CA1237430A - 1-(amino-dihalophenyl)-2-aminoethane derivatives and acid addition salts thereof for enhancing the growth rate of meat-producing animals and improving the efficiency of feed utilization thereby - Google Patents

Abstract

27,968 PHENYLETHANOLAMINE DERIVATIVES AND ACID
ADDITION SALTS THEREOF FOR ENHANCING THE
GROWTH RATE OF MEAT-PRODUCING ANIMALS AND
IMPROVING THE EFFICIENCY OF FEED UTILIZATION THEREBY

ABSTRACT OF THE DISCLOSURE
There is provided a method for enhancing the growth rate of meat-producing animals and improving the efficiency of feed utilization thereby, which involves, orally or parenterally, administering to said animals a growth-enhancing amount of a phenylethanolamine compound or the acid addition salt thereof.

Description

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PHENYEETHANOLAMINE DERIVATIVES AND ACID ADDITION
SALTS THEREOF FOR ENHANCING THE GROWTH RATE OF
MEAT-PP.ODUCING ANIMALS AND IMPROVING THE EFFICIENCY
OF FEED UTILIZATION THEREBY
SUMMARY OF THE INVENTION
.
Substitution products of l~(amino-dihalo-phenyl)2-15 aminoethanes, and the acid addition salts thereof, are dis closed in United States Patent 3,536,712, issued October 27, 1970. Specifically, methods for the synthesis of said com-pounds are disclosed as useful for enhancing the blood circu-lation, and as bronchodilators, analgesics, sedatives, anti-20 pyretics, antiphlogistics and antitussives in warm-bloo~ed animals. However, only the analgesic utility i5 exemplifi~dO
There is no indication or suggestion that ~aid compounds are effective as gro~th-pxomoting agents for meat-producing ani-mals, such as swinc, poultr~, cattle, sheep ox the like; nor 25 is there any suggestion that said compounds improve the effî-ciency of feed utilization by said meat-producing animalsO
In accordance with the process of the invention, it has been found that the growth rate of meat-producing animals such as swine, chickens, turkeys, rabbits~ sheep, goats a~d 30 cattle, including calves, can be increasad and the efficiency of feed utilization thereby measurably improved by the or~l or parentexal administration to said ar~imals of an effective amount of a compound having the structure:

(I) ~ ~H~CH-NR~R3 Z R4 Rl wherein X is hydrogen or halo~en (fluorine, chloriner iodine or bromine, but preferably chlorine or bromine); Y is hydro-gen, NH2 or NHCOR5; Z is hydrogen, halogen (fluorine, chlo-rine, iodine or bromine, but preferably chlo~ine or bromine) 5 or OH; Rl is hydrogen or C1-C4 alkyl; R2 is hydrogen, C1 C4 alkyl (straight or branched-chain) ox C3-C4 alkenyl; R3 is hydrogen, Cl-C6 alkyl (straight or branched-chain), C3-C6 cycloalkyl, methoxypropyl, C3-C4 alkenyl, phenyl, 2-hydroxy-ethyl, a,à-dimethylphenethyl ox benzyl; and when R2 and R3 10 are taken together with the nitrogen to which they are attached, they may represent morpholino or N'-Cl C4 alkyl-piperazino, R4 is hydrogen, hydroxyl or OR6; R5 i9 hydrogen or Cl-C4 alkyl; R6 is Cl-C6 alkyl; with the provisos that when R3 is phenyl, 2-hydroxyethyl, a,a-dimethylphenethyl, 15 cycloalkyl C3-C6, benzyl or methoxypropyl, R2 is hydrogen;
and when Z is OH, X and Y are hydrogen; and when Y is NHCQR5, at lèast one of X and æ is hydrogen; and provided also ~hat at least one of X,Y and Z represents a substituent other than hydrogen; racemic mixtures of the above-identified compounds 20 and the optically active isomers and non-toxic, phanmaGo-logically acceptable acid addition salts thereof.
Preferred compounds ~or use in the method of this invention have the above structure wherein X and Z are each chlorine or bromine; Y is hydrogen or NH2; ~1 is hydrogen or 25 Cl-C4 alkyl; R4 is hydroxyl; or a non-toxic, pharmacolo-gically acceptable acid addition salt thereofO
The most praferred compounds for use in enhancing the growth rate of meat-producing animals and for improving the efficiency of feed utilization thereby are: 4-~mino-a-30 [(tert-butylamino)mlethyl]-3,5-dichlorobenzyl alcohol hydro-chloride; 4-amino-3,5-dibxomo-a-~(diisopropylamino)methyl]-benzyl alcohol hydrochloride; 4-amino-3,5-dichloro-a-~(di-isopropylamino)methyl]benzyl alcohol hydrochloride; 4-amin~-3,5-dibromo-a-[(t _ -butylamino)methyl]-benzyl alcohol 35 hydrochloride; 4-amino-3,5-dichloro-a-[(methylamino)methyl]-benzyl alcohol hydrochloride; 4-amino-3tS-dichloro-a-[(allyl-amino)methyl]benzyl alcohol; 4-amino-3-bromo a-[(tert-3~13~
butylamino)methyl]-5-chlorobenzyl alcohol hydrochloride;
~-[4-amino-3,5-dichlorophenyl]-4-morpholineethanol hydro-chloride; 4~amino-3-bromo-a-[(tert-butylamino)methyl]-S-chlorobenzyl alcohol hydrochloride and a-[(tert-butylamino)-5 methyl]-3,5-dichlorobenzyl alcohol hydrochloride.
It is found, that formula (I) compounds below (wherein Y is hydrogen) can be prepared by .the condensation of an appropriately substitu.ted sytrene oxide with the appro-priately substituted amine in the presence of an inert 10 solvent, such as.a lower alcohol at or near the boiling point of same, as shown below:
X

