1-(aminodihalophenyl)-2-aminoethane derivatives and acid addition salts thereof for the depression of fat deposition in warm blooded animals

1237316 PHENYLETHANOLAMINE DERIV~TIVES AND ACID ADDITION SALTS THEREOF FOR THE DEPRESSION OF FAT DEPOSITION IN WARM BLOODED ANIMALS SUMMARY OF THE INVENTION Substitution products o~ certain l-(aminodihalophenyl)-2-amino ethanes and the acid addition salts thereof 15 are disclosed in United States Patent 3,536,712, issued on October 27, 1970. Specifically, patentees disclose methods for the synthesis of said compounds and state that said compounds are useful for enhancing the blood circulation, and as bronchodilators, analgesics, sedatives, anti20 pyretics, antiphlogistics and antitussives in warm-blood~d animals. Patentees, however, exemplify only the analgesic ; utility.

They do not indicate or suggest that said compounds are useful for lowering the deposition of fat in warmblooded animals, particularly farm and domestic animals, 25 such as swine, poultry, dogs, sheep, goats, cats or cattle.

It is, therefore, surprising to find that a compound of the formula:

y ~ (I) ~ C,H-~H-NR2R3 wherein X is hydrogen or halogen; Y is hydrogen, NHCOR5 or NH2; Z is halogen or OH; Rl is hydrogeAndorg~Cnl-C4 alkyl;

R2 is hydrogen, methyl or ethyl; R3 is~Cl-C5 alkyl, C3-C4 - alkenyl, C3-C5 cycloalkyl~ 2-hydroxyethyl, ~,~ dimethyl35 phenethyl or benzyl; R4 is hydrogen)OH or OR6; R5 is hydro gen or Cl-C4 alkyl; and R6 is Cl-C6 alkyl; with the provisos that when R3 is 2-hydroxyethyl, a,a~dimethylphen ~3~73i6 --2- -- ethyl, cycloalkyl C3-C5~or benzyl, R2 is hydroger~; and when !. Y iS NHCOR5~X is hydro~en and Z is halogen; also, when Z is OH, X and Y are hydrogen; racemic mixtures of the aboveidentified compounds and the optical isomers and non-toxic 5 pharmacologically acceptable acid addition salts thereof, when administered to swine, poultry, such as chickens and turkeys, cattle, sheep, goats or domestic pets, depresses the fat deposition in said animals and/or increases the lean meat to fat ratio of said animals.

It is found that, in addition to the methods of preparation disclosed in the cited art, the ~ormula (I) compounds (wherein ~ is hydrogen) may also be prepared by the condensation of an appropriately substituted styrene oxide with the appropriately substituted amine in the 15 presence of an inert solvent, such as a lower alcohol at or near the boiling point of same, as shown below:

X + HN\ 2 ethanol >

X CH-cH2-N~ 25 OH wherein X and Z are halogen, R2 and R3 are as hereinabove defined and Y is hydrogenO Thus, for instan~e, one mole of 3,5-dichlorostyrene oxide can be reacted with an e~uimolar 30 or excess amount of t-butylamine in ethanol at reflux from about 1 to about 8 hours, or until the reaction is essentially complete and the desired ~-[(t-butylamino)methyl]3,5-dichloroben~yl alcohol is obtained.

The styrene oxide intermediate can be prepared by 35 reducing the corresponding phenacyl bromide with NaBH4 at 5C or lower in the presence of an anhydrous lower alcohol, such as ethanol. Phenacyl bromide intermediate in turn is ~23~3~6 prepared by brominating the appropriately substituted acetophenone with cupric bromide in the presence of chloroform and ethyl acetate. The above sequence may be graphically illustrated as follows:

Cl Cl -CH CuBr2 ~ c-c~2Br O 3 CHCl3/EtO~c > ~ o Cl Cl Cl Nal3H4 >

Alternatively, it formula (I) compounds above ,~ wherein Y is hydrogen may be prepared from the corresponding formula (I) compound wherein Y is amino, via a deamination reaction, as follows:

The amine is dissolved in 50-52% aqueous hypophosphorous acid (H3PO2), the solution is chilled below 10C, and an equimolar or excess amount of sodium nitrite is added as an aqueous solution with stirring over a period of time.

