CS208676B2 - Method of making the heterocyclic trichlormethylderivatives - Google Patents

Description

The present invention provides a process for the production of ruminal metabolic modifying heterocyclic trichloromethyl derivatives in domestic ruminants by reducing methane production and increasing the proportion of propionic acid in ruminal fame, to the detriment of acetic acid.

Various organic compounds containing a trichloromethyl group are known to be effective in reducing methane production during rumen food fermentation. For example, chloral, chloral adducts with starch, cellulose and molasses, trichloroacetamide and various trichloromethyl esters of lower fatty acids such as adipic acid are known to have a beneficial effect on rumen metabolism after ruminant application. Recently, it has been found that a number of trichloromethyl-substituted benzole-1,3-dioxin derivatives are much more effective than the previously known simple trichloromethyl derivatives. The invention represents further progress in the field of benzo [1,3] dioxins.

Accordingly, the present invention provides a process for the preparation of heterocyclic trichloromethyl derivatives of the formula I

(I) in which either X 3 is an oxygen atom, Y represents a radical of the formula -NR 6 - _f wherein R 6 represents a hydrogen atom, a C 1 -C 4 alkyl or alkanoyl group, or a phenyl or X or X group optionally substituted by at least one substituent selected from the group consisting of halogen atoms, nitro groups and alkyl, alkoxy and haloalkyl groups containing from 1 to 4 carbon atoms each, and Z represents a carbonyl group, £ £ represents a radical of the formula -KR-, wherein R represents a hydrogen atom, an alkyl or alkanoyl group each containing from 1 to 4 carbon atoms, or a phenyl group optionally substituted as above for R ⁹ , Y is -NR 4 as defined above, and Z is carbonyl, is -KR ®- as defined above, Y is an oxygen atom and Z represents a methylene group, optionally substituted by a carboxyl or carbamoyl group, an alkoxycarbonyl group C 2 -C 5 or N-phenylcarbamoyl optionally substituted by halogen, nitro or C 1 -C 4 alkyl, alkoxy or haloalkyl and each of r ', R'

R ³ and R ^4, which may be the same or different, is hydrogen or a halo, cyano, formyl, hydroxy, hydroxyiminomethyl, nitro, sulfo, carboxy or its alkali metal salt, alkaline earth metal or ammonium salt, or means zby.

the formula R ', OR', 10 nr ⁸ r ⁹ ,

C0.NR ⁸ R ⁹ ,

O.CH ₂ R ¹⁰ , CO.OR ⁷ , SO ₂ .NR ⁸ R 'or SOg.OR ⁷ , nh.so ₂ r

O.COR '

O.COR

MH, CH ₂ R ^iv , SOg.NR 4 R 'or SOg.OR *, in which the radical is a C 1 -C 4 alkyl group, each of R and R, which may be the same or different, represents a hydrogen atom or (C 1 -C 4) alkyl and ¹⁰ represents a phenyl radical optionally substituted as above for n 5

NR ⁸ COR ⁹

JO except for those compounds in which:

Z represents a carbonyl group and

3 either X is oxygen or imino, Y is imino and R, R, R and R ⁴ are hydrogen, or X is oxygen, Y is imino and either R ² and R ⁴ are chlorine and R ¹ and R ³ or R ³ is acetamido and R ¹ , R ² and R ⁴ are hydrogen, or X is oxygen, Y is acetylimino, R is acetamido and R ¹ , R ² and R ⁴ are hydrogen.

Suitable halogen atoms r ', R ² , R ³ and R ⁴ or suitable halogen substituents of the phenyl radical R ⁹ , R ⁸ or R ¹⁰ are, for example, chlorine, bromine or iodine atoms.

Suitable radicals R ¹ , R ² , R ³ and R ⁴ when R ⁷ , or suitable C 1 and C 4 alkyl groups R 1 or R ⁶ , or suitable C ¹ alkyl substituents up to 4 carbon atoms in the meaning of R @ ⁸ , R @ ⁸ or R @ ¹⁰ , when any of these represents a phenyl radical substituted by a C1 -C4 alkyl group or a suitable C1 -C4 alkyl substituent on the phenyl ring of Z, when this symbol represents an N-phenylcarbamoyl-substituted methylene group, it is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. ,

Suitable radicals for R ^1, R ^2, R ³ and R ^4, if these symbols represent a radical OR ^7, or suitable alkoxy substituents having 1 EŽ 4 carbon atoms for R ^, R ⁸ and R ^10, if any of these symbols represent a phenyl radical substituted by a (C 1 -C 4) alkoxy group or a suitable C 1 -C 4 alkoxy substituent on the phenyl ring of Z, when the symbol represents an N-phenylcarbamoyl-substituted methylene group, is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec. butoxy or tert. butoxyl.

A suitable radical R @ ¹ , R @ ² , R @ ⁴ and R ^{@ 4} when the radical is CO.OR @ 2 or a C2 -C5 alkoxycarbonyl substituent when the radical represents an alkoxycarbonyl-substituted methylene group is: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, butoxycarbonyl sec. butoxycarbonyl.

A suitable remainder of O.COR? for R ^1, R ^2, R or R ⁴ is, for example acetoxy, propionyloxy, butyryloxy or isobutyryloxy.

Suitable radical O.CHgR ® ¹ for ^R], R ² or R ⁴ is, for example benzyloxy, chlorobenzyloxy or methylbenzyloxyskupina.

Suitable radical O.COR ® ¹ for R ^1, R ^2, R or R ⁴ is a benzoyloxy not attach, or chlorbenzoyloxyskupina methylbenzoyloxyskupina.

A suitable halogenoalkyl substituent with 1-4 carbon atoms in any of R * 6 and R ¹ ®, if the symbol represents a haloalkyl substituted phenyl radical, or the phenyl ring of Z when this symbol is N-fenylkarbamoylsubstituovanou methylene group, for example trichloromethyl a trifluoromethyl group, a 2,2,2-trichloroethyl group, a 3,3,3-trifluoropropyl group or a 2,2,3,3,3-pentachloropropyl group.

6

A suitable C 1 -C 4 alkanoyl radical is a formyl, acetyl, propionyl, butyryl or isobutyryl group. _r

Suitable C0.NR radical R ⁸ for R ^1, R ^2, R and R ⁴ is, for example carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl, dipropylcarbamoyl, isopropylkarbamoylová group, butylcarbamoyl group butylcarbamoyl, sec. butylcarbamoyl, tert. butylcarbamoyl or ethylmethylcarbamoyl.

A suitable radical NR @ R @ 1 in the meaning of R @ ¹ , R @ ² , R @ ³ and R @ ⁴ is, for example, amino, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, isopropylamino, butylamino, butylamino, sec. butylamino or ethylmethylamino.

Suitable radical NR @ ⁸ .COR for R ^1, R ^2, R ^4, and R is an acetamido, a methylacetamido-H, N-ethylacetamidoskupina, propylacetamidoskupina N, N-isopropylacetamidoskupina, N butylacetamidoskupina, propionamido, N-methylpropionamidoskupina , N-ethylpropionamido, butyramido, N-methylbutyramido, N-ethylbutyramido, 2-methylpropionamido or N 2-dimethylpropionamido.

Suitable radical SOg.NR ^ R for R \ ^R2, IP, and R ⁴ is, for example sulfamoyl, methylsulfamoyl, dimethylsulfamoyl, ethylsulfamoyl, diethylsulfamoyl, propylsulfamoyl, dipropylsulfamoyl, isopropylsulfamoylová group, butylsulfamoyl group, isobutylsulfamoylová butylsulfamoyl group, sec. butylsulfamoyl or ethylmethylsulfamoyl.

