JPS6122079A - Dialkoxypyridine, manufacture, use and drug - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel dialkoxypyridines, processes for their production, uses thereof and pharmaceuticals containing them. The compounds according to the invention are used in the pharmaceutical industry as intermediates and for the production of drugs.

State of the Art European Patent Application No. 0005129 describes substituted pyridylsulfinylbenzimidazoles which may exhibit gastric acid secretion inhibiting properties. - European Patent Application No. 0074541 describes some benzimidazole derivatives for inhibiting gastric acid secretion. British patent application GB 2082580 describes tricyclic imidazole derivatives that block the secretion of gastric acid and prevent the development of ulcers.

It has now surprisingly been found that the dialkoxypyridines described in detail below exhibit important unexpected properties, which advantageously distinguish them from known compounds.

Description of the invention The subject of the present invention is a compound of the general formula ■ Dragon, in which R1 is completely or mainly substituted by fluorine.
~3C-alkyl group or chlorodifluoromethyl group, and RIF is hydrogen, halogen, trifluoromethyl,
1-3C-alkyl group or □1-3C-alkoxy group optionally substituted completely or mainly by Vc7, or R1 and Hp taken together represent R
1-2C, including the oxygen atom to which 1 is attached, optionally fully or partially substituted by fluorine
- represents an alkylenedioxy group or a chlortriple-oethylenedioxy group; L, R5 represents a 1-3C-alkoxy group, and one friend among the groups R2 and R4 represents a 1-30-
an alkoxy group and the other is a hydrogen atom or 1-30-
represents an alkyl group, and n represents the number 00''R or 1) and salts of the compound.
-Alkyl groups include, for example, 1,1,2-)IJ fluoro-tetraethyl group, perfluoropropyl group, perfluoroethyl group, especially 1,1,2.2-tetrafluoro-tetraethyl group, trifluoromethyl group, 2.2. 2-) Examples include a trifluoroethyl group and a difluoromethyl group.

SO-gens in the sense of the present invention are bromine, chlorine and especially fluorine.

1-30-alkyl group is propyl group, inpropyl group,
The methyl group and especially the methyl group.

In addition to the oxygen atom, the 1-3C-alkoxy group is
-3C-alkyl groups. Particularly preferred is methoxy group.

1-3C completely or mainly substituted by fluorine
-Alkoxy groups include, in addition to the oxygen atom, the above-mentioned 1-30-alkyl radicals substituted entirely or mainly by fluorine. For example, mention may be made of 1,1.2.2-tetrafluoroethoxy, trifluoromethoxy-12,2,2-trifluoroethoxy and difluoromethoxy groups.

Examples of 1-2C-alkylenedioxy radicals optionally fully or partially substituted by fluorine include 1,1-difluoroethylenedioxy radicals (-〇-01P
2-OH2-0-), i+1+2+2-tetrafluoroethylenedioxy group (-o-cv2-ay2-〇-),
1,1.2-)lifluoroethylenedioxy group (-0
-OF2-OHF-0-) and in particular the difluoromethylenedioxy group (-0-OF2-0-) as substituent groups, and ethylenedioxy and methylenedioxy groups as unsubstituted groups. I can do it.

As salts for compounds of the formula I (sulfides) in which n means the number 0, preferably all acid addition salts are taken into account. In particular, pharmaceutically acceptable salts of inorganic and organic acids commonly used in Galenik
aglichen 5alino). For example, pharmaceutically incompatible salts which may initially arise during the production of the compounds according to the invention on an industrial scale are converted into pharmaceutically acceptable salts by methods known to those skilled in the art. can be changed to These include, for example, water-soluble and water-insoluble acid addition salts such as hydrochlorides, hydrobromides, hydroiodides, phosphates, nitrates, sulfates, acetates, citrates, gluconates, etc. acid salts, benzoates,
Hlbenzat (2-(4-hydroxybenzoyl)-benzoate), Fenaigoat (o-[(2'-hydroxy-4-biphenylyl)carbonyl]-benzoate)
, phthylate, sulfosalicylate, maleate, laurate, malate, 7-malate, succinate, oxalate, tartrate, ammonat';
4.4'Nidiaminostilbene-2,2'-disulfo4-))(Fim'bonat 24,
4'-methylene bis-(3-hydroxy-2-naphtonito)), Metembonat
, stearate, tosylate, 2-hydroxy-3-7toate, 3-hydroxy-2-7toate or mesylate) (Mθailat) are suitable.

The salt of the compound (sulfoxide) of formula (1) in which n represents the number 1 is preferably a basic salt, especially a pharmaceutically compatible inorganic base and an organic base commonly used in galenic medicine. Take into account tolerant salts. Examples of basic salts include sodium, potassium, calcium or aluminum salts.

In one aspect (aspect a) of the present invention, R1' represents hydrogen,
A compound of formula 1 and a salt thereof, where R1, R2, R5, R4 and n have the above meanings.

Another aspect (aspect b) of the present invention is that Rj and R1' together and including the oxygen atom to which R1 is attached, 1 to 2
represents a C-alkylenedioxy group and R2, l,
Compounds of formula I and salts thereof, in which R4 and n have the above meanings.

Another aspect of the invention (aspect C) is that R1 and RIF together and including the oxygen atom to which R1 is attached are fully or partially substituted by fluorine.
represents an alkylenedioxy group and R2, R3, R4
and compounds of formula I and salts thereof, where n has the above meaning.

Preferred compounds of embodiment a are those in which R1 is 1,1,2,2-tetrafluoroethyl, trifluoromethyl, 2.2.2
-) Lifluoroethyl, difluoromethyl or clotetradifluoromethyl, R1' is hydrogen, R5 is methoxy, one of R2 and R4 is methoxy and the other is hydrogen or methyl, and n is a number 0 or 1 of formula I and 4'e of the compound.

Particularly preferred compounds of embodiment a are those in which R1 is 1,1°2.
2-y)-t;'Luo aethyl, trifluoromethyl,
2,2.2-) Lifluoroethyl or difluoromethyl, R1' is hydrogen, R5 is methoxy, R2 and R
4, one of which is methoxy, the other is hydrogen or methyl, and n is the number Of or 1, and salts of the compound.

Preferred compounds of this embodiment are such that R1 and 'ft11 together and including the oxygen atom to which R1 is attached represent a methylene- or ethylene-dioxy group, and R5 represents a methoxy group; One of them is methoxy, the other is hydrogen or methyl, and n is several hundred or 1, and salts of the compounds.

Particularly preferred compounds of this embodiment are those in which R1 and R1' together and including the oxygen atom to which R1 is attached represent a methylenedioxy group, R3 is methoxy, and one of R2 and R4 is methoxy. and the other is hydrogen' or methyl and n is a number 0 or 1, a compound of formula I and a salt of the compound.

Preferred compounds of embodiment C are such that R1 and R1' together and including the atom to which R1 is attached represent a difluoromethylenedioxy group or a 1,1,2-trifluoroethylenedioxy group, and R5 is methoxy , R2 and R4
and wherein one of them is methoxy, the other is hydrogen or methyl, and n is a number of the order of 1, and salts of the compound.

Aspect C 4? A preferred compound is one in which R1 and R1' together and R1 containing the oxygen atom to which it is attached represents a difluoromethylenedioxy group, R3 represents methoxy, and one of R2 and R4 represents methoxy. and the other hydrogen t'& is methyl and n is a number 0 or 1, a compound of formula i and a salt of the compound. - Due to the tautomerism of the imidazole ring, the substitution at the 5-position of benzimidazole is identical to the substitution at the 6-position. Appropriately,
In a compound in which R1 and R1' together represent a substituted ethylenedioxy group including the oxygen atom to which R1 is bonded, [1,4]~dioxinoC2,5-L t ) of the benzimidazole moiety 6th place is the same as 7th place.

The objects of the present invention are R, R1', R2, , R
5, R4 and n have the above-mentioned meanings;

The method comprises combining a mercaptobenzimidazole represented by the formula ■ with a picoline derivative represented by the formula (b) a benzimidazole represented by the formula ■ and a mercaptopicoline represented by the formula V; or (Q) a mercaptopicoline represented by the formula ■ o - reacting a phenylene diamine with a formic acid derivative of the formula (1) and optionally then 2-benzimidazolyl-2-pyridyl of the formula (2) obtained by (, ), (b) or (c) oxidation of methyl sulfide and/or converting it into a salt; or (a) a benzimidazole of the formula ■ ■ and a pyridine derivative of the formula X; or (e) a sulfinyl of the formula X ■. Reacting the derivative with the 2-picoline derivative shown in the formula and optionally converting it into a salt (where Y, Z, Z' and f represent suitable leaving groups and M
is an alkali metal atom (Li, Ha or X).

Preparation steps (, ), (b) and (0) lead to the oxidation of the sulfides according to the invention, compound 1, and steps (a) and (e) lead to the oxidation of the sulfides according to the invention, O which ~ leaving group Y, The suitability of Z, Z' or γ is well known to those skilled in the art. A suitable leaving group Y is, for example, a group which together with the sulfinyl group to which it is attached forms a reactive sulfinic acid derivative. Suitable leaving groups Y include, for example, alkoxy, dialkylamino or alkylmercapto groups. Suitable leaving groups Z, Z' or 2' may include, for example, halogen atoms, especially chlorine atoms, or dangerous hydroxyl groups which can be activated by esterification (eg with p-)luenesulfonic acid). The equivalent metal atom M' is, for example, an alkali metal (Li, lia or K), or an alkaline metal (e.g. M?) substituted by a halogen atom (e.g. Br, Grignard reagent), or A metal atom that is optionally substituted with some other metal atom known to react in substitution reactions of metal-organic compounds such as metal-organic compounds.

The reaction between ■ and ■ can be carried out in a known manner in a suitable, especially protic or neutral solvent (for example methanol, impulpanol, dimethylsulfoyacto, acetone, dimethylformamide or acetonitrile) with or without addition of water. It is done except for Nuclear reactions are carried out, for example, in the presence of proton acceptors. Suitable as such are alkali metal hydroxides such as sodium hydroxide, alkali metal carbonates such as potassium carbonate, or tertiary amines such as pyridine, triethylamine or ethyldiisopropylamine. Alternatively, the reaction can also be carried out without a proton acceptor, in which case the acid addition salt can first be separated off in a particularly pure form (depending on the nature of the starting compound on a one-off basis). The reaction temperature can be between 0°C and 150°C, in the presence of a proton acceptor a temperature between 20°C and 80°C, and without a proton acceptor a boiling temperature of 60°C and the agent. - Preferred. Reaction time is 0.5 hours and 2
It is between 4 hours.

In the reaction of ① with V carried out in a known manner, reaction conditions similar to those for the reaction of ② with a plate are used.

The reaction between (1) and (2) is preferably carried out in the presence of a strong acid, such as hydrochloric acid, in a water-containing solvent, especially if the reaction is polar.

4IK is carried out at the boiling temperature of the solvent used.

