CA1039310A - 2-aminomethylphenois - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
2-Aminomethylphenol products and their non-toxic, pharmaceutically acceptable salts useful in the treatment of edema and inflammation are disclosed. The products may be prepared by treating an N-(2-hydroxybenzyl)carboxamide with an aqueous solution of an acid or a base.

Description

` 8 SU~ARY OF THE INVENTION
. 9 This invention relates to 2-aminomethylphenols useful in the treatment of edema and inflammation, processes ll for preparing same, compositions and methods of treating 12 inflammation. Particularly, it relates to 2-aminomethyl-13 4-lower alkyl-6-trihalomethylphenol or its non-toxic, 14 pharmaceutically acceptable salts and its uses as described.
Pharmacological studies employing rats and dogs 16 as the experimental animals indicate that the instant products 17 and compositions containing the active products are effective 18 diuretic and saluretic agents which can be used in the treat-;~ l9 ment of conditions associated with electrolyte and fluid retention. When administered in therapeutic dosages in 21 conventional vehicles, the instant products effectively 22 reduce the amount of sodium and chloride ions in the body, 23 lower dangerous excesses of fluid level to acceptable levels 24 and, in general, alleviate conditions usually associated with edema.

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1 Further, studies employing the mouse ear test and the

2 carrageenin edema test indicate that these compounds are

3 effective antiinflammatory agents useful both topically

4 and systemically.
The compounds of this invention have the 6 following formula:

QH
X `1~' CH2NH2 .'" ' ~
X
I

7 wherein 8 Xl is Cl_7 lower alkyl such as methyl, ethyl, n-propyl, 9 n-butyl, sec-butyl, tert-butyl, l-methylhexyl and the like, cycloalkyl, for example, cycloalkyl 11 containing 5 to 6 carbon atoms such as cyclo-12 pentyl, cyclohexyl and the like;
13 x2 is trihalomethyl such as trifluoromethyl, trichloro-14 methyl and the like.
Also included are their non-toxic, pharmaceutically accept-16 able salts, preferably the non-toxic, pharmaceutically 17 acceptable acid addition salts derived from hydrochloric 18 acid, hydrobromic acid, hydroiodic acid, sulfuric acid, 19 methanesulfonic acid, isethionic acid and the like; salts may also be prepared from the alkali metal bases such as 21 sodium hydroxide potassium hydroxide and the like.

, 1039~10 1 A preferred embodiment of this invention relates 2 to compounds and their use having the following formula:

OH
X ~ CH2NH2 ' . ~
:. X
Ia 4 wherein X3 is lower alkyl particularly tert-butyl; and 6 X is trifluoromethyl and the non-toxic, pharmaceutically : 7 acceptable acid addition salts thereof.
8 Compositions containing this class of compounds exhibit ` 9 particularly good diuretic, saluretic and antiinflammatory activity and represent a preferred sub-group within the 11 scope of this invention.
12 The compositions containing the 2-aminophenols 13 (I) as the active ingredient and also the 2-aminophenols 14 (I) themselves useful as diuretic and saluretic agents, can be administered in a wide variety of therapeutic 16 dosages in conventional vehicles as, for example, by oral 17 administration in the form of a tablet or capsules, by intra-18 venous injection or oral solutions or suspensions. Also, 19 the daily dosage of the products may be varied over a wide range varying from 50 to 2,000 mg. The product is preferably 21 administered in subdivided doses in the form of scored 22 tablets containing 5, 10, 25, 50, 100, 150, 250 and 500 23 milligrams of the active ingredient for the symptomatic 24 adjustment of the dosage to the patient to be treated. An 142~4 I~