~ 7 ~ R ethanol X

tI~ ~ CH-CE2- ~

wherein X and Z are halogen, R2 and R3 are as herein~bove defined and Y is hydrogen. Thus, 3,5-dichlorostyrPne oxide 25 can be reacted with an equimolar or molar excess of t-butyl~
amine in ethanol at reflux from about 1 to about 8 hours~
or until the reaction is essentially complete and the de-sired a-[(t-butylamino)methyl]-3,5-dichlorobenzyl alcohol is obtained as illustrated below:
Cl I Cl ~ ~ + H2NC4H9-t ~ ~ CH-CH2 NH-C4H7 t OH

The thus obtained product can be purified b~ known procedures, such as chromatography or recrystallization o~ salts thereof~

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The a~ove styrene oxide is made by reducing the corresponding phenacyl bromide with NaBH4 at or below 5C
in the presence of an anhydrous lower alcohol, such as ethanolO The phenacyl bromide intermediate is prepared 5 by brominating the appropriately substituted acetophenone with CuBr2 in the presenCe of chloroform and ethyl acetate.
The above sequence may be graphically illustrated as follows:
Cl Cl 10 ~ -C~ CUBr2 _ ~ -CH Br CHC13/EtOAc ~ ~ O 2 Cl C1 C~l NaBH4 EtOH > ~ O

Cl Alternatively, a formula (I) compound wherein Y
is hydrogen may be prepared from the corresponding formula (I) compound wherein Y iS amino, via a deamination reaction, by dissolving the amine in 50-52% aqueous hypophosphorous acid (H3PO2~. The solution is chilled below 10C, and an 25 equimolar or eXce5s amoUnt of sodium nitrite is added as an aqueous solution with Stirring over a period of time. On completion of the addition~ the reaction mixture is warmed to room temperature and stirxed for an additional period of time. The product is then recovered frQm the reaction mix-30 ture by standard laboratory procedures and purified if sodesiredO
Formula (I) compounds wherein R4 is OR6 and R6 is as hereinabove defined san be prepared by converting the corresponding alcohol (R4 = OH) with thionyl chloride under 3i an inert blanket of gas such as nitrogen at a temperature range of from abou~ 0C to 10C~ and pre:Eerably 0 to 5C for a period of time sufficient to essentially complete the re-.

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action. The thus obtained halo compound is isolated by con-ventional laboratory methods and is then reacted with the appropriate alcohol, under an inert blanket of gas, such as nitrogen at a temperature range of from about 0 to 5C. The 5 thus obtained formula (I) product is then isolated by stand-ard laboratory methods and purified, if so desired. The above reaction sequence may be graphically illustrated as follows:
X
lo y~fH CH2 ~ 3 SOC12 >
OH

~ CH-CH2NR2R3 R6OH >

Z
.