Suitable radical SOg.OR ^ for R ^1, R ^2, R ^4, and R is a methoxysulfonyl group, ethoxysulfonylová group, propoxysulfonyl group, isopropoxysulfonylová group, a butoxysulfonyl group, isobutoxysulfonylová group, sec. Terč.butoxysulfonylové butoxysulfonyl group or a group.

Particularly valuable compounds produced by the process of the invention are

3,4-dihydro-6-hydroxy-2-trichloromethyl-2H-benzo [e] - [1,3] oxazin-4-one;

3,4-dihydro-4-oxo-2-trichloromethyl-2H-benzo [e] - [1,3] oxazine-6-carboxylic acid, 6-acetoxy-3,4-dihydro-2-trichloromethyl-2H-benzo [e] ] - [1,3] oxazin-4-one,

6-acetoxy-1,2-dihydro-2-trichloromethyl-4H-benzo [d] - [1,3] oxazine,

1,2-dihydro-2-trichloromethyl-4H-benzo [d] - [1,3] oxazine-4-carboxylic acid and ethyl-1,2-dihydro-2-trichloromethyl-4H-benzo [d] ] - [,, 3] oxazine-4-carboxylate,

As mentioned above, the present invention provides a process for the preparation of heterocyclic trichloromethyl derivatives of the aforementioned general formula (I), characterized in that the compound of the general formula (II)

in which

R ^1, R ^2, R, R, X, Y and Z have the abovementioned meanings, is reacted with chloral optionally in the presence of a solvent, and either simultaneously or subsequently with an acid, then optionally present radicals represented by R ' R @ ² , R @ 1 and R @ 2, when present in the groups X or Y, will be converted to other substituents within the definition of the above symbols by conventional or literature methods.

A suitable acid useful in the above process is, for example, sulfuric acid or hydrochloric acid.

If a solvent is used in the above-described process, it is preferred to use bls (2-methoxyethyl) ether (diethylene glycol dimethyl ether or diglyme). Other solvents lead to partial losses of chlorine from the trichloromethyl group of the product.

Examples of possible transformations of the primary products resulting from the process described above are:

a) alkylation of the hydroxy-substituted product to form an alkoxy-substituted product, alkylation of the carbamoyl-substituted product to form a mono- or di-N-alkylcarbamoyl-substituted product, alkylation of the alkanoylamino-substituted product to form an N-alkyl-alkanoylamino-substituted product, alkylation of the sulfamoyl-substituted or the product or alkylation of the ring-containing product NH to form a ring-containing product N-alkyl;

b) alkanoylation of a hydroxy-substituted product to form an alkanoyloxy-substituted product, alkanoylation of an amino-substituted product to form an alkanoylamino-substituted product, or alkanoylation of an NH-containing ring product to form a N-alkanoyl-containing ring product;

c) esterifying the carboxy-substituted product to form an alkoxycarbonyl-substituted product or esterifying the sulfosubstituted product to form an alkoxysulfonyl-substituted product;

d) «min» »» »of a carboxy-substituted or alkoxycarbonyl-substituted product to form a carbamoyl or mono- or di-N-alkylcarbamoyl-substituted product, or eminating a sulfosubstituted or alkoxysulfonyl-substituted product to form a sulfamoyl- or mono-di-N-alkylsulfamoyl product;

e) hydrolyzing the alkanoyloxy-substituted product to form a hydroxy-substituted product, hydrolyzing the cyano-, alkoxycarbonyl-, carbamoyl- or mono- or di-N-alkylcarbamoyl-substituted product to form a carboxy-substituted product; or hydrolyzing an alkoxyaulfonyl-, sulfamoyl-, optionally mono- or di-N-alkylsulfamoyl-substituted product to form a sulfosubstituted product;

f) dealkylating the alkoxy-substituted product to form a hydroxy-substituted product;

g) reducing the nitrosubstituted product to form an aminosubstituted product or reducing the benzylidene-aminosubstituted product to form a benzylamino-substituted product;

h) oximinating the formyl-substituted product to form a hydroxy-1-methylmethyl-substituted product; _%

i) sulfonated product unsubstituted in the aromatic ring to form a sulfosubstituted product.

As mentioned above, the heterocyclic trihalomethyl derivatives of the above formula (I) reduce methane production and increase the propionic acid content of rumen ruminant juice and are therefore valuable for more efficient breeding of domestic ruminants.

The heterocyclic trihloromethyl derivatives produced by the process of the invention can be used to reduce methane production in rumen ruminants and / or to increase the propionic acid content in rumen juice of domestic ruminants by orally administering to the animals a heterocyclic trichloromethyl derivative of the above formula I, ',

P ·> «t

R, R, R *, X, Ϊ and Z are as defined above.

Accordingly, the compound of formula (I) is preferably administered orally to the animals as a supplement to their normal diet, i.e., mixed with conventional solid feed, pressed feed or salt licks, dissolved in drinking water or, in the case of young animals such as weaned lambs or calves, dissolved in whole milk or skimmed milk. The compound of formula I is incorporated into feed, pressed feed, salt licks, drinking water, whole or skimmed milk in an amount such that each treated animal consumes 0.1 to 30 mg of the compound of formula I per kilogram of body weight, preferably from 0.1 to 10 mg / kg.

Alternatively, the compound of formula (I) may be orally administered to the animals in the form of slow-release intraruminal pellets or boluses so that the animal receives a similar daily dose of the compound of formula (1).

The animals may receive the compounds of the formula I during virtually the entire growth period or only for part of the growth period, for example at the initial stage of the growth period and / or for some time before slaughter. No toxic effects were observed when compounds of formula I were administered at optimal doses to inhibit methane production.

When used for the aforementioned purposes, the compounds of the above formula are conveniently formulated to contain a heterocyclic trichloromethyl derivative of the formula I wherein R ¹ , R ² , R ⁴ , R ⁴ , X, ϊ and Z are as defined above, together with solid or liquid edible, non-toxic diluent or carrier.

A suitable liquid diluent or carrier is, for example, drinking water, whole milk or skim milk.

A suitable solid ingestible, non-toxic diluent or carrier may be, for example, a conventional nutritionally balanced ruminant feed, for example a typical bovine or sheep feed consisting of, for example, cereal products such as barley meal, maize meal or wheat products, nut and seed products. , such as decorticated groundnut or cotton seed cake, or extracted cotton seed cake, along with small amounts of, for example, ground feathers, ground seaweed, bone chips, bone meal, chalk, salt, urea, molasses, vitamins and trace mineral or kaolin, talc, calcium carbonate, fuller's earth, attapulgite, ground oysters or ground limestone, or further may be starch or lactose.

The described composition may be in the form of supplemented feed for direct animal feeding, in which case it contains 3 to 3,000 ppm of a compound of formula I in admixture with a conventional feed for ruminants, or it may be in the form of a concentrated feed supplement (premix) for ruminants to form a feed supplement suitable for direct feeding, wherein the concentrated feed supplement comprises from 0.3% (w / w) to 50% (w / w). the compounds of formula (I) in admixture with either a conventional, nutritionally balanced ruminant feed, an inert solid diluent having no nutritional value, for example ground limestone or starch or lactose.

The compositions may be prepared by a process comprising uniformly mixing the heterocyclic trichloromethyl derivative of formula (1) with a solid edible, non-toxic diluent or carrier.

The compound of formula (I) is preferably diluted in a diluent or carrier sequentially, in two or more successive steps, to achieve uniform mixing.

