DE3636605A1 - Sepn. of enantiomers used as animal growth stimulating additives - by adding di:acetone-2-keto-L-gulonic acid to (amino-dichloro:phenyl)-2-(tert. butyl)-hydroxy-amino-ethanol - Google Patents

Abstract

(A) In a new process for separating the mixture of the enantiomeric forms of 1-(4-amino-3,5-dichlorophenyl) -2-(tert-butyl)-hydroxy-amino-ethanol (I) the mixture is treated with a ca equimolar amount of (-)-diacetone-2-keto-l-gulonic acid (II) in alkanol and the resulting poorly soluble salt of one of the enantiomsis is separated off. (B) The enantiomers of (I) having specific rotations in chloroform of (alpha)30/D=-44.1 deg. (c=1.5) and +52.6 deg. (c=1.6) are new and claimed, as is their use as efficiency promoters in animals. USE - (I) (known from DE3535333) has an efficiency promoting effect in animals, e.g. it exerts growth-promoting effects, improves milk and wool production, improves feed utilisation, and shifts flesh/fat ratios in favour of flesh. The new enantioners have the same activity.

Description

The present invention relates to a method for Separation of the enantiomers of 1- (4-amino-3,5-dichlorophenyl) - 2- (tert-butyl) -hydroxy-aminoethanol and their Use as an animal performance enhancer.

1- (4-amino-3,5-dichlorophenyl) -2- (tert-butyl) -hydroxy- amino-ethanol is the subject of not yet published German patent application P 35 25 333.7 the Applicant.

It is made by using N-t-butyl- (4-amino-3,5- dichlorophenyl) glyoxal nitrone reduced. Because of a The center of asymmetry in the molecule lies as Racemate, d. H. in two mutually enantiomeric forms, in front. There is then a separation of these enantiomeric forms of interest if the two enantiomeric forms are different Possess efficacies.

It was found that the mixture of enantiomers Forms in 1- (4-amino-3,5-dichlorophenyl) -2- (tert-butyl) - can separate hydroxy-amino-ethanol in that it approximately equimolar with (-) - diacetone-2-keto-L-gulonic acid Formula (I)

in alkanol and the resulting sparingly soluble Salt separates one of the enantiomers.

It was the enantiomer of 1- (4-amino-3,5-dichlorophenyl) -2- (tert-butyl) -hydroxy-amino-ethanol with a rotation value in chloroform of
[ α ] = -44.1 ° ( C = 1.5) found.

It was also the enantiomer of 1- (4-amino-3,5-dichlorophenyl) -2- (tert-butyl) -hydroxy-amino-ethanol with a rotation in chloroform of
[ α ] = + 52.6 ° ( C = 1.6) found.

The separation is carried out by mixing 1 mol of 1- (4- Amino-3,5-dichlorophenyl) -2- (tert-butyl) -hydroxy-amino- ethanol dissolved in approx. 2 l alkanol and with a solution of  1-1.2 mol (-) - diacetone-2-keto-L-gulonic acid in approx. 1 l Added alkanol. The less soluble crystallizes Salt one of the two enantiomers and can be separated will. The filtrate is freed from the solvent. The salt of the other enantiomer is thus obtained. Both salts can be mixed with an aqueous solution Solution of a base and one immiscible with water Solvent the free base are separated.

As alkanols come aliphatic C _1-4 alcohols such as. B. methanol, ethanol, isopropanol in question. Ethanol is preferred. 0.5-5 l, preferably 1-3 l, in particular 2 l alkanol per mole of racemate and 0.5-3 l, preferably 0.5-1.5 l, in particular 1 l alkanol, per mole of gulonic acid are used.

The process is carried out at room temperature. To Crystallization can be beneficial in the solution to cool to temperatures from 0 to 20 ° C. Is preferred but also here the crystallization at room temperature.

Inorganic or organic are released to release the base Bases used like alkali or alkaline earth hydroxides, -carbonates, -hydrogencarbonates, -acetates also tertiary amines such as trimethylamine, triethylamine, pyridine. The base is released in a mixture Water and a water-immiscible solvent. As a water-immiscible solvent hydrocarbons such as petroleum ether, Toluene, xylene, chlorinated hydrocarbons such as Methylene chloride, chloroform, carbon tetrachloride.  

The free base can be removed after separating the organic phase isolated from water by distilling off the solvent will.

Like the racemate, the enantiomers are also suitable as Active ingredients to promote performance in animals, e.g. B. for Promotion and acceleration of growth, milk and wool production and to improve feed utilization, the meat quality and the postponement of the Meat-fat ratio in favor of meat. The Active ingredients are used in livestock, breeding, ornamental and hobby animals used.

