CS270448B2 - Method of carbazates production - Google Patents

Abstract

3-Acylcarbazate esters of formula ACONHNHCOOR (I) and their acid-addn. salts are new, where: A=3-10C alkyl, 3-10C alkenyl, 2-10C haloalkyl, CF3, phenyl(1-3C)alkyl, phenyl(2-3C)alkenyl, naphthyl(1-3C)alkyl, phenyl(opt. substd. by 1-4C alkyl, halogen, 1-4C alkoxy and/or OH), (3-7C)cycloalkyl(1-3C)alkyl, nitrofuryl, diphenylhydroxymethyl, or indazolyl opt. mono- or polysubstd. by alkoxy; R=1-4C alkyl; provided that A is not t-Bu when R=Et. Animal feeds or animal feed supplements or concentrates contg. cpds. (I), including (I; A=t-Bu, R=Et), are also new.

Description

(57) The new carbazate of formula I wherein A represents phenyl-C ^^ alkyl, and R is an alkyl _С 1вЛ are prepared by reducing a compound of formula I wherein A represents phenyl-C ₂ _ ₃ alkenyl, and R is as defined above. The reduction is preferably carried out by catalytic hydrogenation or complex metal hydride. The compounds of the formula I can be used in animal production because they increase weight gains and improve feed utilization.

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CS 27o440 B2

The invention relates to a process for the production of carbazates which can be used to increase weight gain and to improve the utilization of pet food.

Ethyl 2,2-dlmethylproplonylcapazate is disclosed in DOS 1618 20, but it is not disclosed that this compound increases weight gains *

The present invention provides a process for the preparation of the novel carbazates of the general formula (i)

(O.

where

A is C ₃ _ _1Q alkyl, ^{C3-lo all << n} · C ^^^ ^ haloalkyl, trifluoromethyl, phenyl-C ^^ alkyl, phenyl-C · _2OT ^ alkenyl, naphthyl-C ^^ alkylphenyl optionally substituted by one or more identical or different substituents from the group consisting of ^C l-4 ^ttlkyl> halogen, C ^^ alkoxy and C ^ hydroxylj ₇ cycloalkyl- C ^^ alkyli furyl optionally substituted nitroskupinouj work nylhydroxy methyl or indazolyl optionally substituted one or more C 1-6 alkoxy groups and

R is alkyl, provided that when R is ethyl, A has a meaning other than tore, buly I, and their acid addition salts.

In preferred compounds of formula I, A is phenyl-C 1-4 alkyl.

The term "alkyl" as used herein refers to straight or branched saturated aliphatic groups having the specified number of carbon atoms, for example n-propyl, n-butyl, tert-butyl, n-hexyl, etc. The term "alkoxy" refers to straight or branched alkyl ether groups containing the specified number of carbon atoms, for example ae is methoxy, ethoxy, isopropoxy, etc., "Phenyl-C alkyl" may preferably be benzyl or / S-phenylethyl, while "Phenyl-C 1-4 alkenyl" may be preferably 2-phenylvinyl . Preferred "C 1-6 haloalkyl groups" may be, for example, 2-chloroethyl, 2-bromoethyl and 3-chloropropyl. The term "halogen" represents fluorine, bromine, chlorine and iodine atoms,

The phenyl group may optionally carry one or more identical or different substituents, for example 2-chloro, 3-chloro, 4-chloro, 3-iodo, 2-hydroxy-, 3-hydroxy-, 4-hydroxy-, 3,4,5-trimethoxyphenyl etc. The "C 1-6 cycloalkyl-C 1-6 alkyl group" may preferably be cyclohexylethyl.

Acid addition salts of the compounds of formula I may be formed with biologically acceptable salts

liable to confusion inorganic or organic acids, for example mineral acids such as kysollna hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid etc. or organic acids such as tartaric acid, succinic acid, citric acid milky ^л NA, fumaric acid, maleic acid, p-toluenesulfonic acid, etc.

A particularly preferred embodiment of the compounds of formula (I) is methyl-3- (β-phenylpropionyl) carbazate.

Further preferred compounds of formula I are the following derivatives:

methyl 3- (3'-chloropropionyl) carbazate, methyl 3- (phenylation tyl) carbazate, methyl 3- (β-cyclohexyl for plonyl) carbazate, and methyl 3- (1-naphthylation yl) carbazate.

