DE957941C - Ver drive for the production of new a, /? - unsaturated carboxamides - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

ISSUED FEBRUARY 14, 1957

GERMAN PATENT OFFICE

PATENT LETTERING

CLASS 120 GROUP 21 INTERNAT. CLASS C 07c -

C 8498 IVbI is ο

Dr. Henry Martin, Zurich, and Hans Zutter, Schaffhausen (Switzerland)

have been named as inventors

CILAG Aktiengesellschaft, Schaffhausen (Switzerland)

Process for the preparation of new a, ^ -unsaturated carboxamides

Patented in the territory of the Federal Republic of Germany on November 25, 1953

Patent application published August 16, 1956

Patent issued January 24, 1957

It has been found that amides of the general formula

Ar -X -CH-CH-Ν;

CO-C = CR ₂

have valuable pharmaceutical properties. For example, they inhibit the growth of pathogens Bacteria and fungi and also have an insecticidal and acaricidal effect. Moreover, you are already calling on your skin in very small dilutions a strong and long-lasting anesthesia results. "■

In the above formula, Ar denotes an aryl radical which is optionally substituted by alkyl, alkoxy groups, halogen and / or nitro groups, X is oxygen or sulfur, R ₂ , R ₃ , R ₄ and R ₅ are hydrogen atoms or low molecular weight alkyl groups and R ₁ is hydrogen , Alkyl, alkenyl or aralkyl radicals.

The new compounds are usually not water-soluble. But they dissolve very well in oils and fats. They can also be converted into water-soluble surface and local anesthetics by adding primary or secondary amines to the double bond of the α, β unsaturated carboxylic acid ester. Therefore, apart from their use for pharmaceutical purposes, the new amides also provide valuable intermediates

Manufacture of usable water-soluble local anesthetics.

Substances that have a certain resemblance to the process products have, are already known. For example, US Pat. No. 2,368,195 disclosed crotonic acid amides suggested as synergists for pyrethrum extracts, while in the German patent application P 18583 IVc / 120 (Patent 933804) Process for the manufacture of fungicides and insect repellants the crotonic acid series has been described.

A comparison of the acaricidal effectiveness of the after

The products which can be produced by the process of the invention and which have those in the above-mentioned references compounds described has shown that those are already fully effective in 2% solution, while these known only work safely in a 5% solution.

The substances obtainable according to the invention have im the rest of the advantage that they practically

Do not irritate the ao table.

The new amides are produced using the following ■ process:

An amine of the formula is acylated

R ₃ R ₄

Ar -X -CH-CH-N:

, R ₁

¹ H.

or its amine salt or its N-metal compound or one of its reactive derivatives, e.g. B. a carbamyl halide, in the usual manner with an a, ß unsaturated carboxylic acid of the formula

= C —COOH

or their reactive functional derivatives, such as halides, anhydrides, mixed anhydrides, Azides, esters or salts.

The following examples illustrate the process of the invention. The parts by weight given in the examples relate to parts of volume like kilograms to liters.

example 1

16.8 parts by weight of i- (p-nitrophenoxy-2-N-ethylaminoethane and 8.1 parts by weight of triethylamine in 100 parts by volume of absolute dioxane are added dropwise, with stirring and cooling, to 9.5 parts by weight of β, jS-dimethylacrylic acid chloride in 50 parts by volume of absolute dioxane The mixture is then stirred for a further 2 hours at room temperature and the precipitated triethylamine hydrochloride is then filtered off with suction

6b high vacuum distilled. This gives the below 0.02 mm at 200-203 ⁰ boiling SS / S-dimethylacrylic acid-N-ethyl-N- / 3- (4'-nitrophenoxyäthyi) -amide as an oil dissolved in 74% yield. The new Araid. Dissolves easily in organic solvents, with the exception of petroleum ether, and is insoluble in water.

Analysis: Calculated C 61.63%, H 6.90%, N 9.58%, found C 61.65%, H 7.14%, N 9.32%.

