DE1923481A1 - Process for the preparation of amides and esters of 1-hydroxy-benzimidazole-2-carboxylic acid - Google Patents

Description

FARBWERKE HOECHST AG., Formerly Meister Lucius & Brüning File number: Fw. 6074

Date: March 6, 1969

Process for the preparation of amides and esters of T-hydroxy benzimidazole-2-carboxylic acid '

The invention relates to a one-step process for the preparation of esters and amides of 1-hydroxy-benzimidazole-2-carboxylic acid. Some representatives of this class of substances are obtained from o-nitroanilides by reduction. (Ber. Dtsch. Former Ges. 43., 3012 (1910), Liebigs Ann. Chem. 5 ^ 7. 38 (1937)) · Base-catalyzed cyclization of N-benzyl-o-nitroanilines produces phenyl-substituted 1-hydroxybenzimxdazoles. The photolysis of N-2,4-dinitrophenylamino acids in water gives 1-hydroxy-6-nitro-benzimidazole derivatives, which are also formed from the ot- (2,4-dinitrophenylamino) acrylic acid esters and bases, which are accessible over several stages. (J. former Soc. (London) 1967 , 1750, 1764).

It has now been found that esters and amides of 1-hydroxybenzimidazole-2-carboxylic acid can be obtained of formula I,

n ²

in which R is a low molecular weight alkoxy group or an amino group, optionally by one or two aliphatic or aromatic

2 3 4 5 radicals is substituted, and R ₁ R ₁ R and R, which can be the same or different, denote hydrogen, halogen, low molecular weight alkyl, alkoxy or carbalkoxy groups or carbonamide groups, obtained by benzfuroxanes of the formula II or II a (tautomeric forms)

Fw. 6074

II

II a

with 1,3-dicarbonyl compounds of the formula III,

RC-CH ₂ -COR ¹

III

in which R has the above meaning and R is an alkyl or Represents alkoxy group with up to 4 carbon atoms, with potassium hydroxide or potassium alcoholates in alcoholic solution implements.

The following can be used as benzfuroxanes: Benzfuroxan, 4 (7) methylbenzfuroxan, 5 (.6) -Methylbenzfuroxan, 5,6-dimethylbenzfuroxan, 5 (6) -n-butylbenzfuroxan, 5 (6) -trifluoromethylbenzfuroxan, 4 (7 ) Methoxybenzfuroxan, 4 ^ 5 (6,7) -diinethoxybenzfuroxan, 5 (6) -ethoxybenzfuroxan, 4 (7) -chlorobenzfuroxan, 5 (6) -horbenzfuroxan, -5.6 (6,7) -dichlorbenzfuroxan, 5 (6) - Bromobenzfuroxan, 5 (6) carboxymethylbenzfuroxan, 5 (6) carbamoylbenzfuroxan,

As 1,3-dicarbonyl compounds, for example, can be used? Ethyl acetate, ethyl acetoacetate, butyl acetoacetate, Acetoacetic acid amide, acetoacetic acid amide, Aceteeeigeäuredimethylamid, Aceteseigsäureauiilid, Acet = eeaigeäure-p-methoxy-anilid, acetoacetic acid-ia-clilöranilid, AcQt B * 8ie * aure-p-raethylanilLd, jß-Ketovalerlaneäisr @@ e Malonic acid diethyloeter, malonic acid diethyl ester

The Heaktlon is preferably carried out _s that iaan a * solution of a ·· 'Benzfuroxane of Porsnel II or II a in. Eisaesea

. _V '.; V, - "- j ^ = 4 009846/1919

- 3 - Fw. 6O74

free alcohol such as methanol or ethanol, a dicarbonyl compound of the formula III is added and, with stirring at about 40-7O C, a small excess of an alcoholic solution of Add dropwise potassium hydroxide or potassium alcoholate (approx. 1.5-2 mol) leaves. Some of the 1-hydroxy-benzimidazole precipitates as the potassium salt and is converted into the free compound by loosening and weak acidification. The remainder is isolated by concentrating the Mother liquor, dissolving the residue in water, removing neutral impurities and acidifying.

The specified conditions are preferred ranges which can also be exceeded upwards or downwards. It's for that Reaction sufficient to use equivalent amounts of the starting materials, In the interest of a higher yield, it is sometimes advantageous to use an excess of the di-carbonyl compound, preferably 0.5 to 1.5 moles to be used.

The inventive implementation is surprising, since it comes from Belgian Patent 69T 97 ^ »is known. that from benz for oxanes and 1,3-Oicarbonylirerbindungen in the presence of weak bases, such as e.g. ammonia, butylamine and cyclohexylamine, exclusively Quinoxaline-di-N-O3c will result. It was not foreseeable that by using a strong base, the condensation takes a different course and the main products are i-hydroxy-benzimidazole-2-carboxylic acids develop.

The products of the invention are important starting materials for the production of pesticides and pharmaceuticals.

example 1

1 -Hydroxy-benziari-dazol- 2.— ethyl carboxylate

13.6 β eenzfuroxane and 2.6 g acetoacetic ester are dissolved in 100 ecm anhydrous! Ethanol and leaves at about 5O C-won with stirring a solution B ₉ H g Ealiuahydroxyd in 1OO ecm added dropwise anhydrous ethanol · The Kaiiuasalz of the i-Hydroxybenzinidazol-2-carbonsäureäthjleeters (i3 "5 β) falls already during the addition of

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- k - Fw. 6074

Base off. The mixture is stirred for about 1 hour, cooled in an ice bath, the precipitate is filtered off and washed with about 100 ecm of ethyl acetate the end. The mother liquor is concentrated in vacuo, the residue is dissolved in 100 ecm of water and extracted three times with 100 ecm of ethyl acetate. The aqueous phase is treated with a little activated charcoal, filtered and acidified with glacial acetic acid. Another 1.5 g separate 1-Hydroxy-benzimidazole-2-carboxylic acid ethyl ester with a melting point of 166 167 C crystalline. Total yield: $ 62

Analysis for C. ) ^H 1 0 ^N 2 ° 3 ⁽ 206.1; I. H , 89 N 13th , 59 13th , 7 Calculated 58 .27 H 5 ,1 13th Λ / Found 58 , 7

In an analogous manner one obtains b) 1-Hydroxy - ^ - methoxy - ^ - chlorobenzimidazole-2-carboxylic acid ethyl ester, 153 C.