On completion of the addition, the reaction mix25 ture is warmed to room temperature and stirred for an additional period of time. The product is then recovered from the reaction mixture by standard laboratory procedures and purified if so desired~ Formula (I) compounds wherein R4 is OR6 and R6 30 is as hereinabove defined may be prepared by converting the corresponding alcohol (R4 - OH) with thionyl chloride under an inert blanket of gas such as nitrogen at a temperature range of from about 0C to 10C, and preferably 0 to 5C for a period of time sufficient to essentially complete the 35 reactionO The thus obtained halo compound is isolated by conventional laboratory methods and is then reacted with the appropriate alcohol, under an inert blanket of gas, ~373~6 --4- Ruch as nitrogen at a temperature range of from about 0 to 5C. The thus obtained formula (I) product is then isolated by standard laboratory methods and purified, if so desiredO The above reaction sequence may be graphically 5 illustrated as follows:

Y~3 CH-CH2NR2R3SOC12 OH Z y ~ CH-CH2NR2R3R6 H >

Cl Y ~ FH CH2~R2R3 (I) OH Z wherein 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 OH in the corresponding 25 R6OH alcohol and saturating the thus obtained solution with dry HCl gasO The reaction mixture is then stirred at room temperature for a period of time sufficient to essentially complete the reaction and the product is then isolated by standard laboratory procedures and purified if 30 so desired. This reaction se~uence may be illustrated as follows:

Y ~C}~-CH2N~2R3 ,~3~ X _CH-CH2NR2R3 3 OH HCl gas OR6 Z (I) ~2~73~L~ --5- wherein X,Y,Z,R2,R3 and R6 are as hereinabove defined~ Among the acid addition salts which can be prepared and used in accordance with the present invention are the hydrochloric acid, phosphoric acid, acetic acid, 5 citric acid, gluconic acid and propionic acid addition salts. In accordance with the process of the invention, it has been found that the depression of fat deposition in swine, poultry, sheep, goats, cattle, and domestic pets can be achieved by administering to said animals an 10 effective amount of a formula I phenylethanolamine or the acid addition salt thereof, in the animal feed. The phenylethanolamine, or acid addition salt may also be administered in the form of an animal feed concentrate as a top dressing for the animals daily ration or it may be 15 administered as a subcutaneous implant in the form of paste or pellets~ Animal feed compositions effective for depressing fat deposition in poultry, swine, sheep, goats, domestic pets and cattle are generally prepared by admixing a 20 formula (I) phenylethanolamine derivative or acid addition salt thereof or an animal feed supplement con~aining said compound with a sufficient amount of animal feed to provide from about 1 tc 1000 ppm of said compound in the feedr Animal feed supplements can be pre~ared by ad25 mixing about 75% ~o 95% by weight of a formula I phenyl ethanolamine derivative or acid addition salt thereof with about 5% to 25% by weight of a suitable carrier or diluent.

Carriers suitable for use to make up the feed supplement compositions include the following: alfalfa meal, soybean 30 meal, cottonseed oil meal, linseed oil meal, sodium chloride, cornmeal, cane molasses, urea, bone meal, corncob meal and the like~ The carrier promotes a uniform distribution of the active ingredients in the finished feed into which the supplement is blended~ It thus performs an important 35 function by ensuring proper distribution of the active ingredient throughout the feed.

If the supplement is used as a top dressing :3L237~3~6 --6- for feed, it likewise helps to ensure uniformity of distribution of the active material across the top of the dressed feed.

The pre~erred medicated swine, cattle and goat 5 feed generally contain from 0~01 to 400 grams of active in gredient per ton of feed, the optimum amount for these animals usually being about 50 to 300 grams per ton of feed.

The preferred poultry and domestic pet feeds usually contain about OoOl to 400 grams and preferably 10 10 to 400 grams of active ingredient per ton of ~eed.

