° C. for 2.5 hours and at 0° C. for 2.5 hours.
Add ice water to neutralize, and add acetate/sic
on silica gel with lohexane (4:1)
Perform chromatography. Approximately 90% 1-diph
fluoromethoxy-2-fluoro-4-nitro
Benzene and 10% 1-difluoromethoxy
2-fluoro-5-nitrobenzene
(NMR-spectrum) 34 g of oil containing (NMR-spectrum) are obtained. (c) Hydrogenate 30 g of the above mixture as in Example 21a.
and acetylation. recrystallized with toluene
21 g (65%) of N-(4
-difluoromethoxy-3-fluorofueni
) Obtain acetamide. (d) 20 g of the above compound in 200 ml of dichloromethane.
22.5ml of 100% nitric acid at 20℃ for 30 minutes to
Add dropwise and stir at room temperature for 15 hours. Example 27c and
Similarly, the yield was 89% and the melting point was 72–74°C (60°C).
N-(4-difluoromethane) (from lohexane)
Toxy-5-fluoro-2-nitropheni
) Obtain acetamide. with 1M hydrochloric acid
Stir in methanol at 60℃ for several hours.
Therefore, with a yield of 95%, 4-
Difluoromethoxy-5-fluoro-2-di
Troaniline and 85% yield as in Example 27e
4-difluoromethoxy-5-fluoro-
1,2-phenylenediamine-dihydrochloro
Get Lido. Decomposes from 210℃. (e) 15 g of the above compound and potassium-O-ethyldi
thiocarbonate according to Example 21e.
let Melting point is 275-276℃ (decomposition, isopropyl
11.1 g (84%) of the title compound (from Nord)
obtain. 29 2,2-difluoro-5H-[1,3]-dio
Xiso[4,5-f]benzimidazole-6
-thiol (a) 4-amino-2,2-difluoro-5-di
Measuring 30g of tro-1,3-benzodioxole
10% Palladium Charcoal 0.5g in Tanol 300ml
Hydrogen at atmospheric pressure and room temperature in a rotating hydrogenation device
Add 2.5 equivalents of methanolic hydrogen chloride solution
Add the solution, filter, concentrate the solution under reduced pressure, and
Add sopropanol and ether until the melting point reaches
35g (97%) of 2,2 at 232-233℃ (decomposition)
-difluoro-1,3-benzodioxole
-4,5-diamine-dihydrochloride was obtained.
Ru. (b) 30 g of the above compound in 300 ml of ethanol with water
in 55 ml (recrystallized with isopropanol)
Potassium-O-ethyldithiocarbonate
Add 24g and 9.2g of sodium hydroxide, 15:00
Heat to boil under reflux for a while. 1.5 water
Pour into water and adjust to pH 14 with sodium hydroxide solution.
clarified with activated form and precipitated with concentrated hydrochloric acid when heated.
and aspirate the precipitate while cold. Melting point is 365 ~
24 g (91%) of the title compound at 370 °C (decomposition)
obtain. 30 6,6-7,trifluoro-6,7-dihyde
Lo-1H-[1,4]-dioxino[2,3-f]
Benzimidazole-2-thiol (a) 2,2,3-trifluoro-2,3-dihydrogen
Dro-1,4-benzodioxin 50g at 5℃
39.5ml of 69% nitric acid and 97% of nitric acid in one hour.
A mixture with 46 ml of sulfuric acid is added dropwise. 1 hour 10℃
Stir at 20°C for 1 hour and at 40°C for 5 minutes.
Pour over 200g of ice and dichloromethane.
Extract, wash with water and dry with magnesium sulfate
and distill under reduced pressure. Boiling point 68.5℃
(0.15mbar) and n²⁰ _D58g (94%) of 1.5080
2,2,3-trifluoro-2,3-di
Hydro-6-nitro- (and 7-nitro)-
A mixture of 1,4-benzodioxins is obtained.
10m fused silica column
Gas chroma by Sa¨ule) (Chrompack)
The totogram shows two peaks with a ratio of 2:3.
vinegar. (b) 35 g of the isomer mixture in 400 ml of ethanol
10% palladium on charcoal 3g at atmospheric pressure and 20
Hydrogenate in a rotating hydrogenation device at ~30℃ and reduce
Concentrate under pressure. 30.5g (100%) of 6-amino
No-(and 7-amino)-2,2,3-trif
fluoro-2,3-dihydro-1,4-benzo
A liquid mixture of dioxin is obtained. (c) 28 g of the above isomer mixture at 20-30°C
A mixture of 15.3 g of hydroacetic acid and 15 ml of glacial acetic acid
Add dropwise, stir at 30℃ for 30 minutes, and add 1ml of water.
