DD149067A5 - PROCESS FOR PREPARING HETEROCYCLIC TRICHLOROMETHYL DERIVATIVES - Google Patents

Abstract

The invention relates to novel heterocyclic trichloromethyl derivatives, in particular 2-trichloromethyl-substituted quinazoline, benzo & d! - & 1,3! -Oxazine and benzo & e! - & 1,3! -Oxazine derivatives, e.g. 1,2-dihydro-2-trichloromethyl-quinazolin-4-one. The compounds of the present invention are at least as effective as trichloromethyl derivatives heretofore known in the art to reduce the formation of methane during ruminating rumen and increase the production of propionate at the expense of acetate and, consequently, the growth rate of the animals and the benefit of feed utilization by the animal Improve animals.

Description

Berlin, March 13, 1980 AP C 07 D / 216 995 - <- 2169 95 56 272/12

Process for the preparation of heterocyclic trichloromethyl derivatives *,

Field of application of the invention

The invention relates to heterocyclic trichloromethyl derivatives which modify the metabolism in the rumen of ruminating domestic animals such that the formation of methane is reduced and the proportion of propionic acid in the rumen fluid is increased at the expense of the acetic acid portion.

Known technical solutions

It is known that various trichloromethyl group-containing organic compounds are effective in reducing methane formation during rumen 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 the metabolism in the rumen when administered to ruminants. Recently, it has now been found that a number of trichloromethyl-substituted benzo [1,3-dioxin derivatives are much more effective than the simple trichloromethyl compounds heretofore known in the art.

Object of the invention

The object of the invention is to bring about further improvements in comparison with benzo-11,3-dioxines.

Essence of the invention

The object of the invention is to provide processes for preparing novel heterocyclic trichloromethyl derivatives.

16995 *

I Ü7 / J _{e> ar} 13.3.1980

AP C 07 D / 216 995 56 272/12

deliver.

According to the invention, a heterocyclic trichloroethyl compound of the formula I is provided:

R ¹ X rii R ³ ' LJI R ⁴

where either:

a) X is an oxygen atom, Y is a radical of the formula -NR-, in which R is a hydrogen atom, a 1-4C-alkyl or alkanoyl radical or a phenyl radical, which is partly replaced by one or more halogen atoms, nitroradicals or 1-4C-alkyl, alkoxy or haloalkyl radicals

21-6995

is substituted, and Z is a carbonyl radical; or

b) X is a radical of the formula -NR-, wherein R is a hydrogen radical, a 1-4C alkyl or alkanoyl radical or a phenyl radical optionally substituted for R as defined above, Y is a radical of the formula -NR as defined above and Z is a carbonyl radical; or

c) X is a radical of the formula -NR - as defined above, Ύ is an oxygen atom and Z is a methylene radical, optionally substituted by a carboxy or Cärbamoylradikai, a 2-5C alkoxycarbonyl radical or an N-phenylcarbamoyl radical optionally substituted by halogen atoms, Nitro radicals or 1-4C alkyl, alkoxy or haloalkyl radicals;

12 3 4

and R , R, R and R, which may be the same or different, are each a hydrogen or halogen atom, a cyano, formyl, hydroxy, hydroxyiminomethyl, nitro or sulforadical, a carboxyradical or an alkali metal, alkaline earth metal or ammonium salt thereof, or a radical of the formula R ⁷ , OR ⁷ , OCH ₀ R ¹⁰ , CO.OR ⁷ , O.COr ', O.COR ¹⁰ , CONR ⁸ R ⁹ , NR ⁸ R ⁹ , NR ³ .COR ⁰ , NH ₄ SO ₂ R ¹⁰ , NH.CIi ^ R ¹⁰ , SO _£ NR ⁸ R ⁹ or SO ₂ .OR ⁷ where R ^{7 is} a 1-4C alkyl radical, R ⁸ and R ⁹ , which may be the same or different each is a hydrogen atom or a 1-4C alkyl radical, and R is an optionally substituted phenyl radical as indicated above for R; wherein those compounds are excluded, wherein Z is a carbonyl radical, and:

I) X is an oxygen atom or an imino radical,

12 3 4

Y is an imino radical and R ₁ R, R and R are all hydrogen atoms; or

II) X is an oxygen atom, Y is an imino radical,

2 4 13

and either R and R are chlorine atoms and R and R are hydrogen atoms, or R is an acetamidoradical

216995 -β-

and R _{7 is} R and R are hydrogen atoms; or

III) X is an oxygen atom / Y is an acetyliminoradical,

ο 12 4

R ° is an acetamidoradical and R, R and R are all hydrogen atoms.

1 2 3 4 A suitable group for one of R, R, R and R, when it is a halogen atom, or for a halogen substituent in a phenyl radical R, chlorine, bromine or iodine atom.

in a phenyl radical R, R or R is, for example, a

A specific group for one of R, R, R, and R when it is a radical of formula R for R or R when it is a 1-4C alkyl radical; for a 1-4C alkyl substituent in R , R or R when it is a 1-4C alkyl substituted phenyl radical; or for a 1-4C alkyl substituent in the phenyl ring of Z, when it is an N-phenylcarbamoyl-substituted methylene radical, is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl or t -Butylradikal.

12 3 4 A particular group for one of R, R, R, and R when it is a radical of the formula OR; for a 1-4C alkoxy substituent in one of R °, R and R, when it is a 1-4C alkoxy-substituted phenyl radical; or for a 1-4C alkoxy substituent in the phenyl ring of Z, if it is an N-phenylcarboxiyl-substituted methylene radical, is a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy or t-butoxy radical.

12 3 4 A special group for one of R ₁ R ₁ R and R when it is a radical of formula CO.OR, or for a 2-5C alkoxycarbonyl substituent in Z when it is a alkoxycarbonylsubstituiertes methyl radical, is a methoxycarbonyl, Ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl or t-butoxycarbonyl radical.

21 69 9 5 - ♦ -

A particular group for one of R _/ R , R and R when it is a radical of formula O, COR is, for example, an acetoxy, propionyloxy, butyryloxy or isobutyryloxy radical.

1 2 3 4 A special group for one of R, R, R and R when it is a radical of formula 0.CH ₂ R, for example, a benzyloxy, chlorobenzyloxy or Methylbenzyloxyradikal.

12 3 4 A special group for one of R, R , R and R-, if

For example, when it is a radical of the formula O.COR, it is a benzoyloxy, chlorobenzoyloxy, or methylbenzoyloxy radical.

A particular group for a 1-4C haloalkyl substituent in one of R, R and R when it is a haloalkyl-substituted phenyl radical or in the phenyl ring of Z when it is an N-phenylcarbamoyl-substituted methylene radical is, for example, a trichloromethyl-, Trifluoromethyl, 2,2,2-trichloroethyl, 3,3,3-trichloropropyl or 2 / 2,3,3,3-pentachloropropyl radical.

A particular group for R or R when it is a 1-4C alkanoyl radical is a formyl, acetyl, propionyl, butyryl or isobutyryl radical.

12 3 4 A special group for one of R , R, R and R, if

S 9 is a radical of the formula CO.NR R is, for example, a carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl, dipropylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, s-butylcarbamoyl , t-butylcarbamoyl or ethylmethylcarbamoyl radical.

A special group for one of R, R, R and R, though

8 is a radical of the formula NR R, is, for example, an amino, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, isopropylamino,

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Butylamino, isobutylamino, s-butylamino, t-butylamino or ethylmethylaminoradkal.

12 3 4 A special group for one of R, R, R and R , if

QQ

it is a radical of the formula NR, COR is, for example, an acetamido, N-methylacetamido / N-ethylacetamido, N-propylacetamido, N-isopropylacetamido, N-butylacetamido, propionamido, N-methylpropionamido, N-ethylpropionamido, butyramido, N-methylbutyramido, N-ethylbutyramido, 2-methylpropionamido or N, -dimethylpropionamidoradical.

if

T L. ό

A special group for one of R , R. R and R

For example, when it is a radical of the formula SO ₂ .NR R, it is a sulfamoyl, methylsulfamoyl, dimethylsulfamoyl, ethylsulfamoyl, diethylsulfamoyl, propylsulfamoyl, dipropylsulfamoyl, isopropylsulfamoyl, butylsulfamoyl, isobutylsulfamoyl , s-butylsulfamoyl, t-butylsulfamoyl or ethylmethylsulfamoyl radical.