The oxidation of the sulfide ■ is carried out in a known manner and under conditions such as are well known to those skilled in the art for the oxidation of sulfides to sulfoxides [see, for example, R, Dra-bowicz and M. , Mik
olajczyk, Organic prep-r
ations and procedures int.
, 14 (1-2) t45-89 (1982) or 1. Block in 8゜Patai, Th
e Chemistry of IF Functiona
lGroups.

8up'lement Fi, Part 1, pp. 339-60B, John Wiley and S.
ong (Enteraclence PublkPQ
JLtiOn), 1980]. As oxidizing agents, all the reagents customary for the oxidation of sulfides to sulfoxides, such as hybohapgonite, in particular peroxy acids such as peroxyacetic acid, trifluoroperoxyacetic acid, L5-dinitoperoxybenzoic acid,
Consideration is given to heroxymaleic acid or preferably m-chloroperoxybenzoic acid.

The reaction temperature is -7 (depending on the reactivity and dilution of the oxidant)
between 0°C and the boiling temperature of the solvent used, but preferably between -50°C and +20°C, expediently between 0°C and 30°C.
It has also been found that oxidation with halogens or with hypohapgenite (for example aqueous sodium hypochlorite solution) carried out at temperatures between 0.degree. The oxidation is preferably carried out in inert solvents such as aromatic or chlorinated hydrocarbons such as benzene, toluene, dichloromethane or chloroform, or in esters such as ethyl acetate or Improvil acetate or in ethers such as dioxane. It is carried out with or without the addition of water.

The reaction between (1) and X is preferably carried out in an inert solvent such as that commonly used for the reaction between erto ions and alkylating agents. Mention may be made, for example, of aromatic solvents such as benzene or toluene. The reaction temperature is generally between 0° C. and 120° C. (depending on the alkali metal atom M and the leaving group 20), with the boiling temperature of 1 L of the solvent used being particularly preferred. For example, [M is Li (9 tium) and 2
is 0! (chlorine) and when the reaction is carried out in benzene, the boiling temperature of benzene (80°C) is particularly preferred.
stomach.

Compound X is reacted with the compound product in known manners as are well known to those skilled in the art for the reaction of metal-organic compounds.

Depending on the nature of the starting compounds, which can optionally also be used in salt form, and depending on the reaction conditions, the compounds according to the invention are obtained initially in neat form or in salt form.

Additionally, a suitable solvent containing the desired acid or base or the desired acid or base, if any, is added first in precisely calculated stoichiometric amounts, such as chlorinated hydrocarbons such as methylene chloride or Chloroform, low molecular weight aliphatic alcohol (ethanol, impropano-AI),
-Til (diisopropyl ether), ketone.

The salt is obtained by dissolving the free compound in (acetone) or water.

Salts are obtained by filtration, reprecipitation or precipitation or by evaporation of the solvent.

The salt obtained can be converted into the free compound by making alkaline or acidifying, for example with aqueous sodium bicarbonate or with dilute hydrochloric acid;
The compound can be converted back into a salt. In this way, the compounds can be purified or pharmaceutically non-acceptable salts can be converted into pharmaceutically acceptable salts.

The sulfoxides according to the invention are optically active compounds.

Accordingly, the present invention encompasses optical enantiomers as well as mixtures of optical enantiomers and compounds. Optical antipodes can be separated by known methods (eg, by preparing and resolving corresponding diastereomeric compounds).

However, the optical enantiomer can also be obtained by asymmetric synthesis, for example, by reacting an optically active pure compound X or a diastereomerically pure compound X with a compound product.
[For this, K, Mn
dersen, Tatra-M+clron Le
tt., 95 (1962)].

The compounds according to the invention are preferably synthesized by reacting compound I with compound 1 and optionally subsequently oxidizing the resulting sulfide 2.

Compounds of the formula IO are partly known (DE-A-31 32 613) or can likewise be prepared according to known examples.

Compound 1 can be obtained, for example, by reacting compound vi with carbon disulfide in the presence of alkali hydroxide or with alkali-σ-ethyldithiocarbonate.

Compound (1) can be synthesized according to the general manufacturing method described in the following reaction formula AK.

Reaction 2: φ1) (A2) (AS)
Similar to this [e.g. J, Org, Ohem, a
4t2097-2910 (1979); J, Or
g, Ohem.

29.1-11 (1964); German Patent Application No. 2,029.556; German Patent Application No. 2,848,531; J, Fluor
ine Oham.

18.281-91 (1981); Bynth
Esis 1980, 727-8], isomeric mixtures can also occur if R1' and R1-0- are not identical substituents.

Compounds N, K and X can be prepared, for example, from compound I by methods already known to those skilled in the scissor art.

Compound (1) is prepared, for example, from compound (2) by methyl ibis, oxidation and subsequent partial protonation using, for example, alkali metal hydrides or alcolades or customary metal-organic compounds. Compound X is Z, ? alik, R.
ocgniki Ohem, 35°475 (196
1) Manufactured as a T-base.

The compounds are novel) and are also the subject of the present invention. The compounds can be prepared in different ways depending on the degree of monosubstitution: Compounds 1, in which 1, R2 and R3 are 1-3C-alkoxy and R4 is hydrogen or 1-30-alkyl.

The compounds can be prepared, for example, by starting from 3-hydroxy- or 3-hydroxy-5-alkylpyridines which are known or can be prepared by known methods (for example by replacing the hydroxy group with potassium hydroxide and benzyl chloride in dimethyl sulfoxide). Benzylation, M-oxidation ([, ta'5 (with l hydrogen peroxide), nitration of the -4 position (e.g. with a mixed acid), nido-group (e.g. by reaction with an alkali-alkoxide) and 1. ~ Exchange with 3C-alkoxy groups, reductive debenzylation (e.g. with hydrogen over palladium/charcoal in acid medium) and simultaneous N-deoxygenation (e.g. by reaction with alkaline formalin solution) for the pyridine nitrogen by conversion of the 3-hydroxy group into a 1-5a-alkoxy group (by reaction) and the temporary introduction of the group 2 (e.g. by reaction with thionyl chloride). In a preferred alternative The iron compound is 3-hydroxy-2 which is known or can be produced by known methods.
Starting from -alkyl- or 3-hydroxy-2,5-dialkyl-pyridine, the AlI of the hydroxy group (e.g. potassium hydroxide and methyl iodide in dimethyl sulfoxide!)? M-oxidation (e.g. with hydrogen peroxide at 30-), nitration at the 4-position (e.g. with nitric acid), nitration at the 4-position (e.g. by reaction with an alkali-alkoxide) and the 1-3C- exchange with alkoxy groups, conversion to 2-acetoxymethylpyridine (e.g. with hot acetic anhydride), saponification to hydroxymethyl groups (e.g. with dilute sodium hydroxide solution) and reaction with thiodichloride (e.g. with dilute sodium hydroxide solution). Transmission is achieved by the introduction of a temporary group 2' (according to K.).

2, R3 and R4 are 1-30-alkoxy (Ij) and R2 is hydrogen; (by alkyl and potassium hydroxide) hydroΦ
Alkylation of the cy group, N-oxidation (e.g. with 3o hydrogen peroxide), nitration of the 4-position (e.g. with nitric acid), (
Exchange of nido tetragroups with 1-50-alkoxy groups (e.g. by reaction with alkali-alkoxides), conversion to 2-7cetoxymethylpyridine (e.g. with hot acetic anhydride), conversion to 2-7cetoxymethylpyridine (e.g. with dilute acetic anhydride), oxidized)+7cum solution)
It is prepared by saponification of the 2-hydroxymethyl group and temporary introduction of the group 2' (for example by reaction with thionyl chloride).

(5) A compound (2) in which R3 and R4 are 1-5C-alkoxy and R2 is 1-30-alkyl;

The compound is e.g. starting from 2-methyl-3-furkyl-4-alkoxy9pyridine CM#, which is known or can be prepared by known methods (see European Patent Application No. 0080602), N-oxidation (in hydrogen peroxide), acetoxylation of the target 5-position (e.g. with acetic anhydride and then sodium hydroxide solution) and subsequent saponification, iodination (e.g. in dimethyl sulfoxide). (by alkyl and sodium hydroxide solution) 5-human I:II? Alkylation of the cy group, (e.g. if
N-oxidation (with m-polyperbenzoic acid), conversion to 2-acetoxymethylpyridine (e.g. with hot anhydride), conversion to 2-hydroxymethyl group (e.g. with dilute sodium hydroxide solution). It is prepared by saponification and temporary introduction of a group 2' (eg by reaction with thionyl chloride).

What reaction conditions (temperature, reaction time, solvent, etc.) are individually required for the production of the compound in the above synthetic route?
Well known to those in the technical field because of their specialized knowledge. Compounds 1i2) The exact preparation of the individual representatives is described in one example.

The production of other representative substances is carried out in an analogous manner.

Compounds V, (1) and (3) are prepared, for example, starting from the compound starting from the compound by methods known to those skilled in the art.

゛ The present invention 811 will be explained in more detail with reference to an example, but the present invention is not limited to the example. Compounds 2 and 3 and salts of these compounds named and described in the examples are preferred objects of the present invention.
2-chloromethyl-4,5-cyme)oxypyridinium chloride 1 to a solution of WLl and 1'H sodium hydroxide solution 20-2-mercap)-51 lifluoromethoxy-1E-benzimidaso/L/1,641 ,57g
Add 20 ml for 2 hours and then 4o1 for another hour:
ethanol in a rotary evaporator (IkPa/40
The colorless precipitate that precipitates out is collected, washed with IN hydroxide solution and water and dried. 2.1 with a melting point of 92-93C
5# (79% of theory) The title compound is obtained.

Similarly, 5-chlorodifluoromethoxy-2-mercapto-IH-benzimidazole, 5-difluoromethoxy-2-mercapto-IH-lomethoxy)-2-mercap)-1,5-benzimidazole, 5-difluoromethoxy- By reacting 2-mercapto-6-medoxy-IH-benzimidazole and 5-difluoromethoxy-6-fluoro-2-mercap)-IH-benzimidazole with 2-chloromethyl-4,5-dimethoxypyridinium chloride, 5-talolodifuno V-olomethoxy-2-[(, If,
5-dimethoxy-2-pyridyl)-methylthio]-+n
-be/shiimidazole, 5-difluoromethoxy-2-[(4,5-dimethoxy-2-pyridyl)methylthio)-1H-benzimidazole (oil), 5,6-bis(difluoromethoxy)-2-[( '+5
-dimethoxy2-pyridi/l/)methylthio]-1
H-benzimidazole, 5-difluoromethoxy-6-methoxy-2-[(4,
5-dimethoxy-2-pyridyl)methylthio]-IH-
Benzimidazole (melting point 159-160j) and 5-difluoromethoxy-6-fluoro-2-[(4,
5-dime)+C2-zelidyl)methylthio]-+H-
Benzimidazole is obtained.

2- (4,5-dimethoxy-
2-pyridyl)methylthio]-5-trifluoromethoxy-1H-benzimidazole o,s to a solution of 6 g-5
5.5 mL of a 0.2 M solution of m-chloroperoxybenzoic acid in methylene chloride are added dropwise and stirred for a further 30 minutes at the above temperature.