Stir at 30 °C for 30 min and distill the solvent under reduced pressure.
Excluded by. By recrystallizing with toluene
isomer acetamino with a melting point of 128-133℃
19 g of a fraction of a mixture of derivatives are obtained. (d) acetic acid suspended in 200 ml of dichloromethane.
To 17 g of isomer mixture of toamino derivatives - 6
Dissolved in 60ml of dichloromethane at -8℃
Add 14 ml of 100% nitric acid dropwise and leave at zero for 2 hours.
°C and stir overnight at room temperature. 110g of ice
Drain, separate the organic phase, wash with water and reduce under reduced pressure.
Concentrate. Residue (19.8g) in 20ml of ethanol
recrystallize with 6-acetamino-2,2,
3-trifluoro-2,3-dihydro-7-
Nitro-1,4-benzodioxin and 7-a
Cetamino-2,2,3-trifluoro-
2,3-dihydro-6-nitro-1,4-be
Obtain 15.5 g of a mixture with nzodioxin. (e) 14.5 g of the above product mixture in methanol
Suspend in 80ml of 5M water while heating to 30℃.
Add 30 ml of sodium oxide solution dropwise. Furthermore
Stir at room temperature for 0.5 hours, pour over 200g of ice,
-amino-2,2,3-trifluoro-2,
3-dihydro-7-nitro-1,4-benzo
Dioxine and 7-amino-2,2,3-tri
Fluoro-2,3-dihydro-6-nitro-
11.7g mixture with 1,4-benzodioxin
get. Transfer the sample to cyclohexane/ethyl acetate
(4:1) by silica gel column.
On a 60MHz device with euterochloroform
NMR-spectrum is identical, melting point is
Two pure types: 110.5~111.5℃ and 120~121℃
Separates into isomers. (f) Add 10.9 g of the above isomer mixture to 300 g of methanol.
10% palladium at room temperature and atmospheric pressure in ml
Hydrogenate with 1g of charcoal in 2.5 hours. 30ml
Add 4M hydrogen chloride in methanol dropwise;
Filter, concentrate under reduced pressure, and add 100 ml of ether.
Stir. 12.6g (98%) of 2,2,3-t
Refluoro-2,3-dihydro-1,4-beta
Zodioxin-6,7-diamine dihydro
Chloride (melting point >250°C) is obtained. (g) 12g of the above compound and (in isopropanol)
recrystallized) potassium-O-ethyldithioca
8.5g of carbonate in 120ml of ethanol and 4M water
Mixed with 20.5ml of potassium oxide aqueous solution for 17 hours
Heat to boil under reflux. 300g ice
Then, adjust the pH to 12-13 with potassium hydroxide solution.
Clarify with activated carbon and precipitate with concentrated hydrochloric acid. Al
Reconstitution with acid from a caustic aqueous-alcoholic solution.
By precipitating and melting the melting point is 309-310.
Obtain 10 g (93 g) of the title compound at °C (decomposition).
Ru. 31 6-chloro-6,7,7-trifluoro-
6,7-dihydro-1H-[1,4]-dioxy
[2,3-f]benzimidazole-2-thi
oar (a) 2-chloro-2,3,3-trifluoro-
2,3-dihydro-1,4-benzodioxy
18.3 ml of 65% nitric acid and 97% sulfur at 5℃
Add dropwise the mixture with 15.4 ml of acid and leave for 2 hours at 5-10
Stir at °C and pour onto ice. Extraction with methylene chloride
2-chloro-2,3,3-trifluoro
rho-2,3-dihydro-6-nitro- (and
7-nitro)-1,4-benzodioxin
21.3 g of the mixture are obtained as an oil. (b) As in Example 30(b), then 2-
Chlor-2,3,3-trifluoro-2,3
-dihydro-1,4-benzodioxin-6
-obtain an oily mixture of (and 7-) amines;
This is the corresponding acetamin according to Example 30(c)
It can be quantitatively converted into a mixture of derivatives. (c) 19g of the above mixture and 190ml of dichloromethane
Stir and react with 16 ml of 100% nitric acid in
The product was dissolved in cyclohexane/ethyl acetate (4:
1) Chromatography on silica gel
- Purify by 6-acetamino-2
-chloro-2,3,3-trifluoro-6,
7-dihydro-7-nitro-1,4-benzo
Dioxine and 7-acetamino-2-chloro
-2,3,3-trifluoro-6,7-dihy
Dro-6-nitro-1,4-benzodioxy
Obtain 15 g of a mixture with chlorine as a pale yellow oil. (d) 5 to 14.5 g of the above mixture in 100 ml of methanol.