A specific group for one of R, R, R and R, when it is a radical of the formula SO ₂ , OR, is a methoxysulfonyl, ethoxysulfonyl, propoxysulfonyl, isopropoxysulfonyl, butoxysulfonyl, isobutoxysulfony1, s -Cutoxysulfonyl or t-Butoxysulfonylradikal.

Particularly valuable compounds according to the invention are 3,4-dihydro-6-hydroxy-2-trichloromethyl-2] H-benzo / ey '- / 3,3-oxazin-4-one, 3,4-dihydro-4-oxo-4-one 2-trichloromettiyl-2j _ [- benzo / e / - / l, 3 / -oxazine-6-carboxylic acid, 6-acetoxy-3,4-dihydro-2-propyl-1-methyl-2'-benzo / e7-i, 37 '-oxazin-4-one, 6-acetoxy-1,2-dihydro-2-triethormethyl-4H-benzoic / ethyl / 1,3-oxazine, 1,2-dihydro-2-trichloromethyl-4l. benzo / cl7- / i, 37-oxazine-4-carboxylic acid and 1-yl-1,2-dihydro-2-trichloromethyl-4H-benzo / cl7- _/ / l _/ 37-oxazine-4 carboxylate,

According to a further feature of the invention, a process for the preparation of a heterocyclic trichloromethyl

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compound of the formula I, which comprises the reaction of a compound of the formula II:

,1

12 3 4 wherein R, R, R, R, X ₁ Y and Z have the above defined meanings FiBbCn ₇ with chloral / optionally in the presence of a solvent and, either simultaneously or sequentially, with an acid, whereby certain desired

Substituents R ¹ , R, R and-R and, if in X or Y.

5 6

R, and R, to other such substituents, as defined above, can be converted to conventional methods currently in use or known in organic chemistry literature.

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

When a solvent is used in the above-mentioned process, bis (2-methoxyethyl) ether, (diethyldiethylene glycol, dimethyldigol, glutamic acid) is preferable. Other solvents tend to cause partial loss of chlorine from the trichloromethyl group of the product.

Examples of optional conversions to the primary products of the above process are:

a) Alkylation of a hydroxy-substituted product to form an alkoxy-substituted product, a carbamoyl-substituted product to form a mono- or di-N-alkylcarbanioyl-substituted product, an alkanoylamino-substituted product to form an N-alkyl-alkanoylamino substituted product, a sulfamoyl-substituted product to form a mono- or di-N-alkylsulfamoyl-substituted

216995 - »-

or a ring NII product to form a ring N-alkyl product;

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

c) esterification of a carboxy-substituted product to form an alkoxycarbonyl-substituted product or a sulfo-substituted product to form an alkoxysulfonyl-substituted product;

d) amination of a carboxy-substituted or alkoxycarbonyl-substituted product to form a carbamoyl or a mono- or di-N-alkylcarbamoyl-substituted product, or a sulfo-substituted or alkoxysulfonyl-substituted product to form a sulfamoyl or mono- or di-N-alkylsulfamoyl-sub-. substituted product;

e) hydrolysis of an alkanoyloxy-substituted product to form a hydroxy-substituted product, a cyano-, alkoxycarbonyl-, carbamoyl- or mono- or di-N-alkylcarbamoyl-substituted product to form a carboxy-substituted product, or an alkoxysulfonyl-, sulfamoyl or mono- or di-N-alkylsulfamoyl-substituted product to form a sulfo-substituted product;

f) dealkylation of an alkoxy-substituted product to form a hydroxy-substituted product;

g) reduction of a nitro-substituted product to form an amino-substituted product or a benzylideneamino-substituted product for formation

216995 - · -

a benzylamino-substituted * product;

h) oxiomination of a formyl-substituted product to form a hydroxyiminomethyl-substituted product;

i) sulfonation of a product unsubstituted in the aromatic ring to form a sulfo-substituted product.

As stated above, the heterocyclic trichloromethyl derivatives of formula I reduce methane formation and increase the proportion of propionic acid in the rumen fluid of ruminants and are therefore valuable for the more effective husbandry of ruminating pets.

According to a further feature of the invention, therefore, there is provided a method of reducing rumen methane formation and / or increasing the proportion of propionic acid in the ruminal fluid of ruminant domestic animals which comprises orally administering a heterocyclic trichloromethyl group.

Compounds of the formula I ₁ in which R, R, R, R, X, Y and Z have one of the meanings given above, to which the animals comprise.

In the method of the invention, the compound of Formula I is preferably administered orally to the animals as an adjunct to their normal diet, i. mixed with a normal solid feed, in food stubs or salt licks, dissolved in drinking water, or, for Oungtiere such as weaned lambs or calves, dissolved in whole milk or skimmed milk. The compound of the formula I is mixed in such an amount in feed, food stalks, salt licks, drinking water, whole milk or skimmed milk that each treated animal from 0.1 mg / kg body weight to 30 mg / kg body weight per day, preferably from 0.1 mg / kg to 10 mg / kg per day of compound of formula I.

216995 - *

The compound of formula I may be administered to the animals, optionally orally, in the form of a pellet or slow release bolus in the rumen so that the animal absorbs a similar amount of the compound of formula I per day.

The animals may receive a compound of formula I substantially throughout their entire growth period, or even during part of their growth period, for example, at the initial stage and / or during the period leading to slaughter. At optimal methane-inhibiting inclusion levels, no evidence of any toxic effect due to the compound of Formol I is observed.

According to a further feature of the invention there is provided a composition comprising a heterocyclic

Contains 1 2 3 4 -Trichlormethylverbindung of formula I wherein R, R, R, R, X _f Y and Z have any of the meanings defined above, together with a solid or liquid edible non-toxic diluent or carrier.

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

A suitable solid, edible, non-toxic diluent or teat may, for example, be a conventional, nutritious balanced rye feed, for example a typical beef or sheep feed ground from cereal products such as barley flour, corn flour or wheat feed, nut and seed products such as nut cake Nuts or cottonseed cakes or cakes of extracted cottonseed, together with smaller amounts of, for example, feather meal, seaweed meal, coarse bone meal, fine bone meal, chalk, salt, urea, molasses, vitamins and trace minerals, or an inert solid diluent or carrier without nutritional value, for example Kaolin, talc, calcium carbonate, fuller's earth, attapulgite,

216995 -S--

ground oyster shells or ground limestone; or it can be starch or lactose.

The composition of the invention may take the form of a supplemented feed for direct feeding to animals, in which case it contains from 3 ppm to 3000 ppm of a compound of formula I / mixed with a conventional crude ruminant feed; or it may take the form of a concentrated premix for dilution with a conventional ruminant feed to produce a supplemented feed suitable for direct feeding, and such premix contains 0.3 % / Ge \ v _# /Vevv./ to 50 % / % W / w of a compound of formula I admixed with either a conventional nutrient-balanced ruminant feed, an inert solid diluent without nutritional value, for example ground limestone, or starch or lactose.

According to a further feature of the invention there is provided a process for the preparation of a solid composition according to the invention which comprises uniformly mixing a heterocyclic trichloroniethyl compound of formula I with a solid, edible non-toxic diluent or carrier.

The compound of formula I is preferably serially diluted with the diluent or carrier in two or more successive stages to ensure uniform mixing. The invention will be explained in more detail below with reference to some examples, which, however, are not limiting.

example 1

Anthranilamide hydrochloride (63.5 g) was refluxed for three hours with anhydrous chloral (650 ml). The resulting solution was evaporated to dryness,

216995

r TA. -

and the residue was triturated with toluene (700 ml) to give a yellow product containing one mole of chloral. This was removed by boiling the product with methanol (2 L) for 15 minutes, cooling the solution, and filtering. The filtrate was concentrated to half its volume, and allowed to cool, to produce 1,2-dihydro-2-trichlormethylchinazolin ~ to obtain 4-one, m.p. 201-202 ⁰ C.