Example 2

14 parts by weight of i- (p-methoxyphenoxy) -2-N-ethylaminopropane and 6.8 parts by weight of triethylamine, dissolved in 150 parts by volume of absolute ether, are added dropwise, with cooling and stirring, to a solution of 7.9 parts by weight of ß, ß-dimethylacrylic acid chloride in 30 Parts by volume of absolute ether. The mixture is then ^{stirred for a further I 1} Z ₂ to 2 hours at room temperature.

The triethylamine hydrochloride formed is extracted with water. The ether solution is washed successively with 2η hydrochloric acid, sodium bicarbonate solution and with water. After drying over potash and evaporation of the ether, the residue is distilled twice in a high vacuum, the β, / 3-dimethylacrylic acid-N-ethyl-N- / 3- (4 '-methoxyphenoxypropyl) amide wins as an oil in 70% yield.

Example 3

16 parts by weight of i- (2 ', 4', 6'-trimethylphenoxy) -2-aminopropane and 8.4 parts by weight of triethylamine in 150 parts by volume of absolute ether are added dropwise with stirring and cooling with a solution of 9.8. Parts by weight of ß, ß-dimethylacrylic acid chloride in 30 parts by volume of absolute ether. Subsequently, the mixture further ^ΐ χ / ₂ is stirred until ζ hours. The ether solution is washed successively with water, 2N hydrochloric acid, dilute sodium bicarbonate solution and with water, then dried over potash and the ether is distilled off. The residue immediately becomes crystalline. After recrystallizing twice from petroleum ether (bp. = 60 to 90 ^0), the compound melts at 112 ⁰ in up. The yield of pure ß, ß-dimethylacrylic acid-N - /? - (2 ', 4', 6'-trimethylphenoxypropyl) -amide is 58%. Analysis: Calculated C 74.14%, H 9.15%, N 5.09%, found C 74.15%, H 9.13%, N 5.33%.

Example 4

20.7 parts by weight of i- (2 ', 4', ö'-trimethylphenoxy) - 2-N-ethylaminopropane and 10.1 parts by weight of triethylamine, dissolved in 150 parts by volume of absolute ether, are added dropwise with stirring and cooling with a solution of 10 , 5 parts by weight of crotonic acid chloride in 30 parts by volume of ether. The mixture is then ^{stirred for a further i x} / ₂ to 2 hours at room temperature. The reaction mixture is then washed successively with water, 2N hydrochloric acid, dilute sodium bicarbonate solution and then with water. After drying the ether solution over potassium carbonate and evaporation of the ether, the residue is distilled twice under high vacuum to give the below 0.01 mm at 146 to 148 ⁰ boiling crotonic acid-N-ethyl-N - ^ - (2 ', 4' , 6'-trimethylphenoxypropyl) amide wins in 71% yield. The oil dissolves well in organic solvents, but not in water.

Analysis: calculated 074.14%, H 9.15%, N 5.09%, found 074.18%, H 8.83%, N 5.30%.

Example 5

In a solution of 24.4 parts by weight of p-chlorophenylmercaptoethylamine and 13.6 parts by weight of triethylamine in 200 parts by volume of absolute ether, 16 parts by weight of β, β-dimethylacrylic acid chloride in 50 parts by volume of ether ^{are added dropwise over a period of 1} _{1/2 hours with stirring.} It. A crystalline precipitate immediately separates out, which is filtered off with suction after stirring for a further 2 hours at room temperature. The filtrate is evaporated. The residue is then washed to remove the Triäthylaminhydrochlorids with water and with sodium bicarbonate and the crystal obtained was recrystallized twice from 75 ° / oig ^em ethanol. This gives / J, / 3-dimethylacrylic acid-N- / S- (4'-chlorophenylmercaptoethyl) amide, melting at 81 to 82 ^{0, in 63% yield.}

Analysis: calculated N 5.19%, Cl 13.15%, S 11.89%, found N 4.98%, Cl 13.26%, S 11.93%.