-~ 039310 ..
1 effective amount of the drug is ordinarily supplied at a 2 dosage level of from about 1 mg. to about 50 mg./kg. of 3 body weight. Preferably the range is from about 1 mg. to 4 7 mg./kg. of body weight. These dosages are well below the toxic or lethal dose of the products. A suitable unit 6 dosage form of the products of this invention can be 7 administered by mixing 50 milligrams of a 2-aminomethyl-8 phenol (I) or a suitable salt thereof, with 149 mg. of 9 lactose and 1 mg. of magnesium stearate and placing the 200 mg. mixture into a No. 1 gelatin capsule. Similarly, 11 by employing more of the active ingredient and less lactose, 12 other dosage forms can be put up in No. 1 gelatin capsules 13 and, should it be necessary to mix more than 200 mg. of 14 ingredients together, larger capsules may be employed.
Tablets may be prepared by mixing the active ingredient with 16 conventional tableting ingredients such as calcium phosphate, 17 lactose, corn starch or magnesium stearate. The liquid 18 forms in which the active ingredients may be incorporated 19 include suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, 21 tragacanth, acacia, methylcellulose and the like~ Other 22 dispersing agents which may be employed include glycerin 23 and the like. For parenteral administration sterile sus-24 pensions and solutions are desired. Isotonic preparations which generally contain a suitable preservative are employed 26 when intravenous administration is desired.
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142~4 IA
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10393~0 1 The compositions containing the 2-aminophenols 2 as the active ingredient and also the 2-aminophenols them-3 selves, useful as topical antiinflammatory agents are 4 particularly effective in topical treatment of dermatologi-cal disorders and like conditions, such as dermatitis 6 (actinic, atopic, contact, eczematoid, seborrheic and 7 stasis), dermatitis herpetiformis, lichen planus, neuro-8 dermatitis, intitrigo, lichen simplex chronicus, pruritus 9 and psoriasis, as well as for topical treatment of inflam-mations of the respiratory and intestinal mucosa such as 11 allergic rhinitis, bronchitis, bronchial asthma, bronchiec-12 tasis, colitis and the like. These 2-aminophenols are 13 ordinarily administered in the form of a pharmaceutical 14 composition comprising the active compound in combination with a pharmacologically acceptable carrier adapted for 16 topical administration. These topical pharmaceutical 17 compositions may be in the form of a cream, ointment, gel 18 or aerosol formulation adapted for application to the skin 19 for treatment of dermatoses; or it may be in the form of a solution, suspension or aerosol adapted for topical spray 21 application to respiratory passages for treatment of nasal 22 allergies, bronchial inflammations, and the like; or in the 23 form of suppositories or enclosed in enteric capsules for 24 treatment of intestinal inflammations. For treatment of dermatological disorders, these topical pharmaceutical com-26 positions containing the presently invented 2-aminophenols 27 ordinarily include about 0.01~ to 0.25%, preferably about 28 0.10~, of the active compound, in admixture with 99.75~

~ 1 to 99.99% (preferably oo.9o%) of gel vehicle comprising - 2 water, at least one organic solvent, and at least one thick-; 3 ening agent. The water ordinarily constitutes from about 4 8% to 18% of the gel vehicle, preferably about 13%. The organic solvent ordinarily constitutes about 60% to 90%
6 of the gel vehicle. Representative solvents are ethyl , 7 alcohol, isopropyl alcohol, propylene glycol, glycerine, 8 2-octyl dodecanol and methyl pyrrolidine, and preferably 9 isopropyl alcohol; propylene glycol mixtures at a ratio of 0.5 to 0.6 parts isopropyl alcohol to 1.0 part propylene 11 glycol. The solubility of the 2-aminophenol compound in 12 the solvent system selected should be such as to obtain 13 maximum partitioning of the active compound from the vehicle 14 to the skin. The thickening agent, preferably hydroxyethyl cellulose, hydroxypropyl cellulose, and the like, ordinar-16 ily constitutes from 0.5 to 4.0% of the gel vehicle.
17 Optionally, a stabilizing agent, such as disodium edetate, 18 sodium citrate, dipotassium edetate, citric acid, and the ~ 19 like, in the proportion of about 0.02% to 0.1% of the gel ;- 20 vehicle may be employed, if desired.
21 A preferred topical pharmaceutical composition is ; 22 prepared as follows: About 2.60 g. of hydroxypropyl 23 cellulose is added to a solution of 0.05 g. of disodium 24 edetate in 13.00 g. purified water while agitating the mixture and maintaining the temperature at about 60C, 26 and the agitation is continued until the hydroxypropyl : 27 cellulose is completely dispersed and wetted. To the 28 resulting dispersed mixture is added, with agitation, a 29 solution containing 0.1 g. of~ for example, 2-aminomethyl-, , . ..