The procedure described above was repeated using the appropriate substituted anthranilamide as starting material to give the following products:

R ⁶

CCI,

R ^v

R ⁶ mp ( ⁰ C)

H H CH ₃ 192 - 194 H ^CH 3 H 158 - IGO M ^CH 3 CII ₃ 188 - 190 Cl H H 224 - 225

Example 2

5-Nitroanthranilamide (6.5 g) and anhydrous chloral (65 ml) were stirred together at ambient temperature until TLC indicated that all 5-nitroanthranilamide had disappeared (6 days). The chloral excess was distilled off and the resulting syrup was heated with concentrated sulfuric acid (125 ml) on a steam bath for 10 minutes. The reaction mixture was cooled and poured into ice / water (1 kg) and the solid product which precipitated was filtered off with water (3 × 200 ml).

2169 95 .- »-

and from ethanol (450 ml) "crystallized, so that l ^ -Dihydro-e-nitro ^ -trichloromethylquinazolin ^ -one, mp 278 - 280 ⁰ C was formed.

Example 3

Salicylamide (4O ₁ O g) and anhydrous chloral (400 ml) were heated together for three hours on a steam bath, the reaction mixture was cooled and the Chloralüberschuß was evaporated under reduced pressure. The thick liquid product was mixed with concentrated sulfuric acid (500 ml) and heated on a steam bath for one hour. The mixture was cooled and poured into crushed ice (3 kg) and the precipitated solid was filtered off, triturated with diethyl ether (300 ml) and refiltered. The solid product was washed with water (1 L), filtered, washed well with water, dried and crystallized from ethanol (400 mL) to give 3,4-dihydro-2-trichloromethyl-2-l-benzo / e / - _i / l _/ 37-oxazin-4-one _/ m.p. 175-177 C.

The procedure described above was repeated using the appropriate substituted salicylamine starting material to give the following compounds:

^0C1 3

R ³ FP. (° C) (Decomposition) br 218-220 HO 238 - .240 CH ₃ 199 - 200 (Decomposition) NO ₂ 201-203 COOH 301 - 303

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Example 4 .

A suspension of S-dihydro-δ-hydroxy-trichloromethyl-2ΓΙ-οεηζο / β / - / ϊ _/ 3 / -οχ3ζίη-4-one (prepared as in Example 3 - 2.5 g) in ethanol (125 ml Etheric sodium hydroxide (32 ml of a 0.36 M solution) was added, and the mixture was stirred for 30 minutes. Omethane (1.5 ml) was added and the solution was heated on a steam bath for one hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in a mixture of diethyl ether (100 ml) and N sodium hydroxide solution (50 ml). The ether layer was separated, the aqueous layer reextracted with ether (100 inl), and the ether extracts were taken together and dried. The solvent was evaporated and the sticky residue was stirred for 15 minutes with petroleum ether (b.p. 60-80 C, 100 mL), then filtered and washed with more petroleum ether to give 3,4-dihydro-6-nietiioxy-2-trichloro .iethyl-2j _ [- benzo / ey '- / i, 3 ^ -oxazin-4-one _/ m.p. 162 165 C.

The procedure described above was repeated using benzyl bromide or n-butyl iodide instead of iodoethane to give:

a) 6-Benzyloxy-3,4-dihydro-2-trichloroniethyl-2] 2-benzenes / e / b: 1 3 / -oxazin-4-one, m.p. 22S-230 ⁰ C; and

b) 6-Butyloxy-3 _/ 4-dihydro-2-trichloromethyl-2 [--benzo / q7- £L, 37-oxazin-4-one, m.p. 140-141 ° C.

The petroleum ether filtrate and washings from the above procedure were taken together, the solvent was evaporated, and the residue was triturated with cyclohexane to give 3,4-dihydro-6-methoxy-3-methyl-2-trichloromethyl-2H-benzo / e; 7- / i, 37-oxazin-4-one ,, melting point 107-110 ⁰ C, was formed.

216995 -S-

Example 5

3 _/ 4-Dihydro-6-hydroxy-2-trichloromethyl-2H-benzo / eJ7 / i: poxazin-4-one (prepared as described in Example 3, 5/0 g) and acetic anhydride (250 ml) were allowed to stand for 40 hours Stirred at room temperature, the mixture was filtered, and the solid product was washed with acetic anhydride, then with Diöthyläther, so that 6-acetoxy-3,4-dihydro-2-trichloromethyl-2H-benzo / eJ? - / l, ^ Oxazine ^ -one, melting point 201 - 203 ⁰ C, was formed.

The procedure described above was repeated using propionic anhydride or p-chlorobenzoyl chloride instead of acetic anhydride to give: a) 3,4-dihydro-6-propionyloxy-2-trichloro-ethyl-2H-b en zo / ej ⁷ -

/ i _/ 3 / '- oxazin-4-one, m.p. 183-1S5 ⁰ C; and - b) 6-p-chlorobenzoyloxy-3,4-dihydro-2-trichloromethyl-2nbenzo / E7 / l, 37-oxazin-4-one, m.p. 220-222 ⁰ C.

Example 6

3 _/ 4-Difiydro-6-hydroxy-2-trichloronyl] -2-l- [-benzo / e7- / 1, 37xoxazin-4-one (prepared as described in Example 3, 10.0 g) was treated with acetic anhydride (200 ml ) Stirred on a steam bath for 2 hours. The reaction mixture was cooled and poured into water (1 L), stirred for 3 hours and filtered. The solid product was washed thoroughly with water and dried to give 6-acetoxy-3-acetyl-3,4-dihydro-2-trichloromethyl-2] _ [- benzo / e7- / 1,3-oxazine-4 -one _/ melting point 138 to 140 ⁰ C, was born.

The procedure described above was repeated using propionic anhydride in place of acetic anhydride to give S, 1-dihydro-S-propionyl-G-propionyloxy-2-trichloromethyl-2H-benzo / ey-1, 37-oxazin-4-one, Melting point 92 - 94 ⁰ C ₁ was formed.

216995 -ie.-

Example 7

3/4-Dihydro-2-triol-2H-benzo / e / - / l, 37-oxazin-4-one (prepared as described in Example 3 - 4.0 g) was treated with acetic anhydride (40 ml) for 10 hours on a steam bath. The reaction mixture was cooled to room temperature, poured into water (400 ml) and stirred for 3 hours, and the precipitating oil was extracted into diethyl ether. The extract was dried, and the solvent was evaporated to leave a residue, which was purified by column chromatography on Silica "Kieselgel 60" (\ Varen2eichen) silica gel, and the column was washed with 10 % / v / v / ethyl acetate Toluene eluted, 25 ml fractions were collected, fractions 1-7 were taken together and the solvent was evaporated to give 3-acetyl-3,4-dihydro-2-t-fichloromethyl-2l2-benzo / e / '- / l _/ 37-oxa2in-4-one was formed as an oil. The nuclear magnetic resonance spectrum in Ilexadeuterio-dimethylsulfoxide showed the following characteristic peaks ( 0 values):

2.6, 3H, singlet, -COCIU

7.1, III, Singulefct, C-2Proton

7.15, 111, double doublet (3 = 8 and 2Hz), C-S proton 7.21, IiI, triplet of doublets (0 = 3 and 2z), C-7 proton

7.7, IH, triplet of doublets (O = S and 2I! Z.), C-G proton 7.9, 111, double doublet (O = S and 2Hz.), C-5 proton

Example S

Dimethylformamide (20 ml) and thionyl chloride (5 ml) were stirred together to give 3,4-dihydro-2-trichloromethyl-2H_-benzo / e / - / l, 3 / -oxazin-4-one (2.0 g) over a period of 15 minutes in small portions, and the mixture was stirred for 43 hours at ambient temperature. The reaction mixture was added to water (100 ml), stirred for one hour and filtered. The solid product was dissolved in toluene and purified by column chromatography on "Kiselgel-60" (trademark) eluting with a

216995 -. »-

Mixture of 5% by volume of ethyl acetate in toluene. The solvent was evaporated and the product was crystallized from petroleum ether (b.p. 60-80 ⁰ C) is crystallized, so that 3-Formy 1-3.4-dihyd Γθ-2-t-rich lormethyl 2 || -benzo / e / - / l _/ ^ oxazin-4-one, mp 114 C, was formed.