Example 2

1-Hydroxy - ^ - methoxy-benzimidazole ^ -carboxylic acid ethyl ester

49.8 g of 5 (6) -methoxybenzfuroxane and 78 g of acetoacetic ester are dissolved in 3OO ecm of anhydrous ethanol and dripping in at about 50 C. Stir a solution of 26 g of potassium hydroxide in 300 ecm of anhydrous Ethanol too. When the addition is complete, the reaction mixture is allowed to cool to room temperature and the reddish precipitate is filtered off with suction away. This is dissolved in approx. 3OO ecm of water, extracted with ethyl acetate, treats the aqueous phase with activated charcoal and acidifies with acetic acid. The ethyl 1-hydroxy-5-methoxy-benzimidazole-2-carboxylate precipitates in the form of shiny flakes and can optionally be recrystallized from ethanol. Yield:

3k, 5 g, m.p. 1 96 ° C. (236 .2) 5, 12th N 1 1 , 86 Analysis for C 11th »12 ^N 2 ° 4 H 5, 1 1 1 , 7 Calculated C. 55 .93 Found 55 .9

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One obtains in an analogous manner

b) 1-hydroxy-S-ethoxy-benzimidazole ^ -carboxylic acid ethyl ester, M.p. 210-212 ° C;

c) 1-Hydroxy-benzimidazole-2-carboxylic acid methyl ester ^ M.p. 160-161 ° C;

d) 1-Hydroxy-5ιo-dimethyl-benzimidazole ^ -carboxylic acid ethyl ester, Mp. 167 C (from dioxane).

Example 3

1-Hydroxy-5-athoxycarbonyl-benzimidazole-2-carbonsaTj.reath.yle st er

20.8 g of 5 (6) -ethoxycarbonyl-benzfuroxane and 26 g of acetoacetic ester are dissolved in 100 ecm of anhydrous ethanol and a solution of 10 g of KOH in 120 ecm of ethanol is added dropwise at about 50 ° C. while stirring. Stir the reaction mixture for about hour hours and sucks the precipitation. By dissolving in water and acidifying the filtered solution with acetic acid, 5-ethoxycarbonylbenzimidazole-2-carboxylic acid ethyl ester is obtained.

The alkaline mother liquor is concentrated in vacuo, the precipitate is taken up in water, and the solution is extracted three times Ethyl acetate and acidify the aqueous phase, which has been clarified with activated charcoal, with acetic acid. The precipitated 5-ethoxycarbonylbenzimidazole-2-carboxylic acid ethyl ester is recrystallized from dioxane together with the majority. M.p. 201 C, yield: $ 38.

Analysis for C 3 ^H i * r; 2 ° 5 I270.3J H 5 , 07 N 10 , 07 Calculated C. 56, 11th 5 , 0 9 ,8th Found 56, 2

Tn is obtained in an analogous manner, one

b) * i-Hydroxy-benziraidazole-S-carboxylic acid anilide, melting point 160 C.

0 0 9 8-A 8- / 1 9-t-a. BAD0RI8INÄ.

Claims (10)

Claims i) 1-Hydroxybenzimidazole-2-carboxylic acid esters and amides of the formula I, .2 R- L.
R. \ 1 \\ - CO-R OH .1 in which R is a low molecular weight alkoxy group or an amino group, which may be replaced by one or two aliphatic or aromatic 2 3-4 5 ■ table radicals is substituted, and R, R, R and F, which are the same or can be different, hydrogen, halogen, low molecular weight Alkyl, alkoxy or carbalkoxy groups or Cajrfooiaaniidgruppen mean. 2) Process for the preparation of esters and amides of ¹ 1-hydroxybenzimidazole-2-carboxylic acid of the formula I, characterized in that benzfuroxanes of the formula II or IT a (tautomeric forms) .2 with a 1,3 dicarbonyl compound of the formula III » RC-CH ₀ -CO-R ¹ U ² III in which R represents an alkyl or alkoxy group with up to h E atoms, is reacted with potassium hydroxide or potassium alcohol in an alcoholic solution. 009846/1919 BAD ORISlNAL - 7 - Fw. 6074 3) 1-Hydroxy-benzijiidazole-2-carboxylic acid ethyl ester. 4) l-Hydroxy - ^ - ethoxy-S-chlorobenzimidazole-2carboxylic acid ethyl ester. 5) ethyl l-hydroxy-5-methoxy-benzimidazole-2-carboxylate. 6) l-Hydroxy-S-ether benziÄidazol ^ -carboxylic acid ethyl ester " 7) l-hydroxy-5, e-dieethyl-benzimidazole ^ -carboxylic acid ethyl ester, 8) 1-Hydroxy-benzimidazole-2-carboxylic acid methyl ester. 9) 1-Hydroxy-5-ethoxy carbonyl-benzimidazole-2-carboxylic acid ethyl ester. 10) 1-Hydroxy-benzieidazole-2-carboxylic acid anilide. 0098 ^ 67 1919