Sodium methylate in methanol at 30 °C
% solution dropwise and without cooling for 1.5 hours.
Stir, pour over ice, neutralize with dilute hydrochloric acid, and dilute
Extract with lormethane and concentrate under reduced pressure. 6-
Amino-2-chloro-2,3,3-triful
oro-2,3-dihydro-7-nitro-1,
4-benzodioxin and 7-amino-2-chloride
Rolo-2,3,3-trifluoro-2,3-
dihydro-6-nitro-1,4-benzodio
12.7 g of the mixture with Xin was obtained as an orange oil.
Ru. (e) 12.4 g of the above mixture was heated with hydrogen as in Example 30(f).
Added. 12.6g (99%) of 2-chloro-2,
3,3-trifluoro-2,3-dihydro-
1,4-benzodioxin-6,7-diami
-dihydrochloride is obtained. (f) 12.4 g of the above compound to 9.1 g as in Example 30(g)
of potassium-O-ethyldithicarbonate and
reaction in ethanol with potassium hydroxide solution
let 9.6g with a melting point of 288-290℃ (decomposed)
(74%) of the title compound is obtained. 32 2-chloromethyl-4,5-dimethoxy-pi
lysinium chloride (a) 2-chloromethyl-4,5-dimethoxy-
pyridinium chloride 2-Hydroxymethyl in 40 ml of methylene chloride
-5g of 4,5-dimethoxypyridine at 0℃
Add 10 ml of methylene chloride to the cooled solution for 1 hour.
Add dropwise 3 ml of thionyl chloride dissolved in
The reaction mixture was stirred for 4 hours at 20°C.
Color it red, add 5 ml of toluene, and rotary evaporate.
Concentrate completely in a generator (30℃/5mbar). oil
Dissolve the residue in 50 ml of hot isopropanol.
and add a small amount of Tonsil. ) clear
Strain, filter and concentrate again. toluene 10ml
crystallize the solution with petroleum ether.
Ru. After cooling in an ice bath, aspirate and add petroleum ether.
Wash with water and dry. 4.6g (70% of theoretical amount)
The title compound 2-chloromethyl-4,5-di
Methoxy-pyridinium chloride is a colorless solid.
Obtained as a solid substance; decomposes at 160-61°C. (b) 2-hydroxymethyl-4,5-dimethoxy
C-pyridine: 4,5-dimethoxy-2-methane
19g of tilpyridine-1-oxide for 30 minutes
Then, add 60 ml of acetic anhydride heated to 80℃ until the temperature is
Add so that the temperature does not rise above 100℃. Furthermore
Excess acetic anhydride is distilled off under reduced pressure at 85°C after 45 minutes.
to remove the intermediate 2-acetoxymethyl
- Consisting essentially of 4,5-dimethoxypyridine
Remove the oily, dark-colored residue from 2N sodium hydroxide.
Stir for 1 hour at 80°C with 80 ml of the solution.
After dilution with 80 ml of water and cooling, 8 times
Extract with 100ml each of methylene chloride and combine.
The organic phase was diluted twice with 1N sodium hydroxide solution.
Washed, dried, concentrated, crystalline cutlet color
The resulting residue is recrystallized from toluene. melting point
14 g (74% of theory) of 2-hydride at 122-24°C
Roxymethyl-4,5-dimethoxypyridine
get. (c) 4,5-dimethoxy-2-methylpyridine
-1-oxide: 5 in 170ml of dry methanol
-methoxy-2-methyl-4-nitropyridi
Add 30% sodium to a suspension of 16.9 g of carbon-1-oxide.
Add 20ml of thorium methylate solution dropwise at 15:00
Stir at 20°C for 4 hours and then at 50°C for 4 hours.
I carefully gave concentrated sulfuric acid while cooling on ice.
Bring the pH to 7, concentrate, and dissolve the residue in methylene chloride.
Mix thoroughly with 200ml to remove insoluble components.
Separate, add 10ml of toluene, and concentrate again.
Dry. 15.2g (98% of theory) of 4,5-
Dimethoxy-2-methylpyridin-1-oxy
Sid was obtained as colorless crystals with a melting point of 118-121℃.
Ru. (d) 5-methoxy-2-methyl-4-nitropy
Lysine-1-oxide 5-meth into 35 ml of 60% nitric acid heated to 60°C.
xy-2-methylpyridine-1-oxide
21.2g was added at a temperature of the reaction mixture that did not exceed 80℃.
Add as much as you like. Stir at 80℃ for 1 hour until completely dissolved.
Add another 13 ml of 100% nitric acid to react with
and further stirred at 60-70°C for 2 hours. rear
Pour over 300g ice for processing. precipitated
Remove the yellow precipitate with a Nutsuchie, wash with water,
dry. The dry solid material is dissolved in methylene chloride.