~-CH2NR2R3 (I) 25wherein X,Y,Z,R2,R3 and R6 are as hereinabove defined.
Alternatively, a formula ~I) compound wherein R4 is OR6 may be prepared by dissolving the corresponding formula (I) compound wherein R4 is O~ in the corresponding R60H alcohol and saturating the thus obtained solution 30with dry HCl gas. The reaction mixture is then stirred at room temperature for a period of time sufficient to essen-tially complete the reaction and the product is then iso-lated by standard laboratory procedures and purified, if so desired. This reaction sequence may be illustrated as 35follows:

~37~30 Y ~ fH-CH2NR2R3 HCl gas ~ ~ 1 2N~2R3 wherein X,Y,Z,R2,R3 and R6 are as hereinabove de~ined.
In the present specification and claims the term 10 a,a-dimethylphenethyl means a structure having the following configuration: . CH-C-CH
When orally administered in the feed, generally about 0.01 to 300 grams per ton of feed of the above-identified phenylethanolamine derivative or acid addition salt thereo~, is effective for enhancing the growth rate and improving the efficiency of feed utilization by the 20 above~mentioned meat-producing animals.
Since the effective and preferred dietary levels of the active ingxedient vary somewhat from species to speries in the above-mentioned animals said levels for each animals species are listed in Table I below on a 25 gram per ton of feed basis:

E~fective Pre~erred Feed Level Level Compound _g/Ton _g/Ton Animal 30 Formula (I) ~ ~ u 0.1-200 1-100 Sheep, Goat 0.01-50 0.1-10 Chicken~, Rabbit~
0.01-50 0.1 10 Turkeys ~

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Animal feed compositions which will provide th~
desired growth promotion and feed efficiency in the above-mentioned animals can be prepared by admixing the phenyl-ethanolamine derivative or acid addition salt thereof, or 5 an animal feed supplement containing said compound, with a sufficient ~uantity of an appropriate animal feed to provide the desired level of active compound in said feed.
Animal feed supplements can be prepared by admix-ing about 10% to 75~ by weight of the phenylethanolamine de-10 rivative or acid addition salt thereof, with about 90% to25~ hy weight of a suitable carrier or diluent. Carriers suitable for use to make up the feed supplement compositions include the following: alfalfa meal, soybean meal, cotton-seed oil meal, linseed oil meal, sodium ch~oride, cornmeal, 15 can molasses, urea, bone meal, corncob meal and the like.
The carrier promotes a uniform distribution of the active in-gredient in the finished feed into which the supplement is blended. It thus performs an important function b~ ensuring proper distribution of the active ingredient throughout the ~0 feed.
If the supplement is used as a top dressing for feed it likewise helps to ensure uniformity of distribution of the active material across the top of the dressed feed.
For parenteral administration the phenylethanol-25 amine derivative may be prepared in the form of a paste orpellet and administered as an implant, usually under the skin of the head or ear of the animal in which enhanced growth rate and/or improved efficiency of feed utilization is sought.
In practice, parenteral administration generally 30 involved injection of a sufficient amoun~ of the above said ethane derivative to provide the animal with from 0.001 to 50 mg/kg of body weight of the active ingredient. The pre-ferred dosage level for swine is 0.09 to 50 my/kg of body weight and for cattle the range of from 0.001 to 25 mg/kg o~
35 body weight of the active phenylethanolamine derivative is pre~erred. The preferred dose level of said ethane deriva-tive for ?o~ltry is about 0.001 to 35 mg/kg of animal body ~ ~3t7~3~, weight and the preferred dose level of said ethanol deriva-tive for sheep and goats is 0.001 to 40 mg/kg of animal body weight. The preferred dose level for rabbits is 0.001 to 35 mg/kg of animal body weight.
S Paste formulations can be prepared by dispersing the active ethanol derivative in a pharmaceutically accept-able oil such as peanut oil, sesame oil, corn oil or the like.
Pellets containing an efective level of the phenyl-10 ethanolamine derivative can be prepared by admixing the above-said active ingredient with a diluent such as carbowax, bio-degradable polymers, carnauba wax, or the like. A lubricant, such as magnesium stearate or calcium stearate may be added to improve the pelleting process if desired.
It is, of course, recognized that more than one pellet may be administered to an animal to ~chieve the de-sired dose level which will provide the increased growth rate and/or improve efficiency of feed utilization by said animal.
Moreover, it has been found that additional implants may also 20 be introduced periodically during the treatment period in order to maintain the proper drug release rate in the animal's body.
In addition to-enhanced growth promotion and im-proved eficiency of feed utilization by meat-producing ani 25 mals, the compounds of the present invention have the added advantage that, at selected levels of administration, they depress the deposition of fat in said animals and improve the carcass quality thereof by increasing the ratio of lean meat to fat in the animals receiving them~ This biological 30 response has substantial advantage to poultrymen and swine producers since administration of said compounds at selected levels yields leaner animals which command premium prices from the meat industry.
These and other ad~antages of the present invention 35 will become apparent from the examples set ~oxth below. Such examples are provided only by way of exemplification and are not intended to ba expressions of limitations on the inven-~3 7 ~