For parenteral administration the phenylethanolamine derivative may be prepared in the form o~ a paste or pellet and administered as an implant, usually under the skin of the head or ear of the animal in which depres15 sion of fat deposition is sought.

In general parenteral administration involvesinjection of a sufficient amount of the above-said ethane derivative to provide the animal with 0~001 to lO0 mg/kg/ day of body weight of the active ingredient. The preferred 20 dosage for swine, cattle, sheep and goats is in the range of from .001- to 50 mg/kg/day of body weight of the active I~ de~ a ~,ve ! '` e~hane ~4~w~*1~4~e; whereas, the preferred dose level of said ethane derivative for poultry and domestic pets is usually in the range of from ~001 to 35 mg/kg/day of body 25 weight.

Paste formulations can be prepared by dispersing the active ethane derivative in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.

` Pellets containing an effective level of the phenylethanolamine derivative can be prepared by admixing the above-said active ingredient with a diluent such as carbowax, carnuba wax, or the like, and a lubricant, such as magnesium or calcium stearate, can be added to improve 35 the pelleting process.

It is, of course, recogni2ed that more than one pellet may be administered to an animal to achieve the ~373~6 --7- desired dose level which will provide the antilipogenic effect desiredO Moreover, it has been found that implants may also be made periodically during the animal treatment period in order to maintain the proper drug level in the 5 animal's bodyO The method o~ the present invention has several advantages; for the pet owner or veterinarian who wishes to trim unwanted fat from pet animals, the present invention provides the means by which this can be accomplished.

10 For the poultry men and swine raisers, using the method of the present invention yields leaner animals which command higher prices from the mea~ industry. Surprisingly, it is also noted that feed efficiency and animal growth rate are significantly enhanced when the compounds of -the present 15 invention are administered to swine and poultry at selected dose levels.

These and other advantages will become apparent from the examples set forth below. Such examples are provided only for exemplification of the invention and are 20 not to be considered as limiting the invention.

EXAMPLE 1 E~aluation of test compounds as antilipogenic a~ents Mouse tests CFI female mice from Carworth Farms are received 25 when they are six weeks old. They are house~ ten to a cage in air-conditioned rooms (22C to 25C~ with automatically controlled lights, 14 hours on and 10 hours off.

The basal diet used in these studies is Purina Laboratory Chow (see description below)~ which is supplied ad libitum.

The following is a description of the diet to which the growth-promoting compounds wPre added.

DIET Guaranteed Analysis Crude protein not less than 23O0% Crude fat not less than 4.5% Crude fiber not more than6O0% Ash not more than 9.0 ~373~ ~ --8- Ingredients Meat and ~one meal, dried skimmed milk, wheat germ meal, fish meal, animal liver meal, dried beet pulp, ground extruded corn, ground oat groats, soybean meal, dehydrated 5 alfalfa meal, cane molasses, animal fat preserved with BHA, vitamin B12 supplement, calcium pantothenate, choline chloride, folic acid, riboflavin supplement, brewer's dried yeast, thiamin, niacin, vitamin A supplement, Dactivated plant sterol, vitamin E supplement, calcium 10 carbonate, dicalcium phosphate, iodized salt, ferric ammonium citrate, iron oxide, manganous oxide, cobalt carbonate, copper oxide, zinc oxide. Water is also allowed ad libitumO Thirteen days after arrival, the mice are 15 weighed in groups of ten and assigned at random to the different treatments. The concentration of the different compounds in the diet is indicated in the following tables. Twelve days later the mice are weighed again and the experiment terminatedO At least three cages (30 mice) 20 of untreated controls are included in each test. Test data are provided in Table I below wherein data are reported as percent body fat, percent change in body fat from controls and gain per mouse in gramsO ~373~6 g ~-1 r.~ O ~J C ~ 'I '-- -- N ;l ~ O O c a~ a~ U ~ _, _ o o o~ C2 31~ N N --I _ O O r~ ~ a~ ~ ~ ~ c ^l ` c~ :.ie ,_~ 3 ~ N N N m~ O n ~ ~' e~ o o ~ O O c~ ~1 e .