After addition of 0.3 - of triethylamine, the cold reaction mixture is stirred in a solution of 10 d of 5% sodium thiosulfate and 10 m of 5% sodium carbonate and, after separation of the phases, extracted three more times with Tom methylene chloride, The combined organic phases were washed once with 5 ml of IJ solution, dried, and the desiccant (magnesium sulfate) was removed.
Concentrate. The residue was crystallized with diisopropyl ether,
It is then recrystallized from methylene chloride/diisopropyl ether. The title compound is obtained as a colorless solid with a melting point of 159-61 pi (decomposition), 27 Ji' (72% of theory).

Similarly, by oxidizing the other sulfide of Example 1 with m-chloroperoxybenzoic acid, 5-chlorodifluoromethoxy-2-[(4,5-dimethoxy-2-pyridyl)
Methylsulfinyl]-IH-benzimidazole, 5-difluoromethoxy-2-[(4,5-dimethoxy-2-pyridyl)methylsulfinyl]-1'H-benzimidazole [melting point 159 mm (decomposition)], 5.6 -bis(difluoromethoxy)-2-[('e5
-dimethoxy2-pyridyl)methylstv7ynyl)-1H-benzimidazole, 5-difluoromethoxy-6-methoxy-2-[('*5-dimethoxy2
-pyridyl)methylsulfinyl]-1H-bency8
midasole, and 5-difluoromethoxy-6-fluoro-2゜2- [
(4,5-dimethoxy-2-pyridyl)methylsulfinyl"l-'+H-benzimidazole is obtained.

Following the procedure described in Example 1, 2-mercapto-5
-(1,1,2.2-tetrafluoroethoxy)-1H
-Benzimidazole 1,07g and 2-chloromethyl-
By reacting 0.90 g of 4,5-dimethoxypyridinium chloride in 15 d of ethanol by adding 17 g of 0.5 N sodium hydroxide solution, 1,4 ny
The title compound is obtained as a yellow oil. Crystallization with petroleum ether gives the product in the form of colorless crystals with a melting point of 125 to +271. Yield: 1,20 I (72 I of theory).

4 2-[(4,5-Dimethoxy-2-pyridyl)dazole Following the procedure described in Example 2, 2-[(4,5-dimethoxy-2-birisol)methylthio-5-(1,1,
2.2-Tetrafluoroethoxy)-1H-benzimidazole 0.7677 was chlorinated after extraction by oxidation with 19 d of a 0.1 M solution of m-chloroperoxybenzoic acid (2) in 3.0 ml of methylene chloride for 40 t'. A solution of the product in methylene is obtained. After drying over magnesium sulfate, the desiccant is removed from F, concentrated and the residue is crystallized from methylene chloride/diynpropyl ether. Melting point is 16
0.6417 in the form of colorless crystals of 0 to 162 υ (decomposition)
(82% of theory) of the title compound is obtained.

ethoxy)-1H-benzimidazole 2-mercapto-5-(2,2,2-)lifluoroethoxy)-1■-
Add 1.0 g of benzimidazole to 15 g of ethanol and
2-chloromethyl-4,5-dimethoxypyridinium chloride dissolved in 8.5-N sodium hydroxide solution
．． Add 90I and stir for 20 hours. After addition of 30i1 of water, extraction was carried out with three 301111 portions of methylene chloride, the methylene chloride phase was washed once with 0.1N sodium hydroxide solution, the combined organic phases were dried over magnesium sulfate and the desiccant was removed by p. After separation, concentrate completely. Melting point is 55
1.51 g (94% of theory) of the title compound are obtained as an amorphous solid residue of ~57 mm.

12-2-2-[(4,5-dimethoxy-2-pyridyl)methylthio)-5-(2,2,2-)lifluoroethoxy)
-IH-benzimidazole 0.8i to dioxane 15
- and dissolved in 2.5 ml of 1M sodium hydroxide solution.
let Over a period of 2 hours, a mixture of 3.5% 8% sodium hypochlorite solution and 3.5% 1N sodium hydroxide solution is added dropwise at 0 to 5μ without cooling. After addition of 5 WL of a sodium thiosulfate solution of 5-1, it is concentrated to dryness, the residue is taken up in water and brought to pH 7 with phosphate buffer.

The precipitated solid substance is collected, dried, and acetate/
Recrystallize with diisopropyl ether.

Melting point is 142-143'? : (decomposition) gives 0.459 (55% of theory) of the title compound as colorless crystals.

Following the procedure described in Example 1, 2-mercapto-5
-(1,1,2.2-tetrafluoropethoxy)-1H
-benzimidazole 1,079 and 2-chloromethyl-
0.969 of 4,5-dimethoxy-3-methylpyridinium chloride is 0.5N hydroxylated in 12mj of ethanol) By adding 17d of IJium solution and reacting, 1,4677 with a melting point of 127-128m is produced. (83% of theory) of the title compound (colorless powder) is obtained.

Following the procedure described in Example 2, 2- [(4°5-
Dimethoxy-3-methyl-2-pyridyl)(methylthio)-5-(1,I,2,2-tetrafluoroethoxy)-1H-benzimidazole 0.99II'tm of m-thalolberoxybenzoic acid in methylene Oxidation with a 0.2M solution 12-40t- and a reaction time of 1.5 hours gives a pale yellow oil of 0.81.

Recrystallization twice from methylene chloride/diisopropyl ether gives the title compound in the form of colorless crystals with a melting point of 125 h (decomposition), o, so ll (-54% of theory).

Example IK describes nine operating method buttons, thus 5-difluoromethoxy-2-mercapto-1R-benzimidazole
Oj 8 Ii (2mMo1) and 2-dibromethyl-4
,5-dimethoxy-3-methylpyridinium chloride 0
．． 489 (211M01) was reacted in 10 g of ethanol by adding 8.8 g of 1N sodium hydroxide solution to give 5.77 g after 2 hours and 9 hours, with a melting point of TOO~
+02t of 0.64 Jir (theoretical amount of 84 Jir) of the title compound (colorless crystalline powder) is obtained.

2-Mercapto-5-(1,1,2,
2? 1 to a solution of (tetrafluoroethoxy)-1H-benzimidazole o, 461/ (“1.7 mMo1)
．． Add 2-'F chlorotyl-3,4-dimethoxy-pyridinium chloride Oj 8 i (1,7 mmO'l): after stirring for 1 hour at 20 υ, add water 10 x 1
' is added dropwise; then stirred again for 4 hours at 20 m/s. The precipitated solid material is separated, washed with 0.01N sodium hydroxide solution and then with water until neutral, and dried to constant weight.

0.65 as a colorless crystalline powder with a melting point of 98-102 mm
9 (90% of theory) of the title compound are obtained.

Similarly, 5-difluoromethoxy-2-mercapto-I
H-benzimidazole and 5-difluoromethoxy-
By reacting 6-methoxy-2-mercapto-1H-benzimidazole and 2-chloromethy with -5,4-dimethoxypyridinium chloride, 5-difluoromethoxy-2- ) Methylthio)-1H-benzimidazole (melting point 104-to8t1') and 5-difluoromethoxy-
6-Methoxy-2-[(3,4-dimethoxy-2-pyridyl)methyl"J-,IK-benzimidazole (melting point 1:17-+get) is obtained.

Following the procedure described in Example 1, 2-mercapto-5
-trifluoromethoxy-1B-benzimidazole 1
．． 15g and 2-chloromethyl-4,5-dimethoxy-3
- 1.20 g of methylpyridinium chloride and 2.0 g of 0.5N sodium hydroxide solution in Impropatool 20-
By adding 0.5- and reacting, 1,4 o
9 (70% of theory) of the title compound are obtained. Recrystallization with diisopropyl ether/petroleum ether gives a product with a melting point of 94-97 t'.

Similarly, 2-mercapto-5-(2,2-)lifluoroethoxy)-1H-benzimida f-ol, 5-chlorodifluoromethoxy-2-mercap)-IH-benzimidazo-, s, =, 5.6-bis(difluoromethoxy)-2-mercapto-IH-benzimidazole,
5-difluoromethoxy-2-mercapto-6-medoxy 1E-benzimidazole and 5-difluoromethoxy-6-fluoro-2-mercapto-+H-benzimidazole and 2-chloromethyl-4,5-dimethoxy-
By reacting with 5-methyl-pyridinium chloride, 2-[(4,5-dimethoxy-3-methyl-2-biridyl)methylthio), 5-(2,2,2-)lifluoroethoxy)'- IH-benzimidazole, 5-chlorodifluoromethoxy-2-, [(4,5-dimethoxy-3-methyl-2-pyridi/)methylthio')
-1H-benzimidazole, 5,6-bis(difluoromethoxy)-2-[(4,5-dimethoxy-3-methyl-2-pyridyl)methylthio)-+H-benzimidazole, 5-difluoromethoxy-6-methoxy -2-
[(4,5,-dimethoxy-3-methyl-2-pyridyl)methylthio]-IH-benzimidazole and 5-difluoromethoxy-6-fluoro-2-[(8,
s-dimethoxy-3-methyl-2-pyridyl)methylthio]-1H-benzimidazole is obtained.

two! Following the procedure described in Example 2, 2-[(7I.

5-dimethoxy-3-methy/L/-2-pyridyl)methylthio)-5-trifluoromethoxy-1H-benzimidazole 0.24 Ii was dissolved in a 0.2 M solution of m-taloloberoxybenzoic acid in methylene chloride.3. 0.1911 (theoretical amount of 76
%) of the title compound is obtained as a colorless powder.
~159 decomposition.

Similarly, 2-[(4,5-dimethoxy-3-methyl-2-pyridyl)methylsulfinyl"l-5-(2゜2.2-
) Lifluoroethoxy)-II-benzimidazole, 5-chlorodifluoromethoxy-2-[(4,5-dimethoxy-5-methyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5- Difluoromethoxy-2-[(4,5-dimethoxy-3-methyl-2-pyridyl)methylsulfinyl]-
1m-benzimidazole [melting point 153-135. nothing(
decomposition)], 5.6-bis(difluoromethoxy)-2-
[(4,5-dimethoxy-3-methyl-2-pyridyl)
methylsulfinyl]-+H-benzimidazole, 5-difluoromethoxy-6-methoxy-2-(C4,
5-dimethoxy-3-methyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 5-difluoromethoxy-6-fluoro-2-[(4,
5-dimethoxy-3-methyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole, 2-[(5,4-dimethoxy-2-pyridyl)methylsulfinyl l-5-(1,1,2. 2-TetrafluoroeFxy)-1H-benzimidazole [melting point 117
-119 (decomposition)] and [5-difluoromethoxy-2-(5,4-dimethoxy-2-pyridyl)methylsulfinyl]-IH-benzimidazole [melting point 13
6 (decomposition)] is obtained.

5-methyA/-2-pyridyl)methylthio] 2 t in ethanol + om and 10 d of 1N sodium hydroxide solution
h,2-difluoro-5a-(1,s]-dioxolo"
0.961 i of 2-chloromethyl-4,5-dimethoxy-3-methylpyridinium chloride is added to a solution of 092 g of benzimidazole-6-thiol. The yellow reaction mixture was stirred for 1 hour at 20 t', +od water was added again, during which time a colorless solid material precipitated out, stirred for a further 5 hours, -filtered and IN-hydroxylated.
Wash with Jum solution and water and dry to constant weight. The amorphous powder is recrystallized from methylene chloride/pyl ether. 1.5p (95% of theory) of the title compound is obtained in the form of colorless crystals with a melting point of 160-61 mm.