10393~0 1 4~t-butyl-6-trifluoromethylphenol hydrochloride dispersed 2 in a mixture of 30.00 g. of anhydrous isopropyl alcohol 3 and 54.25 g. of propylene glycol. The resulting gel mix-4 ture is stirred vigorously at room temperature for a period of approximtely 15 minutes thereby forming a pharmaceutical 6 composition adapted for the treatment of topical anti-7 inflammatory conditions.
8 The compositions containing the 2-aminophenols 9 as the active ingredient and also the 2-aminophenols them-selves, useful as systemic antiinflammatory agents may be 11 orally, rectally or parenterally administered to patients 12 in a non-toxic pharmaceutically acceptable carrier.
13 The non-toxic pharmaceutical carrier may be, 14 for example, either a solid or a liquid. Exemplary of solid carriers are lactose, corn starcn, gelatin, talc, 16 sterotix, stearic acid, magnesium stearate, terra alba, 17 sucrose, agar, pectin and acacia. Exemplary of liquid 18 carriers are peanut oil, olive oil, sesame oil and water.
19 Similarly, the carrier or diluent may include a time delay material such as glyceryl monostearate or glyceryl 21 distearate alone or with a wax.
22 Several pharmaceutical forms of the therapeuti-23 cally useful compositions can be used. For example, if 24 a solid carrier is used, the compositions may take the form of tablets, capsules, powders, troches or lozenges, 26 prepared by standard pharmaceutical techniques. If a 27 liquid carrier is used, the preparation may be in the 28 form of a soft gelatin capsule, a syrup, an aqueous solu-29 tion or a liquid suspension. Suppositories may be prepared i~ a conventional manner by mixing the compounds of this ... . . . .

`. 1 invention with a suitable non-irritating excipient which ; 2 is solid at room temperature, but liquid at the rectal ' 3 temperature. Such materials are cocoa butter and poly-` 4 ethylene glycol. Gels and lotions for topical application S may be prepared in a conventional manner. The active com-6 pounds are administered in an amount sufficient to treat 7 inflammation; that is, to reduce inflammation. Advantageous-8 ly, the sompositions will contain the active ingredient in 9 an amount of from about 0.1 mg. to 50 mg. per kg. body weight per day (5 mg. to 3.5 g. per patient per day), preferably 11 from about 1 mg. to 15 mg./kg. body weight per day (50 mg.
12 to 1 g. per patient per day).
13 Various tests have been carried out to show the - 14 ability of the compounds described herein to exhibit -reactions that can be correlated with antiinflammatory 16 activity in humans. One such test used is the carrageenin 17 test which is known to correlate well with antiinflammatory ' 18 activity in humans and is a standard test used to determine 19 antiinflammatory activity. This test shows the ability of ~; 20 compounds to inhibit edema induced by injection of an 21 inflammatory agent into the tissue of the foot of a rat 22 against non-inflammed controls. This test is generally `~ 23 outlined by C. A. Winter, Proc. Soc. Exptl. Biolog. & Med., :
24 1962, III, 544. The correlation has been shown by the activities of compounds known to be clinically active, - 26 including Indocin~ Asprin~ Butazolidin~ Tandearil~ Cortone~

27 Hydrocortone~ Decadron~

28 The following examples are illustrative of how to 29 prepare various compositions containing the active ingre-dien~ts of this invention. However, the examples are merely 31 illustrative and should not be construed as limiting the 32 scope of the i~vention.

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.. . . .

1422~IA

, ~.0393~0 1 EX~MPLE 1 2 Tablets containing 100 mg. of active ingredient per tablet 8 Per Tablet 4 2-Aminomethyl-4-tert-butyl-6-trifluoromethylphenol hydro-chloride 100 mg.
Calcium Phosphate 40 mg.
6 Lactose 38 mg.
7 Corn Starch 20 mg.
8 Magnesium Stearate 2 mg.
9 200 mg.
The 2-aminomethyl-4-tert-butyl-6-trifluoromethyl-11 phenol hydrochloride is mixed with the calcium phosphate and 12 lactose for ten minutes and then passed through a mill to 13 reduce the particle size. The combined ingredients are 14 remixed for five minutes and corn starch is passed through a No. 60 sieve (U.S. Sieve Series) onto the ingredients.
16 The combined ingredients are again remixed for five minutes 17 and then magnesium stearate is added through a No. 60 sieve.
18 After remixing for two minutes the ingredients are compressed 19 into tablets.
Similar dry-filled capsules, tablets, elixirs and 21 suspensions can be prepared by replacing the active ingredient 22 of the above example by any of the other compounds described 23 in the foregoing general disclosure and the specific examples 24 which follow.