The invention is illustrated by the following non-limiting examples.

He did

63.5 g of enthranilamide hydrochloride were refluxed with 650 ml of anhydrous chloral for 3 hours. The resulting solution was evaporated to dryness and the residue was triturated with 700 ml of toluene to give a yellow product containing 1 mol of chloral. This chloral was removed by boiling the product in two liters of methanol for 15 minutes, cooling the solution and filtering. The filtrate is concentrated to half volume and allowed to cool. 1,2-dihydro-2-trichloromethylquinazolin-4-one is obtained, m.p. 201-202 ° C.

By repeating the above procedure using an appropriately substituted anhranilemide as the starting material, the following products are obtained:

R ³ R5 R ⁶ mp ¹ H H ^CH 3 192 to 194 H CH 2 H 15 »to 160 H ^CH 3 ch ₃ 188 to 190 Cl II H 224 to 225

Example 1 «d 2

6 ₍ 5 g of S-nitroentranyl amide was stirred with 65 ml of anhydrous chloral at room temperature until the reaction mixture contained no more 5-nitroanthianeamide (6 days) according to thin layer chromatography. Heat on a steam bath for 10 minutes with 125 ml of concentrated sulfuric acid.

The resulting mixture was cooled, poured into 1 kg of ice-water, the precipitated solid product was filtered off, washed three times with 200 l of water each time and crystallized from 450 ml of ethanol. There was thus obtained 1,2-dihydro-6-nitro-2-trichloromethylquinazolin-4-one, m.p. 278 DEG-280 DEG.

Example 3

40.0 g of salicylamide, together with 400 ml of anhydrous chloral, were heated on a steam bath for 3 hours, then the reaction mixture was cooled and the excess chloral was evaporated under reduced pressure. The syrup-like residue is mixed with 500 ml of concentrated sulfuric acid, heated on a steam bath for 1 hour, then cooled and poured onto 3 kg of crushed ice. The precipitated solid product is filtered off, triturated with 300 ml of diethyl ether, filtered off, washed thoroughly with water and, after drying, crystallized in 400 ml of ethanol. There was obtained 3,4-dihydro-2-trichloromethyl-2H-benzo [e] - [1,3] oxazin-4-one, m.p. 175-177 ° C.

The above procedure was repeated except that the appropriately substituted salicylamide was used as the starting material. The following compounds are obtained:

O

R ³ tare temperature li (° C) Br 218 to 220 HIM 238 to 240 (decomposition) ch ₃ 199 to 200 no ₂ 201 to 203 COOH 301 to 303 (decomposition)

He attaches

To a suspension of 2.5 g of 3,4-dihydro-6-hydroxy-2-trichloroethyl-2H-benzo [e] - [1,3] oxazin-4-one (prepared as described in Example 3) in 125 ml of ethanol 32 ml of a 0.3634 solution of sodium hydroxide in ethanol are added with stirring, the resulting mixture is stirred for 30 minutes, then 1.5 ml of iodomethane is added and the solution is heated on a steam bath for 1 hour. The solvent was evaporated under reduced printing and the residue was dissolved in a mixture of 100 ml of diethyl ether and 50 ml of 1N sodium hydroxide solution. The ether layer was separated, the aqueous layer was re-extracted with ether (100 ml), the ether extracts were combined and dried. The solvent is evaporated, the sticky residue is stirred for 15 minutes with 100 ml of petroleum ether (b.p. 60-80 ° C), then filtered off and washed with further petroleum ether. There was obtained 3,4-dihydro-6-methoxy-2-trichloromethyl-2H-benzo [e] - [1,3] oxazin-4-one, m.p. 162-165 ° C.

The procedure described above is repeated except that benyl bromide, resp. n-butyl iodide. They'll get

(a) 6-benzyloxy-3,4-dihydro-2-trichloro-ethyl-2H-benzo [e] -1,3,3-oxazin-4-one, m.p. 228-230 ° C; and

b) 6-butyloxy-3,4-dihydrop-2'-trichloromethyl-2H-benzo [3-oxazin-4-one, m.p. 140-141 ° C.

The petroleum ether filtrate and washings from the above procedure were combined, the solvent was evaporated and the residue triturated with cyclohexane. There was obtained 2,3-dihydro-6-methoxy-3-methyl-2-trichloromethyl-2H-benzo [e] - [1,3] oxazin-4-one, m.p. 107-110 ° C.

Annex 5

5.0 g of 3,4-dihydro-6-hydroxy-2-triohormomethyl-2H-benzo [e] - [1,3] oxazin-4-one (prepared as described in Example 3) together with 250 ml of acetic anhydride was stirred at room temperature for 40 hours, then the reaction mixture was filtered and the solid product was washed first with acetic anhydride and then with diethyl ether to give 6-acetoxy-3,4-dihydro-2-trichloromethyl-2H-benzo [e] - [ M.p. 201-203 ° C; 1,3'-oxazin-4-one;

The procedure described above was repeated except that propionic anhydride and acetic anhydride were used instead of acetic anhydride. p-chlorobenzoyl chloride. The following compounds are obtained:

(a) 3,4-dihydro-6-propionyloxy-2-trichloromethyl-2H-benzo [e] - [1,3] oxazin-4-one, m.p. 183-85 ° C; and

b) 6-p-chlorobenzoyloxy-3,4-dihydro-2-trichloromethyl-2H-benzo [e] - [1,3] oxazin-4-one, m.p. 220-222 ° C.

Example 6

10.0 g of 3,4-dihydro-6-hydroxy-2-trifluoromethyl-2H-bensa [e] - [1,3] oxazin-4-one (prepared as described in Example 3) together with 200 ml of acetic anhydride Stir for 2 hours on a gently bath. The reaction mixture was cooled, poured into 1 liter of water, stirred for 3 hours and then filtered. The solid product was washed thoroughly with water and dried to give 6-acetoxy-3-acetyl-3,4-dihydro-2-trichloromethyl-2H-benzo [e] - [1,3] oxazin-4-one, m.p. 138 up to 140 ° C.

The above procedure was repeated using propionic anhydride instead of acetic anhydride. There was obtained 3,4-dihydro-3-propionyl-6-propionyloxy-2-trichloromethyl-2H-benzo [e] - [1,3] oxazin-4-one, m.p. 92-94 ° C.

Example 7

4.0 g of 3,4-dihydro-2-trihloromethyl-2H-benzo [e] - [1,3] oxosin-4-one (prepared as described in Example 3) together with 40 ml of acetic anhydride, Stirring while heating on a steam bath. The reaction mixture was cooled to room temperature, poured into 400 ml of water, stirred for 3 hours, then the oily material was extracted with diethyl ether. The extract was dried, the solvent was evaporated and the oily residue purified by silica gel column chromatography using 10% (v / v) ethyl acetate in toluene as eluent. Fractions of 25 ml are collected. Fraction δ. 1-7 were combined and the solvent was evaporated to give oily 3-acetyl-3,4-dihydro-2-trichlomethyl-2H-benzo [e] - [1,3] oxazin-4-one.

The NMR spectrum of the product, measured in hexadeuterodimethylsulfoxide, contains the following characteristic signals (a-values):

2.6, 3H, singlet, -COCH3

7.1, 1H, singlet, proton at Cg

7.15, 1H, double doublet (J = 8 and 2 Hz), proton at 0θ

7.21, 1H, doublet triplet (J = 8 and 2 Hz), proton at 0?

7.7, 1H, doublet triplet (J = 8 and 2 Hz), proton at Cg

7.9, 1H, double doublet (J = 8 and 2 Hz), proton at Cg.