Similarly, 6,6.7-)lifluoro-6,7-sihydro-1H-[1,a]-dioxin ["2.3-f)
Benzimidazole-2-thiol, 6-chloro-6,7,7-)lifluoro-6,7-"dihydro-IH-(1,4')-dioxin [2,3-f
] Benzimidazole-2-thiol or 6,7-sihydro-1H-(1,4)-dioxin (2,3-f
) 6.6.7-Drifluoro6.7-dihydro2- by reacting benzimidazole-2-thiol with 2-chloromethyl-4,5-dimethoxy-3-methylpyridinium chloride.
[(4,5-dimethoxy-3-methyl-2-pixy/
(2,3-t)benzimidazole, 6-chloro-6
,7,7-dorifluoro6,7-dihydro 2-[(
4,5-dimethoxy-3-methy)v-2-pyridyl)methylthio'J-+H-(t,4)-dioxin(2,
3-f) Benzimidazole and 6,7-sihydro2-[(4,5-dimethoxy-3
-Methyl-2-pyridyl)methylthio]-IE-(1,
4)-Dioxine [: 2.3-f''J benzimidazole is obtained.

2-difluoro-6-[(4
,5-dimethoxy-5-methyl-2-pyridyl)methylthio)-5H-(1,3)-dioxo(4',5
f) Add 21 yd of a 0.1 M solution of m-chloroperoxybenzoic acid in methylene chloride to a -40 mm cooled suspension of 0.801 benzimidazole in 10 minutes. Stirring is continued for a further 20 minutes, the temperature being raised to -20p, 0.5 wdt of triethylamine is added and the reaction mixture is dissolved in 4 rJxl of a solution of in each case 5 g of sodium thiosulfate and 5 g of carbonate. After separation of the poured layer, the aqueous phase is further extracted with two FBI 20 ml portions of methylene chloride; the combined organic phase is washed with a mixture consisting of 5 ml each of a solution of sodium thiosulfate and sodium carbonate, dried and concentrated. do. The residue is recrystallized from methylene chloride/diisopropyl ether. 0.62
9 ('75% of theory) of the title compound is obtained: decomposition point 189-90 m.

Similarly, the other sulfurized vipers mentioned in Example 15 were prepared by m-oxidizing with loroperoxybenzoic acid to produce 6.6.7-) refluoro-6, fudihydro-4-2.
- [(4,5-dimethoxy-3-methyl-2-pyridyl)methylsulfinyl]-1B-[1,4]-dioxin (: 2,5- f ) benzimidazole, 6
-chloro-6,7,7-)lifluoro-6,7-sihydro2- [(A,5-dimethoxy-6-methyl-2-
pyridyl)methylsulfinyl]-tH-(r,I)-
Dioxine[2,3-f]benzimidazole and 6,7-dihydro2-[(4,5-dimethoxy-3
-methyl-2-pyridyl)methylsulfinyl] -i
H-(1,a)-dioxin[cy,3-f,)benzimidazole is obtained.

15,,6-[(4,5-dimethoxy-2-pyridyl) 5E-(1,s
)-dioxo(4,5-f"l-benzimidazole-6-thiol 0.859 and 2-chloromethyl-4,
0.98 fl of 5-dimethoxypyridinium chloride was 1N hydroxylated in ethanol/L/1 atd and water 10-1) and reacted by adding it to 8.5 d' of IJ solution. Therefore, the reaction time was 20 hours. After that and the solvent was concentrated under reduced pressure to a volume of 10 ml, a brownish-brown and supersolid material was obtained. The iL product is dissolved in 50 yd of methylene chloride, clarified with bleach (e.g. TO0841), concentrated, crystallized by addition of diimpropyl ether, and the now pale yellow solid material is thoroughly boiled in 5 d of methanol. 0.9 as a colorless solid substance with a melting point of 198-200 mm
0 g (60% of theory) of the title compound are obtained.

16.6-[(45-dimethoxy-2-pyridyl)methylsulfini#)-5B-(1,3]-dioxolo-
[4,5-di] Following the procedure described in Example 14, 6-di
[4,5-dimethoxy-2-pyridyl)methylthio)-
By oxidizing 0.7 g of 5H-(1,3]-dioxoro(A,5-f)benzimidazo-/W with 25 yd of a 0.1 M solution of m-chloroperoxybenzoic acid,
After recrystallization from diethyl ether, the melting point is 199fi.
0.279 of the title compound is obtained in the form of colorless crystals (decomposition).

Following the procedure described in Example 13, 2.2-thifluoro5n-(1,s)-dioxo[4°5-f)-beydiimidazole-6-thiollo, 6911 (3mM
0.67 Jil (s mMo1) of -5,4-dimethoxypyridinium chloride in a mixture of 1 aw Lt of ethanol and 10 m of water.''!!2
After a reaction time of 10 hours, a melting point of 18
As a colorless powder with fine crystals of 5 to 187 mm 1.o 5
1 (92% of theory) of the title compound are obtained.

Similarly 1'(,5R-(1,3)-dioxolo[4,5-
6-[(5,4-dimethoxy-
2-Biridylnemethylthio)-5m-[1,x')-dioxo(4,5'-f]benzimidazole (melting point 1
55-157 mm) are obtained.

5n-(1,x)-dioxo(4,5-f)benzimidazo-AI-6-thiol 0,78.9 (4mM
ol) to 2-oomethyl-4,5-dimethoxy-3-
Methylpyridinium chloride 8,'q s i (4mM
Boil the mixture together with o1) in 30 g of ilepropanol while stirring. The precipitated solid substance is weighed, thoroughly stirred together with isopropanol, weighed again, and dried until it reaches a constant weight. The dihydrochloride salt of the title compound was prepared as a colorless solid substance with a melting point of 206υ (decomposition) at 1,o fi
(59% of theory) is obtained.

2,2-difluoro-5H in midazole ethanol 9d and water 4d
-(1j)-dioxo(4,5-t)]benzimidazole-6-thiol o6qlil1'' and 2-chloromethy/I/-4,5-dimethoxypyridinium chloride to a heated solution of 0.67Ii at 5 otK, 1 I in minutes
N hydroxide) IJum solution 6.3- is prepared. The clear reaction mixture is cooled to 2°C, and a colorless precipitate separates out after a short time. The mixture was further stirred at 20υ for 5 hours, suctioned off using a Nutsche, washed with 1N hydroxide solution and water, and dried to a constant weight. The raw color 11 solid material is dissolved in 10 mK of methylene chloride, the insoluble components are filtered off, Solution F is concentrated and crystallized by adding diisopropyl ether and cooling. Melting point is 189-91
1.02 g (90% of theory) of the title compound are obtained.

Similarly, 6,6,7-drifluoro6,7-sihydroIH-(t,4)-dioxin(2,3-f]benzimidazo-/I/-2-thiol, 6-chloro-6,7
,7-) refluoro-6,7-sihydro-tE-(1,
4)-Dioxine (2,3-f')benzimidazole-2-thiol, also Jd6,7-sihydro IH-
By reacting with (1,4)-dioxin[2,5-f)be/shiimidazole-2-thiol-2-chloromethyl-4,5-dimethoxy-pyridinium chloride, 6.6.7-)refluoro-6 ,7-sihydro2-[(4,5-dimethoxy-2-pyridyl)methylthio)-1H7(1,4)-dioxin[2,3-f
) benzimidazole, 6-chloro-6,7,7-)lifluoro-6゜7-sihydro2- [(4,5-dimethoxy-2-pyridyl)methylthio]-+H-(1,4]-didioxin 2
．． 3-f) benzimidazole and 6,7-sihydro2-[(4,5-dimethoxy-2
-pyridyl)methylthio]-+H-[1,4]-dioxino(2,3-f)benzimidazole is obtained.

2.2-difluoro-6-(: (4,5-diphthoxy-2-pyridyl)methylthio"l -5H-(1,s)-
Dioxo(4,5-f)benzimidazole 0.7.
6. P is dissolved in 10 g of dioxane and 2 d of IN sodium hydroxide solution. While cooling on ice, first add an equimolar amount of -1 equivalent to 1 mole of hydroxide) - Titrate with an aqueous solution of nine sodium hypochlorite, then add 1 equivalent again after 1 hour, and after 3 hours. Half an equimolar amount of hypochlorite (IJ) is added in such a way that a complete reaction is achieved. After a reaction time of 4 hours, 5 Wll of 5% sodium thiosulfate solution and an additional 25 yrl of dioxane were added, the upper dioxane phase was separated, and the -times 5111
(thiosulfate) solution and concentrated in a rotary evaporator. The oily residue was dissolved in 2° of water and ethyl acetate + Oi.
1 oard of pH 6,8p buffer to pH 17. Suction the precipitated 9 solid substances with Nutsche P
Take the sample, wash with water, thoroughly stir with acetone, and dry. 0.7ji (3m! 87% of theory) of the title compound is obtained in the form of colorless crystals; 211-213
Disassembled by.

Similarly, 2,2-difluoro-6-[(5,6-simethoxy2
-pyridyl)methylsulfinyl"]-51(-('t
5]-Dioxoro(4,5'-f''l-benzimidazole [melting point 177-178 (decomposition)], 6-[
(4,5-dimethoxy-3-methyl-2-pyridyl)methylsulfinyl')-5H-(1,5]-dioxoro[4,5-f)-benzimidazole, 6.6. -trifluoro-6,7-dihydro-2-
[(4,5-dimethoxy-2-pyridyl)methylsulfinyl] -1H-(1,4]-didioxin 2.5
-,f]benzimidazole, 6-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-5H
-(1,5l)-dioquine (4,5-f) benzimidazole [melting point 170-171υ (decomposition)], 6-chloro-6+7+' -) refluoro-6 fudihydro 2- [(4,5-dimethoxy- 2-pyridyl)
methylsulfinyl') -1H= (1,+)-dioxin (2,3-f')benzimidazole and 6,7-sihydro2- [(4,5-dimethoxy-2
-pyridyl)methylsulfinyl]-+H-C1,4]
-Didioxin 2.3-f''l benzimidazole is obtained.

(a) 1-nitro-4-(1,1,2.2-tetrafluoroethoxy)be/kun 5'4'fr: Ethanol 30
Hydrogenate with 0.5 g of 1 Ω% palladium on charcoal in a rotary hydrogenation apparatus at atmospheric pressure for 1 hour at 20-45 mm, remove the catalyst, and concentrate the solution under reduced pressure at 4°C. 4 = (
1,1,2,2-tetrafluoroethoxy)aniline in glacial acetic acid.

-, 23 ml of acetic anhydride are added at room temperature, 24 ml of water is added after 30 minutes, and after a short time the solution is concentrated under reduced pressure at 50 pi, and 5001111 of ice water is added. Melting point is 121-12
s 6 g (97%) of 2υ N −(A −(1,1
, 2-tetrafluoroethoxy) phenyltoacetamide is obtained.