Example 6

15.1 parts by weight of i-phenoxy-2-N-methylaminoethane and 10.1 parts by weight of triethylamine in 100 parts by volume of ether are added dropwise with stirring and cooling with a solution of 11.85 parts by weight of β, / S-dimethylacrylic acid chloride in 50 parts by volume of ether. The reaction mixture is further stirred overnight at room temperature. The precipitated triethylamine hydrochloride is filtered off with suction and the residue of the evaporated filtrate is distilled twice in a high vacuum, the β, β- dimethyl acrylic acid - N - methyl - N - / S'-phenoxyethylamide boiling ^{below 0.015 mm} at 131 to 132 ^{0 in 82% strength} Yield wins.

Analysis: calculated 072.07%, H 8.21%, N 6.00%, found C 71.80%, H 7.95%, N 5.92%.

This amide can also be obtained by heating 10 parts by weight of N - (/ S-phenoxyethyl) -N-methylcarbamic acid chloride with the calculated amount of the sodium salt of β, / S-dimethylacrylic acid in absolute dioxane for a few hours until no more carbon dioxide evolution can be detected . After the sodium chloride has been filtered off with suction and the dioxane has been evaporated, the residue is distilled twice in a high vacuum, the amide being obtained in a satisfactory yield.

Example 7

By reacting 35.8 parts by weight of i-phenoxy-2-N-ethylaminopropane with 20.9 parts by weight

Crotonic in the presence of 20.2 parts by weight of triethylamine in ether one gains under 0.01 mm at 138-139 ⁰ boiling crotonic-N-ethyl-N - / - phenoxypropylamid.

Example 8

By reacting 20 parts by weight of i-phenoxy-2-N-ethylaminoethane with 14.3 parts by weight of ß, / S-dimethylacrylic acid chloride in ether in the presence of 12.2 parts by weight of triethylamine, the lower 0.01 mm 'at 134 to 135 ^{0 is obtained} β, / S-dimethylacrylic acid-N-ethyl-NT / S'-phenoxyethylamide in a yield of 86%.

Example 9

20 parts by weight of i-phenoxy-2-N-ethylaminoethane are in ether with 12 parts by weight of crotonic acid chloride in the presence of 12.4 parts by weight Triethylamine implemented. The crotonic acid-N-ethyl-N- / S-phenoxyethylamide boiling below 0.01 mm at 133 ° to 134 ° is obtained in a yield of 86.9%.

Example 10

25.8 parts by weight of i- (2'-methylphenoxy) -2-N-methylaminopropane are reacted with 15.1 parts by weight of crotonic acid chloride in ether in the presence of 14.5 parts by weight of triethylamine. Obtained 78.2% crotonic acid-N-methyl-N - / - (2-methylphenoxypropyl) amide, the below 0.07 mm at 153-154 ⁰ boils.

Example 11

21 parts by weight of i- (2 ', 4'-dimethylphenoxy) -2-methylaminopropane are reacted in ether in the presence of 11 parts by weight of triethylamine with 11.4 parts by weight of crotonic acid chloride. Here receives 62.3% of the crotonic acid-N-methyl-N- / 9- (2 ', 4'-dimethylphenoxypropyl) -amide boiling below 0.02 mm at 136 to 138 °.

The following amides of the general formula can also be prepared using the process mentioned at the outset

Ar - O - CH ₂ - CH - R _K

CH,

R ₁ -N-CO-CH = C '

getting produced:

Ar R ₆ R ₁ R ₂ Kp. Mm Hg or (F.) so!
the same
the same H
H
H
H -CH ₃
-C ₃ H ₇ (n)
-C ₃ H ₇ (n).
- C ₃ H ₇ (iso) H
H
CH ₃
H 0.015 ¹ S ¹ to 132 ⁰
0.05 142 to 143 ⁰
0.07 153 to 154 ⁰
0.06 135 to 136 ⁰

Ar

Kp. Mm Hg or (F.)

the same
the same
the same

the same
the same
the same
the same
the same
the same
the same
the same

the same
the same
the same
the same
the same
the same
the same

CH,

H ₃ C

CH,

CH,

H ₈ C

CH,

CH,

CH,

H ₃ C

H H H H

CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ CH ₃

CH ₃ CH ₈ CH ₃ CH ₃ CH ₃ CH ₃ CH ₃

H H H H

CH ₃ CH ₃ CH ₃

CH ₃ CH ₃

CH ₃ CH ₃ CH ₃

CH ₃ CH ₃ CH ₃ CH ₃

CH ₈ CH ₃

-C ₃ H ₇ (ISO) C ₄ H ₉ (Ii)