Boil thoroughly with 200ml of water, strain, and dry.
Let dry. Concentrate the liquid and add additional thin layer chromatography.
Isolate the pure product matoographically.
22.3g (87% of theory) with melting point 201-202℃
5-methoxy-2-methyl-4-nitropyri
Obtain gin-1-oxide; yellow crystals (e) 5-methoxy-2-methylpyridine-1-
Oxide: 5-methoxy-2 in 300ml of glacial acetic acid
-To a solution of 60.9 g of methylpyridine at 60°C 30%
Add 120g of hydrogen peroxide solution dropwise over 1 hour,
Stir for 3 hours. The activity is increased by adding manganese dioxide.
to decompose excess percompound, and then
The residue was heated in 500 ml of ethyl acetate.
Clear, reconcentrate and distill at 0.3 mbar.
Ru. 54g (77% of theory) of 5-methoxy-
2-methylpyridine-1-oxide quickly
Obtained as a solidifying oil (boiling point 130°C); melting point
80-84℃. (f) 5-methoxy-2-methylpyridinemethano
in 400 ml of alcohol and 500 ml of dimethyl sulfoxide.
To a solution of 84g of potassium hydroxide in 1 hour,
Add 150ml of droxy-6-methylpyridine
Ru. After removing methanol with a rotary evaporator, ice
While cooling, add 100ml of dimethyl sulfoxide.
Add 213g of dissolved methyl iodide dropwise,
Stir at 20 °C for an hour and steam distill the reaction mixture.
do. The distillate is continuously extracted with methylene chloride in an extractor.
The extract is concentrated. 85g
(56% of theory) of 5-methoxy-2-methylene
Lupyridine is obtained as a colorless oil. 33 2-chloromethyl-4,5-dimethoxy-3
-Methylpyridinium chloride (a) 2-chloromethyl-4,5-dimethoxy-
3-methylpyridinium chloride Following the procedure described in Example 32(a), 2-
Hydroxymethyl-4,5-dimethoxy-3
-2.7g of methylpyridine and 4g of thionyl chloride
By reacting in 25 ml of methylene chloride.
After a reaction time of 1 hour, a simplified work-up
chloride by adding 10ml of toluene.
Remove methylene and excess thionyl chloride by distillation.
Then, suck out the precipitated crystals and dry them.
Possibly 3.45g (99% of theoretical amount)
Obtain the compound as colorless crystals; 125-26°C
Decomposed with. (b) 2-hydroxymethyl-4,5-dimethoxy
C-3-methylpyridine 4,5-dimethoxy-2,3-dimethylpi
4.5 g of lysine-1-oxide and 20 g of acetic anhydride
Heat to 110 °C for 30 min in ml and then rotary evaporate
Concentrate in a container. Intermediate 2-acetoxymethy
-4,5-dimethoxy-3-methylpyridi
The oily residue consisting of 3N sodium hydroxide
Stir in 30 ml of solution at 80°C for 2 hours, then cool to 50°C.
Extract with 30 ml of methylene chloride and combine.
The organic phase was diluted twice with 2N sodium hydroxide solution.
Wash, dry, concentrate and remove the residue from petroleum ether.
Stir to mix, vacuum, and dry.
Ru. 4.0g (89% of theory) with a melting point of 91-92℃
2-hydroxymethyl-4,5-dimethoxy
C-3-methylpyridine is obtained. (c) 4,5-dimethoxy-2,3-dimethylpi
Lysine-1-oxide: 4,5-dimethoxy
-6.3g of 2,3-dimethylpyridine was added to methoxychloride.
20 g of m-
Add chlorperoxybenzoic acid, first at 2 o'clock.
Stir at 20°C for 4 hours and then at 40°C for 4 hours.
After adding 20ml of 5N sodium hydroxide solution,
three times 5% sodium thiosulfate and 5%
Wash with a mixture consisting of sodium carbonate-solution.
Then, the aqueous phase was re-extracted twice with methylene chloride and
The combined organic layers were dried with magnesium sulfate.
and concentrate. 4.6g (66% of theoretical amount) 4,
5-dimethoxy-2,3-dimethylpyridine
-1-oxide is obtained. Methylene chloride/meth
R at Nord 19:1_f− value will be 0.25. (d) 4,5-dimethoxy-2,3-dimethylpi
lysine Following the procedure described in Example 32(f), 5-
Hydroxy-4-methoxy-2,3-dimethy
9.18 g of lupyridine to 50 g of dimethyl sulfoxide
ml of sodium hydroxide and then iodine.