CS 270447 B2 (iv)

The invention consists in reacting a carboxylic acid of the formula IV

A - C - OH wherein R is as defined above, or a reactive derivative thereof with a carbazate of formula V (V) wherein R is as defined above and, if desired, converting a compound of formula I to another compound of formula 1, and, if desired, converting a compound of Formula I to its acid addition salt.

An acid halide may advantageously be used as the reactive carboxylic acid derivative of the formula IV. An ester or anhydride thereof, preferably an acid chloride, an acid ester or a mixed anhydride with a C 1-4 alkanoic acid may be used.

The reaction of the acid chloride of formula IV and the carbazate of formula V may be carried out in the presence or absence of an acid binding agent. Inorganic bases such as alkali metal hydroxides, alkali metal carbonates or bicarbonates or organic bases such as pyridine, triethylamine may be used for this purpose. etc. The reaction may be carried out in an inert solvent. Nitrile, for example acetonitrile, halogenated hydrocarbons, for example methylene chloride, aromatic hydrocarbons, for example benzene or toluene, or alcohol, for example methanol or ethanol may be used as reaction medium. Acetonitrile may be used as reaction medium. ° C and boiling point of the reaction mixture · It is preferred to work under reflux.

The reaction of the carboxylic acid ester of the formula IV and the carbazate of the formula V can advantageously be carried out in an inert solvent with heating.

The reaction of the carboxylic acid anhydride of the formula IV and the carbazate of the formula V can be carried out in excess of the acid anhydride.

The reaction of the free carboxylic acid of the formula IV and the carbazate of the formula V can advantageously be carried out in the presence of a dehydrating agent, for example dicyclohexylcarbodiimide.

The compound of formula (I) may be isolated from the reaction mixture by known methods, for example by crystallization in the cold, by evaporation or by pouring into water, etc.

The compound of formula I may be converted into another compound of formula I · Thus, a compound of general formula I wherein A represents phenyl-C ₂ _ ₃ alkenyl, reduced to the corresponding compound of formula I wherein A represents phenyl-C ₂ ^ This reaction may be carried out by catalytic hydrogenation, for example in the presence of a palladium or platinum catalyst, or by a complex metal hydride, for example sodium hydride. The reduction can be carried out in an inert organic solvent as reaction medium.

The compound of formula (I) may be converted to an acid addition salt by known methods. For example, an equimolar amount or a small excess of the corresponding acid may be added to a solution of a compound of formula I in an inert organic solvent.

The starting materials of the general formula V are known (j. Am. Chem. Soc. 75, 2259-61 (1953)). The starting materials of formula IV are well known and generally available commercial products.

Compounds of Formula I Can Be Used in Livestock Breeding · These compounds have the valuable effect of increasing weight gain accompanied by a significant increase in feed utilization

CS 27o448 B2 in domestic animals * especially pigs * poultry and ruminants, especially lambs.

The effects of weight gain on the compounds of Formula I are illustrated by the following test, the results of which are summarized in Table 1. The test was performed on lambs, fed for 4 days and the test compound was administered at a dose of 50 mg / kg. Results are mean values from three experiments. The table shows the increase in weight gain and feed utilization value. Methyl 3- (6-phenylproplonyl) carbazole was used as the test compound

Table 1

Values not treated methyl-3- (Β-Phenylproplonyl) control carbazate average starting weight * kg 16.3 16.3 average final weight, kg 27.2 29.5 average daily weight gain, g 27o 33o average daily weight gain. relative to control,% loo 122.2 average daily food consumption, g 1 o97 95o use of feed, kg 4.2 3.3 the use of feed in relation to control, % loo 78.6 Increase in weight gain a improving the feed utilization of the compounds of formula 1 is further illustrated in Table 2 * Tested 2o lambs were fed for 4o days and tested the compounds were administered at a dose of 50 ° mg / kg. Compounds were used as test compounds of Example 3 and R art of sin. Table 2 Values untreated Rumehsin compound of control of Example 3 average starting weight, kg 16.3 16.4 16.3 average final weight, kg 27.1 27.4 27.5 average daily weight gain, g 27o 275 281 average daily weight gain, relative to control,% loo Ю2 Ю4 average daily food consumption, g 1 o97 1 οββ 1 o85 use of feed, kg 4.1 4.0 3.9 the use of feed in relation to control, % loo 98 95

The compounds produced by the process of the invention do not have antibiotic effects and therefore do not have adverse side effects of antibiotics.

The compounds of formula I have the excellent property of not having a mutagenic effect.