Example 9

A suspension of powdered 3,4-dihydro-4-oxo-2-trichloromethyl-2H-benzo / e / - /, 1'-oxazine-6-carbonyl chloride (5.0 g) in n-butanol (100 ml ) was heated on a steam bath for 30 minutes the solution was cooled to ambient temperature and the solvent was evaporated under reduced pressure and the sticky solid residue was triturated with petroleum ether (boiling point 60 -.. SO ⁰ C) triturated, filtered, washed with petroleum ether and from crystallized n-butanol, so that 3-butyl-3,4-dihydro-4-oxo-2-trichloromethyl-2h [-benzo / e7 / l, 37-oxazine-6-carboxylate, melting point 134 - 136 ⁰ C, was formed.

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

A suspension of 3,4-dihydro-4-oxo-2-trichloromethyl-2] - benzo / e / - / i, 37-oxazine-6-carboxylic acid (21 g) in thionyl chloride (400 ml) was stirred to give 4 Cooked for hours under reflux cooling. The solution was cooled and the excess thionyl chloride was evaporated under reduced pressure to SO ^0C. The solid product was air dried for thirty minutes, then stored in a vacuum desiccator.

The procedure described above was repeated using methanol in place of n-butanol to give 3,4-dihydro-4-oxo-2-trichloro-thy-2H [-b enzo / ö / - /! -6-carboxylate in 37-oxaz, melting point 213-220 ⁰ C, was formed.

21 69

Example 10

Powdered 3,4-dihydro-4-oxo-2-trichloromethyl-2-benzo-e / - / i, 3 / -oxazine-6-carbonylchloride (5.0 g) was stirred while a solution of n-propylamine (5 ml in methanol (100 ml), the resulting solution was stirred for 30 minutes, and the solvent was evaporated under reduced pressure to give a sticky solid residue. The residue was triturated with water and the resulting suspension was stirred for 30 minutes and filtered. The solid product was washed with water, dried and crystallized from ethanol, so that 3,4-dihydro-4-oxo-N-propyl-2-trichlorniethyl-2j | -benzo / e / - _</ i _/ 3 / oxazin -6-carboxamide, melting point 228-230 ⁰ C, was formed.

The procedure described above was repeated using ammonia or diethylamine in place of n-propylamine to give: 3,4-dihydro-4-oxo-2-trichloromethyl-2] 1-benzo / e / - / i, 37- oxazin-6-carbQxamid, melting point 2G3 265 ⁰ C (with decomposition); or.

3-.4-dihydro-N _, -IM-diethyl-4-oxo-2-tricyl) -oromethyl-2] _ [- bcnzo / c / - _a / l, 3 / '- oxazine-6-carboxamide, m.p. 162-164 ⁰ C.

Example 11

A solution of o-aminobenzyl alcohol (2.4 g) in toluene (5 ml) was stirred at ambient temperature while anhydrous chloral (2.0 ml) was added dropwise. The mixture was stirred for 30 minutes and evaporated to dryness to give a slurry which was crystallized from aqueous ethanol to give 1,2-dihydro-2-trichloroethyl-4-yl-benzo / 9 / -l, 37 '. Oxazine, melting point 90 92 ° C, was formed.

The procedure described above was repeated using the appropriate substituted o_-aminobenzyl alcohol as the starting material, to give the following analogous products:

2169 95 «

a) 1, 2-dihydro-6-methyl-2-trichloromethyl-4H_-benzo / a '_> 7- / l _/ S ⁷ -b)

oxa2in ₇ Melting point 102 ⁰ C;

oxazine, melting point 144 ^° C.

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

A suspension of 2-amino-5-nitrobenzaldehyde (6.0 g) in ethanol (250 ml) was stirred at ambient temperature while sodium borohydride (1/6 g) was added in small portions and the reaction mixture was stirred for one hour. The reaction mixture was acidified with 2N hydrochloric acid to destroy excess sodium borohydride and then basified to pH 3 to 9 with solid sodium carbonate and extracted with diethyl ether (3 x 200 ml). The extracts were pooled and dried, the solvent was evaporated and the residue was crystallized from water (about 200 ml) crystallized out, so that the required 2-amino ^ 5-nitrobenzyl alcohol, m.p. 141-142 ⁰ C was _1;

c) l _/ 2-dihydro-6-iodo-trichlorormetiiyl-4H_-benzo / d / - / l, 3 ⁷ -oxazine, m.p .: 113 ⁰ C;

d) l _/ 2-dihydro-G-methoxy-2-triclilorr, ictiiyl-4H-bcnzo / cJ7- / i, 37-oxazine, mp 112 ⁰ C.

The 2-amino-5-methoxy-benzyl alcohol used in the preparation of this compound can be prepared as follows:

A solution of 5-methoxy-2-nitrobenzaldehyde (2.3g) in ethanol (100ml) was stirred at ambient temperature, sodium borohydride (0.6g) added and stirring continued for 2 hours. Water (100 ml) was added and the solution was acidified with 2N hydrochloric acid and extracted with ether (3 x 100 ml). The extracts were taken together and dried, and the solvent was mixed.

216995 - »-

evaporated / so that S-methoxy ^ -nitrobenzyl alcohol was formed.

This alcohol (2.1 L) was dissolved in ethanol (100 mL), Adams platinum oxide catalyst was added, and the mixture was shaken with hydrogen at ambient temperature and pressure until 950 mL of hydrogen was absorbed (theoretical amount = 900 mL). The hydrogenated mixture was filtered through Celite "Supercel" (Trade Mark), and the solvent was evaporated to give 2-amino-5-methoxybenzenyl alcohol as a brown solid; e) 1, 2-dihydro-2-trichloromethyl ~ ^ ^ 4H benzo / cly ^r - / l, 3 / '- oxazin-6-carbonitrile, mp 109 ⁰ C,

The 4-amino-3-hydroxymethylbenzonitrile used as starting material in the preparation of this compound was obtained as follows:

2-Amino-5-iodobenzyl alcohol (12 g) and copper (I) cyanide (5/4 g) in dry dimethylformamide (10 ml) were heated on a steam bath for SO hours, then cooled to ambient temperature and poured into a solution of ferric chloride ( 10 g) in water (100 ml). This mixture was exhaustively extracted with ether (14 x 60 ml), the extracts were taken together and dried, and the solvent was evaporated. The residue was chromatographed on a silica gel column and elution with ether gave the required 4-amino-3-hydroxymethylbenzonitrile as a brown-yellow solid,

Example 12

The maturity of the heterocyclic trichloromethyl compounds of the present invention to inhibit methane formation in the rumen fluid can be demonstrated by an in vitro assay as follows:

Rumen fluid from two young steers receiving the same hay / concentrate feed is

2169 9 5 - »-

gene, collected on a routine basis. Sampling time is largely standardized and the liquid from the two animals is brought together on a 50/50 parts basis. Large particles are removed by filtering the combined liquid through four layers of muslin cloth. The filtrate is then described in the ratio of one volume of filtrate to three volumes of artificial rumen fluid (prepared as described by GL, Bales and others, Oournal of Dairy Science, 1976, Vol. 59, p. 1850, omitting acetic acid). diluted, and the pH of the mixture is adjusted to 6.9 - 7.0 with saturated aqueous Natriumcarbqnatlösung. Aliquots (50 ml) of this mixture are dispensed into 100 ml Erlenmeyer's flasks containing dried, ground hay (0.5 g), and each flask is used to test a test compound at a specific concentration.

The test compound is added as a solution in ethanol to the contents of the flask, the flask is flushed with carbon dioxide gas, sealed with a suba-cap and incubated at 39 C for 15-16 hours. After one hour, a needle with a fine orifice is inserted through the suba seal to reduce the gas pressure, and the needle is removed 30 minutes before the end of the incubation period. The fermentation is then stopped by placing the flask in ice, and after a cooling period of 15 minutes, the gas above the liquid is analyzed for methane by gas chromatography, and that to produce a 50% decrease in methane formation (ED in μg / ml ) required concentration of the test compound is calculated.