By reacting with 8.95g of methyl uride
7.4 g (74% of theory) of 4,5-dimethoxy
-2,3-dimethylpyridine as a colorless powder
Obtained as an oil that crystallizes; mp 36-38°C. (e) 5-hydroxy-4-methoxy-2,3-
Dimethylpyridine: 4-methoxy-2,3-
1000g of dimethylpyridine-1-oxide
Acetic anhydride 3 in 7 hours with stirring at 100℃
and further stirred at 100°C for 3 hours. cooling
completely concentrated at 70°C/10 mbar, then
10−²Distill at mbar. Boiling zone of 95-145℃
The fraction between (intermediate 5-acetoxy
-4-methoxy-2,3-dimethylpyridine
and 2-acetoxymethyl-4-methoxy-3
- methylpyridine) is taken.
(952g), 2N sodium hydroxide heated to 50℃
Add to the solution 3.5 for 30 minutes. 50°C until a clear solution forms (approximately 3 hours)
Stir with water, cool, and add chloride solution three times.
Extract with tyrene. Combine the organic phases twice
Again with 0.5 increments of 1N sodium hydroxide solution
extract and then add the combined aqueous phases to a semi-concentrated
Adjust the pH to 7.5 with concentrated hydrochloric acid while stirring.
Remove the precipitated solid substance, wash it, and make it constant weight.
Dry until dry. 5- with a melting point of 274-76℃
Hydroxy-4-methoxy-2,3-dimethy
Obtain Lupyridine. 34 2-chloromethyl-3,4-dimethoxy-pi
lysinium chloride (a) 2-chloromethyl-3,4-dimethoxy-
Pyridinium chloride: the procedure described in Example 32a.
2-Hydroxymethyl-
3.38g of 3,4-dimethoxypyridine and nitrogen chloride
2 ml of onyl in 30 ml of methylene chloride.
After a reaction time of 2.5 hours by letting
By the post-processing method described in Example 33a, 4.2 g
93% of the theoretical amount of the title compound with a melting point of 151-152
Obtained as a colorless solid substance at °C (decomposition). (b) 2-hydroxymethyl-3,4-dimethoxy
Cypyridine 2-acetoxymethyl-3,4-dimethoxy
4.8g of cypyridine was dissolved in 2N sodium hydroxide.
After adding 15ml of liquid, stir vigorously at 80℃.
from the initial two-phase mixture to a homogeneous solution.
A liquid is produced. After 2 hours, cool and add 30ml five times.
Extracted with methylene chloride and combined organic
Phase twice with 5 ml of 0.3N sodium hydroxide.
solution, dry with potassium carbonate, filter
, concentrate and stir the distillation residue with petroleum ether.
and mix. 3.6g (96% of theory) of 2-hybrid
Droxymethyl-3,4-dimethoxypyridi
as a colorless solid substance with a melting point of 87-89℃.
obtain. (c) 2-acetoxymethyl-3,4-dimethoxy
Cypyridine: in 25 ml of acetic anhydride at 85°C for 1 hour
3,4-dimethoxy-2-methylpyridine-
Add 4.8g (28mMol) of 1-oxide and leave for 1 hour.
Stir at the same temperature for a while, concentrate completely under reduced pressure,
Tube distillation equipment with colored oily residue
(Kugelrohrdestille) at 1 Pa.
5.3g (90% of theory) of 2-acetoxymethylene
Obtain 3,4-dimethoxypyridine;
Point 125-130℃. (d) 3,4-dimethoxy-2-methylpyridine
-1-oxide 3-methoxy-2-methyl-4-nitropi
Dry 4.5g (25mMol) of lysine-1-oxide.
30% sodium solution in 75 ml of dry methanol.
40℃ for 16 hours after adding 4.7ml of tyrate solution
Stir with Then cool and bring to pH 7 with concentrated acid.
filter, concentrate completely in vacuo, and leave an oily red
Place the colored residue in 50ml of toluene and re-incubate.
Separate the insoluble components and concentrate the liquid to dryness.
do. A yellow oily residue crystallizes in an ice bath;
Add this with 30ml of petroleum ether (50/
70) Stir thoroughly at 40℃. take and desiccate
Pale yellow with a melting point of 111-113℃ when dried in a
5.2g (88% of theory) 3, in the form of colored crystals
4-dimethoxy-2-methylpyridine-1-
Get oxide. (e) 3-methoxy-2-methyl-4-nitropy
Lysine-1-oxide: 3- in 12 ml of glacial acetic acid
Methoxy-2-methylpyridin-1-oxy
Add 8 ml of concentrated nitric acid to 2 ml of 5.4 g of nitric acid at 80℃ for 6 hours.