26 A mixture of 250 parts of 2~aminomethyl-4-tert-27 butyl-6-trifluoromethylphenol hydrochloride and 25 parts 28 of lactose is granulated with suitable water, and to this 29 is added 100 parts of maize starch. The mass is passed through a 16 mesh screen. The granules are dried at a ., _ g _ ' ,, -- , , . ,~ , . . .. . .
,. . .. .

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1039~10 1 temperature below 60C. The dry granules are passed through 2 a 16 mesh screen, and mixed with 3.8 parts of magnesium 3 stearate. They are then compressed into tablets suitable 4 for oral administration.
25, 100 or 500 parts of 2-aminomethyl-4~tert-6 butyl-6-trifluoromethylphenol hydrochloride may be used 7 in place of 250 parts above to produce tablets suitable 8 for oral administration according to the method of this 9 invention.

11 A mixture of 50 parts of 2-aminomethyl-4-methyl-12 6-trifluoromethylphenol hydrochloride, 3 parts of the 13 calcium salt of lignin sulfonic acid and 237 parts of water 14 is ball-milled until the size of substantially all of the particles is less than 10 microns. The suspension is 16 diluted with a solution containing 3 parts of sodium 17 carboxymethylcellulose and 0.9 parts of the butyl ester 18 of p-hydroxybenzoic acid in 300 parts of water. There is 19 thus obtained an aqueous suspension suitable for oral administration for therapeutic purposes.

.: .
21 2-aminomethyl-4-tert-butyl-6-trichloromethyl-: 22 phenyl hydrochloride may be used in place of the allylamino 23 compound in the above example to obtain a suspension suitable ` 24 for oral administration.

. 25 EXAMPLE 4 .
26 (1) Tablets - 10,000 scored tablets for oral 27 use, each containing 500 mg. of active ingredient are 28 prepared from the following ingredients:

1~224IA
" .

1039310 Gm.
22-aminomethyl-4-tert-butyl-6-trifluoromethylphenol hydrochloride 5000 3Starch, U.S.P. 350 4Talc, U.S.P. 250 5Calcium Stearate 35 6 The 2-aminophenol compound is granulated with a 7 4% w./v. aqueous solution of methylcellulose U.S.P.
8 (1500 cps.). To the dried granules is added a mixture 9 of the remainder of the ingredients and the final mixture compressed into tablets of proper weight.
11 (2) Capsules - 10,000 two-piece hard gelatin 12 capsules for oral use, each containing 250 mg. of active 13 ingredient are prepared from the following ingredients:
14 Gm.
2-aminomethyl-4-tert-butyl-6-trifluoromethylphenol hydrochloride 2500 16 Lactose, U.S.P. 1000 17 Starch, U.S.P. 300 18 Talc, U.S.P. 65 19 Calcium Stearate 25 The 2-aminomethyl compound is mixed with the 21 starch lactose mixture followed by the talc and calcium 22 stearate. The final mixture is then encapsulated in the 23 usual manner. Capsules containing 10, 25, 50 and 100 mg.
24 of active ingredient are also prepared by substituting 100, 250, 500 and 1000 gm. for 2500 gm. in the above formualtion.
26 (3) _oft elastic capsules - One-piece soft 27 elastic capsules for oral use, each containing 500 mg. of 28 active material are prepared in the usual manner by first 29 dispersing the active material in sufficient corn oil to 10~9310 1 render the material capsulatable.
2 (4) Aqueous suspension - An aqueous suspension 3 for oral use containing in each 5 ml., 1 gm. of active 4 ingredient is prepared from the following ingredients:
Gm.
6 2-aminomethyl-4-tert-butyl-6-trifluoromethylphenol hydrochloride 2000 7 Methylparaben, U.S.P. 7.5 8 Propylparaben, U.S.P. 2.5 9 Saccharin sodium 12.5 Glycerin 3000 11 Tragacanth powder 10 12 Orange oil flavor 10 13 F.D. & C. orange dye 7.5 14 Deionized water, q.s. to 10,000 ml.