The following results were achieved:

216995

- aa -

CCI,

R ³ R ⁵ R ^{6 ED} 50 H H H 0.3 H H CH ₃ 0.3 H CH ₃ H 1.0 H CH ₃ CH ₃ 1.0 NO ₂ H H 3.0 Cl H H 0.3

R ^v

R ³ H R ^{5 ED} 50 br H 0.5 HO H 0.5 CH ₃ O H 0/5 ", CH ₃ CO.O H 0/5 C ₆ H ₅ .CH ₂ O H 0.3 CH ₃ (CH ₂ ) ₃ O H 10.0 C ₂ H ₅ CO ₄ O H 3/0 ^CH 3 H 0.3 NO ₂ H 1.0 HO. CO H 1/0 p-C1.C ₆ H ₄ CO.O H 0.3 CH ₃ (CH ₂ ) ₂ NII.C0 H 1.0 NH ₂ CO H 0.3 CH ₃ (CH ₂ ) ₃ 0.CO H 0/3 (C ₂ H _{5) 2} N.CO H 1.0 CIUO. CO H 0.3 CH ₃ O Il 3.0 CH ₃ CO ₄ O CII ₃ 3.0 C ₀ H.CO.O t ~ 0 CH ₃ CU 1.0 H C ₀ IUCO 2 0 0.3 H CII ₃ CO 1.0 11 CU 0.5

21 6995 Λ-

^ED 50

H 1.0

CH ₃ 3.0

NO ₂ 0.5

I 1.0

CH ₃ O 0.3

CN 0.3

Example 13 "

2-Amino-3-i: iethylbenzyl alcohol (1.7 g) and anhydrous chloral (2.4 ml) were mixed with external ice-cooling for 10 minutes, and the mixture was allowed to stand for half an hour. Subsequently, the mixture was chromatographed on silica, and elution with diethyl ether / petroleum ether (boiling point 60-80 ⁰ C), volume ratio 7: 3, gave 1 ^ -Dihydro-S-methyl ^ -trichlorncthyl ^ tN-benzo / cl / - ^ [, 37-oxazine, which was crystallized from aqueous ethanol, m.p. 69-70 ⁰ C.

The procedure described above was repeated using the appropriate o-aminobenzyl alcohol as the starting material to give the following analogous products: a) e-chloro-1-dihydro-trichloromethyl-1H-benzo / 3-y / 3 oxazine, melting point 68-70 ⁰ C. in this case, the reaction was terminated by two-minute heating on a steam bath, and the chromatography solvent was ether / petrol in the volume ratio 8: 2nd

The 2-amino-5-chlorobenzyl alcohol used in the preparation of this compound was prepared from 5-chloro-2-nitrobenzyl alcohol according to the general procedure described in the last section of Example 11 (d) but under

Use of 10% palladium on charcoal catalyst instead of Adams platinum oxide catalyst recovered.

b) Methyl l, 2-dihydro-2-trichloromethyl-4 ^ -benzo / d / - / I 3 / oxazine-4-carboxylate, crystallized from cyclohexane, mp 114 - 115 ⁰ C. would In'diesem case the reaction was terminated by briefly heating the reactants on a steam bath / and the chromatography solvent was ether / gasoline in the volume ratio of 6: 4,

The mefchyl ε-aminophenyl glycate (methyl σί-2-aminophenyl glycolate) used as the starting material in the above procedure was recovered as follows: ε-nitromandelic acid (5 g) and thionyl chloride (50 ml) were mixed, refluxed for one hour on a Boiled steam bath and cooled, then the thionyl chloride excess was removed on a rotary evaporator at room temperature. The crude p_-nitromandeloyl chloride obtained was mixed thoroughly with methanol (70 ml), and after the initial vigorous reaction subsided, the mixture was refluxed for one hour on a steam bath, cooled, and Solvent was evaporated under reduced pressure. The υ 1 recovered on this was chromatographed on silica and the eluicum with diethyl ether / petroleum ether (boiling point 60 - SO ⁰ C) in the volume ratio 6: 4 gave methyl ε-nitromandelate. The thus obtained methyl o-nitroinandelate was reduced according to the general procedure described above under a), so that the required starting material was formed;

c) At hy 1-1,2-dihydro-2-t rich Io rmethy 1-41 i-benzo / c) / - /, ^ oxazin-4-carboxylate, crystallized from cyclohexane, mp 127-128 ⁰ C. In this case, the reaction arose by brief heating of the reactants

21 69 95 Λ-

steam bath, dilution of the product with water and extraction with ether, drying of the ether extract and evaporation of the solvent before chromatography.

Cm if *

ends. The product was subjected to chromatography on silica and eluted with ether / gasoline in a volume ratio of 8: 2.

The ethyl o-aminomandelate used as the starting material in the above process was obtained by the reaction sequence described in the last part of b above, but substituting the ε-nitromandeloyl chloride with ethanol instead of methanol;

d) Butyl l, 2-dihydro-2 ~ trichloromethyl-4 [[- benzo / d / - / l, 3 / -oxazine-4-carboxylate, crystallized from cyclohexane, mp 110-111 ⁰ C, In this case the reaction was terminated by briefly heating the reactants on a steam bath, and the chromatographic solvent was 6: 4 vol.

The butyl ε-nitromandelate used as the starting material in the above process was prepared by the reaction sequence described above in the last part of b but using n-butanol instead of methanol;

e) N-phenyl-1,2-dihydro-2-trichloromethyl-412-benzo / cl / - / 1,3-oxazine-4-carboxamide, melting point 139-140 ⁰ C,

The N-phenyl-o-nitromandelamide used as starting material in the above process was prepared by the reaction sequence described above in the last part vpn b but using aniline instead of methanol.

Example 14

Methyl 4-amino-3-hydromethylbenzoate (1 g) and anhydrous chloral (1 ml) were mixed together, initially with

2 *

216995. - a -

external ice-cooling and then on a steam bath for 5 minutes. The product was dissolved in ethyl acetate (100 ml) and the solution was washed with water (50 ml) and dried. The solvent was evaporated and the residue was crystallized from a mixture of ethyl acetate and Petrolüther (boiling point GO - 30 ⁰ C) crystallized so that methyl-, 1,2-dihydro-2-trich Iormethyl ^^ - benzo / d / - / !, 3 / -OXaZIn-G-carboxylate, mp 178-179 ⁰ C, was formed.

The methyl 4-amino-3-hydroxymethylbenzoate used in the above process as starting material was obtained by reducing dimethyl 4-amino- iso phthalate (5 g) in ether (100 ml, dried Upper sodium) with Lithiumaluminiutnhydrid (2 g) won. The mixture was stirred at room temperature for three hours, then water was added cautiously. The organic phase was separated and dried, the solvent was evaporated and the residue was purified by chromatography on silica gel eluting with diethyl ether / petroleum ether (b.p. boiling point GO-SO ⁰ C) in the volume ratio 4: 1. The product thus obtained was crystallized from ethyl acetate / petroleum ether (boiling point 60 - SO C), so that the required Aucgangsmaterial, melting point 116 - 117 ⁰ C, was formed.

The procedure described above was repeated using the appropriate ε-aminobenzyl alcohol as starting material to give the following analogous products:

a) l _/ 2-dihydro-2-trichlorometfiyl-4i | -benzo / cJ7- / l, 3 / -oxazine-4-carboxylic acid, crystallized from aqueous acetic acid, mp 141 - 143 ⁰ C. In this case, the reaction product in Diethyl ether dissolved in ethyl acetate instead.

b) Propyl 1,2-dihydro-2-trichloromethyl-4lj-ben2o / 37- _/ 37-oxazine-4-carbodate, crystallized from cyclohexane, m.p. 115-116 ° C. In this case, the reaction product was simply extracted with cyclohexane and the solution was treated with decolorizing carbon before crystallization.

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

Ε-Nitromandelic acid (12 g) and thionyl chloride (75 ml) were refluxed on a steam bath for one hour. The mixture was then cooled, the thionyl chloride over wass was evaporated under reduced pressure and the residue was mixed with propanol and refluxed on a steam bath for one hour. The Propanolüberschuß was evaporated and the residue was purified by chromatography on silica eluting with Diäthylüther / Petrolüther (b.p. 60-30 ⁰ C) in Volumenveriiültnis 7: 3 so that propyl-o-nitromandelat originated. The propyl o-nitromandelate was then hydrogenated according to the general procedure described in the last part of Example 13 (a) to give the required starting material.

c) IsopΓopyl-l, 2-dihydro-2-trichloromethyl-4l · [-benzo / c] / - / ϊ _/ 37-oxazin-4-carboxylate, crystallized from cyclohexane as described above in b, melting point 141-142 ⁰ C.