Example e

To a mixture of 20 ml of dimethylformamide and 5 ml of thionyl chloride is added in small portions over 15 minutes 2.0 g of 3,4-dihydro-2-trichloromethyl-2H-benzo [e] - [1,3] oxazin-4- The mixture was stirred at room temperature for 48 hours. The reaction mixture is added to 100 ml of water, stirred for 1 hour and then filtered. The solid product was dissolved in toluene and purified by silica gel column chromatography using 5% (v / v) ethyl acetate in toluene as eluent. The solvent was evaporated and the product crystallized from petroleum ether (b.p. 60-80 ° C). There was obtained 3-formyl-3,4-dihydro-2-trichlonaethyl-2H-benzo [e] - [1,3] oxazin-4-one, m.p. 114 ° C.

Example 9

A suspension of 5.0 g of 3,4-dihydro-4-oxo-2-trichloromethyl-2H-benzo [e] - [1,3] oxazine-6-carbonyl chloride powder in 100 µl of n-butanol and heated on a steam bath for 30 minutes . The reaction solution was cooled to room temperature and the solvent was evaporated under reduced pressure. The sticky solid residue is triturated with petroleum ether (b.p. 60-80 ° C), then filtered off, washed with petroleum ether and crystallized from n-butanol. Butyl 3,4-dihydro-4-oxo-2-trifluoromethyl-2H-benzo [e] - [1,3] oxazine-6-carboxylate is obtained, m.p. 134-136 ° C.

The 3,4-dihydro-4-oxo-2-trichloromethyl-2H-benzo] - [1,3] oxazine-6-carbonyl chloride used as starting material in the above process can be obtained as follows:

A suspension of 2.1 g of 3,4-dihydro-4-oxo-2-trichloromethyl-2H-benzo [e] - [1,3] oxazine-6-carboxylic acid in 400 ml of thionyl chloride is heated to boiling under stirring for 4 hours. under reflux. The reaction solution was cooled and excess thionyl chloride was evaporated under reduced pressure below 80 ° C. The solid product was air dried for 30 minutes and then stored in a vacuum desiccator.

The above procedure was repeated using methanol instead of n-butanol. Methyl 1-3,4-dihydro-4-oxo-2-trichloromethyl-2H-benzo [e] - [1,3] oxazine-6-carboxylate, m.p. 218-220 ° C.

Example 10

To 5.0 g of powdered 3,4-dihydro-4-oxo-2-trichloromethyl-2H-benzo [e] - [1,3] oxazine-n-carbonyl chloride · a solution of 5 ml of n-propylamine in 100 ml of methanol.

The resulting solution was stirred for 30 minutes, then the solvent was evaporated under reduced pressure.

The solid sticky residue was triturated with water, stirred for 30 minutes, filtered, washed with water and crystallized from ethanol after drying. 2,3-dihydro-4-oxo-N-propyl-2-trichloromethyl-2H-benzo [e] - [1,3] oxazine-6-carboxamide, m.p.

The above procedure was repeated using ammonia and ammonia instead of n-propylamine. diethylamine. The following compounds are obtained:

3,4-dihydro-4-oxo-2-trichloromethyl-2H-benzo [e] - [1,3] oxime-6-carboxamide melting at 263-265 ° C with decomposition, and 3,4-dihydro N, N-diethyl-4-oxo-2-trichloromethyl-2H-benzo [e] - [1,5] oxazine-6-carboxamide, m.p. 162-164 ° C.

He did!

To a solution of 2.4 g o-aminobenzyl alcohol in 5 ml toluene was added dropwise 2.0 ml of common chloral with stirring at room temperature. The reaction mixture was stirred for 30 minutes, then evaporated to dryness and the oily residue crystallized from aqueous ethanol. There was thus obtained 1,2-dihydro-2-trichloro-208676 methyl-4H-benzo [d] - [1,3] oxazine, m.p. 90-92 ° C. The procedure described above was repeated using the appropriately substituted o-aminobenzyl alcohol as the starting material. The following analogous products are obtained:

(a) 1,2-dihydro-6-methyl-2-trichloromethyl-4H-benzo [d] - [1,3] oxezine, m.p. 102 ° C;

b) 1,2-dihydro-6-nitro-2-trichloromethyl-4H-benzo [d] - [1,3] oxazine, m.p. 144 ° C.

The 2-emino-5-nitrobenzyl alcohol used as the starting material for the preparation of this compound can be prepared as follows:

A suspension of 6.0 g of 2-amino-5-nitrobenzaldehyde in 250 ml of ethanol is added in small portions with stirring at room temperature 1.6 g of sodium borohydride, the reaction mixture is stirred for 1 hour, then acidified with 2N hydrochloric acid to quench excess sodium borohydride. The mixture was basified to pH 8-9 by addition of solid sodium carbonate and extracted three times with 200 ml of diethyl ether each time. The extracts were combined and, after drying, the solvent was evaporated. The residue is crystallized from about 200 ml of water to give the desired 2-amino-5-nitrobenzyl alcohol, m.p. 141-142 ° C.

(c) 1,2-dihydro-6-iodo-trichloromethyl-4H-benzo [d] - [1,3] oxazine, m.p. 113 ° C;

d) 1,2-dihydro-6-methoxy-2-trichloromethyl-4H-benzo [d] - [1,3] oxazine, m.p. 12 ° C.

The 2-amino-5-methoxybenzyl alcohol used as the starting material for the preparation of this compound can be obtained as follows:

To a solution of 2.3 g of 5-methoxy-2-nitrobenzaldehyde in 100 ml of ethanol is added 0.6 g of sodium borohydride while stirring at room temperature, stirring is continued for 2 hours, then 100 ml of water are added, the resulting solution is acidified with 2N acid. hydrochloric acid, and extracted with ether (3.times.100 ml). The extracts were combined and dried and the solvent was evaporated to give 5-methoxy-2-nitrobenzyl alcohol.

2.1 g of this alcohol are dissolved in 100 ml of ethanol, platinum (IV) oxide (Adems catalyst) is added and the mixture is shaken under a hydrogen atmosphere at room temperature and under normal pressure until 950 ml of hydrogen are consumed (theoretically required = 900 ml) . The hydrogenated mixture was filtered through diatomaceous earth and the solvent was evaporated to give 2-amino-5-methoxybenzyl alcohol as a brown solid.

e) 1,2-dihydro-2-trifluoromethyl-4H-benzo [d] - [1,3] oxazine-6-carbonitrile, m.p. 109 ° C.

The 4-amino-3-hydroxymethylbenzonitrile used as the starting material for the preparation of this compound can be obtained as follows:

2 g of 2-amino-5-iodobenzyl alcohol and 5.4 g of copper cyanide in 10 ml of dry dimethylformamide are heated on a steam bath for 30 hours, then cooled to room temperature and poured into a solution of 10 g of ferric chloride in 100 ml of water. The mixture was extracted with ether (14 x 60 mL) until exhaustion, the extracts were combined and dried to evaporate the solvent. The residue is chromatographed on a silica gel column. Elution with ether gave the desired 4-amino-3-hydroxymethylbenzonitrile as a yellow-orange solid.