■ C ₄ H ₉ (n) CH ₂

CH _a

CH ₃ CH ₃

-CH ₂

-C ₃ H ₇ (Ii)

-C ₃ H ₇ (Ii)

-C ₃ H ₇ (ISo)

-C ₃ H ₇ (ISo)

-C ₄ H ₉ (Ii)

-C ₄ H ₉ (Ii)

-CH ₂

-CH ₁

CH ₃ CH ₃ C ₂ H ₅ C ₂ H ₆

CH ₃ CH ₃ C ₂ H ₆ C ₂ H ₆

CH ₃

C ₂ H ₆

C ₂ H ₆

CH ₃ CH ₃

CH ₃

C ₂ H ₆

C ₂ H ₅

CH ₃ CH ₃ C ₂ H ₅ C ₂ H ₅

CH ₃ CH ₃ C ₂ H ₅

CH ₃

H
CH ₃

CH ₃

H
CH ₃

H
CH ₃

H
CH ₃

CH ₃

H
CH ₃

H
CH ₃

H
CH ₃

H
CH ₃

H
CH ₃

CH ₃

H
CH ₃

H
CH ₃

CH ₃

H
CH ₃

H
CH ₃

H
CH ₃

CH ₃
CH ₃

0.03 141 to 143 ⁰

0.03 140 to 141 °

0.07 155 to 156 ⁰

0.03 190 to 191 °

0.03
0.04
0.05
0.03
0.05
0.04
0.07
0.04

0.05

0.03
0.02
0.01
0.03

0.02
0.02
0.02
0.015

0.03

0.015

0.015

0.02
0.02

0.02
0.02
0.02

0.02
0.02
0.02
0.02

0.02
0.02
0.01

193 to 194 ⁰

147 to 148 ⁰

152 to 153 ° 141 to 142 ⁰

144 to 145 ⁰ 151 to 152 ⁰ 156 to 157 ⁰ 195 to 196 ⁰

198 to 199 ⁰ (99 to 100 °) (? I to 71.5 °) 140 to 141 ° 140 to 141 ° 138 to 139 ⁰

146 to 148 °

145 to 146 ⁰

148 to 149 ⁰

147 to 148 ⁰ 151 to 152 ⁰

147 ⁰ 137 to 138 ⁰

140 to 141 °

141 to 143 ⁰

145 to 148 ⁰

142 to 143 ⁰

146 to 148 ° 140 to 141 °

148 to 149 °

149 to 150 ⁰

151 to 152 ⁰

153 to 154 °

(106 to 107.5 °) (in up to 112 °)

152 to 153 ⁰ 160 to i6i ° 152 to 153 °

Ar R ₅ Ri R ₂ Kp. Him Hg or (F.) CH ₃ CH ₃ H 0.02 153 to 154 ⁰ HgCO- ^ V- CH ₃ CHg CH ₃ 0.02 159 to 16 ° CHg C ₂ H ₅ H 0.015 154 to 156 ⁰ CHg CH ₃ H 0.015 157 ^to ! 58 ° C] / \. CHg CHg CH ₃ 0.02 152 to 153 ⁰ - \ / CHg C ₂ H ₆ H 0.03 161 to 162 ° CHg C ₂ H ₆ CH ₃ 0.02 152 to 154 ⁰ / —V- CHg CH ₃ H 0.02 I59bisi6o ° \ / CH ₃ CHg CH ₃ 0.04 160 to 16 ° Cl CHg C ₂ H ₅ H 0.03 158 to 159 ° CHg C ₂ H ₅ CH ₃ 0.02 155 to 157 ⁰ Q ₂ N- / y ~ H CHg CH ₃ 0.02 192 to 195 ⁰