(1)) Add 55 g of the above compound to 38 g of dichloromethane.
100% nitric acid 5Ez+t/ was added dropwise within 10 minutes at room temperature, and the mixture was further stirred for 6 hours. The organic solution is then washed with aqueous sodium carbonate and water, dried over magnesium sulfate and concentrated. (from cyclohexane)
65. Melting point is 80-81υ. i9 (+'oo%) N-
(Q) to obtain (2-nitro-4-(1,1,2,2-tetrafluoroethoxy)phenyltoacetamide)
Dissolve the above compound 6sli in 450 g of methanol and 6M hydroxide at room temperature) Add 106 g of IJ solution dropwise, cool in a water bath, and add 900 g of water dropwise to give a solution of 55.9 (98%). 2-nitro-4-(1,1,2
, 2-tetrafluoroethoxylate)-aniline (melting point 85-86 mm).

(d) 33 g of the above compound was mixed with about 6 g of inpropanol.
Hydrogenation was carried out with 1 g of 10-palladium charcoal in a rotary hydrogenator at room temperature without pressure. The catalyst was removed by suction and dissolved with hydrogen chloride in 4M ether to a melting point of 275-27.
4-(1, 1, 2) of 54.9 (89%) of 6 mu (decomposition)
．． 2-Tetrafluoroethoxy)-1,2-phenylenediamine-dihydrochloride is precipitated.

(el the above compound ssgr1c ethanol 550
d1 Add 60 d of water, 8.9 I of sodium hydroxide and 2311 (fc) potassium-〇-ethyldithiocarbonate (recrystallized with impropatur) and heat under reflux for 15 hours to boil. Add 1.2 g of ice water and hydroxide)
I) pH+ 3-14K with rum solution, clarified with activated carbon and precipitated with dilute hydrochloric acid to pH 5.5. (From Improper Tools) Melting point is 316~? Title compound 2 of i+9j'
7Ii (91%) is obtained.

22- 2-Mercapto-5-trifluoromethoxy Similarly to Example 21(e), 4-trifluoromethoxy-1,
2-phenylenediamine-dihydrochloride (0,A,
55, 254o8'6, 1961) and potassium
〇-Ethyldithiocarbonate and sodium hydroxide solution are reacted in ethanol with a yield of 75% and a melting point of 305-307 mm (decomposition, from toluene)
The title compound is obtained.

(a150,9 l -(2,2,2-)lifluoroethoxy)-4-nitrobenzene (8ynthssis1
980, page 727) is hydrogenated and acetylated analogously to Example 21(a). 50 II (95%) of N-(
4=-(2,2,2-)lifluoroethoxy)phenyl]acetamide (melting point 140-141 mm) is obtained.

(b) The above compound 42gt-+oo% nitric acid 9.7
Stir at room temperature for 18 hours in 290d of glacial acetic acid with
Precipitate with water. 47 g (94%) of N-[2-nitro-4-(2,2,2-)lifluoroethoxy)phenyltoacetamide (melting point 117-118 υ) are obtained.

(C) The above compound 47.9 was hydrogenated analogously to Example 21(c) to yield 58.7 g (97 g) of 2-nitro 4- (2,2,2-trifluoroethyl) )-aniline (melting point 84-85 mm) is obtained.

(d) Example 2 + [(1
) to obtain 4-(2,2,2-)lifluoroethoxy)-1,2-phenylenediamine dihydrochloride of 43JF (94ti) with a melting point of 230 to 233t' (decomposition). .

(e) Example 21 Similar to (e), compound 31
5 g to 5 ap (94%) of the title compound (mp 288~
290 mu].

24.5-chlorodifluoromethoxy-2-mer(a)
10.0II of N(4-(ryo-lodifluoromethoxy)phenyl)-7cetamide (melting point 101-106°C
, 4-p-difluoromethoxyaniline and acetic anhydride) and 100s nitric acid 12.5. Dig l0 #
) Z fi 780m! Stir at 20 η for 4 hours in a vacuum chamber.

Neutralize with an aqueous potassium hydrogen carbonate solution, and remove the organic layer t-11m from 11.4! I(9,6)ON-(4-chlorodifluoromethoxy-2-nitrophenyl)-7cetamide (melting point 89-91°C) is obtained.

(b) The above compound 10 in methanol 200zz at 5°C.
．． 50- of sodium methylate in methanol to 5i
Solution 8. , 6@t, stirred without cooling for 2 hours, added ice water, brought to volume 6, and added 8.77 (97%) of 4-chlorosif A/olomethoxyy-2-nitroaniline (melting point 40~ 42°C) t-obtained.

(0) The above compound 8.5IIt-10%'O parasiu 1. Akio, methanol 200 without pressurizing with sg
Hydrogenate in mJI, add concentrated hydrochloric acid and filter.

Concentrate and stir with diisprobil ether.

8.5 p (5'7%) of 4-chlorodifluoromethoxy-1,2-7 enylenediamine dihydrochloride is obtained.

(dJ m Compound 8.5I Example 21 (e)
Similarly, 6.6 with a melting point of 268-270℃ (decomposition)
J (72%) of the title compound is obtained.

2&5--difluoromethoxy-2-mercapto-IH
-Benzimidazole (a) 11.8 ll (D N -(4-difluoromethoxy7 x nyl)-7cetamide (L, M, J
agupO1'5kii et al.' J, General
ChemiBtry (USSR) 59,190 (19
69)) is stirred for 1.5 hours at room temperature with 12.1 fi7 of 100 dihydrochloric acid in 7200 WLl of dichloromethane.

21 (b), 113N (92 wholesale summer - [
(4-difluoromethoxy-2-nitro)phenyl]-
Acetamide (melting point 71-75°C) is obtained.

(b) 4-difluoromethoxy-2-nitroaniline (melting point 6
8-70°C).

(C) 4-difluoromethoxy-1,2-phenylenediamine-dihydrochloride is obtained in a yield of 94% in the same manner as in Example 24c.

(d) Similar to Example 24e with a yield of 78- and a melting point of 25
The title compound is obtained at 0-252° C. (from isopropanol).

(I!L) 500 ml of water and 400 ml of dioxane
,,z Medium Brenzka Chicken 100. p, sodium hydroxide 220I and sodium dithionite 1. Rium 60jl
27511 chlorodifluoromethane at 50-55°C into a solution of L, N, 5eaova
) etc., Zh, Org, KhLm 6.56B (197
0). '6・1~b/1, 0~1
, 11 cPa to obtain a mixture of 1,2-bis(difluoromethoxy)benzene and 2-difluoromethoxyphenol, which was diluted with cyclohexane/ethyl acetate.
Separation is by chromatography on silica gel with 4:1.

(1)) Dichlormefi 1,2 in 7150 ml
-bis(difluoromethoxy)benzene + stt and 1
00 nitric acid 15. The solution of j is stirred at room temperature for 7 hours. Neutralize with potassium bicarbonate solution.

Separate the organic layer and add cyclohexane/ethyl acetate (4:1).
) by silica gel dariha madography ``o1
, 2-bis(difluoromethoxy)-4-nitrobenzene is obtained. This was hydrogenated and acetylated as in Example 21a to give M-(3,4-bis(difluoromethoxy)).
phenyl]acetamide (melting point 81-83°C).

Similarly to Example 21, N −(4,5-bisM −(4,
5-bis(difluoromethoxy)-2-nitro7enyl]acetamide (melting point 65-67°C).

M-(4,5-bis(difluoromethoxy)-2-nitro)aniline (melting point 107-109'C), 4,5
-bis(difluoromethoxy)-1,2-phenylenediamine dihydrochloride and a melting point of 285-287°C (
Decomposition; from isopropanol) to obtain the title compound.

-le(&) water 500,j and dioxane 5QOtnl
Medium guaiacol 55.5 N and sodium hydroxide 13
Chlorodifluoromethane at 60 °C into St of 09 sa
Introduce y. The mixture is filtered at 10° C., the organic layer is separated, dried over anhydrous potassium carbonate and distilled. 1-difluoromethoxy-2-methoxybenzene having a boiling point of 75 to b is obtained.

(1)) The above compound 4 in dichloromethane 250@I
1 in dichloromethane 90 fij at 0-5°C to a solution of 7I
A solution of 33.8 fiJ of 0.00% nitric acid was added dropwise.

After 30 minutes, add ice urine zso,z and neutralize with potassium bicarbonate. The dried organic phase was concentrated under reduced pressure to obtain a residue.
Recrystallize from cyclohexane. s3'&(s+o%) of 1-difluoromethoxy-2-methoxy-5-nitrobenzene (melting point 48-49°C) is obtained. This is hydrogenated and acetylated as in Example 21a. N with 90% yield
-(3-difluoromethoxy-4-methoxyphenyl)
Acetamide (melting point 129-130°C) is obtained.

(C) The above compound 4611 was added to 55 ml of 100 s nitric acid.
Nitrate in dichloromethane as in the previous recipe.

N-(5-difluoromethoxy-4-methoxy-2-nitrophenyl)acetamide (melting point 11
6-117°C) t-obtained.

(Phrase Compound 54JI in methanol 810TrL)
50-methanolic sodium methylate for 1 hour in
Stir with 44-8 ml of gift at room temperature.

Concentrate under reduced pressure and add ice water and glacial acetic acid until pH 8.99
% yield of 5-difluoromethoxy-5-me,toxy-2-nitroaniline (melting point 144-145°C).

(θ) The above compound 251i is hydrogenated according to Example 21t1 with 1.25 jl of 10% palladium on charcoal in 500.1 methanol. 2611 (88%) of 3-difluoromethoxy-4-methoxy-1,2-phenylenediamine dihydrochloride with a melting point of 218-220°C (decomposed) is obtained.

(f) Potassium in the above compounds 25.9 and 191.
〇-Ethyldithi 1 carbonate is reacted according to Example 21a. 2o with a melting point of 280-282°C (decomposition: from isopropanol)! The title compound with I<o9ti) is obtained.

-24- (a) 1-difluoromethoxy-2-fluorobenzene (boiling point 76°C/10 a) from 2-fluorophenol and chlorodifluoromethane in the same way as N27&;
n p =1.4540) is obtained.

(1)) Said compound 30 in dichloromethane 300TrL1! ! To, 38.4 凰 of nitric acid for 100 seconds at -10℃! is added dropwise and stirred for 1 hour at -10°C and for 2.5 hours at 0°C. Add ice water, neutralize, and chromate on silica gel with acetate/cyclohexane (4:1).
・Graph. An oil of 541 is obtained containing about 90% of 1-difluoromethoxy-2-fluoro-4-nitrobenzene and 10% of 1-difluoromethoxy-2-fluoro-5-nitrobenzene and t-(NMR-spectrum). .

(Q) The above mixture 5ait'Ii1'' is hydrogenated and acetylated as in Example 21a. Recrystallized from toluene to obtain N-(4-difluoromethoxy- 3-fluorophenyl)acetamide is obtained.