Add in four parts and stir overnight at the same temperature.
Then, add 8 ml of nitric acid again in three parts over 6 hours.
Then, stir for another 15 hours. After cooling, ice
(40g) and 10N sodium hydroxide solution.
to pH 6, and the precipitated by-product (3-methoxy
(2-methyl-4-nitropyridine)
Separate and extract four times with 50 ml of methylene chloride.
After drying, the combined organic phases are completely concentrated and the remaining
Reconstitute the residue with a small amount of methylene chloride/petroleum ether.
crystallize. 4.2g (57% of theory) of the title compound
obtained in the form of yellow crystals with a melting point of 103-104°C.
Ru. (f) 3-methoxy-2-methylpyridine-1-
oxide 3-methoxy-2-methylpyridine 15.3g
(0.124Mol) in 100ml of glacial acetic acid, 80
Divide 40ml of 30% hydrogen peroxide into 4 parts at ℃
Add in time. Stir for an additional 3 hours, then reduce pressure
(1.5kPa) and add twice 50ml of acetic acid.
Add and concentrate completely in each case. hypercompound
Ball tube furnace after no longer detected
(Kugelrohrofen). 120℃
(1.5Pa)
Thoroughly stir the solid material in ethyl ether.
Remove and dry. 12g (60% of theoretical amount)
3-methoxy-2-methylpyridine-1-
Oxide in the form of colorless crystals with a melting point of 72-78℃
Get it. (g) 3-methoxy-2-methylpyridine Following the procedure described in Example 32f, 3-
Hydroxy-2-methylpyridine 13.7g
(125mMol) and 9.2ml of methyl iodide in 3M
Add 46ml of methanolic potassium hydroxide solution
3 hours reaction time
followed by 15.5 g (90% of theory) of 3-methoxy
-2-Methylpyridine was obtained as a colorless oil.
Ru. Industrial utility Dialkoxypyridine represented by the general formula and its
salts have a value that makes them industrially usable.
Possesses valuable pharmacological properties. they are warm-blooded animals
Significantly suppresses gastric acid secretion and furthermore, significantly suppresses gastric acid secretion.
Shows enteroprotective effects in warm-blooded animals. This gastrointestinal protective effect
is no longer observed with doses below the acid secretion inhibitory dose.
Ru. Furthermore, the compounds according to the invention have virtually no side effects.
It is outstanding because it has no cancer and a wide range of treatments.
There is. In this context, “gastrointestinal protection” refers to e.g.
Microorganisms, bacterial toxins, drugs (e.g. certain anti-inflammatory drugs)
and rheumatology drugs), chemicals (e.g. ethanol
), caused by stomach acid or stress conditions.
Gastrointestinal diseases, especially inflammatory diseases and injuries of the gastrointestinal tract
Wounds (e.g. gastric ulcer, duodenal ulcer, stomach
Treatment and treatment of an irritated stomach caused by inflammation, hyperacidity, or drugs.
This refers to the treatment of Another advantage of the compounds according to the invention is their chemical stability.
The nature of this is relatively large. The compounds according to the invention are surprising due to their excellent properties
Preferably, compounds known from the state of the art
I can see that it is significantly better than anything else. child
Dialkoxypyridine and its drugs by the properties of
Scientifically acceptable salts are used in human and veterinary medicines.
suitable for use in drugs, where they are particularly suitable for use in gastrointestinal
disease and due to increased gastric acid secretion
used for the treatment and/or prevention of such diseases.
It will be done. Therefore, another object of the present invention is to treat the above-mentioned diseases.
This invention for use in the treatment and/or prevention of
It is a compound according to Akira. In exactly the same way, the present invention also relates to the treatment of said diseases and/or
according to the present invention in the manufacture of drugs used for prophylaxis.
This includes the use of compounds that A further object of the invention is one or more of the following:
There are also many dialkoxypyridines and
and/or a pharmaceutically acceptable salt thereof.
It's a drug. This drug has been approved by a person known in the art.
Manufactured by well known methods. as a drug
Pharmacologically active compounds (=active ingredients) according to the invention
) may be used as is or preferably combined with suitable auxiliaries.
In addition, tablets, sugar-coated tablets, capsules, suppositories, etc.
drugs (e.g. as TTS), emulsions, suspensions or solutions
It is used in liquid form and the content of active ingredients is particularly favorable.
or between 0.1% and 95%. Which auxiliary agents are suitable for the desired formulation depends on the skill in question.
well-known by those in the field based on their specialized knowledge;
ing. Solvents, gelling agents, suppository bases, tablet aids
In addition to the carrier materials and other active ingredients, e.g.