Example 12

The ability of the heterocyclic trichloromethyl derivative of the invention to inhibit methane production from rumen can be conveniently demonstrated by an in vitro assay performed as follows:

Two bulls, fed the same forage consisting of hay and concentrate, are routinely harvested from the rumen era. Care is taken to ensure that the rumen sampling times from both animals are the same as possible and that the glory samples from both animals are combined at a 50:50 ratio. 2Secured rumen glory samples are removed by filtering through four layers of muellin, filtrate, and diluted 1 volume of filtrate: 3 volumes of rumen glory (prepared as described by GL Beles et al in Journal of Dairy Science, 1976, £ 2) (page 1850, but excluding acetic acid) and the pH of the mixture is adjusted to a pH of 6.9 to 7.0 with a saturated aqueous solution of sodium carbonate. Samples of this 50 ml mixture were transferred to conical flasks containing 0.5 g dry ground hay and each flask was used to test the efficacy of the test substance at a certain concentration.

The test compound is placed in a conical flask in the form of an ethanolic solution, the flask is flushed with solid carbon dioxide, sealed with a cork stopper, and incubated at 39 ° C for 15-16 hours. After 1 hour, the gas pressure in the flask is released by piercing the stopper with the needle and the needle is removed 30 minutes before the end of the incubation period. The fermentation was stopped by placing the flask in ice. After cooling for 15 minutes, the gas over liquid is analyzed by gas chromatography for methane content and the concentration of test compound required to induce a 50% reduction in methane production (ED? Vpg / ml) is calculated.

In the above test, the following results were obtained:

fl ⁶

O

Ip H ⁵ B ^{6 SD} 5Ú H H H 0.3 H H ch ₃ 0.3 H CH ₃ H i, o H ^c «3 ch ₃ 1.0 NO- H H 3.0 WHOSE H H 0.3

H ^J R ' ^ED 50 H H 0.5 Br H 0.5 HIM H 0.5 ^CH 3 ° H 0.5 CHjCO.O H 0.3 c ₆ h ₅ .ch _? 0 H 10.0 CH ₃ (CH ₂ ) ₃ O H 3.0 c ₂ h ₅ co.o H 0.3 ch ₃ H 1, 0 NOg H 1.0 Η0. what H 0.3 p-Cl.C ₆ H ₄ C0.0 H 1.0 CH ₃ (CH ₂ ) ₂ NH.CO H 0.3 NHgCO H 0.3 CH ₃ (CH ₂ ) ₃ O.CO H 1.0 (C ₂ H ₅ ) ₂ N.CO H 0.3 CH.jO.CO H 3.0 CH ₃ O ch ₃ 3.0 CH ₃ C0.0 CHjCO 1.0 C ₂ H ₅ CO.O c ₂ h ₅ co 0.3 H CH ₃ CO 1.0 II hco 0.5

R ³ ED ₅₎ Η 1.0 ch ₃ 3.0 mo ₂ 0.5 X 1.0 ch ₃ o 0.3 CN 0.3

Example 13

1.7 g of 2-amino-3-methylbenzyl alcohol are stirred together with 2.4 ml of anhydrous chloral for 10 minutes under external cooling with ice, then left to stand for 1/2 hour and then chromatographed on silica gel with diethyl ether / petroleum ether ( bp 60-80 ° C) in a 7: 3 v / v ratio as eluent. 1,2-Dihydro-8-methyl-2-trichloromethyl-4H-benzo [d] - [1,3] oxazine is obtained, which melts at 69-70 ° C after crystallization from aqueous ethanol.

By repeating the above procedure using the appropriate o-aminobenzyl alcohol, the following analogous products are obtained as starting material:

(a) 6-chloro-1,2-diliydro-g-trichloromethyl-4H-benzo [d] - [1,3] oxazine, m.p. 68-70 ° C. In this case, the reaction was terminated by heating on a steam bath for 2 minutes and using a 8: 2 mixture of ether and petroleum ether as eluent for chromatography.

The 2-amino-5-chlorobenzyl alcohol used as the starting material in the preparation of this compound is obtained from 5-chloro-2-nitrobenzyl alcohol according to the general procedure described in the last paragraph of Example 11 (d) using as catalyst 10 instead of platinum oxide. % palladium on coal.

b) Methyl 1,2-dihydro-2-trichloromethyl-4H-benzo [d] -0,3'-oxazine-4-carboxylate, m.p. 114 DEG-115 DEG C. after crystallization from cyclohexane. In this case, the reaction is terminated by briefly heating the reagents on a steam bath and using a 6: 4 by volume mixture of ether and petroleum ether as the eluent.

The o-aminomandelic acid methyl ester (ethyl-alpha-2-aminophenyl glycolate) used as starting material in the above process can be prepared as follows:

g of o-nitromanedioic acid are mixed with 50 ml of thlonyl chloride, the mixture is refluxed for 1 hour, then cooled and the excess thlonyl chloride is evaporated at room temperature on a rotary evaporator. The crude o-nitromanedioic acid chloride thus obtained was carefully mixed with 70 ml of methanol, after the initial vigorous reaction, the mixture was refluxed for 1 hour, then cooled and the solvent was evaporated under reduced pressure. The oily residue is chromatographed on a silica gel column using a 6: 4 by volume mixture of diethyl ether and petroleum ether (b.p. 60-80 ° C). The o-nitromanedioic acid methyl ester thus obtained is reduced using the general procedure described in (a) above to give the desired starting material.

c) Ethyl 1 _t 2-dihydro-2-trichloromethyl-4H-benzo [d] - [1,3] oxa «yn-4-carboxylate of melting point after crystallization from cyclohexane to 127, 28 ° C. In this case, the reaction is terminated by briefly heating the reactants on a steam bath, the reaction product is diluted with water and extracted with ether, the ether extract is dried and the solvent is evaporated before the residue is chromatographed. A mixture of ether and petroleum ether (8: 2 by volume) was used as eluent in silica gel column chromatography.

The o-aminobutyric acid ethyl ester used as starting material in the above-described process is obtained by the sequence of reactions described in the last part of the above-mentioned b) with the proviso that the o-nitromanedioic acid chloride is reacted not with methanol but with ethanol.

d) Butyl 1,2-dihydric-2-trichloromethyl-4H-benzo [d] - [1,3] oxazine-3-carboxylate, melting point after crystallization from cyclohexane 110-11 ° C. In this case, the reaction is terminated by briefly heating the reagents on a steam bath and using a 6: 4 mixture of ether and petroleum ether as the eluent.

The o-nitroanedioic acid butyl ester used as the starting material in the above-described process is prepared by the sequence of reactions described in the last part of b) above, using n-butanol instead of methanol.

e) H-phenyl-1,2-dihydro-2-trichloromethyl-4H-benzo [d] - [1,3] oxazine-4-carboxamide, m.p. 139-140 ° C.

The o-nitromanedioic acid N-phenylamide used as starting material in the above process is obtained by the sequence of reactions described in the last part of b) above, using aniline instead of methanol.

Example 14 g of methyl 4-amino-3-hydroxymethylbenzoate is stirred with 1 ml of anhydrous ethanol, initially under external cooling with ice and then for 5 minutes under heating on a steam bath. The reaction product is dissolved in 100 ml of ethyl acetate, the solution is washed with 50 ml of water, dried, the solvent is evaporated and the residue is crystallized with a mixture of ethyl acetate and petroleum ether (b.p. 60-80 ° C). There was obtained methyl 1,2-dihydro-2-oxochloromethyl-4H-benzo [d] - [1,3] oxazine-6-carboxylate, m.p. 178-179 ° C.