This is very important in cattle breeding, since a significant number of known weight gain promoters cannot be added to the feed at all or only in a very limited amount because

CS 27ο44β B2 these active substances have a mutagenic effect,

From the above data, it is apparent that the weight gains of the animals fed the feed containing the compounds of formula I are significantly higher than in the control group. At the same time, the same weight gains can be achieved with significantly reduced feed. If this feed contains a compound of formula I, this is evidence of improved feed utilization.

The following examples illustrate the invention without limiting it in any way.

Example 1

Methyl 1-3- (β-phenylproplonyl) carbazate

33.7 g (0.2 mol) of 4- (enylpropionyl chloride) are added dropwise to a solution of 18 g (0.2 mol) of methyl carbazate and 100 ml of acetone-tril and the reaction mixture is heated to boiling for 15 hours, clarified and cooled. There was thus obtained 36.85 g of the title compound, yield 80 °, 7%, mp 118 ° C.

Example 2

Methyl 3- (6-phenylacryloyl) carbazate

To a solution of 27 g (0.3 mol) of methyl carbazate and 25o ml of acetone is added a solution of 5 g (0.3 mol) of cinnamic acid chloride in 100 ml of acetone, the reaction mixture is boiled for 15 hours, cooled and the precipitated white crystals filtered . 62.6 g of the title compound are obtained, yield

94.8%, mp 165 ° C.

Example 3

Methyl 3- (3'-chloropropionyl) carbazate

63.5 g (0.5 mol) was added dropwise to a solution of 45 g (0.5 mol) of methyl carbazate in 375 ml of acetone.

3-chloropropionyl chloride, The reaction mixture is heated to boiling for 16 hours, clarified and cooled, and the precipitated crystals are filtered off. There was thus obtained 7.5 g of the title compound as white crystals. Yield

78.3%, mp 129 ° C.

Example 4

Methyl 3- (p-chlorobenzcyl) carbazate

36.0 g (0.4 mol) of methylcarbazate and 70.0 g (0.4 mol) of p-chlorobenzoyl chloride were reacted according to the procedure of Example 1. 74.5 g of the title compound are obtained, yield 81.5%, m.p.

Example 5

Methyl 3- (phenylacetyl) carbazate.

154.6 g (1.0 mol) of phenylacetyl chloride are added to a solution of 9.0 g (1.0 mol) of methyl carbazate and 500 ml of acetone / tril. The reaction mixture was heated to boiling for 15 hours and clarified. The residual oil is poured into 50 ml of water, which soon solidifies. 158.4 of a white compound are obtained, yield

76.1%, mp 94-95 ° C,

CS 27ο44β B2 р й е d м £ т invention

1.

A process for the preparation of carbazates of the formula I

A - C - NH - NH - C - OR (|)

II - II o where

A represents ^C alogenalkyl, trifluoromethyl ethyl, phenyl-C ^^ alkyl, phenyl-C ^^ alkenyl, naphthyl-C ^^ alkyl; phenyl optionally substituted by one or more identical or different substituents selected from the group consisting of C ^ _ ₄ alkyl , halogen, C 1-4 alkoxy and hydroxyl are cycloalkyl-C 1-4 alkyl, ruryl or substi

Claims (5)

bolded triphenylhydroxymethyl or indazolyl optionally substituted with one or more C 1-4 alkoxy groups; and R represents ^{с а} ^ .4 ^ ^{1с УЬ} with the proviso that when R is ethyl, A is other than tertiary butyl, and acid addition salts thereof, wherein e by reacting к ar boxes hunting and acid of formula IV A-C-OH II o wherein A is as defined above, or a reactive derivative thereof and a carbazate of general formula V H _O N-NH-C-OR Wherein R is as defined above, and if desired, the compound of formula I is converted to another compound of formula I, and, if desired, the compound of formula I is converted to its editoral salt and acid; 2. 5. A process according to claim 1, wherein the reactive derivative of the acid of the formula IV is a halide, ester or anhydride thereof. 3. Process according to Claims 1 and 2, characterized in that ae the acid chloride, the C 1-4 alkyl ester or the mixed anhydride formed with the C 1-4 alkanoic acid is used as the reactive derivative. 4. The method of claims 1 to 3, wherein the reactive acid derivative is an acid chloride, 5 · 2. The process of claim 1 wherein the reaction is carried out with a free carboxylic acid of formula (IV) in the presence of a dehydrating agent, for example dicyclohexylcarbodimide.