g tion.
E _Evaluation of Test comPounds as Animal Growth Promoters CFI female mice from Carworth Farms are received 5 when they are six weeks old. They are housed ten to a cage in air-conditioned rooms (72F to 76F) with automatically controlled lights, 14 hours on and 10 hours off. The basal diet used in these studies is Purina Laboratory Chow (see description b~low), which is supplied ad libitum. Water is 10 allowed ad libitum.
Thirteen days after arrival, the mice are weighed in groups of ten and assigned at random to the dif~erent treatments. The concentration of the different compounds in the diet is indicated in the following tables. Twelve days 15 later the mice are weighed again and the experiment terminated.
Test data are provided in Table II below wherein data are re-ported as percentage gain over controls. The ollowing is description of the diet to which the growth~promoting com-pounds were added.
DIET
Guaranteed Anal~sis Crude proten not less than 23.0%
Crude fat not less than~.5%
Crude fiber not more than6.0%
Ash not more than 9.o%
Ingredients Meat and bone meal, dried skimmed milk, wheat germ meal, fish meal, animal liver meal, dried beet pulp, ground extrud-ed corn, ground oat groats, soybean meal, dehydrated alfalfa 30 meal, cane molasses, animal fat preserved with BHA, vitamin B12 supplement, calcium pantothenate, choline chloride, folic acid, riboflavin supplement, brewer's dried yeast, thiamine~
miacin, vitamin A supplement, D-activated plant sterol, vita-min E supplement, calcium carbonate, dicalcium phosphate, 35 iodized salt, ferric ammonium citrate, iron oxide, manganous oxide, cobalt carbonate, copper oxide, zinc oxide.

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The procedure described above is repeated for theevaluation of each of the following compounds using di~fer-ent control animals for each test. Twelve days after the tests are started the animals are weighed and the test term-5 inated. The results of each test are reported in Table IIIbelow as weight gains for each test group and percent gain for each test group over the weight gains obtained by the control animals in the specific test in which the compound is evaluated.

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The pxocedure o~ Example 1 is used in this evalua-tion. The diet is the same as described in said example and 5 data obtained are reported as percent gain over controls.
Data are reported in Table IV below.

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EX2~LE 3 Evaluation of test compounds_as antilipogenic agents and animal growth promoting agents The procedure of Example 1 is repeated excepting 5 that three cages of 10 mice are used for each txeatment level and after the final weights ha~e been taken, all mice are necropsied and the percent body fat for each treatment group determined. The method for determining percent body fat ôf the animals is hereinafter described. Data obtained are re-10 ported in Table V below.A. Preparation of carcasses:
Stomach and intestines are removed from each mouse.
All other viscera, including skin and fur, remaininy intact.
Each cage of mice (10) is weighed and autoclaved at 120C
15 tl5 psi) or 30 minutes. Carcasses from each cage are then homogenized. The homogenate is weighed and duplicate 5-gram samples are removed for analysis.
B. Fat analysis:
Fifteen mililiters of concentrated hydrochloric 20 acid is added to each 5-gram sample and mixed well. Samples are heated in an 84C water bath for 2 hours and then remove~
Thirty ml of petroleum ether is added to each sample, 15 ml at a time and mixed well on a vortex mixer. Aqueous and or-ganic phases are separated by low speed centrifugat on and 25 thP ether layer (containing fat) is extracted into tared 30 ml beakers~ Beakers are let to dry overnight and the beaker containing fat is reweighed to determine grams of fat per five grams of homogenate. Total body fat in the carcass is calculated as follows:
r~amsfat 1 rgramstotal J
Linsample J Ihomogenate 7~ fat = ~ ~~ x 100 j ~am weight~ ~ rcarcassweight Lofsample ~ Lof mice(g) --23~