The methyl 4-amino-3-hydroxymethylbenzoate used as the starting material in the above process is obtained by reducing 5 g of di-ethyl-4-aminoisophthalate in 100 ml of ether dried over sodium by treatment with 2 g of lithium aluminum hydride. The mixture was stirred at room temperature for 3.5 hours, then 50 mL of water was carefully added. The organic phase is separated and dried, the solvent is evaporated and the residue is purified by chromatography on silica gel using a 4: 1 by volume mixture of ether and petroleum ether (b.p. 60-80 [deg.] C.). The product thus obtained, after crystallization from a mixture of ethyl acetate and petroleum ether (b.p. 60-80 ° C), affords the desired starting material melting at 116-117 ° C.

By repeating the above procedure using the appropriate o-aminobenzyl alcohol as starting material, the following analogous products are obtained:

(a) 1,2-dihydro-2-trifluoromethyl-4H-benzo [d] - [1,3] oxazine-4-carbuxylic acid, m.p. 141-143 ° C after crystallization from aqueous acetic acid. In this case, the reaction product was not dissolved in ethyl acetate but in diethyl ether.

b) Propyl 1,2-dihydro-2-trifluoromethyl-4H-benzo [d] [1,3] oxezine-4-carboxylate, m.p. crystallization from cyclohexane 115-116 ° C. In this case, the reaction product is simply extracted with cyclohexane and the solution is clarified with activated carbon before it is allowed to crystallize.

The o-aminomandelic acid propyl ester used as starting material in the above process can be obtained as follows:

g of o-nitromanedioic acid together with 75 ml of thionyl chloride was heated to reflux for 1 hour. The reaction mixture was cooled, the excess thionyl chloride was evaporated under reduced pressure, the residue was stirred with propanol and refluxed for 1 hour. The excess propanol was evaporated and the residue was purified by chromatography on silica gel using diethyl ether / petroleum ether (b.p. 60-80 ° C) 7: 3 by volume. The o-nitromanedioic acid propyl ester thus obtained is then hydrogenated using the general procedure described in the last part of Example 13a) to give the desired starting material.

c) Isopropyl 1,2-dihydro-2-trichloromethyl-4H-benzo [d] - [1,3] oxazine-4-carboxylate, which melts at 141 DEG C. after crystallization from cyclohexane as described in (b) above. to 142 ° C.

The o-aminobutyric acid isopropyl ester used in the above process as a starting material is obtained by the sequence of reactions described in the last part of the above-mentioned b) using isopropanol instead of propanol.

Did he?

8.8 g of 5-acetoxy-2-aminobenzylalcohol are dissolved in 150 ml of dry diethyl ether, 9.6 ml of anhydrous chloralv are added to the solution with stirring over 5 minutes (and the reaction mixture is stirred at room temperature overnight). the residue is crystallized by stirring in a mixture of 50 ml of methanol and 25 ml of water to give 6-aethoxy-1,2-dihydro-2-trichloromethyl-4H-benzo [d] - [1,3] oxazine mp 155-157 ° C.

The 5-8-cetoxy-2-aminobenzyl alcohol used as starting material in the above process is obtained as follows:.

A mixture of 4 g of 5-hydroxy-2-nitrobenzaldehyde and 10 ml of acetic anhydride is heated on a steam bath for 1 hour, then poured into 100 ml of water and extracted three times with 50 ml of diethyl ether each time. The extracts were combined, dried and the solvent was evaporated. The remaining 5-acetoxy-2-nitrobenzaldehyde is dissolved in 100 ml of absolute ethanol and 1.5 g of sodium borohydride are added portionwise under ice-cooling and stirring. The reaction mixture was stirred at room temperature for 1 hour, then 100 mL of water was added and the resulting mixture was extracted three times with 70 mL of ether each time. The extracts were combined and, after drying, the solvent was evaporated. 5-Acetoxy-2-nitrobenzyl alcohol is obtained which, by hydrogenation according to the general procedure described in the last part of Example 13a), gives the desired starting material.

Example 16 g of 3,4-dihydro-2-trichloromethyl-2H-benzo [e] - [1,3] oxazin-4-one (prepared as described in Example 3) is suspended in 100 ml of ethanol, 63 ml of solution are added. 1.0 g of sodium hydroxide in 83 ml of ethanol was added and the resulting mixture was stirred for 15 minutes to give a clear solution. To this solution was added 5 mL of iodomethane, and the reaction mixture was refluxed for 30 minutes. The solvents were evaporated, the residue was dissolved in toluene / ethyl acetate (7: 3 by volume) and chromatographed on silica gel using the same solvent mixture as eluent. The first 100 ml of eluate are collected, the solvent is evaporated and the residue is crystallized by trituration with petroleum ether (b.p. 60-80 ° C). There was obtained 3,4-dihydro-3-methyl-2-trichloromethylbenzo [e] - [1,3] oxazin-4-one, m.p. 82-84 ° C.

Add 1 a 17

The procedure described in Example 3 was repeated except that the corresponding salicylamide was always used as the starting material. The following analogous products are obtained:

a) 3,4-dihydro-4-oxo-2-trichloromethyl-2H-benzo [f] - [1,3] oxazine-6,8-dicarboxylic acid, m.p. crystallized from ethanol with decomposition of 305-307 ° C .

b) 3,4-dihydro-β-hydroxyiminomethyl-2-trichloromethyl-2H-benzo [e] - [1,3] oxazin-4-one, melting point 228-230 ° C after crystallization from ethanol.

5- (hydroxyiainomethyl) salioylamide. used as starting material in the above process can be obtained as follows:

To 1.6 liters of a saturated solution of ammonia in methanol was added 6.0 g of methyl 5 (hydroxyiminomethyl) salicylate in a single portion. The resulting solution is stirred at room temperature for 24 hours, then evaporated to dryness and the residue is triturated with 200 ml of ethanol to give the desired starting material, m.p. dec. 225-227 ° C.

o) 3,4-Dihydro-2-trichloromethyl-2H-benzo [a] [1,3] oxazine-6-carbaldehyde, m.p. 203 DEG-206 DEG. In this case, the suspension obtained after pouring the reaction mixture on ice is filtered, the product is washed and, after drying, crystallized from 200 [mu] l of aqueous ethanol (1: 1). The first crystallized material is discarded, the mother liquors are evaporated to dryness and the residue is dissolved in 250 ml of ethyl acetate. The ethyl acetate solution is washed with 100 ml of 1H sodium hydroxide solution and then with water, dried and evaporated to give the desired product.

The 5-formylsallcylamide used as starting material in this process is obtained by hydrolyzing 5- (hydroxyiminomethyl) salicylamide [prepared as described in b) above with 5K hydrochloric acid and extracting the reaction mixture with ethyl acetate. The product thus obtained melts after crystallization from ethanol with decomposition at 188-190 ° C.

(d) 6-acetamido-3,4-dihydro-2-trichloromethyl-2H-beMO [e | Oxazin-4-one having a melting point after crystallization from ethanol with a decomposition of 228-230 ° C.

(e) 3,4-Diltydro-6-methoxy-amino-2-trichloromethyl-2H-benzo [e] - [1,3] oxazin-4-one, m.p.

Example 18

1.0 g of 3,4-dihydro-4-oxo-2-trichloromethyl-2H-benzo [e] - [1,3] oxazine-6-carboxamide (prepared as described in Example 10) together with 20 ml The reaction mixture was then cooled to room temperature and poured into 200 ml of ice-water. After stirring for 1 hour, the resulting white suspension is filtered, the product is washed with water, dried at 60 DEG C. and extracted three times with 200 ml of toluene each time. The toluene extracts were combined and the solvent was evaporated. There was obtained 3,4-dihydro-4-oxo-2-trichloroethyl-2H-benzo [e] - [1,3] oxazine-6-carbonitrile, m.p. 212 DEG-214 DEG.

