DE1173082B - Process for the preparation of N-mono-substituted ª ‡ -hydroxycarboxylic acid amides - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school Class: C 07 c

German class: 12 ο -16

Number: 1173 082

File number: F 37003IV b / 12 ο

Filing date: June 6, 1962

Opening day: July 2nd, 1964

According to the well-known reaction of Passerini (Gazz. Chim. Ital., Vol. 51, 1921, p. 181; Vol. 53, 1923, P. 410; Vol. 61, 1931, p. 964) isonitriles with carbonyl compounds in the presence of organic Carboxylic acids converted to N-monosubstituted «-Acyloxysäureamiden.

A corresponding reaction in the presence of mineral acids has not yet become known, which is quite understandable, since isonitriles are generally cleaved in the presence of mineral acids will.

It has now been found that N-monosubstituted «-hydroxycarboxamides can be produced, by isonitriles in the presence of aqueous mineral acids with carbonyl compounds, if appropriate in the presence of an inert organic solvent.

The course of the reaction in the process of the invention is shown by the following reaction scheme illustrates:

R ₂
R ₁ -NC + C = O

Process for the preparation of N-monosubstituted ct-hydroxycarboxamides

Applicant:

Paint factories Bayer Aktiengesellschaft,

Leverkusen

Named as inventor:

Dr. Ilse Hagedorn, Freiburg,

Dr. Ulrich Eholzer, Leverkusen

R ₃

HIGH

R ₁ -NH-CO-C-OH

In the reaction scheme, R ₁ denotes an alkyl, cycloalkyl or aryl group, R ₂ denotes a hydrogen atom, an alkyl or aryl group and R ₃ denotes an alkyl or aryl group.

It was surprising that the reaction of isonitriles with carbonyl compounds in the presence of aqueous mineral acids do not decompose the isonitriles.

According to the process of the invention, it is possible to obtain N-monosubstituted -hydroxycarboxamides simple way and in good yields in a one-step process, while this has been done so far was only possible after cumbersome multi-stage process with poor yields.

Those producible by the method of the invention Compounds are not only valuable intermediates, they are also pharmacological in nature Properties.

example 1

1 g of tert-butyl isonitrile, 10 cc of anhydrous acetone, and 3.82 cc η-sulfuric acid (molar ratio isonitrile to acid = 1: 1) were combined at ⁰ ° C, and the mixture is allowed to stand for 17 hours at 0 ⁰ C. After neutralization with sodium carbonate, the reaction mixture is concentrated to dryness in vacuo and the residue is extracted with anhydrous ether. When the ethereal filtrate was concentrated, the -hydroxy-isobutyric acid-tert-butylamide crystallized out.

The yield is 1.43 g (62% of theory). Colorless leaves of petroleum ether; F. = 97 to 98 ⁰ C (sublimed).

C ₈ H ₁₇ NO ₂ ; Molecular weight = 159.2
Calculated ... C 60.35, H 10.76, N 8.80%;
Found ... C 60.25, H 10.52, N 8.92%.

Example 2

1 g of cyclohexylisonitrile, dissolved in 10 ecm acetone, is mixed with 4.21 ecm η-sulfuric acid ^{at 0 ° C.} After 3 hours of standing at 0 ⁰ C, the mixture is neutralized with a sodium carbonate solution, evaporated to dryness in vacuo and taken up with anhydrous ether. After the ether has been distilled off, the residue solidifies.

The yield is 1.21 g (71% of theory) of a-hydroxy-isobutyric acid-cyclohexylamide. After recrystallization from ether, crystals are obtained; F. = 82 to 83 ⁰ C.

C ₁₀ H ₁₉ NO ₂ ; Molecular weight = 185.2

Calculated ... C 64.80, H 10.34, N 7.35%;
Found ... C 64.86, H 10.16, N 7.48%.

409 628/32 ;;

Example 3

2 g cyclohexylisonitrile, 20 cc of isobutyraldehyde and 25 cc of dioxane are added at 0 ° C with 8.42 cc of n-Schwef elsäure and allowed to stand for 16 hours at 5 to 10 ⁰ C. After neutralization, the mixture is evaporated in vacuo, the residue is extracted with anhydrous dioxane and the filtrate is evaporated to dryness. The residue is recrystallized from a mixture of acetone and petroleum ether.

The yield is 3.2 g (87.9% of theory) of a- hydroxy- β -methyl-butyric acid-cyclohexylamide. After recrystallization from ethyl acetate, colorless crystals are obtained; M.p. = 126.5 to 127.5 ° C.

C ₁₁ H ₂₁ NO ₂ ; Molecular Weight = 199.3 Calculated ... C 66.30, H 10.62, N 7.03%; Found ... C 66.47, H 10.78, N 7.04%.

B e i s ρ i e 1 4

(Produced in a different way by Tigerstedt, reports of the German chemical society,

Vol. 25, p. 2930)

390 mg JOE Naphthylisonitril dissolved in 2 cc of dry acetone are heated at 35 ° C and treated with 2 drops of 2N sulfuric acid and 3 drops of water and the mixture was held for 2 hours at 35 ⁰ C. After cooling, the precipitate which has separated out is filtered off with suction and washed with petroleum ether.

The yield is 351 mg (60.8% of theory) of Λ-hydroxy-isobutyric acid-ß-naphthylamide. After recrystallization from aqueous acetone, colorless crystals are obtained; F. = 160 to 161 ⁰ C.