The livestock and breeding animals include mammals such as e.g. B. cattle, pigs, horses, sheep, goats, rabbits, Rabbits, fallow deer, fur animals such as mink, chinchilla, Poultry such as B. chickens, geese, ducks, turkeys, Pigeons, fish such as B. carp, trout, salmon, eels, Tench, pike, reptiles such as B. snakes and Crocodiles.

Ornamental and hobby animals include mammals and dogs and cats, birds such as parrots, canaries, fish such as ornamental and aquarium fish e.g. B. Goldfish.

The active ingredients are independent of the gender of the Animals during all growth and performance phases of the Animals used. The active ingredients are preferred during the intensive growth and performance phase  used. The intensive growth and performance phase lasts from one month to 10 years, depending on the animal species.

The amount of active ingredients that the animals achieve the desired effect can be administered because of the favorable properties of the active ingredients largely can be varied. It is preferably about 0.001 up to 50 mg / kg, in particular 0.01 to 5 mg / kg body weight per day. The appropriate amount of the active ingredient as well as the appropriate duration of administration depend in particular on the type, age, gender, growth and Performance phase, health status and the type of Holding and feeding the animals and are by everyone Expert easily identified.

The active ingredients are the animals according to the usual Methods administered. The mode of administration depends especially on the type, behavior and state of health of animals.

The active substances can be administered once. The Active ingredients can also be used throughout or during part of the growth and performance phase be administered temporarily or continuously.

With continuous administration, the application one or more times a day in regular or irregular Intervals.  

It is administered orally or parenterally in for this suitable formulations or in pure form.

The active ingredients can be used alone or in the formulations in a mixture with other performance-enhancing active ingredients, mineral feed, trace element compounds, Vitamins, non-protein compounds, dyes, Antioxidants, flavors, emulsifiers, flow aids, Preservatives and pressing aids are available.

Other performance-enhancing active ingredients are:
e.g. B. antibiotics such as tylosin and virginiamycin. Mineral feeds are e.g. B. dicalcium phosphate, magnesium oxide, sodium chloride.
Trace element compounds are e.g. B. iron fumarate, sodium iodide, cobalt chloride, copper sulfate, zinc oxide.
Vitamins are e.g. B. Vitamin A, Vitamin D ₃ , Vitamin E, B Vitamins, Vitamin C.
Non-protein compounds are e.g. B. biuret, urea. Dyes are e.g. B. carotenoids such as citranaxanthin, zeaxanthin, capsanthin.
Antioxidants are e.g. B. ethoxyquin, butylhydroxy-toluene.
Flavorings are e.g. B. Vanillin.
Emulsifiers are e.g. B. Lactic acid esters, lecithin.
Flow aids are e.g. B. sodium stearate, calcium stearate.
Preservatives are e.g. B. citric acid, propionic acid.
Pressing aids are e.g. B. lignin sulfonates, cellulose ethers.

The active ingredients can also be administered together with the feed and / or the drinking water.

The feed includes single feed of plant origin such as hay, beets, grain by-products, feed materials of animal origin such as meat, fats, Dairy products, bone meal, fish products, feed materials such as vitamins, proteins, amino acids, e.g. B. DL-methionine, salts such as lime and table salt. To the feed also include supplementary, finished and compound feed. These contain feed materials in a composition who have a balanced diet regarding the Energy and protein supply as well as the supply with Ensures vitamins, mineral salts and trace elements.

The concentration of the active ingredients in the feed is usually about 0.01 to 500 ppm, preferably 0.1 to 50 ppm.

The active ingredients as such or in the form of Premixes or feed concentrates added to the feed will.

Example of the composition of a chick rearing feed containing the active ingredient according to the invention:
200 g wheat, 340 g maize, 361 g soybean meal, 60 g beef tallow, 15 g dicalcium phosphate, 10 g calcium carbonate, 4 g iodized table salt, 7.5 g vitamin-mineral mixture and 2.5 g active ingredient premix result after careful mixing 1 kg of feed.

One kg of feed mix contains:
600 IU vitamin A, 100 IU vitamin D ₃ , 10 mg vitamin E, 1 mg vitamin K ₃ , 3 mg riboflavin, 2 mg pyridoxine, 20 mcg vitamin B ₁₂ , 5 mg calcium pantothenate, 30 mg nicotinic acid, 200 mg choline chloride, 200 mg Mn SO ₂ × H ₂ O, 140 mg Zn SO ₄ × 7 H ₂ O, 100 mg Fe SO ₄ × 7 H ₂ O and 20 mg Cu SO ₄ × 5 H ₂ O.