61) The above compound 2 in 200 mj of dichloromethane
To Qjl 20℃te 100%17) Nitric acid 22.5mj
Add dropwise for 30 minutes and stir at room temperature for 15 hours. Similar to Example 27c with a yield of 89s and a melting point of 72-74
C. (from cyclohexane) ON-(4-difluoromethoxy-5-fluoro-2-nitrophenyl)acetamide is obtained. By stirring for several hours at 60 °C in methanol with 1M hydrochloric acid, the melting point was 95-95 °C in a yield of 95 °C.
4-difluoromethoxy-5-fluoro- at 97.5°C
4-difluoromethoxy-5-fluoro-1,2-phenylenediamine-dihydrochloride is obtained analogously to 2-nidro-marin and Example 27e in a yield of 85. 210℃
Decomposed from.

(e) React the compound 15jl with potassium-〇-ethyldithiocarbonate according to Example 21e.

11. With a melting point of 275-276°C (decomposition, from Improper Tools). The title compound is obtained IN (84%).

-6-thiol (a) 4-amino-2,2,-difluoro-5-nitro-1,5-penzoleoquinol 609 in methanol'5
Hydrogenated with 10-palladium on charcoal 0.5.9 in a rotary hydrogenation apparatus at atmospheric pressure and room temperature in 00TrLj to give 2.5
Add an equivalent amount of methanolic hydrogen chloride solution, filter, concentrate the solution in vacuo, add Impropatol and ether, give 35J (97%) with a melting point of 232-263°C (decomposition).
2,2-difluoro-1,5-benzodioquine-4,5-diamine-dihydrochloride is obtained.

(1)) To the above compound 601 in 5001 rL of ethanol, 55. Potassium-〇-ethyldithiocarbonate 241 (recrystallized with Improper Tool) and sodium hydroxide in J? , 2I and heat to boil under reflux for 15 hours. Pour into 1.5 ml of water, make 14 ml with sodium hydroxide solution, clarify with active substance, precipitate with concentrated hydrochloric acid when hot, and suction the precipitate when cold. Melting point is 565
'24II (91%) C) title compound is obtained at ˜370° C. (decomposition).

3[L 6,6.7-Ore on truffle. 6.7-dihydro(a)2,2,5-trifluoro-2,
3-dihydro-1,4-penzdioxin 50I at 5°C
A mixture of 59.5 mj of 69% strength nitric acid and 461 mj of 97 molar sulfuric acid is added dropwise over the course of 1 hour.

1 hour at 101°C, 1 hour at 20°C and 5 minutes at 40°C
Stir and pour over 200ml of ice.

Extract with dichloromethane, wash with water, dry over magnesium sulfate and distill under reduced pressure.

Boiling point 68.5℃ (θ, 157X bar)
1, soa.

A mixture of 2,2,5-trifluoro-2,3-dihydro-6-nitro-(and 7-nitro)-1,4-benzodioxin of 58 # (9'4) is obtained. 111
1yaO#! Fused silica column (IPuaed 5ili
ca 5auce) (Ohrompack) shows a 2:3 ratio of these two peas. 30
Hydrogenate in a rotary hydrogenator at °C and concentrate under reduced pressure.

so, 5y (io.

H), 6-amino-(and 7-amino-) 2.2.
A liquid mixture of 5-trifluoro4-2,3-dihydro-1,4-benzodioxin is obtained.

(c)2+3. To the above isomer mixture of P at 20-50°C, a mixture consisting of 15.5.9 ml of acetic anhydride and 15 ml of glacial acetic acid is added dropwise, stirred for 60 minutes at 60°C, and 1@1 of water is added.
Add J'i, stir for 60 minutes at 30°C, and remove the solvent by distillation under reduced pressure.

The melting point is 128-15 by recrystallizing with toluene.
7Laximine 19J'' of a mixture of isomeric acetamino derivatives at 3°C.

(10 to 179 isomeric mixtures of acetamino derivatives suspended in dichloromethane 200 TIL1 dissolved in dichloromethane 60, j at -6 to -8°C)
Add 14.7 drops of nitric acid.

and stirred for 2 hours at θ°C and overnight at room temperature. ice 11
Pour into 09 and separate the organic phase.

Wash with water and concentrate under reduced pressure. The residue (19.8p) is recrystallized from 20 mt of ethanol. 6-acetamino-2
,2,3-)lifluoro-2,5-dihydro-7-nitro-1,4-pendzidioxin and 7-acetamino-2
15.59
get.

(e) Suspend 14.5JI of the above product mixture in 80fiJ methanol and add 5M while heating to 30°C.
30 ml of sodium hydroxide solution are added dropwise. Further 0.
Stir at room temperature for 5 hours, pour into 200 l of ice, and add 6-amino-2,2,5-trifluoro-2,3-dihydro-7-
Nitro-14-benzodioxin and y-amino-2゜2
．． 3-) Refluoro-2,6-dihydro 0-6-nitro-1,4-benzodioxin mixture N, 7j' is obtained. The sample was analyzed by a silica gel column in 7 chlorohexane/ethyl acetate (4:1) and by a 60 M&N NMR spectra in deuterochloroform A.M. 120-121
Separate into two pure isomers at °C.

(f) Hydrogenate the above isomer mixture IG, 9N in 500.4 methanol at room temperature and atmospheric pressure over 11 g of palladium on charcoal for 2.5 hours. 4 of 50m1
M of hydrogen chloride in methanol is added dropwise, filtered, concentrated under reduced pressure and stirred with 100 fiJ of ether. 12
．． 6N (981%) of 2.2.5-trifluoro-2,3-dihydro-1,4-benzodioxin-6
,7-diaminecyhydrocuride (melting point>250°C)t
- get.

(g) 8.5 N of the above compound 12jl and potassium-〇-ethyldithiocarbonate (recrystallized with ingropanol) were mixed with 20.5 ml of 4M aqueous potassium hydroxide solution in ethanol 120,j for 17 hours. Heat to boil under reflux. Pour into 300 I of ice, bring to pH 12-13 with potassium hydroxide solution, clarify with activated carbon, and precipitate with concentrated hydrochloric acid. By re-precipitating with acid from an alkaline aqueous-alcoholic solution, a melting point of 509
1o at ~310°C (decomposition)! 1 (93%) of the title compound is obtained.

(a) 2-chloro-2,5,5-trifluoro-2゜5
-dihydro-1,4-benzodioxin 181 to 65- nitric acid 1B, 3.7 and 97% sulfuric acid i5.4.4 at 5 °C
Add the mixture dropwise, stir at 5-10°C for 2 hours, and pour on ice. Extract with methylene chloride and extract with 2. S
, 5-trifluoro-2,5-dihydro-6-nitro-
21.3 Jj of a mixture of (and 7-nitro)-1,4-benzodioxin are obtained as an oil.

(1)) Similarly to example s o(b) then 959b
2-chloro-2,5,5-trifluoro-2, with a yield of
An oily mixture of S-dihydro-1,4-benzodioxin-6-(and 1-)amine is obtained;
) to the corresponding mixture of acetamino derivatives.

(C) The above mixture 19 #t dichloromethane 190
Stir with 161 rLj of 100% O nitric acid in
The reaction product was mixed with cyclohexane/ethyl acetate (4:1).
It is made by glueing with silica gel according to the technique. 6-acetamino-2-chloro-2,3,3-trifluoro-6,7-sihydro-7-nitro-1,4-
Benzodioxine and 7-acetamino-2-chloro-2
,5,S-trifluoro-6,7-sihydro-6-nitro-1,4-benzodioxin mixture 15.9f
i- Obtained as a pale yellow oil.

14.5j of the above mixture in (Q methanol 100m)
30% of sodium methylate in methanol at 5°C to l
% solution is added dropwise, stirred without cooling for 1.5 hours, poured onto ice, neutralized with dilute hydrochloric acid, extracted with dichloromethane and concentrated 3 times under reduced pressure. 6-Amino-2-chlorodi-2,5゜3-trifluoro-2,5-dihydro-7
- Nitro 1.4-penzdioxin,! =7-7 minnow 2-chloro2.5.5- trifluoro-2,3-
A mixture with dihydro-6-nitro-1,4-benzodioxin 12.7.9 is obtained as an orange oil.

(-) The above mixture 12.41 t-Example 30 (f
). 12,6jl (99%) of 2-chloro-2,5,3-)lifluoro-2,3-dihydro-1,4-benzodioxin-6,7-cyamine dihydrochloride are obtained.

(f) Example 3 (+ (
Similarly to g), react with potassium 0-ethyl dithiocarbonate of 9.11 and potassium hydroxide solution in ethanol. Melting point: 288-290℃ (decomposition) oq, 6
ji (7t%) tv The title compound is obtained.

62.2-Chlorotetramethyl-4,5-dimethoxy-pyridinium chloride (a) 2-chloromethyl-4,5-dimethoxypyridinium chloride 2-hydroxymethyl-4,5 in 40 mj of methylene chloride
-To a solution of dimethoxypyridine 5JF cooled to 0°C 1
31 t" of thionyl chloride dissolved in 10 t of methylene chloride are added dropwise and then stirred for 4 h at 20° C., during which the reaction mixture is colored red, 5 tJ of toluene is added and evaporated completely on a rotary evaporator. Concentrate (30℃/5 m
bar). The oily residue is dissolved in 50 mj hot isopropanol, clarified with a small amount of Tonal, filtered and concentrated again. Put toluene in io@j.

The solution is crystallized with petroleum ether. After cooling in a water bath, remove with suction F, wash with 1 petroleum ether, and dry. 4.61
(Theoretical amount of 704) of the title compound 2-chloromethyl-4
,5-dimethoxy-pyridinium chloride as a colorless solid; decomposition at 160-61<0>C.

(cut 2-hydroxy dimethyl-4,5-dimethoxy-
Pyridine 4,5-dimethoxy-2-methylpyridine-1
- oxide 19 J't-to 60 TLz of acetic anhydride heated to 80°C for 30 minutes.

Add so that the temperature does not rise above 100℃. 4 more
After 5 minutes at 85° C., the excess acetic anhydride was removed by distillation under reduced pressure and the intermediate 2-acetoxymethyl-4,5-dimethoxypyridine was dissolved in a virtually oily dark residue tube with 80 mj of 2M sodium hydroxide solution. Stir together for 1 hour at 80°C. After dilution with water aoHz and cooling, extraction was carried out with 8% portions of methylene chloride. The combined organic phases were washed twice with 1N sodium hydroxide solution, dried and concentrated to give a crystalline and colored residue. recrystallize with toluene. 2-Hydroxymethyl-4,5-dimethoxypyridine of 141i (theoretical amount of 74ti) is obtained with a melting point of 122 DEG -24 DEG C.

(c) 4,5-dimethoxy-2-methylpyridine-
To a suspension of 5-methoxy-2-methyl-4-nitroviridine-1-oxide 16.9 II in 170 mJ of dry methanol 30% sodium methoxy 2-
20 ml of the solution are added dropwise and stirred for 15 hours at 20°C and then for 4 hours at 50°C. While cooling on ice, carefully add concentrated sulfuric acid to bring the pH to 5pHy.