The isopropyl o-aminomandlass used as the starting material in the above process was recovered by the reaction sequence described above in the last part of b but using isopropanol instead of propanol.

216995 -S-

Example 15

δ-Acetoxy-Z-ominobenzyl alcohol (S ₇ S g) was dissolved in dry diethyl ether (150 mL), anhydrous chloral (9/6 mL) was added with stirring for 5 minutes, and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was crystallized on stirring with a mixture of methanol (50 ml) and water (25 ml) to give 6-acetoxy-1,2-dihydro-2-trichloromethyl-4H.

methyl-4]] - benzo / d / - / l, 3 / -oxazine, m.p. 155-157 ⁰ C.

The 5-acetoxy-2-aminobenzyl alcohol used in the above process-as starting material was obtained as follows:

A mixture of 5-hydroxy-2-nitrobenzaldehyde (4 g) and acetic anhydride (10 ml) was heated on a steam bath for one hour, then poured into water (100 ml) and extracted with diethyl ether (3 x 50 ml). The extracts were taken together and dried, and the solvent was evaporated. The residue of 5-acetoxy-2-nitrobenzaldehyde was dissolved in absolute ethanol (100 ml): and stirred and ice-cooled while sodium borohydride (1.5 g) was added portionwise. The reaction mixture was stirred for one hour at room temperature, then water (100 ml) was added and the mixture was extracted with ether (3 × 70 ml). The extracts were taken together and dried, and the solvent was evaporated to give 5-acetoxy-2-nitrobenzyl alcohol, which was purified by the method described in the. hydrogenated in the last part of Example 13 a) so that the required starting material was formed,

Example 16

3 _/ 4-Dihydro-2-trichloromethyl-2I2-benzo / e / - / 1, 37-oxazin-4-one (prepared as described in Example 3, 5 g) was suspended in ethanol (100 ml), 63 ml of a Solution of sodium hydroxide (1.0 g) in ethanol (83 ml) was added, and

216993 - £ -

the mixture was stirred for 15 minutes to give a clear solution, iodomethane (5 ml) was added and the solution was refluxed for 30 minutes The solvents were evaporated and the residue was dissolved in a mixture of toluene and Ethyl acetate (7: 3 by volume) and chromatographed on silica with elution with the same solvent mixture, the first 100 ml of eluate were collected, the solvent was evaporated and the residue was crystallized after trituration with petroleum ether (boiling point 60.degree.-80.degree. so that S ^ -D

methylbenzo / E7 / i, 37-oxazin-4-one, mp 82-84 ⁰ C, was formed.

Example 17

The procedure described in Example 3 was repeated using the appropriate salicylamide starting material to give the following analogous products:

a) 3 _# 4-dihydro-4-oxo-2-trichloromethyl-2j ^ -benzo / e / - / l, 3 / oxazine-6,8-dicarboxylic acid, crystallized from ethanol, melting point 305-307 ⁰ C, ( with decay);

b) 3,4-Dihydro-G-hydroxyindinomethyl-2-trichloromethyl-1- l2U- benzo / e / - / !, 3y'-oxazin-4-one, crystallized from ethanol, m.p. 228-230 ⁰ C (with decay).

The 5- (hydroxyiminotethyl) salicylamide used as starting material in this process can be obtained as follows:

Methyl 5- (hydroxyiminomethyl) salicylate (16.0 g) was added in one portion to a saturated solution of ammonia in methanol (1.6 L). The solution thus obtained was incubated for 24 hours at room temperature.

216995 - »-

stirred door and then evaporated to dryness and the residue was treated with ethanol (200 ml) triturated, so that the required starting material originated, mp 225-227 ⁰ C (with decomposition);

c) 3 _/ 4-dihydro-2-trichloro-methyl-2 H-benzoZeZ- / 1 / 3Z-oxazine-6-carbaldehyde, m.p. 203-206 ⁰ G. In this case, the suspension obtained by pouring the reaction mixture onto ice was filtered off , washed, dried and crystallized from aqueous ethanol, 1: 1 (200 ml). The first crystallization material was discarded, the mother liquors were evaporated to dryness, and the residue was dissolved in ethyl acetate (250 ml). The ethyl acetate solution was washed with N sodium hydroxide solution (100 ml), then with water and dried, and evaporation of the solvent gave the required product.

The 5-formylsalicylamide used as the starting material in this process was crystallized by hydrolyzing 5- (hydroxyiminoethyl diethyl) salicylamine (prepared as described in b above) with 5N hydrochloric acid and extracting the reaction mixture with ethyl acetate, m.p. 138-190 ⁰ C (with decomposition) from ethanol, won.

d) 6-acetamido-3,4-dihydro-2-trichloromethyl-2H benzoZV _r '- / ^1/3 -7-oxazin-4-one, auskristallioiert from ethanol, mp 228-230 ⁰ C (with decomposition);

e) 3,4-dihydro-6-tosylamino-2-trichlorniethyl-2Hi-benzoZeZ-ZlißZ-oxazin-4-one, crystallized from ethanol, melting point 278-230 ⁰ C (with decomposition).

- 21 -

Example 18

_{3/4-dihydro-4-oxo} ~ 2-trichlorinetliyl-2 - [[benzo _</ e / - 2.oxazin- · 6-carboxamide / l _/ ^ (prepared as described in Example 10, 1.0 g) and thionyl chloride (20 ml) were refluxed together for one hour, cooled to room temperature and poured into ice-water (200 ml). After stirring for one hour, the white suspension formed in this way was filtered off, washed with water, dried at 60 C and extracted with toluene (3 × 200 ml). The toluene extracts were taken together and the solvent was evaporated to give 3,4-dihydro-4-oxo-2-trichloromethyl-2] j-benzo / e / - / i, 37-oxazine-6-carbonitrile, m.p. 212- 214 C, was created.

Example 10

5-Amino-N- (1-hydroxy-2,2,2-trichloroethyl) salicylamide (23.0 g) and concentrated sulfuric acid (115 ml) were heated on a steam bath for one hour, then poured onto ice (1 liter) , The resulting mixture was stirred for 30 minutes and filtered. The filtrate was adjusted with 5 N sodium hydroxide solution to pH 5 and stirred for 30 minutes, and the solid product was filtered off, washed with water and dried at 60 ⁰ C so that G-Amino-3,4-diiiydro-2-triciilormethyl- 2 | 2-benzo / e / ⁷ - / i, 37'oxazin-4-one, m.p. 172-174 ⁰ C, was formed.

The 5-amino-N- (1-hydroxy-2, 2, 2-trichloro) salicylic id used as starting material in this process can be obtained as follows:

5-NitrosalicyaLamid (10.0 g) and anhydrous chloral (100ml) were heated together on a steam bath overnight, the solution was cooled and the Chloralüberschuß was evaporated under reduced pressure at 50 ⁰ C. The oily residue was triturated with toluene (100 ml) for 30 minutes, and the solid product was filtered off and crystallized from benzene to give N ~ (1-hydroxy-2,2,2-trichloroethyl) -5-nitrosalicylamide, mp 223 - 225 ⁰ C, was created.

216995 - »-

N- (1-Hydroxy-2 _/ 2,2-trichloroethyl) -5-nitrosalicylamide (69g) was stirred in glacial acetic acid (1380ml) and zinc dust (109g) was added portionwise over 3 hours at a temperature of 30-37 ⁰ C added. The resulting suspension was filtered, the residue was washed with glacial acetic acid and the combined filtrate and washings were evaporated under reduced pressure at 50 ° C to a dark oil. The oil was mixed with 2N hydrochloric acid, roasted for 30 minutes and filtered. The residue was washed with 2N hydrochloric acid, and the filtrate and washings were taken together and neutralized with 2N sodium hydroxide. The neutralized mixture was stirred for 30 minutes and filtered. The solid product was washed with water, dried and extracted with ethyl acetate (3x11). The extracts were then taken together and evaporated to dryness to give the required starting material.