~ V c ol s~ t i, :~373~ --10- Percent Body Fat Determination of Mice A. Preparation of Car _sses:

Stomach and intestines are removed from each mouseO All other viscera, including skin and fur, remain 5 intact. Each cage of mice (10) are weighed and added to a 1000 ml beaker and autocalved at 120C (lo 05 kg cm 2 pressure~ for 30 minutes. Carcasses from each cage are then blended and homogenizedO The homogenate is weighed and duplicate 5-gram samples are removed for analysisO 10 B. Fat Anal~sis:

Fifteen milliliters (ml) of concentrated hydrochloric acid is added to each 5-gram samples and mixed well.

Samples are heated in an 84C water bath for 2 hours. To extract the fat, thirty ml of petroleum ether is added to 15 each sample, 15 ml at a time, and mixed well on a Vortex mixerO The aqueous and organic phases are separated by low speed centrifugation and the ether layer (containing fat) is extracted into tared 30 ml beakers. After evaporating to dryness the beaker containing fat is reweighed 20 to determine grams of fat per five grams of homogenate.

Total body fat in the carcass is calculated as follows:

rgrams fa~ rgrams tot Ln sampl ~ homogenat ~ % Fat = _ - X 100 r ram weigh~ rcarcass weigh ~f sample ~ Lf mice (g) EXAMPLE 2 Antilipo~enic Evaluation of test compo_nds - Mouse_St~ CFI female mice, 55 days old, are weighed in groups of 10 and allotted to cages to minimize weight variation among cages~ Treatments are randomly assigned to cages.

Each of the treatments are tested in 3 replicates, 35 iOeO, in 3 cages of 10 mice each. There are 10 cages of 10 control mice each. Drugs are mixed in the diet at the dosage level indicated. Feed and water are offered ad ~;~3731~ libitum for 12-day test period. Feed spilled is collected during the test period. At the end of the test period, the collected feed is weighed and the mean feed consumption per cage of ten mice is determined for each treatment.

5 The mice are weighed as a group of 10 and the weight gain determined. The mice are sacrificed by cervical dislocation.

The right uterine fat pad of each mouse is removed. The fat pads for each cage of lO mice are weighed as a unit.

To establish the correlation between the percent relO duction in fat pad weights of treated animals and percent reduction in total body ~at of treated animals, animals from several treatment groups are evaluated for total body fat using the body fat determination described in Example l.

Data obtained are reported in Table II for those groups 15 upon which such determination had been madeO From percent reduction in fat pad weight and the total fat determinations for the groups tested, it can be seen that a reduction in fat pad weights o-f animals is generally indicative of a reduction of total body fat of the treated animals.

~73:~ ~ ~ !~ '1''' l ` ll ~'' c c~ ~ ~ ~ ~ ~ ~ 9~ a~ 3 I, ¦ T ~ O S ~ O ~ S S ~ O _ ~ ,c o ~s C O ~-s 'o o o ~o ~o ~ ~ ~1 ~. ~ a:

~373~l6 --13- - 10 ol~ ~ s N 0~ U~ ~ I N c ~ 7 ~ ol~ N N ~ U~ ~ _~ _ O N --I 3 ;~ ;~ ~ s ~ s ~ s ~ s ~ ~ ~ s ~ ~23~3i~ --14- ~,: ~ ~ ~ rl ~ ~ ~1~ ~ ~ ~ o~ j 3; 3~3v~ ~ ~ u o ~1 u u A O ~373~6 EXAMPT.~ 3 Antilip-ogenic evaluation of test compounds - Rat study The procedure employed and the diet used for evaluation of test compounds as antilipogenic agents mice, 5 are described in Example 1, excepting that the treatment period is fourteen days and 10 rats, one per cage, are used for each treatment.

Percent body fat is determined in the same manner as described in Example 1, excepting that the skin and 10 organs are removed before the carcasses are homogenized.

Results of this study are reported in Table III below.