The residue was thoroughly stirred with 200 mj of methylene chloride, and the insoluble components were separated.

Add 10.4 g of toluene and concentrate again to dryness. 1s
, 4,5-dimethoxy-2- of z# (theoretical amount of 98th)
゛Methylpyridine-1-oxide with a melting point of 118-121
Obtained as colorless crystals at °C.

cd) 5-Methoxy-2-methylpyridine-1-oxide 21.2.9 5-methoxy-2-methylpyridine-1-oxide 21.2.9 to 60% nitric acid heated to 60 °C 0 reaction mixture Add so that the temperature does not exceed 80℃.

Stir at 80°C for 1 hour, then add 1 hour more for complete reaction.
Add 3 ml of 100% nitric acid and leave at 60-70 ml for another 2 hours.
Stir at °C. Pour into 5oaII ice for work-up. Collect the yellow precipitate using Nutsche, wash with water,
dry. The dried solid substance was dissolved in methylene chloride 200M.
Boil thoroughly with Ll, filter and dry. Concentrate the P solution and isolate the pure product by additional thin layer chromatography. 22.51 with a melting point of 201-202°C
1 (87% of theory) of 5-methoxy-2-methyl-4
-ditropyridine-1-oxide; yellow crystals (e) 5-methoxy-2-methylpyridine-1-oxide in 5 ozt of glacial acetic acid 60'C to St of 5-methoxy-2-methylpyridine 60.99 "t" 30% (D hydrogen peroxide solution 1-20 Iit) Soak for 1 hour and stir for 5 hours.To determine the activity, add manganese oxide to decompose excess decomposed compounds, then filter and concentrate. The residue was heated in 500 ml of ethyl acetate and concentrated again.

Distill at Ojmbar. 54. Iit (theoretical quantity 77
H) 5-methoxy-2-methylpyridine-1-oxide is obtained as a rapidly solidifying oil (boiling point 130°C); melting point 80-84°C.

(f) 5-methoxy-2-methylpyridine methanol 4
150 TIL of 6-bitroxy-6-methylpyridine are added in 1 hour to a solution of 84 Jl' of potassium hydroxide in 0 oz and 500 ml of dimethyl sulfoxide. After the methanol was removed in a rotary evaporator, methyl iodide 213II dissolved in 100 ml of dimethyl sulfoxide was mixed with ice-cooling, stirred for 15 hours at 20° C., and the reaction mixture was steam distilled. The distillate is extracted continuously with methylene chloride in an extractor and the extract is concentrated. 85y(
56% of theory) of 5-methoxy-2-methylpyridine was obtained as a colorless oil.

(a) 2-Chloromethyl-4,5-dimethoxy-3-methylpyridinicum chloride According to the procedure described in Example 32(a).

After a reaction time of 1 hour by reacting 2.71 2-hydroxymethyl-4,5-dimethoxy-6-methylpyridine with thionyl chloride 4y in methylene chloride 25, J.

A simplified work-up method is used, namely by adding 10 ml of toluene, removing methylene chloride and excess thionyl chloride by distillation, and vacuuming the precipitated crystals and drying.

5.451 (099% of theory)O Obtain the title compound as colorless crystals.Decomposition at 1125-26°C.

(b) 2-Hydroxymethyl-4,5-dimethoxy-6-methylpyridine 4.5-dimethoxy-2,3-dimethylpyridine-1 nioxide 4.5 J 1'-acetic anhydride 20 @3 in
The mixture is heated to 110° C. for 0 minutes and then concentrated using a rotary evaporator.

Intermediate 2-acetoxymethyl-4,5-dimethoxy-
Oily residue consisting of 3-methylpyridine f5M sodium hydroxide solution30. After cooling, the mixture was stirred at 80° C. for 2 hours at 80° C., and after cooling was extracted with five portions of methylene chloride. The combined organic phases were washed twice with 2N sodium hydroxide solution, dried, concentrated and the residue was extracted with petroleum chloride. Stir to mix with ether.

Vacuum and dry. 4. Melting point is 91-92°C. O
2-hydroxymethyl-4,5 of N (theoretical amount of 89 cups)
-dimethoxy-6-methylpyridine is obtained.

(c) 4,5-dimethoxy-2,5-dimethylpyridine-1-oxide Dissolve 6.51 ml of 4,5-dimethoxy-2. - Add chlorberoki-7benzoic acid, first at 20°C for 2 hours and then at 40°C for 4 hours.
Stir at "C. 2.77 L of 5M sodium hydroxide solution.
After addition of 1 ml, the aqueous phase was extracted five times with methylene chloride and the combined organic phases were washed five times with a mixture of 5 ml of sodium thiosulfate and 5% sodium carbonate solution.
Dry with magnesium ftaate and concentrate.

4.61 (66% of theory) of 4,5-dimethoxy-2
, 5-dimethylpyridine-1-oxide is obtained. Methicin chloride/methanol 19:1 gives an Rf value of 0.25.

(J 4.5-dimethoxy-2,3-dimethylpyridine 5-hydroxy-4-methoxy-2,3-dimethylpyridine 9.1
8 JF (dimethyl sulfoxy)' in 50 mj, firstly with sodium hydroxide 3,6I and then with methyl iodine 8
．． 95JI gives 7.4N (74% of theory) 4,5-dimethoxy-2,5-dimethylpyridine as a colorless, slowly crystallizing oil; mp 56
~38℃.

(e) 5-hydroxy-4-methoxy-2,3-dimethylpyridine 4-methoxy-2,3-dimethylpyridine-
1-oxide 1ooo 1't Acetic anhydride 3 in 7 hours with stirring at 100°C! and further stirred at 100° C. for 3 hours. Allow to cool, concentrate completely at 70°C/10 mbar and firstly distill at 10”-2 mbar.95-1
7 Lac 7'E/(intermediate 5-acetoxy-4-methoxy-2゜6-dimethylpyridine and 2
-acetoxymethyl-4-methoxy-3-methylpyridine) was taken, and Q(95211) was prepared at 50°C.
Add over 60 minutes to 3.5 kg of 2N sodium hydroxide solution heated to .

Stir at SO °C until a clear solution results (approximately 6 h),
Cool and extract with five 1j portions of methylene chloride. The combined organic phases are extracted again with five 0.5 portions of 1× sodium hydroxide solution and the combined aqueous phases are then brought to 7.5 ml with half-concentrated hydrochloric acid without stirring. . Collect the precipitated solid substance t-F.

Wash and dry until constant weight. Melting point is 274~
5-hydroxy-4-methoxy-2,3-dimethylpyridine at 76°C is obtained.

(a) 2-Chloromethyl-6,4-dimethoxy-pyridinium chloride Example 52aVc 2-Hydroxymethyl-6,4-dimethoxypyridine 5.58& and thionyl chloride 2@j are dissolved in methylene chloride 30
After a reaction time of 2.5 hours, 4.2 l (theoretical amount of 95 g) of the title compound was purified by the work-up method described in Example 55a, with a melting point of 1.
Obtained as a colorless solid at 51-152°C (decomposed).

(b) 2-hydroxymethyl-6,4-dimethoxypyridine 2-acetoxymethyl-6,4-dimethoxypyridine 4
．． 81 is stirred vigorously at 80 DEG C. to which 15 t of 2N sodium hydroxide solution is added; a homogeneous solution forms from the initial two-phase mixture. Cool after 2 hours.

Extract with 30.7 portions of methylene chloride once.

5. Pour the combined organic phases five times. Wash with 8,3 ml of sodium hydroxide solution, dry over potassium carbonate, filter, concentrate and stir the distillation residue with petroleum ether.

2- and droxymethyl- of 3,6I (theoretical amount of 96T)
3,4-dimethoxypyridine is obtained as a colorless solid with a melting point of 87-89°C.

(c) 2-acetoxymethyl-6,4-dimethoxypyridylene acetic anhydride 25.44C 6,4 in 1 hour at 85°C
-dimethoxy-2-methylpyridine-1-oxide 4-
8j' (28@Mo1) 1'- was added, stirred for 1 hour at the same temperature, completely concentrated under reduced pressure, and the colored oily residue was transferred to a tube distillation apparatus (Kugelrohrdeatil).
ls ) and distilled at I Pa. 5451 (theoretical quantity 9
0%) of 2-acetoxymethyl-6,4-dimethoxypyridine; boiling point 125-1'50°C.

(+1) 5.4-dimethoxy-2-methylpyridine-1-oxide 3-methoxy-2-methyl-4-nitropyridine -1
- Oxide 4-5F (25gMol) in 75TIL of dry methanol! After adding 60 g of sodium methylate solution 4.7.4, the mixture is stirred for 16 hours at 40°C. It was then cooled, brought to pH 7 with concentrated sulfuric acid, filtered and completely concentrated under reduced pressure, and the oily reddish residue was dissolved in toluene SO
rrLt, insoluble components are separated again, and the P solution is concentrated to dryness. A yellow oily residue crystallizes in a water bath; this is then combined with 5 of petroleum ether (50/70)
Stir thoroughly at 40°C. dried in a desiccator to form pale yellow crystals with a melting point of 111-113°C.
．． 2:I (88% of theory) of 5,4-dimethoxy-2
-Methylpyridine di-1-oxide is obtained.

(e) 6-medium 2-methyl-4-nitropyridine-1-oxide glacial acetic acid 12. 3-methoxy-2- in j
Methylpyridine-1-oxide 5.41 at 80℃・6
Add concentrated nitric acid 8.7 hours in four parts of 2@l each,
- Stir at the same temperature at night, add 8 m7 of nitric acid in three portions over 6 hours, and stir for a further 15 hours. After cooling, add ice (4
0N) and pH 6 with 10M sodium hydroxide solution.
The precipitated by-product (5-methoxy-2-methyl-
4-nitroviridine) was extracted from house to house with 50 g of methylene chloride four times. After drying 1, the combined organic phases are concentrated completely and the residue is recrystallized from a small amount of methylene chloride/petroleum ether. 4.2# (theoretical amount of 57-) of the title compound is obtained in the form of yellow crystals with a melting point of 103-104°C.

(t) S-methoxy-2-methylpyridine-1-oxide 3-methoxy-2-methylpyridine 15451 (0,
124 Mol) was dissolved in 100 fij (C) of glacial acetic acid.

, 30-g of peroxide at 80°C, J t-4.

Divide into 6 hours and add. Stir for a further 3 hours, then concentrate under reduced pressure (1.5 kPa), add twice-50 WLl of acetic acid and concentrate completely in each case. After the decomposition products are no longer detected, the bulb-tube furnace (Kugelrohro
fen). The 7-lactone distillate at 120° C. (1.5, Pa) is thoroughly stirred in a small amount of diethyl ether, and the solid material is separated and dried. 12I (60 theoretical amounts) of 3-methquine-2-methylpyridine-
The 1-oxide is obtained in the form of colorless crystals with a melting point of 72-78°C.

(g) 5-methoxy-2-methylpyridine Example 52f
3-Hydroxy-2-methylpyridine, 15.71 (125 HMOl) and methyl iodide, 9.2@J, are reacted by adding 46@J of 5M methanolic potassium hydroxide solution according to the procedure described in Possibly after a reaction time of 3 hours 1S,5II (theoretical amount of 9
0%) of 3-methoxy-2-methylpyridine as a colorless oil.