16 Gel Formulation 17 0.1 mg. disodium edetate 18 1.30 mg. of purified H2O
19 300 mg. isopropanol 26 mg. hydroxypropylcellulose ... .
21 q.s.a.d. 1 gm. propylene glycol 22 1.09 mg. 2-aminomethyl-4-tert-butyl-6-trifluoro-methylphenol hydrochloride 24 Ointment Formulation 50 mg. wool alcohols B.P.
26 150 mg. amichol C
27 350 mg. wax white Be square 170/175C.
q.s.a.d. 1 gm. isopropyl myristate ,, ;

~, , , ~ . .. ,, ., _ _, ,, ,, ... ., . ,, . _ _ . _ , .... .,,, _ _ 14224I~
, 1 1.09 mg. 2-aminomethyl-4-tert-butyl-6-trifluoro-methylphenol hydrochloride 2 .4~ citrate acid anhydrous ;- 3 0.58~ sodium phosphate dibasic anhydrous 4 The 2-aminomethylphenols (I) described above may be prepared by one of two methods which comprises 6 ~1) treating an N-(2-hydroxybenzyl)carboxamide (II) with 7 an aqueous solution in the presence of an acid or base 8 or (2) subjecting a substituted 2-hydroxybenzaldehyde 9 (III) to reduction.
The first of the above-mentioned processes 11 comprises treating an N-(2-hydroxybenzyl)carboxamide 12 (II, infra) with an aqueous solution in the presence of an 13 acid, preferably a mineral acid such as hydrochloric acid, 14 hydrobromic acid, sulfuric acid, hydroiodic acid and the like;
in addition to the mineral acids, bases may also be employed, 16 for example, the alkali metal bases such as sodium hydroxide, 17 potassium hydroxide and the like. Any solvent which is 18 inert or substantially inert to the reactants may be lg employed such as ethanol, acetic acid and the like. The reaction may be conducted at a temperature in the range of 21 from about 20C to about 110C for a period of time of 22 from about 15 minutes to about five hours; however, the - 23 reaction is generally conducted at the reflux temperature 24 of the particular solvent employed for a period of time of about one and one-half hours. The following equation 26 illustrates this reaction employing a mineral acid, HR , 27 such as hydrochloric acid, hydrobromic acid, hydroiodic 28 acid, sulfuric acid and the like.

.

.
., . . ~ .

.
1039~10 :: OH OH
X ¦ CH2NHR \~cH NH~Rl) : ~J HR /H20 .', Xl xl ; .
. IC

OH
X~CH2NH2 .,, ~ 11 ~ Xl "
: I
1 wherein Xl and x2 are as defined for Formula I above; R is 2 an acyl radical, for example, (Cl 5 alkanoyl), formyl, halo-3 acetyl such as chloroacetyl and the like, carbamoyl, mono-, 4 nuclear aroyl such as benzoyl and the like, hydroxy substi-tuted mononuclear aroyl such as _-hydroxybenzoyl and the -~ 6 like or trihalomethylcarbonyl such as trichloromethylcar-7 bonyl and the like and Rl is the anion derived from an acid, . 8 or example, a mineral acid such as hydrochloric acid, 9 hydrobromic acid, hydroiodic acid, sulfuric acid and the like. The product is usually obtained in the form of an 11 acid addition salt and the free amine can be generated by '. 12 known neutralization methods.
It~
13 The second method for preparing the 2-aminomethyl-14 phenols (I) comprises subjecting a substituted 2-hydroxy-benzaldoxime (III, infra) to reduction, for example, by 16 hydrogenation such as catalytic hydrogenation employing a . 17 noble metal such as rhodium, ruthenium and the like, prefer--- lD, _ lV39~10 1 ably on a carrier such as carbon and the like. The reduction 2 is generally conducted employing as the solvent a lower 3 alkanol such as ethanol, methanol and the like in the 4 presence of mineral acid such as sulfuric acid and the like. The following equation illustrates this process:
OH OH
X~_/ ~ ~ CH=NOH X ~ ~ ~I~2NE~3R
~ J Reduction ~ ~ ~