1 ~37316 --16- v ~ ol O~ O ~O c ~-- c ¦ ~ = ~ _ L ~ O U~ ~- Cl t = 1~'1 N ~i n x V~ C~ c t~ t~ 3 V L C ~ ~ 3 C V ~ ~n~ E- 8 Z o '¦ V ~'V~ ~ o t., q C~ ~73~6 EXAMPLE 4 Preparation of a-[(t-Butylamino)methyl]-3,5-dichlorobenzyl alcohol hydrochloride A solution containing 3.5 g of 3,5-dichlorosty5 rene oxide in 50 ml of absolute ethanol and 20 ml of t butylamine is heated gently at reflux for 8 hours and the mixture is evaporated to drynessO The clear yellow syrup is dissolved in 75 ml of ethanol and 25 ml of H2O, and the solution is cooled to 5C and acidified with 3N HCl. This 10 solution is evaporated to dryness under vacuum and the re sidual white solid is recrystallized from acetone to afford 2.81g, m.p. 218-221C.

Anal~ Called for C12H17NOC12HCl: C, 48~26; ~I, 6.08; N,4.69 Found: C, 48.69; H, 6.17; N, 4066.

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 arids, 20 such as H2SO4, H3PO4, HNO3, CH3SO3H, toluenesulfonic acid and pamoic acid~ The intermediate 3,5-dichlorostyrene 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 te~perature, which is obtained by gradual melting of the ice bath overnightD The mixture is quenched with 100 ml of H2O, the aqueous mixture is cooled to 5~C, 30 and carefully acidified to pH 3 with concentrated HCl. The mixture is extracted with 3~0 ml of CH2C12 and the extract is dried over MgSO4, filtered, and evaporated to dryness under vacuum to afford the epoxida as a clear yellow oil.

The phenacyl bromide intermediate for the above35 mentioned styrene oxide is prepared by brominating 10 gof 3,5-dichloroacetophenone in 50 ml of CHC13/50 ml of EtOAc with 23O6g of CuBr2. The mixture is heated at reflux ~Z3~3~L~ -18 for 205 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 CHC13 and the combined filtrates are twice 5 decolorized with activated carbon, filtered and evaporated to dryness under vacuum to afford the orange oil of the 3,5dichlorostyrene oxideO EXAMPLE 5 The following 3,5-dichlorophenyl compounds (A) 10 related to the title compound of Example ~ are prepared by the method described in example 6 by substituting tbutyl amine with R2R3NH as hereinbelow de~.ined.

Cl ~f CH2NR2R3 OH Cl A Compound R2 R3 H H 2 H CH3 3 H C2H5 4 H l-C3H7 H n-C H 6 H n-C6H13 7 H cyclohexyl 8 H CH2-cH=cH2 9 H CH2-CH=CH-CH3 H CH2C--CH 11 H phenyl 12 H methoxypropyl ~2373~6 --19- A (continued) Compound R2 R3 13 H benzyl 14 CH3 CH3 C2H5 C2H5 16 CH~CH=CH2 CH2CH=CH2 17 i-C H l-C H 18 CH2-CH=CH ~CH -CH=CH 10 19 H cyclopropyl -cH2-cH2-o-cH2-cH 21 H n-butyl 22 ( H3)2 CH2 EXAMPLE 6 Pre~aration of a-[(t-Butylamino)methyl]-3,5-dibromobenzyl alcohol Xydrochloride This title compound is prepared from 3,5-dibromo20 styrene oxide in the same manner as described in Example 4.The starting materials for this styrene oxide are ~imilarly prepared starting with 3',5'-dibromoacetophenone.

The corresponding ~-L(isoProPYlamino)methYl]3,5-dibromobenzyl alcohol hydrochloride is prepared by sub 5 stituting isopropyl amine for t-butyl amine.

- EXAMPLE 7 Preparation of m-Hydroxy-~-r(isoprop~lamino~methyl~benzyl alcohol hydrochloride In 135 ml o~ 95% ethanol, 36.75 g of m-hydroxy30 acetophenone, 36.5 ~ of benzyl chloxide, 1.75 g of KI, and24.6 of K2C03 are stirred and heated at reflux for 5 hours.