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-24~ 743~

EXAMP~E 4 Evaluation of test compounds_as animal feed additives for the enhancement of the growth rate of poultry One day old Hubbard X Hubbard Cxossbred Chicks, 5 randomly allotted to pens of ten chicks (5 males and 5 fe-males) each.
Eight pens of chicks are used for unmedicated con-trols, and four pens of chicks are used at each level of drug. The duration of the experiment is 28 days.
The controls are offered an unmedicated diet of Broiler Ration No. 453 (composition given below) and water ad libitum. Medicated chicks are offered the same diet con-taining the test drug at the levels indicated abo~e, and water ad libitum. The weight of the chicks is determined 15 at the beginning and on completion of ~he experiments. Weight gains and the amount of feed consumed are also determined.
The thus obtained data are averaged and summarized in Table VI
below, wherein the percent improvem~nt in weight gains and feed/gain ratios are given.

Component Percent by Weight Ground yellow corn 53.45 Soybean oil meal (49%) 28.00 Menhaden fish meal (60%) 5.0 Corn gluten meal (60%) 5.00 Dehydrated aIfalfa meal (17%) 2.00 Stabilized fat 4.00 Dicalcium phosphate 1.20 Ground limestone 0.5û
Sodium chloride 0.30 Trace minerals mixture~ 0.05 Vitamin premix*~ 0-50 100.00 -25-~Z3~7~3~

~Trace Mineral Mixture 1 lb/ton furnishes Manganese12 . 50 % 62 . 5 ppm Iron 6.0û 30.0 Zinc 5.00 25.0 Copper 0 . 65 3. 25 lodine 0 ~ 3 5 1. 7 5 Cobalt 0 . 25 1. 25 Calcium minimum 15.30 Calcium maximum 17 . 35 $*Vitamin Pre ix for l-tonWeight in Gram DL Methionine 453. 6 BHT ~butylated hydroxy toluene) 1}3.6 Vitamin A ( 30, 000 mcg/g)100.0 Vitamin D3 (200,000 mcg/g)5 0 Vitamin E (20,000 mcg/lb) 45.4 Riboflavin 4.0 Niacinamide 25.0

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Evaluation of test compounds as animal feed addi-tives for the enhancement of growth rate and improvement in feed efficiency of mice.
Four-week old female outbred rats (5-gram range) from Charles River Breeding Laboratories, 251 Ballardvale Street, Wilmington, Massachusetts 01887, are housed 2/cage in air-conditioned rooms ~72F to 76F) with automatically controlled lights, 14 hours on and 10 hours off. The basal 10 diet used in these studies is Purina Laboratory Chow which is supplied ad libitum. Water is also given ad libitum.
Four days after arrival, the animals are weighed and allotted to treatment groups to minimize weight varia-tion. Ten rats are used per treatment group. Drugs are 15 administered in the eed at 2 ppm, 10 ppm and 50 ppm for a period of 12.5 weeks. Animals are weighed weekly and feed consumption corrected for spillage recorded daily. The results of this trial are shown below in Table VII.

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~-[(Tert-butylamino)methyl]-3,5-dichlorobenzyl Alcohol Hydrochlorlde A solution containing 305 g of 3,5-dichlorostyrene 5 oxide in 50 ml of absolute ethanol and 20 ml of t-butyl-amine is heated gently at reflux for 8 hours and the mixture is evaporated to dryness, The clear yellow syrup is dis-solved in 75 ml of ethanol and 25 ml of H20, and the solution is cooled to 5C and acidified with 3N HCl. This 10 solution is evaporated to dryness in vacuo and the residual white solid is recr-stallized from acetone to afford 2.81 g, mOp. 218-221C.
Anal . Called for C12H17NOC12HCl: C, 48026; H~ 6.08; H, 4.69.
Found: C, 48049; H, 6.17; N, 4.66.
The free base of the title compound is obtained by neutralization of the title compound with aqueous 10~
NaOH. Other salts of the free base are then obtained by treatment of the free base in the above-mentioned procedure (aqueous ethanol) with addition of the appropriate acids~
2 4~ H3P04~ HN03/ CH3S03H, toluenesulfonic acid and pamoic acidO
The intermediate 3,5dichlorostyrene oxide needed for preparing the title compound is made by reducing 28.4g of 3,5-dichlorophenacyl bromide in 125 ml of absolute ethanol 25 at 5C with 8g of NaBH4, added portionwise. After the addition is completed, the reaction mixture is stirred 16 hours at ambient temperature, which is obtained by gradual melting of the ice bath overnight. The mixture is quenched with 100 ml of H20, the agueous mixture is cooled to 5C, 30 and carefully acidified to pH 3 with concentrated HClo The mixture is extracted with 300 ml of CH2C12 and the extract is dried over MgS04, filtered, and evaporated to dryness in vacuo to afford the epoxide as a clear yellow oil.
The phenacyl bromide intermediate for the above-35 mentioned styrene oxide is prepared by brominating 10 g of3,5-dichloroacetophenone in 50 ml of CHC13/50 ml o EtOAc with 23.6 g of CuBr2. The mixture is heated at reflux for ~l~3~L3~