Antioxidants, dispersants, emulsifiers, antifoaming agents, taste correction
agents, preservatives, solubility aids, or especially penetration enhancers
and complex-forming substances (e.g. cyclodextrin)
) can be used. The active ingredient can be used orally, parenterally or transdermally.
I can be there. Generally, one or more active ingredients are administered orally.
Approximately 0.001 to approximately 20, especially 0.05 per kg of body weight
to 5 mg, especially in daily doses of 0.1 to 1.5 mg, if
to achieve the desired result in several doses, especially 1 to 4 doses.
It is said that it is advantageous to administer medication to obtain the desired results.
was found in human drugs. Place of parenteral treatment
If the active ingredient is administered intravenously or
(if prescribed) generally use lower dosages
be able to. Optimization of the active ingredients required in each case
Determination of appropriate dosage and administration method is a matter of expertise for each specialist.
It can be done easily based on knowledge. The compounds and/or salts according to the invention may be used to treat the aforementioned diseases.
If it is to be used therapeutically, the preparation may be used in combination with other drugs.
e.g. antacids e.g. aluminum hydroxide, aluminium
Magnesium acid; tranquilizer e.g. benzo
Diazepines e.g. diazebam; antispasmodics e.g. pie
Tamiperine, camilofin; anticholinergic drug example
Fuencycrimine, Fuencarbami
local anesthetics such as tetracaine, procaine;
optionally further enzymes, vitamins or amino acids.
one or more pharmacologically active acids
It can also contain ingredients. In this connection, in particular, the compounds according to the invention and other
Acid secretion inhibitors such as H₂- blocking agents (e.g.
tidine, ranitidine), and even so-called peripheral
anticholinergic drugs (e.g. pirenzepine, terenze)
pine, zolenzepine) and gastrin antagonism
Combinations with substances with additive or synergistic main effects
intensify in a sense and/or eliminate side effects or
It can be mentioned with the intention of reducing it. pharmacology Significant gastroprotective action and gastroprotection of the compounds according to the invention
The secretion suppressing effect was confirmed in animal experiments using the model shay rat.
It can be proven using Te. Compounds tested
Number the objects as follows:Serial number Compound name 1 2-[(4,5-dimethoxy-2-pyridyl)
Methylsulfinyl]-5-trifluorometho
xy-1H-benzimidazole 2 2-[(4,5-dimethoxy-3-methyl-2
-pyridyl)methylsulfinyl]-5-tri
Fluoromethoxy-1H-benzimidazole 3 2-[(4,5-dimethoxy-2-pyridyl)
Methylsulfinyl]-5-(1,1,2,2-
Tetrafluoroethoxy)-1H-benzimida
sol 4 2,2-difluoro-6-[(4,5-dimeth
xy-2-pyridyl)methylthio]-5H-[1,
3]-Dioxolo[4,5-f]benzimida
sol 5 2,2-difluoro-6-[(4,5-dimeth)
xy-2-pyridyl)methylsulfinyl]-
5H-[1,3]-dioxolo[4,5-f]be
Nzimidazole Pyloric ligation (4 hours, so-called shay latte) and
and oral administration of 100 mg/Kg of acetylsalicylic acid.
Occurrence of gastric damage caused by
(Magenla¨sionbildung) and 4 hours in Lazte
Effect of the compounds according to the invention on the gastric secretions of
are shown in the table below.

[Table] The test for the prevention of ulcers is carried out using the so-called
Shay ratte method: Shay ratte (female,
180-200g (4 animals per cage on high iron bars) developed ulcers by pyloric ligation (under diethyl ether anesthesia) and oral administration of 100mg/10ml/Kg of acetylsalicylic acid. let The substance to be tested was administered orally (10
ml/Kg). The wound is closed using a Mitsiel hook. At 4 hours, the animals are killed by atlas dissection in ether vapor and the stomachs are removed. The stomach was cut longitudinally, fixed on a cork board, and examined under a stereomicroscope for 10 minutes after measuring first the amount (volume) of secreted gastric juice and later its HCl content (titrated with sodium hydroxide solution). Examine the number and size (=diameter) of the cankers present at double magnification. The product of the degree of severity (as a scalar of the next rating) and the number of lesions is used as the individual damage index. Scalar rating: No erosion 0 Diameter of erosion 0.1-1.4 mm 1 1.5-2.4 mm 2 2.5-3.4 mm 3 3.5-4.4 mm 4 4.5-5.4 mm 5 >5.5 mm 6 Average damage index of control group (=100%) The reduction in the mean damage index of each treated group compared to the previous study is used as a measure of the effectiveness in preventing injury. ED25 and ED50
represent the dose that reduces the mean injury index and HCl-secretion by 25% and 50% compared to the control, respectively. Toxicity The LD50 of all compounds tested was
1000mg/Kg [oral] or more.