C ₁₄ H ₁₅ NO ₂ ; Molecular Weight = 229.2 Calculated ... C 73.34, H 6.59, N 6.11%; found ... C 73.06, H 6.54, N 5.85%.

Example 5

1 g 2,6-Dimethylphenylisonitril is dissolved in 10 cc of acetone, are added after cooling the mixture to 0 ⁰ C with 3.82 cc η-sulfuric acid and the mixture allowed to stand for 10 hours at 0 ⁰ C. After concentration to a third of the volume, the mixture is cooled and the precipitate is filtered off with suction.

The yield is 1.41 g (89% of theory) of (X-hydroxy-isobutyric acid- (2,6-dimethylanilide). After recrystallization from acetone, crystals are obtained; F. = 172 to 173 ^° C.

C ₁₂ H ₁₇ NO ₂ ; Molecular Weight = 207.3 Calculated ... C 69.53, H 8.27, N 6.76%; Found ... C 69.78, H 8.06, N 6.68%.

The reaction can also be carried out with catalytic amounts of sulfuric acid. After 2 hours of boiling acetone in a yield of 45%, at 8tägigem standing at 0 ⁰ C 24% of theory is then obtained.

Example 6

2 g of 2,6-Dimethylphenylisonitril, 20 cc of methyl ethyl ketone and 25 cc of dioxane is η-ecm sulfuric acid at 0 ° C with 7.64 (molar ratio isonitrile to acid = 1: 1) was added and the mixture for 8 hours at 5 to 1O ⁰ C ditched. After neutralization with sodium carbonate, the mixture is concentrated to dryness in vacuo, extracted with dioxane and the filtrate is evaporated.

The yield is 2.14 g (63% of theory) \ hydroxy "t-methyl-butyric acid (2,6-dimethylanilide) After recrystallization from acetone, colorless flakes obtained;. Mp = 155-156 ⁰ C. .

C ₁₃ H ₁₉ NO ₂ ; Molecular Weight = 221.3 Calculated ... C 70.56, H 8.65, N 6.33%; found ... C 70.61, H 8.79, N 6.42%.

Example 7

To 1 g of 2,6-dimethylphenylisonitrile and 5 ecm of benzaldehyde 3.82 ecm η-sulfuric acid and 20 ecm dioxane are added at 0 ° C. After standing for 24 hours 0 ° C, the mixture is neutralized, evaporated to dryness in vacuo and the residue with anhydrous Dioxane stripped. When the filtrate is concentrated, a yellow oil remains, which when it is added flocculates the solid product with ether.

The yield is 1.21 g (62% of theory) «-hydroxyphenylacetic acid (2,6-dimethylanilide). After recrystallization from a mixture of acetone and petroleum ether is the F. = 140-141 ⁰ C.

C ₁₈ H ₁₇ NO ₂ ; Molecular Weight = 255.3 Calculated ... C 75.27, H 6.71, N 5.49%; Found ... C 75.54, H 6.78, N 5.45%.

Example 8

3.9 g of 2,6-dimethylphenylisonitrile are dissolved in 30 ecm of acetone and 6 g of 90% phosphoric acid are added at 0 ° C. The mixture is ^{kept at 0 °} C. for 4 hours, then the crystalline precipitate formed is filtered off with suction.

The yield of * -hydroisobutyric acid (2,6-dimethylanilide) is 3.65 g (79% of theory); M.p. = 172 to 173 ° C.

Example 9

A similar approach yields 50% with 0.8 ecm aqueous sulfuric acid and 0.8 ecm of water, 3.95 g (86% of theory) of x-hydroxyisobutyric acid (2,6-dimethylanilide).

Example 10

3 cyclohexylisonitrile g in 20 cc of dioxane is treated with 30 cc of acetone and added ecm at 0 ⁰ C 30 In-SaIzsäure. The mixture remains stand for 4 hours at 0 ⁰ C and 20 hours at 2O ⁰ C. After the mixture has been neutralized with sodium carbonate, it is evaporated to dryness in vacuo and the residue is extracted with anhydrous ether. When the ether was stripped off, the colorless residue solidified.

The yield of α-hydroxy-isobutyric acid-cyclohexylamide is 3.65 g (72% of theory); F. = 82 to 83 ° C.

Example 11

A similar approach as in Example 10 gives with dilute phosphoric acid (6 g of 90% phosphoric acid in 20 ecm of water) 4.0 g of x-hydroxy-isobutyric acid-cyclohexylamide (= 79% of theory). With dilute nitric acid (3 ecm 65% nitric acid in 20 ecm of water) are 30% of theory of * -hydroxy-isobutyric acid-cyclohexylamide obtain.

Claims (1)

Claim: Process for the preparation of N-monosubstituted -hydroxycarboxamides of the general formula R ₂ R ₁ -NH-CO-C-OH R » 10 nitriles of the general formula R ₁ -NC in which R _{1 has} the above meaning, in the presence of aqueous mineral acids with carbonyl compounds of the general formula R ₂ C = O in which R ₁ denotes an alkyl, cycloalkyl or aryl radical, R ₂ denotes a hydrogen atom, an alkyl or aryl radical and R ₃ denotes an alkyl or aryl radical, characterized in that the isoins of R ₂ and R _{3 have} the above meaning , optionally in the presence of an inert organic solvent, reacted. 409 628/325 6.64 © Bundesdruckerei Berlin