2.5 hours and cooled to room temperature. After stirring for 16 hours at room temperature, the mixture is cooled in ice for 2 hours and filtered. The filter cake is washed with 50 ml of CHCl3 ~nd the combined filtrates are twice de-5 colorized with activated carbon, filtered, and evaporatedto dryness in vacuo to afford the orange oil of the 3,5-dichlorostyrene oxide.
EXAMP~E 7 The following 3,5-dichlorophenyl compounds (A) re-lO lated to the title compound o~ Example 6 are prepared by the method described in Example 6 by substituting t-butyl amine with R2R3NH amines.

~ H--CH2--NR2 R3 A
Compound R2 R3 ~ l H H

3 H C2H5

4 H i C3H7 H n-C3H7 6 H n C6H13 7 H cyclohexyl 8 H CH2-CH=CH2 9 H CH2-CH=CH-CH3 H CH C=CH
~ 2 --31- ~23~74~

A (Continued) Compound R2 R3 H phenyl 12 H methoxypropyl 13 H benzyl 16 C~I2CH=CH2 CH2CH=CH2 17 l-c3H7 i ~3H7 18 CH2~CH=CH2 -CH2-CH=CH2 19 H cyclopropyl -CH2 CH2-O-CH2-cH2 21 H n-butyl 22 H C(CH3)2-CH2 ~-~(Tert-butylamino)methyl]-3,5~dibromobenzyl Alcohol_Hydro~
20 chloride This title compound is prepared from 3,5-dibromo-styrene oxide in the same manner as described in Example 6.
The starting materials for this styrene oxide are similaxly prepared starting with 3',5'-dibromoacetophenone.
The corresponding ~-[(isopropylamino)methylJ-3,5-dibromobenzyl alcohol hydrochloride is prepared by substitut-ing isopropyl amine for t-butyl amine.

m-Hydroxy-a-[(isopropylamino)meth~l]benz~ Alcohol Hydrochlo-30 ride In 135 ml of 95~ ethanol, 36.75 g of m hydroxyaceto-phenone, 36.5 g of benzyl chloride, 1.75 g of KI, and 24.6 g of ~2CO3 are stirred and heated at reflux for 5 hours. The mixture is cooled, evaporated _ vacuo to remove ethanol and 35 100 ml of H2O is added. The mixture is then extracted with diethyl ether three times to afford 350 ml of extractt which is further washed with 50 ml of H2O, saturated NaHCO3 solu---32~ 7~3~

tion (2 x 50 ml), 50 ml of H2O, and 50 ml of brine in succes-sion~ The filtrate is dried over Na2SO4 and evaporated to dryness. The residual oil is distilled to afford 49.13 g of m-benzyloxyacetophenone, b.p. 145-147C/002 mm. Bromination

5 of 186 g of this acetophenone is accomoplished with 349 g of CuBr2 in lQ of CHCL3/1.5 Q of ethanol heated at reflux.
A N2 sweep is used to remove HBr generated. After 4 hours, the mixture is filtered and the filter cake is washed with CHC13 (2 x 100 ml). The filtrate is evaporated in vacuo to 10 afford an oil, which is dissolved in 200 ml of absolute ethanol (2 x 50 ml)~ and dried to afford 64.28g m-benzyl-oxyphenacyl bromide, mOpO 57-58C. Further cooling of the filtrate affords 34g. A 64 g-sample of the phenacyl bromide is added to a stirred mixture containing 212 ml of i-propyl-15 amine in 425 ml of e~hanol under N2 atmosphere at 5C. Thetemperature rises to 12C and a clear solution is obtained.
The solution is poured into ice (2 L) containing 500 ml of concentrated HCl and 1500 ml of H2O. After stirring for 20 minutes, the mixture is filtered and the solid is washed 20 with H2O. On drying this gives 98064g, m.p. 200-203C dec.
This solid is dissolved in 400 ml of r~fluxing methanol, 400 ml of isopropyl alcohol is added, and the solution is concentrated to 400 nl. On cooling and collecting crystals, 54.36 of ketoamine melting at 213-215 d~c is obtained. This 25 material (1~ g) is added to 150 ml o~ methanol which contains 2 g of 5% Pd/carbon and hydrogenated in a Paar vessel at 42 p.s.iOg~ o~ H2. The mixture is filtered and the filtrate is evapoxated. ThP residue is mixed with 50 ml of isopropyl alcohol and evaporated to dryness to afford a syrup, which is 30 mixed with 100 ml of ethanol. They crystals are collected, washed with diethyl ether and dried to give 10.77 g, m.p.
129-132C, o~ the title compound.
By substituting tert-butylamine for isopropyl-amine, _-hydroxy-a-[(tert-butylamino)methyl]benzyl alcohol 35 hydrochloride, mOp. 150-154C dec. is obtained. Substitution of isopropylamine with diisopropylamine, benzyl~mine and allyamine affords _-hydroxy-a-~(diisopropylamino~methyl~-7~3~