Dialkoxypyridine and its salts represented by the general formula ■,
They have valuable pharmacological properties that make them industrially usable. They significantly suppress the secretion of gastric acid in warm-blooded animals and even more.

Shows pronounced gastrointestinal protective effects in warm-blooded animals. This gastrointestinal protective effect is already observed with doses below the acid secretion suppressing dose. A further compound according to the invention is:

It is outstanding because it has virtually no side effects and is highly effective in treatment. In this context, ``gastrointestinal logging'' refers to 1 gastrointestinal diseases that can be caused, for example, by microorganisms, bacterial toxins, drugs (e.g. certain anti-inflammatory and rheumatological drugs), chemicals (e.g. ethanol), gastric acid or stress conditions. , especially the treatment and treatment of gastrointestinal inflammatory diseases and injuries, such as gastric ulcers, duodenal ulcers, gastritis, hyperacidity or irritation caused by drugs.

Another advantage of the compounds according to the invention is their relatively high chemical stability.

The excellent properties of the compounds according to the invention surprisingly show that they are significantly superior to the compounds known from the state of the art. This property makes dialkoxypyridines and their pharmaceutically acceptable salts suitable for use in human and veterinary medicine, where they are particularly suitable for use in gastrointestinal diseases and due to increased gastric acid secretion. It is used for the treatment and/or prevention of such diseases.

Therefore, one object of the present invention is a compound according to the invention for use in the treatment and/or prevention of the above-mentioned diseases.

The invention likewise includes the use of the compounds according to the invention in the manufacture of medicaments for use in the treatment and/or prophylaxis of the above-mentioned diseases.

A further subject of the invention is a medicament containing one or more dialkoxypyridines of the general formula 1 and/or their chestnut-acceptable salts.

The medicament is manufactured by methods known and well known to those skilled in the art. As a drug, the pharmacologically active compound (=active ingredient) according to the invention can be used as such or preferably in combination with suitable auxiliaries in the form of tablets, dragees, capsules, suppositories, mouthwashes (for example as TTS), emulsions. Used in the form of a suspension or solution, the content of active ingredient is particularly preferably between 0.1% and 95%.

Which auxiliaries are suitable for the desired formulation is well known to those skilled in the art on the basis of their expertise. solvent,
Gelling agents, suppository bases, tablet auxiliary materials and other active ingredient carriers, such as antioxidants, dispersants, emulsifiers, antifoaming agents.

Taste modifiers, preservatives, solubility aids, in particular penetration enhancers and complexing substances (eg cyclodextrins) can be used.

The active ingredient can be used orally, parenterally or transdermally.

Generally, the active ingredient or ingredients are administered orally from about o,ooi to about 20 per gram of body weight. Especially '0.0
5 to 5. In particular, it has been found in human medicine that it is advantageous to administer the drug in a daily dose of 0.1 to 1.5 mJF, sometimes in several doses, especially in 1 to 4 doses, in order to obtain the desired result. found. In the case of parenteral treatment, similarly or (if the active ingredient is administered intravenously) generally lower dosages can be used. The determination of the optimum dosage and method of administration of the active ingredient required in each case
Each expert can easily perform it based on their specialized knowledge.

If the compounds and/or salts according to the invention are to be used in the treatment of the diseases mentioned above, the preparations may include other drug groups such as antacids such as aluminum hydroxide, magnesium aluminate; tranquilizers such as benzodiazepines such as diazepam; antispasmodics such as vietamiverine. , camylofin; anticholinergics such as oxyphencyclimine, 7-encarbamide; local anesthetics such as tetracaine, procycline;
Optionally, it may also contain one or more pharmacologically active ingredients such as enzymes, vitamins or amino acids.

In this connection, it is particularly possible to combine the compounds according to the invention with other acid secretion inhibitors, such as H2-31 antagonists (e.g. cimetidine, ranitidine), and also with so-called peripheral anticholinergic drugs (e.g. pirenzepine, telenzepine, zolenzepine). Combinations with and with gastrin antagonists may be mentioned with the intention of increasing the main effect in an additive or synergistic sense and/or eliminating or reducing side effects.

Pharmacology The remarkable gastroprotective and gastric secretion suppressive effects of the compounds of the present invention can be demonstrated in animal experiments using a 5-hay rat model. The tested compounds were numbered as follows: Tests for anti-cancer activity were carried out using the so-called 8-may rat method in which rats (female rats) were kept in a fasted state for 224 hours.

180-200 Il, 4 animals per cage on high iron bars) were treated with pyloric ligation (under diethyl ether anesthesia) and oral administration of 7 cetylsalicylic acid at 100 V10 mj/9. bring about The substance to be tested was administered orally (1 o mj
/kl! )Administer. The wound is closed using a Mitschel hook. At 4 hours, the animals are killed by decapitation in ether vapor and the stomachs are removed. The stomach was cut longitudinally, fixed on a cork board, and examined with a stereomicroscope, after first measuring the amount (volume) of gastric juice secreted and later measuring its HOj content (titrated with sodium hydroxide solution). Examine the number and size (diameter) of cankers present under 10x magnification. The product of the degree of severity (according to a scalar of the next rating) and the number of lesions is used as the individual damage index.

Score scalar 12 No difference 0 Diameter of the pipe 0.1-1.41111 11;5
~2.4Wl 2 2.5-3.4wx 5 3.5-44m4 4.5-5.4sm 5 >5.5cm 6 Each treated compared to the average damage index (=100cm) of the control group The reduction in the average damage index of the group is used as a measure of the effectiveness in preventing injury. XD25 and KD50 are respectively,
Average damage index and HOj-secretion compared to control
and represents the dose that reduces the dose by 50%.

The LD50 of all compounds tested for toxicity was 1000 in mice.
wdi/qt (oral) or higher.

Claims (1)

[Claims] 1. General formula I ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R1 is 1 substituted completely or mainly by fluorine)
~3C-alkyl group or chlorodifluoromethyl group and R1' is hydrogen, halogen, trifluoromethyl, 1-3
C-alkyl or -1-3C-alkoxy optionally substituted completely or mainly by fluorine, or R1 and R1' together and including the oxygen atom to which R1 is attached; , a 1-2C-alkylenedioxy group optionally fully or partially substituted by fluorine or a chlorotrifluoroethylenedioxy group, R3 represents a 1-3C-alkoxy group, the radicals R2 and One of R4 represents a 1-3C-alkoxy group, the other represents a hydrogen atom or a 1-3C-alkyl group, and n represents the number 0 or 1) and a salt of the compound . 2. R1 is a 1-3C-alkyl group completely or mainly substituted with fluorine or a chlorodifluoromethyl group, and R1' is hydrogen, halogen, trifluoromethyl, 1-3
a C-alkyl group or a 1-3C-alkoxy group optionally substituted completely or mainly by fluorine, R3 is a 1-3C-alkoxy group, one of the groups R2 and R4 is a 1-3C-alkoxy group; and on the other hand a hydrogen atom or a 1-3C-alkyl group and n represents the number 0 or 1, as well as salts of the compounds. 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 chlorotrifluoro R3 is an ethylenedioxy group, R3 is a 1-3C-alkoxy group, one of the groups R2 and R4 is a 1-3C-alkoxy group, the other is a hydrogen atom or a 1-3C-alkyl group, and n is the number 0 or 1. Compounds of formula I according to claim 1 and salts of said compounds. 4, R1 is 1,1,2,2-tetrafluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl,
difluoromethyl or chlorodifluoromethyl, R
1' represents hydrogen, R3 represents methoxy, one of R2 and R4 represents methoxy and the other hydrogen or methyl, and n represents the number 0 or 1, the formula according to claim 2 Compounds of I and salts 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 formula I as claimed in 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 formula I according to claim 3 and salts thereof, having the meaning given in claim 3. 7. Compounds of formula I and acid addition salts thereof according to any one of claims 1 to 6, wherein n means the number 0. 8. Compounds of the formula I according to any of claims 1 to 6, and their salts with bases, wherein n represents the number 1. 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 and 2,2-difluoro-6-[(4,5-dimethoxy-2
-pyridyl)methylsulfinyl]-5H-[1,3]
A compound selected from the group consisting of -dioxolo-[4,5-f]benzimidazole and salts thereof. 10. Use according to any of claims 1 to 9 for use in the treatment and/or prevention of gastric and/or intestinal diseases and such diseases based on increased gastric acid secretion. dialkoxypyridine and its pharmaceutically acceptable salts. 11. General formula I ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R1 is 1 substituted completely or mainly by fluorine.
~3C-alkyl group or chlorodifluoromethyl group and R1' is hydrogen, halogen, trifluoromethyl, 1-3
C-alkyl or -1-3C-alkoxy optionally substituted completely or mainly by fluorine, or R1 and R1' together and including the oxygen atom to which R1 is attached; , a 1-2C-alkylenedioxy group optionally fully or partially substituted by fluorine or a chlorotrifluoroethylenedioxy group, R3 represents a 1-3C-alkoxy group, the radicals R2 and One of R4 represents a 1-3C-alkoxy group, the other represents a hydrogen atom or a 1-3C-alkyl group, and n represents the number 0 or 1) and a salt of the compound (a) Mercaptobenzimidazole shown by formula II ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) and formula III ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) or (b) a benzimidazole represented by the formula IV ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) and mercaptopicoline represented by the formula V ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (V) or (c) o-phenylenediamine represented by formula VI ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VI) and a formic acid derivative represented by formula VII ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VII) reacted and optionally then formula VII obtained according to (a), (b) or (c)
I ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VIII) Oxidizing and/or converting the 2-benzimidazolyl-2-pyridylmethyl-sulfide shown by (d) Formula IX ▲ Mathematical formula, chemical formula, There are tables, etc. ▼ (IX) Benzimidazole shown by formula X ▲ Numerical formulas, chemical formulas, tables, etc. There is a reaction between a sulfinyl derivative represented by ▼ (X I ) and a 2-picoline derivative represented by formula However, Y, Z, Z' and Z'' represent appropriate leaving groups, M represents an alkali metal atom (Li, Na or K), and M
' represents an equivalent metal atom and R1, R1', R2
, R3, R4 and n have the meanings given above. 12. One or several general formulas I ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R1 is 1 substituted completely or mainly by fluorine.
~3C-alkyl group or chlorodifluoromethyl group and R1' is hydrogen, halogen, trifluoromethyl, 1-3
C-alkyl or -1-3C-alkoxy optionally substituted completely or mainly by fluorine, or R1 and R1' together and including the oxygen atom to which R1 is attached; , a 1-2C-alkylenedioxy group optionally fully or partially substituted by fluorine or a chlorotrifluoroethylenedioxy group, R3 represents a 1-3C-alkoxy group, the radicals R2 and One of R4 represents a 1-3C-alkoxy group, the other represents a hydrogen atom or a 1-3C-alkyl group, and n represents the number 0 or 1) Dialkoxypyridine and/or its pharmaceutical properties Drugs containing legally acceptable salts.