The ~ixture is cooled, evaporated under vacuum to remove ethanol and 100 ml of H20 is added. The mixture is then extracted with diethyl et~ex three times to afford 350 ml 35 of extract, which is further washed with 50 ml of H20, satu rated NaHC03 solution (2 x 50 ml), 50 ml of H20, and 50 ml of ~rine in succession. The filtrate is dried over Na2S04 ~2373~i -20 and evaporated ~o dryness. The residual oil is distilled to afford 49O13 g of m-benzyloxyacetophenone, b.p. 145147C/0.2 mm. Bromination of 186 g of the latter acetophenone is accomplished with 349 g of CuBr2 in 1 Q of 5 CHCL2/1.5 Q of ethanol heated at reflux. A N2 sweep i~ used to remove HBr generated. After 4 hours, the mixture is filtered and the filter cake is washed with C~C13 (2 x 100 ml).

The filtrate is evaporated under vacuum to afford an oil, which is dissolved in 200 ml of absolute ethanol and the 10 solution is cooled. The crystals are collected, washed with ethanol (2 x 50 ml), and dried to afford 64.28 g m-benæyloxyphenacyl bromide, m.p. 57-58C.

Further cooling of tne filtrate affords 34 g. A 64 g sample of the phenacyl bromide is added to a stirred mixture containing 212 ml of i-propyl15 amine in 425 ml of ethanol under N2 atmosphere at 5C. Thetemperature rises to 12C and a clear solution is obtained.

The solution is poured into ice (2) 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 with 20 H2O. On drying this gives 98.64 g, m.p. 200-203C dec. This solid is dissolved in 400 ml of refluxing methanol~ 400 ml of isopropyl alcohol is added, and the solution is concentrated to 400 ml. On cooling and collecting crystals, 54.36 of ketoamine melting at 213-215 decc is obtained. This mat~ri2~ al (16 g) is added to 150 ml of methanol which contains 2 gg of 5% Pd/ carbon and hydrogenated in a Paar vessel at 2.94 kg cm of H2 pressureO The mixture is filtered and the filtrate is evaporated. The residue is mixed with 50 ml of isopropyl alcohol ~nd evaporated to dryness to afford a syrup, 30 which is mixed with 100 ml o ethanol. The crystals are col lected, washed with diethyl ether and dried to give 10.77 g, m.p. 129-132C, of the title compound.

By substituting t-butylamine fox isopropylamine, m-hydroxy-~-[(t-butylamino)methyl]benzyl alcohol hydro35 chloride, m.p. 150-154C dec. is obtained. Substitution of isopropylamine with diisopropylamine, benzylamine and allylamine affords m-hydroxy-~-~(diisopropylamino)methyl~ ,~ r ~23733~ -21 benzyl alcohol, m-hydroxy-a-[(benzylamino)methyl]benzyl alcohol, and m-hydroxy-a-[(allylamino)methyl]benzyl alcohol hydrochlorides, respectively.

EXAMPLE 8 5 Preparation of 4-Amino-~ t-butylamino)methyl]-3,5-diiodo benzyl alcohol hydrochloride In 10 ml of acetic acid, 0.42 of p-amino-a-~(tbutylamino)methyl]benzyl alcohol is stirred under N2 atmosphere and 0~48 g of N,N-dichlorobenzenesulfonamide and 0.6 10 g 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~ CH30H/CH2C12 to aford 0022 g of the 15 title 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 under vacuum.

Isopropyl alcohol is added and the mixture is evaporated 20 to dryness. This process is repeated twice and the residue is crystallized from methanol/isopropyl alcohol by allowing methanol to evaporate until crystals form (methanol is used to dissolve the crude material before isopropyl alcohol is added). On cooling, 2 g of the title compound is obtained 25 melting at 187C dec. Anal.

Calc'd for C12 HlgI2N20; C, 29002; H, 2D86; N, 5.640 Found: C, 29.11; H, 3.64; N, 5.64.