Example 19

A mixture of 23.0 g of 5-amino-N- (1-hydroxy-2,2,2-trichloroethyl) silyl amide and 115 ml of concentrated sulfuric acid was heated on a steam bath for 1 hour and then poured onto 1 liter of ice. The resulting mixture was stirred for 30 minutes, then filtered, the filtrate was adjusted to pH 5 with 5N sodium hydroxide solution, and stirring was continued for 30 minutes. The precipitated product is filtered off and, after washing with water, dried at 60 ° C. 6-Amino-3,4-dihydro-2-trichloromethyl-2H-benzo [e] - [1,3] oxazin-4-one is obtained, m.p. 172-174 ° C.

The 5-amino-N- (1-hydroxy-2,2,2-trichloroethyl) salicylemide used as starting material in the above process can be obtained as follows:

10.0 g of 5-nitrosalycylamide, together with 100 ml of anhydrous chloral, are heated on a steam bath over the nose, the resulting solution is cooled and the excess chloral is evaporated under reduced pressure at 50 ° C. The oily residue was triturated with 100 ml of toluene for 30 minutes, the solid material was filtered off and crystallized from benzene. N- (1-Hydroxy-2,2,2-trichloroethyl) -5-nitrosalicylamide, m.p. 223-225 ° C.

To 69 g of K- (1-hydroxy-2,2,2-trichloroethyl) -5-nitrosalicylamiide in 1380 ml of glacial acetic acid, 109 g of zinc are added in portions over a period of 3 hours at 30-37 ° C. of dust. The resulting suspension is filtered, the residue is washed with glacial acetic acid, the filtrate is combined with the washings and evaporated under reduced pressure at 50 ° C. The dark oily residue was treated with 2M hydrochloric acid, stirred for 30 minutes, then filtered. The filter residue is washed with 2H hydrochloric acid, the filtrate is combined with the washings and neutralized with 2K sodium hydroxide. The neutralized mixture is stirred for 30 minutes, then filtered, the solid is washed with water and, after drying, extracted three times with 1 liter of ethyl acetate each time. The extracts were combined and evaporated to dryness to give the desired starting material.

Example 20

X

A suspension of 5.1 g of 6-p-chlorobenzylidenanino-3,4-dihydro-2-trichloromethyl-2H-benzo [e] - [1,3] -oxazin-4-one in 3 liters of ethanol was converted to 50 ° C by heating. to a solution to which 4.6 g of sodium borohydride was added over 30 minutes. The reaction mixture is cooled, the solvent is evaporated off under reduced pressure at 40 ° C, the residue is stirred with 50 ml of water, the pH of the mixture is adjusted to 8 with 2N hydrochloric acid 1767676, after 15 minutes the solid product is filtered off and washed with water. dried. This product is dissolved in 1 liter of diethyl ether, washed successively with water, 2N hydrochloric acid, water, 2N sodium hydroxide solution and again with water, and dried. Evaporation of the solvent gave 6-p-chlorobenzylamino-3,4-dihydro-2-trichloromethyl-2H-benzo [d] - [1,3] oxazin-4-one, m.p. 156-158 ° C.

6-p-chlorobenzylldenamino-3,4-dihydro-2-trichloromethyl-2H-benzo [e] - [1,3] oxazin-4-one, used as starting material in this process, can be obtained by a solution of 1 g of 6-amino-3,4-dihydro-2-trichloromethyl-2H-benzo [e] - [1,3] oxazin-4-one (prepared as described in Example 19) in 60 ml of ethanol is mixed with a solution of 0.5 g of p-chlorobenzaldehyde in 15 ml of ethanol, the mixture was heated on a steam bath for 10 minutes, and the desired solution crystallized from the resulting solution with cooling, m.p. 246-249 ° C.

Example 2,

A mixture of 10 g of 3,4-dihydro-2-trichloromethyl-2H-benzo [e] - [1,3] oxazin-4-one (prepared as described in Example 3) and 100 ml of concentrated sulfuric acid is heated at room temperature for 18 hours. steam bath, then pour over 400 g of ice. The resulting solution was saturated with sodium chloride and extracted four times with 100 ml of ethyl acetate each time. The extracts were combined, dried, the solvent was evaporated and the residue crystallized from glacial acetic acid. There was obtained 3,4-dihydro-2-trichloromethyl-2H-benzo [e] - [1,3] oxazine-6-sulfonic acid melting above 260 ° C.

Example 22

The procedure described in Example 1 was repeated except that the anthranilamide was replaced with 5-methoxycarbonylanthranilamide and 76 ml of bis- (2-methoxyethyl) ether was used as the diluent. Methyl 1,2-dihydro-4-oxo-2-trichloroethylquinazoline-6-carboxylate is obtained, m.p. with decomposition at 249 ° C.

Example 23

A mixture of 5 g of N- (1-hydroxy-2,2,2-trichloroethyl) -5-methoxycarbonylanthranilamide and 100 ml of concentrated sulfuric acid is heated on a steam bath for 15 minutes, then cooled and poured onto a minimum amount of ice. The precipitate formed is filtered off and, after drying, dissolved in 200 ml of hot ethanol. The ethanol solution is concentrated to a volume of 20 ml, the precipitated solid is filtered off and discarded. The filtrate is further concentrated to a volume of 10 ml, the product formed after this second concentration is filtered off and, after drying, crystallized from a mixture of equal parts of glacial acetic acid and water. 1,2-dihydro-4-oxo-2-trichloromethylquinazoline-6-carboxylic acid is obtained, m.p.

The N- (t-hydroxy-2,2,2-trichloroethyl) -5-methoxycarbonylanthranilamide used as starting material in the above process can be obtained as follows:

A mixture of 70 g of 5-methoxycarbonyl-2-nitrobenzoic acid and 350 ml of thionyl chloride is heated on a steam bath for 5 1/4 hours, then cooled and the remaining thionyl chloride is evaporated under reduced pressure. The residue was dissolved in 700 ml of toluene and ammonia gas was bubbled into the solution for 1-3/4 hours under ice-cooling. The precipitated solid is filtered off, washed first with toluene and then with petroleum ether (b.p. 60-80 ° C), then stirred with water for 1 hour and dried after further filtration. 5-Methoxycarbonyl-2-nitrobenzamide is obtained.

g of 5-methoxycarbonyl-2-nitrobenzemide is dissolved in 600 ml of methanol, 3 g of 10% palladium on carbon catalyst are added and the mixture is hydrogenated for 6 hours at a temperature of about 35 ° C. The catalyst is filtered off, extracted with 350 ml of methanol under reflux for 20 minutes under nitrogen and filtered again. The two filtrates are evaporated to dryness, the residues are combined and crystallized from 3 liters of water. 188 DEG-193 DEG C., yielding 5-methoxycarbonylanthranilamide.

A mixture of 1.0 g of 5-methoxycarbonylenthranilamide, 5 ml of anhydrous chloral and 20 ml of bis- (2-methoxyethyl ether) was heated on a steam bath for 20 minutes and then evaporated to dryness under reduced pressure. and purified by column chromatography on 250 g of silica gel, eluting with a mixture of ethyl formate and toluene (7: 3 by volume), collecting 50 ml fractions.

Fractions 10-13 were combined and evaporated to dryness. The residue solidifies after stirring with petroleum ether (b.p. 60-80 ° C). The desired N- (1-hydroxy-2,2,2-trichloroethyl) -5-methoxycarbonylanthranilamide, m.p. 93 DEG C., is obtained.