The following report shows the superior acaricidal effect and good mucosal tolerance of the 25 recognize connections that can be established according to the method. There will be the acaricidal properties and the Mucosal compatibility of five aryloxyalkyl

amides of α, / 3-unsaturated low molecular weight fatty acids with those of crotonic acid-N-ethyl-o-toluidide (compound F; USA.iEatentschrift 2 368 195) compared:

O - CH ₂ - CH ₂ - N - CO - CH == C:

XH ₃

• O-CH ₂ -CH ₂ -N-CO-CH = CH-CH ₃

CH ₈ C

CH,

O - CH ₉ -CH-N-CO-CH = CH- CH,

CH ₃

DH ₃ C

CH ₃

O - CH ₃ - CH - N - CO - CH = C '

CH,

XH,

CH,

CH,

E HX

O - CH ₂ - CH - N - CO - CH = CH - CH ₃

CH ₃

N-CO-CH = CH-CH ₃
C ₂ H ₆

The above compounds were tested in 5 ° / _o sodium and 2 ° / _o strength acetone solution. In the following
The table shows the results.

link
3 number weak
movable Mites motionless Hours since Passed away and
concentration Mites 27 Start of experiment Mites
in 7o 5 A 5% 27 31 (32) 2 100.0 27o 32 - 35 5 97.0 B 5% 35 2 28 2 100.0 Q a ° / o 30th - 31 5 ' 93.5 C 5% 31 3 25th 2 100.0 2 ° / o 28 - 26th 5 89.0 D 5% 26th 2 35 2 100.0 ■ a% 37 - 25th 5 94.0 E 5% 25th 2 36 2 100.0 2 7o 38 4th 32 5 95.0 F 5% 36 16 21 2 89.0 2 _0/0 37 5 57.0

The compounds A, B and F were tested ₀ strength acetone solution in io ° / and the time, in the dead ioo ° / ₀ of the mites. When using the compounds A and B _{two hours} had died ioo% of the mites, while at the junction F after 27 hours until 92 ° / ₀ of the mites had died after ¹ Z.

One drop each of compounds A to F was added instilled in the conjunctival sac of the rabbit and after 24 hours or 48 hours the result was determined:

Compound A: After 24 hours without findings;

Compound B: very slight reddening of the conjunctiva after 24 hours, no findings after 48 hours; Compound C: No findings after 24 hours;

Compound D: after 24 hours slight reddening of the conjunctivae, after 48 hours without findings; Compound E: after 24 hours without any findings;

Compound F: Redness and swelling of the eyelids after 24 hours, always after 48 hours reddening and swelling still noticeable.

Compounds A to E are superior to compound F in the mite test in their action against mites and, moreover, do not cause irritation to the rabbit eye, while compound F produced a strong irritant effect.

Claims (1)

Claim: Process for the production of new α, / 3-unsaturated Carboxamides of the general formula R ₄ Ar -X -CH-CH- CO-C = CR ₂ in which Ar is an aryl radical optionally substituted by alkyl, alkoxy groups, halogen and / or nitro groups, X is oxygen or sulfur, R ₁ is hydrogen, an alkyl, alkenyl or aralkyl radical, R ₂ , R ₃ , R ₄ and R ₅ are hydrogen atoms or low molecular weight alkyl radicals, characterized in that an amine of the general formula R4 Ar -X-CH-CH-N; , R ₁ or its salts, its N-metal compound or its carbamic acid halide with an α, β- unsaturated carboxylic acid of the formula = C-COOH or their functional derivatives - in both formulas have Ar; X and R ₁ to R _{5 have} the same meaning as above - acylated in the usual way. Considered publications: P. Karr er, textbook of the organ. Chemistry, 11th edition, 1950, p. 233, section 3; P. 250, para. 5; P. 474, section 7; Gattermann-Wieland, The Practice of Organic Chemists, 34th Edition, 1952, p. 114, paras. 7, 8; C. Weygand, Organic-chemical Experimentierkunst, 2nd edition, 1948, pp. 401 to 404, p. 548, last Paragraph, p. 549, Paragraph 1 to Section la; German patent application P 18583 IVc / 12 ο ns (Patent No. 933,804). © 609 579/514 S. (609 797 2.57)