benzyl alcohol, m-hydroxy-a-[(benzylamino)methyl]benzyl alcohol, and m-hydroxy-a-~(allylamino)methyl]benzyl alcohol hydrochlorides, respectively.

5 4-Amino-a[(tert-butylamino)methyl]-3,5-diiodobenzyl Alcohol Hydrochloride In 10 ml of acetic acid, 0.42 g of p~amino-~-[(tert-butylamino)methyl]benzyl alcohol is stirred under N2 atmosphere and 0.48g of N,N-dichlorobenzenesulfonamide and 10 0.6g of NaI are stirred under N2 atmosphere for 20 minutes.
After 3 days, the mixture is poured into ice and the mixture is basified with 50% aq. NaOH. This mixture is extracted with CH2C12 (3 x 25 ml) and chromatographed on a SiO2 plate using 1% NH40H/20% ~H30H/CH2C12 to afford 0.22g o the title 15 compound. The reaction is repeated on a larger scale (8X) and the eluted crude product is dissolved in 100 ml of ethanol/10 ml of H20, stirred and 10% HCl is added to give pH 3. The mixture is evaporated to dryness in vacuo. Iso-propyl alcohol is added and the mixture is evaporated to 20 dryness. This process is repeated twice and the residue is crystallized from methanol/isopropyl alcohol by allowing methanol to evaporate until crystals from (methanol is used to dissolve the crude material before isopropyl alcohol is added). On cooling, 2g of the title compound is obtained 25 melting at 137C dec.
Anal. Calc'd for C12HlgClI2N20: C,29.02, H,2.86, N,5~640 Found: C, 29.11; H, 3.64; N, 5.64.

-[~Tert-butylamino)methyl]-3,5-dichlorobenzyl~Alc hol Hydro-30 chloride An alternate procedure for preparing the title com-pound and the compounds described in Example 7 i5 exempli-fied. Thus, 10 g of 4-amino-a-[(tert-butylamino)methyl]-3,5-dichlorobenzyl alcohol is added to 100 ml of 50-52% H3P02 35 and the mixture is stirred and cooled to 8C in iC2 while 2.77 g of NaN02 in 15 ml of ~2 is added over 65 minutes.
Foaming occurs and is controlled with antifoaming silicone.

~3~ 3~

After 2Q minutes, the mixtu~e is stirred 2 hours withou-t cooling~ The mixture is then poured into ice-~2O mixture and 50~ aq. NaOH solution is added until the mixture is al-kaline. The alkaline mixture is extracted with CH2C12 three 5 times to give 200 ml of solution, which is washed with 25 ml of 2% NaOh and dried over MgSO4 and evaporated to dryness ln vacuo to give 9.13 g of brown oil. On standing, the oil solidifies, and it is dissolved in 100 ml of ethanol contain-ing 10 ml of ~2 The solution is acidified to pH 3 with 10 10~ HCl and evaporated to dryness. The residue is treated with 50 ml o isopropyl alcohol and evaporated to dryness.
This procedure is repeated to afford an off-white solid which is dissolved in methanol. The solution is evaporated in vacuo to afford a syrup, which is diluted with 50 ml of iso-15 propyl alcohol and allowed to stand. The crystals whichform are collected, washed with isopropyl alcohol and dried to yield 7.8 g, m~p. 217-221C dec., of the title compound~
The compound described in Example 6 is similarly prepared. Deamination of 4-amino-3,5-dibromo-~-[(tert-butyl-20 amino)methyl]benzyl alcohol affords 3,5-dibro~o-~-[(tert-butylamino)methyl]benzyl alcohol, m.p. 249-251C dec.