Example 24

A mixture of 0.5 g of 1,2-dihydro-4-oxo-2-trichloroethylquinazoline-6-carboxylic acid, 6 ml of ethanol and 3 ml of concentrated sulfuric acid was refluxed for 1.5 hours, then heated to reflux for 1.5 hours. filter and pour the filtrate onto a minimum of ice. The precipitate formed is filtered off and dried after washing with water. Ethyl 1,2-dihydro-4-oxo-2-trichloroethylquinazoline-6-carboxylate is obtained, m.p. 243-244 ° C.

Example 1 and d 25

A mixture of 3.0 g of 1,2-dihydro-2-trichloromethylcninazolin-4-one, 25 ml of acetic anhydride and a few drops of concentrated sulfuric acid is heated on a steam bath for 1.5 hours, the resulting solution is cooled and poured into 250 ml of water. . The mixture was stirred for 2 hours, then filtered, the filter residue was washed with water and, after drying, crystallized from ethanol. There was obtained 1,3-diacetyl-1,2-dihydro-2-trichloromethyllohinazolin-4-one, m.p. 152-154 ° C.

Example 26

The methane production inhibition assay described in Example 12 was repeated with various other compounds of the invention. The results are shown below. These results are expressed as percent inhibition of methane production caused by administration of 1 µg / ml test compound, with the exception of the compounds marked with an asterisk (*), which were administered at a dose of 3 µg / ml.

R ¹ X -R ⁵ 0 R ⁵ inhibition of methane production (in%) at a dose of i pg / ml R ¹ R ³ H CN H 87 * COOH COOH H 38 H CHO H 47 H HO.N: CH H 41 H nh ₂ H 98 H CH 2 CONH H 96 H p-CH ₃ .C ₉ H ₄ SO ₂ NH H 94 H p-c.c ₆ h..ch ₂ hn H 86 * H s ° ₃ ^h H 11 H H ch ₃ 100 ALIGN!

inhibition of methane production (in%). at a dose of 1 µg / ml

100 ALIGN!

100 ALIGN!

100 ALIGN!

14 46 24

38 12 57

Η ³

Η

Η

Η

Η

Η

Η

Η

Η

Η

Η

Η

NO. 1

ΟΗ ^ Ο.ΟΟ

CHjCO.O

Η

Η

Η

Η

Η

Η

Η

Η

Η

Η

Η

COOH ch ₃ o.co.

CgHjO.CO n -C ^H OO.CO i-C.jHH7O.CO n -C ^HgO.CO

CgHgNH.CO

H

COOH

CgHgO.CO

Example

CHjCO

H

H

ch ₃ co

H

H inhibition of methane production (in%) at a dose of 1 µg / ml

5 «

71 *

Feed supplements suitable for addition to ruminant feed may be prepared by incorporating 20, 30, 40 or 50 g of the heterocyclic trichloromethyl derivative of the formula I into a standard ruminant feed such that the final weight of the premix is 500 g.

A suitable standard feed for cattle may be, for example, a mixture of the following composition:

pressed barley 85% by weight extracted soybean meal 10% by weight molasses 4% by weight mixture of vitamins and minerals 1% by weight and suitable standard feed for sheep may be a mixture of the following composition:

crushed barley 60% by weight wheat bran 1% by weight corn germ meal 10% by weight soya bean meal 6% molasses 7.5% by weight mixtures of vitamins and minerals 1.5% by weight.

The individual components of the above mixtures can vary widely depending on local feed requirements and the availability of the individual components.

Example 28

Feed suitable for direct feeding of bovine animals is obtained by thoroughly mixing 500 g of the premix prepared as described in Example 27 with 4.5 kg of the standard bovine feed described in Example 27, and then thoroughly mixing the resulting mixture with 995 kg of standard feed. A supplemented feed containing 20, 30, 40 and 40%, respectively, is obtained. 50 g of heterocyclic trichloromethyl derivative per 1 ton of feed, depending on the concentration of the active substance in the premix.

Example 29

Feed suitable for direct feeding of sheep may be obtained by mixing 500 g of the premix prepared by the procedure described in Example 27 with 4.5 kg of the standard sheep feed described in Example 27 and mixing the resulting mixture thoroughly with 995 kg. feed. A supplemented feed containing 20, 30, 40 or 50 g of the heterocyclic trichloromethyl derivative of the formula I per tonne of feed is obtained, depending on the concentration of the active compound in the premix.

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of heterocyclic trichloromethyl derivatives of the general formula I R ¹ (I) wherein either X or X or X Is an oxygen atom, Y is a radical of the formula -NR-, wherein R is a hydrogen atom, an alkyl or alkanoyl group having 1 to 4 carbon atoms, or a phenyl group optionally substituted by at least one substituent selected from halogen, nitro and alkyl , alkyloxy and haloalkyl group containing from 1 to 4 carbon atoms, and Z represents a carbonyl group, represents a radical of the formula -NR ⁸ -, wherein R ⁸ represents hydrogen, an alkyl or alkanoyl group containing from 1 to 4 carbon atoms or phenyl, optionally substituted as above for R ⁹ , Y is -NR ⁹ - and Z is carbonyl, is -NR ⁸ - as defined above, Y is O and Z is methylene, optionally substituted carboxy or carbamoyl, C 2 -C 5 alkoxycarbonyl or N a phenylcarbamoyl group optionally substituted by halogen atoms, nitro groups or alkyl, alkoxy or haloalkyl groups containing from 1 to 4 carbon atoms each, and 206676 Each of R, R, ^RJ and R, which may be the same or different, represents a hydrogen or halogen atom, a cyano group, a formyl group, a hydroxy group, a hydroxyiminomethyl group, a nitro group, a sulfo group, a carboxyl group or an alkali metal salt thereof , an alkaline earth metal or an ammonium salt, or is a radical of formula R ⁷ , OR ⁷ , O.CHgR ¹⁰ , CO.OR ⁷ , O.COR ⁷ , O.COR ¹⁰ , CO.KR ⁸ R ⁹ , NH.SO ² R ¹⁰ , NR ⁸ R ⁹ , NR ⁸ .COR ⁹ , NH.CH ₂ R ¹⁰ , SO _2. NR ⁸ R ⁹ or SO ₂ .OR ⁷ , in which: R ⁷ represents an alkyl group having 1 to 4 carbon atoms, Q each of R and R, which may be the same or different, represents a hydrogen atom or a C 1 -C 4 alkyl group, and r 10 represents a phenyl radical optionally substituted as described above for R ⁵ , except for those compounds, in which Z is a carbonyl group and either X is an oxygen atom or an imino group, Y is an imino group, and R ¹ , R ² , R ³ and R 6 are hydrogen atoms, OA or X represents oxygen, Y represents NH and either R and R represent chlorine atoms, Ar 'and R ³ are hydrogen or R ³ is an acetamido ar \ R ^2, and R is a hydrogen atom, or X represents oxygen, Y represents acetyliminoskupinu, R ³ is a 12-pin acetamido group and R, R and R are hydrogen atoms, characterized in that the compound of formula XI R ¹ (II) wherein r 1, R ² , R ³ , r 1, X, Y and Z are as defined above, reacted with chloral, optionally in the presence of a solvent, and either simultaneously or 1 2 Ί followed by acid, whereupon any optionally present radicals R, R, R and R ' and R < ⁹ > and R < ^{8 &gt}; when present in the radicals X or Y are converted to other substituents falling within the above definitions. 2. The process of claim 1 wherein the solvent is bis (2-methoxyethyl) ether.