Claims (1)

[Claims] 1. General formula (In the formula, R1 is a 1-3C-alkyl group or chlorodifluoromethyl group completely or mostly substituted with fluorine, and R1' is a hydrogen atom, halogen, trifluoromethyl group, 1-3C- an alkyl group or a 1-3C-alkoxy group optionally fully or partially substituted by fluorine, or R1 and R1' together and including the oxygen atom to which R1 is attached, optionally fully or a 1-2C-alkylenedioxy group or a chlorotrifluoroethylenedioxy group partially substituted by fluorine, R3 is a 1-3C-alkoxy group, one of the groups R2 and R4 is a -3C-alkoxy group, the other is a hydrogen atom or a 1-3C alkyl group, n is a number 0 or 1) and salts of the compound. 2 R1 is a 1-3C-alkyl group or chlorodifluoromethyl group completely or mostly substituted with fluorine, and R1' is a hydrogen atom, halogen, trifluoromethyl group, 1-3C-alkyl group, or R3 is a 1-3C-alkoxy group, one of the groups R2 and R4 is a 1-3C-alkoxy group, optionally fully or partially substituted by fluorine; and the other is a hydrogen atom or a 1-3C-alkyl group, and n represents the number 0 or 1, and a salt of the compound. 3 R1 and R1' together and including the oxygen atom to which R1 is attached, represent a 1-2C-alkylenedioxy group optionally fully or partially substituted by fluorine or a chlorotrifluoroethylene dioxy group. oxy group, R3 is 1-3C-alkoxy group, one of the groups R2 and R4 is 1-3C-alkoxy group, the other is hydrogen atom or C-atom number 1
3 to 3 alkyl groups, n represents the number 0 or 1, and a salt of the compound as claimed in claim 1. 4 R1 is 1,1,2,2-tetrafluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl or chlorodifluoromethyl, R1' is a hydrogen atom, R3 is methoxy, R2 and R4 represents methoxy, the other represents hydrogen or methyl, and n represents the number 0 or 1, and a salt thereof. 5 R1 and R1' together and including the oxygen atom to which R1 is bonded represent a methylene- or ethylene-dioxy group, and R2, R3, R4 and n have the meaning given in claim 3, A compound of the formula according to claim 3 and a salt thereof. 6 R1 and R1' together and including the oxygen atom to which R1 is bonded represent a difluoromethylenedioxy group or a 1,1,2-trifluoroethylenedioxy group, and R2, R3, R4 and n are Compounds of the formula according to claim 3 and salts thereof having the meaning according to scope 3. 7 n means the number 0, claim 1
A compound of the formula according to any one of Items 1 to 6 and an acid addition salt thereof. 8 n means the number 1, claim 1
A compound of the formula according to any one of Items 1 to 6 and a salt thereof with a base. 9 2-[(4,5-dimethoxy-2-pyridyl)
Methylsulfinyl]-5-trifluoromethoxy-1H-benzimidazole, 2-[(4,5-dimethoxy-3-methyl-2-
pyridyl)methylsulfinyl]-5-trifluoromethoxy-1H-benzimidazole, 2-[(4,5-dimethoxy-2-pyridyl)methylsulfinyl]-5-(1,1,2,2- Tetrafluoroethoxy)-1H-benzimidazole, 2,2-difluoro-6-[(4,5-dimethoxy-2-pyridyl)methylthio]-5H-[1,3]
-dioxolo-[4,5-f]benzimidazole, 2,2-difluoro-6-[(4,5-dimethoxy-2-pyridyl)methylsulfinyl]-5H-
[1,3]-dioxolo-[4,5-f]benzimidazole and 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-
A compound according to claim 1 selected from the group consisting of 1H-benzimidazole and salts thereof. 10 One or more general formulas as gastroprotective and gastric secretion suppressing substances (In the formula, R1 is a 1-3C-alkyl group or a chlorodifluoromethyl group completely or mostly substituted with fluorine, and R1' is a hydrogen atom, halogen, trifluoromethyl group, 1-3C-alkyl group, or a 1-3C-alkoxy group optionally fully or partially substituted by fluorine or R1 and R1′ together and including the oxygen atom to which R1 is attached, optionally fully or partially substituted R3 is a 1-3C-alkoxy group, one of the groups R2 and R4 is a 1-2C-alkylenedioxy group or a chlorotrifluoroethylenedioxy group substituted with fluorine; 3C-alkoxy group, the other is a hydrogen atom or a 1-3C alkyl group, n represents a number 0 or 1) and/or a pharmaceutically compatible salt thereof. Drugs that do.