EXAMPLE 9 PrePar tion of =~(t-Butylamino)methyl]-3,5-dichlorobenzyl alcohol hydrochloride To a suitable reaction vessel are added 10 g of 4-amino-~-[(t-butylamino)methyl]3,5-dichlorobenzyl alcohol and 100 ml of 50-52% H3P02.

The mixture is stirred and cooled to 8C while 2077 g of NaN02 in 15 ml of H20 is added slowly over 65 minutes.

Foaming occurs and is controlled 35 with a silicone antifoam agent. After 20 minutes, the mix ture is stirred 2 hours without cooling. The mixture is then poured into ice-H20 mixture and 50~ aq.

NaOH solution is ~3~3~i added until the mi~ture is alkaline. The alkaline mixture is extracted with CH2C12 three times to give 200 ml of solution, which is washed with 25 ml of 2% NaOH and dried over MgSO4 and evaporated to dryness under vacuum to give 9.13 5 g of brown oilO On standing, the oil solidifies, and it is dissolved in 100 ml of ethanol containing 10 ml of H2O. The solution is acidiied to pH 3 with 10% HCl and evaporated to dryness.

This procedure is repeated to afford an off-white solid which is dissolved in methanol. The solution is evap10 orated under vacuum to afford a syrup, which is diluted with50 ml of isopropyl alcohol and allowed to stand. The crys tals which form 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 4 is similarly prepared. Similarly, deamination of 4-amino-3,5-dibromo-~~(t-butylamino)methyl]benzyl alcohol affords 3,5-dibromo-~[(_-butylamino)methyl]benzyl alcohol, m.p. 249-251 dec.

EXAMPLE 10 20 Preparation of 4-Amino-3,5-dichloro-~-methoxyphenethylamine hydrochloride Under N2 atmosphere, llg of ~-amino-a-[(t-butylamino)methyl]-3,5-dichlorobenzyl chloride is added to 75 ml of methanol at 0C. After 20 minutes, the cooling bath 25 is removed and the reaction mixture is stirred at ambient temperature. After the reaction is completed, the mixture is evaporated th dryness under vacuum.

The residue is stirr~d in 75 ml of H2O and the mixture is made alkaline with 6N NaOH solution and e~tracted with CH~C12 (3 x 50 ml).

The organic 30 phases are dried over MgSO4 and evaporated to dryness to afford an orange oil. This oil is dissolved in 150 ml of absolute EtO~ and acidified with HCl/isopropyl alcohol solution to pH ~ The solution is evaporated to dryness and the residue is stirred in 7S ml of ethyl acetate. A~ter cooling, 35 this affords a pale yellow solid which is collec~ed to give .97 g of the title compound, m.p. 195-198C dec.

Similarly, substitution of ethyl alcohol, isopropyl ~23~7316 -23 alcohol, _-butyl alcohol and n-hexyl alcohol affords the corresponding ~-ethoxy, ~-ispropoxy, n-butoxy, and n-hexyloxyphenethylamine hydrochlorides~ E~AMPLE 11 5 Preparation of 4-Am.ino-a-[(t-butylamino)methyl]-3,5-dichloro benzyl chloride Under N2 atmosphere, 27.72 g of 4-amino-a-[(t-butylamino)methyl]-3,5-dichlorobenzyl alcohol is added to 200 ml of thionyl chloride stirred at 0-5C. After addition is com10 pleted, the reaction mixture is stirred at ambient tempera ture for 3 hoursO Subsequently, the mixture is evaporated to dryness under vacuum to afford 37 D 34 g of yellow solid, which is used as is.

EXAMPLE 12 15 Preparation of 4-Amino-3,5-dichloro-~-methoxyphenethylamine hydrochlorideO In a suitable, reaction vessel 100 ml of methanol, 10 g of 4-amino-a-[(t-butylamino)meth. r~ dichlorobenzyl alcohol is stirred in an ice bath of dry HCl gas is intro20 duced into the solutionO After saturation of the solution,the mixture is stirred at room temperature for an hour and evaporated to drynessO The solid is then stirred in ethyl acetate to afford the title product, which is collected by filtration.