2.5 g of active ingredient premix contain z. B. 10 mg of active ingredient, 1 g DL-methion, rest soybean meal.

Example of the composition of a pig rearing feed containing the active ingredient according to the invention:
630 g feed grain meal (composed of 200 g corn, 150 g barley, 150 g oat and 130 g wheat meal), 80 g fish meal, 60 g soy meal, 60 g tapioca flour, 38 g brewer's yeast, 50 g vitamin-mineral mixture for pigs, 30 g linseed cake flour, 30 g corn gluten feed, 10 g soybean oil, 10 g sugar cane molasses and 2 g active ingredient premix (composition e.g. as with chick feed) result in 1 kg feed after careful mixing.

The specified feed mixtures are for rearing and Fattened by preferably chicks or pigs, however, they can be of the same or similar composition also used for feeding other animals will.

Example 1a

7.2 g (0.0246 mol) of racemate of 1- (4-amino-3,5-dichlorophenyl) - 2- (tert-butyl) -hydroxy-aminoethanol are in 50 ml ethanol dissolved and with 7.2 g (0.0259 mol) (-) - diacetone 2-keto-L-gulonic acid, dissolved in 30 ml of ethanol, transferred. By rubbing with a glass rod the Crystallization brought about and after standing overnight the crystal mash sucked off.

The mother liquor is largely spun in in vacuo, the residue is taken up in aqueous NaHCO ₃ solution / methylene chloride and the organic phase is spun in after drying over MgSO ₄ . The (-) - enantiomer is obtained as a glass-like resin.
Yield: 2.7 g
[ α ] = -44.1 ° (CHCl ₃ C = 1.5)

Example 1b

The separated crystals are recrystallized again from 50 ml of ethanol.
Yield: 5.5 g
Fp .: 178 ° (dec.)

The salt is hydrolyzed with aqueous NaHCO ₃ solution / methylene chloride. The organic phase dried over MgSO ₄ and evaporated.
Yield: 2.6 g of glassy resin
[ α ] = + 52.6 ° (CHCl ₃ , C = 1.6)

The preparation of the racemate of 1- (4-amino-3,5-dichlorophenyl) - 2- (tert-butyl) -hydroxy-aminoethanol takes place as follows:

1.8 g of NaBH _{4 were} added in portions at room temperature to 7 g of Nt-butyl- (4-amino-3,5-dichlorophenyl) glyoxal nitrone in 150 ml of methanol. After 3 to 4 hours, the mixture was concentrated using a rotary evaporator, 100 ml of 10% HCl were added to the residue in the cold, the mixture was extracted three times with 25 ml of ether and the aqueous phase was alkalized with cooling using 120 ml of 10% aqueous sodium hydroxide solution. The aqueous phase is extracted several times with dichloromethane, the organic phase is dried over sodium sulfate and concentrated. The residue was dissolved in 50 ml of ether and treated with 150 ml of a saturated ethereal oxalic acid solution. The resulting precipitate of the oxalate was isolated and recrystallized.
Yield: 2.7 g
Mp: 95 to 100 ° C (oxalate)

Preparation of N-t-Butyl- (4-amino-3,5-dichlorophenyl) - glyoxal nitrone

5 g t-butylhydroxylamine · HCl, 2.6 g sodium acetate and 5.7 g of 4-amino-3,5-dichlorophenylglyoxal hydrate were added to 100 ml of ethanol stirred for 2.5 hours at room temperature. It was filtered, the filtrate was concentrated to 10 ml and added 20 ml of water. After an hour under Cooling to 1 ° C, the resulting precipitate was filtered off and recrystallized from methanol / water (mp .: 173 ° C).

Claims (5)

1. A method for separating the mixture of the enantiomeric forms of 1- (4-amino-3,5-dichlorophenyl) -2- (tert-butyl) -hydroxy-amino-ethanol, characterized in that the mixture is approximately equimolar with (-) - Diacetone-2-keto-L-gulonic acid of the formula (I) reacted in alkanol and the resulting sparingly soluble salt of one of the enantiomers is separated off. 2. Enantiomer of 1- (4-amino-3,5-dichlorophenyl) -2- (tert-butyl) -hydroxy-aminoethanol with a rotation value in chloroform of
[ α ] = -44.1 ° ( C = 1.5). 3. Enantiomer of 1- (4-amino-3,5-dichlorophenyl) -2- (tert-butyl) -hydroxy-aminoethanol with a rotation value in chloroform of
[ α ] = + 52.6 ° ( C = 1.6). 4. Use of the enantiomers according to claims 2 and 3 to promote performance in animals. 5. Use of the enantiomers according to claims 2 and 3 for the production of performance enhancing funds for Animals.