Example 20

A suspension of δ-p-chlorobenzylideneamino-S ^ -dihydro-2-trichloromethyl-2JH-benzo / e / - / l, 3 / -oxazin-4-one (5.1 g) in ethanol (3 l) was added 50 ⁰ C is heated, so that a solution was recovered, and sodium borohydride (4.6 g) was added over a period of 30 minutes. The reaction mixture was then cooled and the solvent evaporated at 40 C under reduced pressure. The residue was mixed with water (50 ml), the pH was adjusted to 8 with 2N hydrochloric acid, and after 15 minutes the solid product was filtered off, washed with water and dried. This product was dissolved in diethyl ether (1 liter), and the solution was washed successively with water, 2N hydrochloric acid, water, 2N sodium hydroxide solution and water, and then dried. By evaporation of the solvent was ep-chlorobenzylamino-S ^ -dihydro ^ -trichlormethyl ^ jH-benzo- / e / - / l, 3 / oxazin-4-one, m.p. 156-158 ⁰ C.

The 6-p-chlorobenzylideneamino-3,4-dihydro-2-trichloromethyl-2Hl · used as starting material in this process

benzo / * ep ^r - / l _/ § ⁷ -oxazin-4-one can be prepared by mixing ethanolic solutions of 6-amino-3,4-dihydro-2-trichloromethyl-2-yl-benzo / e / - /! L, J ^ -oxazin-4-one (obtained as described in Example 19 -Ig in 60 ml) and p-chlorobenzaldehyde (0.5 g in 15 ml), heating the mixture over a period of 10 minutes on a steam bath and allowing to crystallize Product can be recovered from the solution on cooling. Melting point 246-249 ° C.

Example 21

A mixture of 3 _/ 4-dihydro-2-trichloromethyl-2jJ-benzo / e7- / 1, ^ oxazin-4-one ClO g, recovered as described in Example 3) and concentrated sulfuric acid (100 ml) was added for 18 hours heated on a steam bath and placed in ice (400 g). The resulting solution was saturated with sodium chloride and extracted with ethyl acetate (4 × 100 ml). The extracts were taken together and dried, the solvent was evaporated and the residue was crystallized from glacial acetic acid to give 3,4-dihydro-2-trichloro-methyl-2H-UCnZo / (-) 37-oxazine-6-sulfonic acid was formed, melting point> 260 ⁰ C.

Example 22

The procedure described in Example 1 was repeated using 5-methoxycarbonylanthaVnilamid in place of anthranilanide and using bis (2-methoxyethyl) ether (76 ml) as diluent, so that methyl-l _/ 2-dihydro-4-oxo 2-trichloromethylquinazoline-6-carboxylate, mp 249 C (with decomposition) was formed.

Example 23

N- (1-Hydroxy-2,2,2-trichloroethyl) -5-methoxycarbonylanthran-1-amide (5 g) and concentrated sulfuric acid (100 ml) were heated together on a steam bath for 15 minutes, cooled and applied to a minimum of ice cast. That way

ff iXit Γ ¹ ". ';

Formed Rti & feEat was filtered off, dried and in

216995 - »-

dissolved in hot ethanol (300 ml). The ethanol solution was concentrated to 20 ml and the resulting solid was filtered off and discarded. The filtrate was further concentrated to 10 ml, and the product thus obtained was filtered off, dried and crystallized from glacial acetic acid / water 1: 1 / so that 1-dihydro-oxo-trichloromethylquinazoline-G-carboxylic acid, melting point> 230 ⁰ C, was created.

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

5-Methoxycarbonyl-2-nitrobenzoic acid (70 g) and thionyl chloride (350 ml) were heated together on a steam bath for 5 1/4 hours, the reaction mixture was cooled, and the residual thionyl chloride was evaporated under reduced pressure. The residue was dissolved in toluene (700 ml) and the solution was cooled in ice while allowing ammonia to bubble through for 1-3/4 hours. The solid product obtained in this way was filtered off, washed with toluene and then with petroleum ether (boiling point 60 ° C.) and then stirred with water for one hour, filtered off and dried to give 5-methoxycarbonyl-2-nitrobenzamide.

5-Methoxycarbonyl-2-nitrobenzamide (28g) was dissolved in methanol (600ml), 10% palladium on charcoal catalyst (3g) was added and the mixture was hydrogenated at about 35 ° C for 6 hours. The catalyst was filtered off, extracted with methanol (350 ml) at reflux temperature under a nitrogen atmosphere for 20 minutes and filtered again. Both filtrates were evaporated to dryness, and taken together residues were crystallized from water (3 1), so that 5-methoxycarbonyl · anthranilamide, melting point 188-193 ⁰ C, was formed.

2169 95

5-Methoxycarbonylanthranilamide (1/0 g), anhydrous chloral (5 ml) and bis (2-methoxyethyl) ether (20 ml) were heated together on a steam bath for 20 minutes, then evaporated to dryness under reduced pressure. The residue solidified on stirring with diethyl ether, and it was filtered off and purified by chromatography on silica gel (250 g). The column was eluted with a mixture of ethyl formate and toluene (7: 3 by volume) and 50 ml fractions were collected. Fractions 10 to 13 were taken together and evaporated to dryness and the residue solidified on stirring with petroleum ether (b.p. 60-80 ° C) such that the required starting material is N- (1-ylydroxy-2 _/ 2 _/ 2 -triclilorethyl) -5 Methoxycarbonylanthranilamid, melting point 93 -C (with -Zerfall), was formed.

Example 24

L _/ 2-Dihydro-4-oxo-2-trichloromethyl-quinazoline-6-carboxylic acid (0/5 9) / ethanol (6 ml) and concentrated sulfuric acid (3 ml) were heated together under reflux for 1.5 hours on a steam bath. The reaction mixture was filtered and the filtrate was poured onto a minimum amount of ice. The precipitate thus obtained was filtered, washed with water and dried to give ethyl l _/ 2-dihydro-4 ~ oxo-2-trichlormethylchinazolin-6-carboxylate, melting point 243 - 244 ° C was created.

Example 25

1, 2-Dihydro-2-trichloromethylquinazolin-4-one (3.0 g), acetic anhydride (25 ml) and a few drops of concentrated sulfuric acid were heated together on a steam bath for 1 1/2 hours and the resulting solution was cooled and poured into water (250 ml). The mixture was stirred for two hours and then filtered and the residue was filtered off, washed with water, dried and crystallized from ethanol to give I ₁ 3-iacetyl-1, 2.

216995

-3S-

dihydro-2-trichloromethylquinazolin-4-one _/ m.p. 152 ⁰

154 ⁰ C, was written ·.

Example 26

The methane inhibition test described in Example 12 was repeated for various other compounds to give the following results. The results are expressed as the percentage inhibition of methane formation caused by 1 μg / ml of a test compound, except for the compounds marked ⁺ , for which 3 μg / ml was used.

R ¹ '

R ¹ H R ³ CN R ⁵ % Methane inhibition at 1 μg / ml. COOH COOH H 87 ⁺ H CHO H 38 H Ho.b: CH H 47 H NH ₂ H 41 H CH ₃ COiMM H 98 H H P-CH ₃ .C ₆ H ₄ SO ₂ NH P-CLC ₆ H ₄ .CH ₂ NH H 96 H SO ₃ H H H 94 86 ⁺ H H H 11 ^CH 3 100

R ¹ R ³ R ¹¹ H % Methane inhibition at 1 μg / ml ^CH 3 H H 100 H Cl H 100 ii CH ₃ O.CO H 100 H _CH3 CO.0 COOH 30 H H Cl I ₃ O. CO 14 H H C ₂ H ₅ O.CO 46 Ή H HC ₃ Il ₇ CCO 24 H H 1-C ₃ H ₇ O.CO 31 H H nC ₄ H _g 0.C0 37 H H C _r H_NH.CO I ² H H 57

R ^v

% Methanine ligation at 1 xig / ml

H .CO CH ₃ CO CH ₃ CO COOH H H C ₂ H ₅ O H H

90

71 ^Ί

216995 - ^M ~

Example 27

Premixes suitable for incorporation in feed for ruminants may be prepared by mixing 20, 30, 40 or 50 g of a heterocyclic trichloroethyl compound of formula I into a standard ruminant feed so that the final weight is 500 g. For example, a suitable standard ruminant feed for cattle may include:

Barley flakes 85 %,%

Extracted soybean meal 10% by weight

Molasses 4%

Vitamin / mineral mixture "1% by weight,%

and a suitable standard hay protein feed for sheep may include, for example:

Barley flakes 60% by weight

VVeizenfuttermittel 15 Gew. ^

Corn germ meal 10% by weight

Extracted Sojabohnenniehl 6 wt.%

Molasses 7.5% by weight

Vitamin / mineral mixture 1/5 wt.%

but the individual components can be varied widely according to the local feeding conditions and the availability of feed components.