4-Amino-3,5-dichloro-~methoxyphenethylamine hydrochloride Under N2 a~mosphere, 11 g of 4-amino-~-[(tert-butyl-25 amino)methyl]-3,5-dichlorobenzyl chloride is added to 75 ml of methanol at 0C. After 20 minutes, the cooling bath is removed and the reaction mixture is stirred at ambient tem-perature. After the reaction is completed, the mixture is evaporated to dryness in vacuo. The residue is stirred in 30 75 ml of H2O and the mixture is made alkaline with 6N NaOH
solution and extracted with CH2C12 (3 x 50 ml). The organic phases are dried over MgSO4 and evaporated to dryness to afford an orange oil. This oil is dissolved in 150 ml of absolute EtOH and acidified with HCl/isopropyl alcohol solu-35 tion to pH 2. The solution is evaporated to dryness and theresidue is stirred in 75 ml of ethyl acetate. After cooling, this affords a pale yellow solid which is collected to give

6.97 g of the title compound, m.p. 195-198C dec.
Similarly, substitution of ethyl alcohol, isopropyl alcohol, _-butyl alcohol and n-hexyl alcohol affords the corresponding ~-ethoxy, ~-isopropoxy, n-butoxy, and _-hexyl-5 oxy phenethylamine hydrochlorides.

4-Amino-a-[ltert-butylamino)methyl]-3~5-dichloroben2yl chlo-ride Under N2 atmosphere, 27~72 g of 4-amino-a [( ert-lO butylamino)methyl]-3,5-dichlorobenzyl alcohol is added to 200 ml of thionyl chloride stirred at 0-5%C. After addition is completed, the reaction mixture i5 stirred at ambient temperature for 3 hours. Subsequently, the mixture is evap-orated to dryness in vacuo to afford 37.34 g of yellow solid, 15 which is used as is.

Alternate Procedure for 4-Amino-3,5~dichloro-~-methoxy-phenethylamine h~drochloride I. lO0 ml of methanol, lO g of 4-amino-a-~(tert-20 butylamino)methyl]-3,5-dichlorobenzyl alcohol is stirred in an ice bath and dry ~Cl gas is introduced into the solu-tion. After saturation of the solution, the mixture is stirred at ~oom temperature ~or an hour and evaporated to dryness. The solid is then stirred in ethyl acetate to 25 afford the title product, which is collected by filtration.

Claims (7)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A compound of formula:

wherein X is halogen;
Y is hydrogen or NH2;
Z is halogen;
R1 is hydrogen or C1-C4 alkyl;
R2 is hydrogen,C1-C4 alkyl or C3-C4 alkenyl;
R3 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, methoxypropyl, C3-C4 alkenyl, phenyl, 2-hydroxethyl, .alpha., .alpha.-dimethylphenethyl or benzyl;
and when R2 and R3 are taken together with the nitrogen to which they are attached, they may represent morpholino or N'-C1-C4 alkyl-piperazino;
R4 is hydroxy or OR6;
R6 is C1-C6 alkyl;
with the provisos that when Y is NH2 then R4 is OR6; and when Y is hydrogen, R2 is hydrogen;
racemic mixtures of the above-identified compounds and the optically active isomers and non-toxic, acid addition salts there-of.

2. The compound according to Claim 1 wherein X and Z each are chlorine or bromine;
Y is hydrogen or NH2;
R1 is hydrogen or methyl;
R2 is hydrogen;
R3 is hydrogen or C1-C4 alkyl; and R4 is hydroxy or methoxy.

3. .alpha.-[(t-Butylamino)methyl]-3,5-dichlorobenzyl alcohol hydrochloride.

4. 4-Amino-N-t-butyl-3,5-dichloro- .alpha.'-methoxyphenethylamine hydrochloride.

5. .alpha. -[(Isopropylamino)methyl]-3,5-dichlorobenzyl alcohol hydrochloride.

6. .alpha. -[(t-Butylamino)methyl]-3,5-dibromobenzyl alcohol hydrochloride.

7. 4-Amino-N-t-butyl-3,5-dibromo-.alpha.'-methoxyphenethylamine hydrochloride.