Example 28

A feed suitable for direct feeding to cattle can be obtained by intimately mixing 500 g of a premix obtained as described in Example 27 with 4.5 kg of the standard cattle feed described in Example 27 and then uniformly mixing the mixture thus obtained with 995 kg of the standard feed so that a supplemented feed containing 20, 30, 40 or 50 g of the heterocyclic trichloromethyl compound per tonne of feed is produced, depending on the concentration of the compound in the premix.

216995 -. »-

Example 29 .

A feed suitable for direct feeding to sheep can be obtained by mixing a masterbatch as described in Example 27 with 4.5 kg of the standard sheep nut described in Example 27 and then further dividing the thus obtained mixture into 995 kg Feed to provide a supplemented feed containing 20, 30 or 40 grams of a heterocyclic trichloromethyl compound of formula I per tonne of feed, depending on the concentration of the compound in the premix.

Claims (1)

03/13/1980 21 6995 "^" - AP C 07 D / 216 995 56 272/12 Erfindungsanapruch 1 # Process for the preparation of heterocyclic trichloromethyl compounds of the formula I: characterized in that either: a) X is an oxygen atom, Y is a radical of the formula -NR-, where R ^{5 is} a hydrogen atom, a 1-4C-alkyl or alkanoyl radical or a phenyl radical which is optionally substituted by one or more halogen atoms, nitroradicals or 1-4C-alkyl radicals. Alkoxy or haloalkyl radicals, and Z is a carbonyl radical; or b) X is a radical of the formula -NR -, wherein R is a hydrogen atom, a C 1-4 alkyl or alkanoyl radical or a phenyl radical which is optionally substituted as defined above for R- ', Y is a radical of the formula NR is as defined above and Z is a carbonyl radical; or c) X is a radical of the formula -NR - as defined above, Y is an oxygen atom and Z is a methylene radical, partially substituted by a carboxy or carbamoyl radical, 2-5C-alkoxycarbonyl radical or an N-phenylcarbamoyl radical optionally substituted by Halogen atoms, nitroradicals or 1-4C-alkyl, alkoxy or haloalkyl radicals; .21 6995 - ^ 2-13.3.1980 AP C 07 D / 216 56 272/12 and R, R ₁ R "and R, which may be the same or different, are each a hydrogen atom or halogen atom, a cyano, formyl, hydroxy, hydroxyiminomethyl, nitro or sulforadical, or a carboxyradical or an alkali metal, alkaline earth metal or ammonium salt thereof, or a radical of the formula R ^7, OR ⁷ , O.COR ¹⁰ , CO.NR ⁸ R ⁹ , NH.SO ₂ R ¹⁰ , NR ⁸ R ⁹ , NR ⁸ .COR ⁹ , HH.CH ₂ R, SO ₂ .NR ⁸ R ⁹ or SO ₂ ORT, where R ^{7 is} 1-4C-alkylene radical, R and R ⁹ , which may be the same or different, each represents a hydrogen atom or a 1- R is a 40-alkyl radical and R is an optionally substituted phenyl radical as defined above for R except those compounds wherein 2 is a carbonyl radical and I) X is an oxygen atom or an imino radical, Y is an imino radical and
V / asser st off atoms are; or Y is an imino radical and R ¹ , R ² , B? and R ⁴ all II) X is an oxygen atom, Y is an imino radical and 'either R and R are chlorine atoms and R and R are V / oxygen atoms, or R is an acetamidoradi radical i3t and 12 4.
R, R and R are hydrogen atoms; or III) X is an oxygen atom, Y is an acetyliminoradical radical i3t, R is an ac et amidoradika!
V / are all off atoms, 12 4 is an acetamido radical and R, R and R are all characterized in that a compound of the formula II: 21 $ 9 95 - $ 3- ^ 13.3.1980 AP C 07 D / 216 995 56 272/12 Z.YH wherein R, R, R, R, X, Y and Z have the meanings given above, with chloral, optionally hi presence of a solvent, and simultaneously or sequentially with an acid, followed by certain if desired 1 9 "5 Λ Substituents R, R, R ^ and R and, in the presence in 5 6
X or Y, R * and R can be converted into other such substances as defined above, according to conventional methods currently used or known in the literature of organic chemistry. 2 · Method according to item 1, characterized in that the. Solvent bis (2 ~ methoxyethyl) ether is · 3 · Method according to item 1, characterized in that 12 3 4 R, R, R "and R, which may be the same or different, are each a hydrogen, chlorine, bromine or iodine atom, or a cyano, formyl, hydroxy, hydroxyiminomethyl, nitro, sulfo , Carboxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy , s-butoxy, t-butoxy, benzyloxy, chlorobenzyloxy, methyl-benzoyloxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, acetoxy, Propionyloxy, butyryloxy, isobutyryloxy, benzoyloxy, chlorobenzoyloxy, methylbenzoyloxy, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, propyl 2 1 69 95 ~ * 4- 13.3.1980 AP C 07 D / 216 995 56 272/12 carbamoyl, dipropylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, s-butylcarbamoyl, t-butylcarbamoyl, ethylmethylcarbamoyl, amino, methylamino, dimethylamino), ethylamino, diethylamino, propylamino, dipropylamino, , Isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, Äthylmethylamino-, acetamido, N-methylacetamido, N-Äthylacetamido-, N-Propylacetamido-, N-Isopropylacetamido-, N- Butylacetamido, propionamido, N-methylpropionamido, N-xthylpropionamido, butyramido, N-ethylbutyramido, N-ethylbutyramido, 2-methylpropionamido, l, ί, 2-dimethylpopanamido, benzylamino, chlorobenzylamino, Bromobenzylaraino, (methylbenzyl) amino, (ethylbenzyl) amino, lethoxybensylamino, ethoxybenzylamino, (trichloromethylbenzyl) amino, sulfamoyl, methylsulfamoyl, dimethylsulfamoyl, ethylsulfamoyl, diethylsulfamoyl, propylsulfamoyl, dipropylsulfamoyl, isopropylsulfamoyl, , Butylsulfamoyl, ethylmethylsulfamoyl, methoxysulf onyl, ethoxysulfonyl, propoxysulfonyl, isopropoxysulfonyl, butoxysulfonyl, isobutoxysulfonyl, s-butoxysulfonyl or t-butoxysulfonyl radical; the radicals -IiR "^ - and -ITR-, which may be the same or different, are each an imino, methylimino, ethylimino, acetylimino or propionylimino radical, and Z is a carbonyl, methylene, carboxymethylene, Is methoxycarbonylmethylene, ethoxycarbonylmethylene, propoxycarbonylmethylene, isopropoxycarbonylmethylene, butoxycarbonylmethylene or benzamidomethylene radical, Process according to item 1, characterized in that R, 2 3 4- R, R and R, which may be the same or different, each represents a hydrogen, chlorine, bromine or iodine atom or a cyano, pormyl, hydroxy, hydroxyiminomethyl, nitro, sulfo, carboxy, methyl , Methoxy, butoxy, benzyloxy, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, acetoxy, propionyloxy, p-chlorobenzoyloxy, carbamoyl, 21 699S - * ⁵ - 13.3.1980 AP C 07 D / 216 56 272/12 Are methylcarbamoyl, dipropylcarbamoyl, amino, acetamido, p-chlorobenzylamino or tosylarainoradical, the radical -NR- is an imino, methylimino, pormylimino, acetylimino or propionyliminoradical, the radical -HR - an imino, Is methyl-imino- or acetyliminoradical; and Z is a carbonyl, methylene, carboxymethylene, methoxycarbonyline, glycine, ethoxycarbonylmethylene, propoxyo-carbonyl-ethylene, isopropoxycarbonylmethylene, butoxycarbonylmethylene or benzamidomethylene radical.