, Xl xl Ic III ~
; OH
~3~ 2 2 ,, Xl 6 wherein Xl and x2 and Rl are as defined above. The 7 product is usually obtained in the form of an acid addition . . , 8 salt and the free amine can be generated by known neutra--- 9 lization methods.
The N-(2-hydroxybenzyl)carboxamides (II, supra) 11 employed as starting materials in the preparation of the 2-12 aminomethylphenols (I) are prepared by treating an appro-13 priately substituted phenol (IV, infra) with an N-hydroxy-14 methylcarboxamide, for example, N-hydroxymethylurea, 2-halo-N-hydroxymethylacetamide such as 2-chloro-N-hydroxy-16 methylacetamide and the like, N-hydroxymethyl mononuclear 17 arylcarboxamide such as N-hydroxymethylbenzamide and the 18 like, N-hydroxymethyl hydroxy substituted arylcarboxamide , ,"., _- . ,., .. , _ ~ 14224IA

; . , 1 such as N-hydroxymethylsalicylamide and the like or N-2 hydroxymethyltrihaloacetamide such as N-hydroxymethyl-3 trichloroacetamide and the like in the presence of a 4 strong mineral acid such as hydrochloric acid, sulfuric acid and the like. The reaction may be conducted 6 employing as the solvent an excess of the mineral acid 7 employed or with a solvent which is inert or substantially 8 inert to the reactants employed, for example, a lower 9 alkanol such as ethanol and the like or a lower alkanoic acid such as acetic acid and the like. The N-(2-hydroxy-11 benzyl)carboxamides (II) may be isolated and purified;
12 however, it has been found that by employing the crude 13 N-(2-hydroxybenzyl)carboxamides satisfactory results are 14 obtained. The following equation illustrates this process:
OH OH
X~ ~ CH2NHR
j~ + HOCH2NHR >

,. Xl xl . . .
IV II
wherein Xl, X2 and R are as defined above.
16 The 2-hydroxybenzaldoximes (III, supra) employed 17 may be prepared by treating an appropriate phenol with 18 chlorofornl in the presence of a base or a mixture of bases 19 such as sodium carbonate and calcium hydroxide which yields the correspondingly substituted 2-hydroxybenzaldehyde then 21 the 2-hydroxybenzaldehyde (V, infra) is treated with a 22 hydroxylamine hydrohalide such as hydroxylamine hydro-23 chloride and the like in the presence of a base such as 2~ sodium acetate and the like. This reaction is generally ~J39310 l conducted in a lower alkanol solvent such as ethanol and 2 the like. The reaction is conveniently conducted at the 3 boiling point of the particular solvent employed. The 4 following equation illustrates this process:
' OH OH
'' x2 ~ CHCl3 ~ )/

Ca (C)32 ~->
X X

IV V

, ~HONH2 ' OH
'- X \ ~ CH=NOH
.. ~

., Xl ', III
', S wherein Xl and x2 are as defined above.
6 The following examples illustrates the preparation 7 of the 2-aminomethylphenols (I). However, the examples are 8 illustrative only and it will be apparent to those having 9 ordinary skills in the art that all of the products embraced by Formula I, supra, may also be prepared in an analogous 11 manner by substituting the ,,appropriate starting materials for , 12 those set forth in the examples.

,~ - 17 . ~s~ , .. ,., s,. ~

10393~0 Preparation of 2-aminomethyl-4-tert-butyl-6-trifluoro-methylphenol hydrochloride A. Preparation of 2-trifluoromethyl-4-tert-butylphenol . A mixture of 2-trifluoromethylphenol (25 g., 0.15 molès), tert-butyl alcohol (12 g., 0.16 mole), trifluoroacetic acid (100 ml.) and 96~ sulfuric acid - (2 ml.) is stirred at about 20C for 48 hours. The mixture then is evaporated as far as possible under reduced pressure at 35-40C. The residue is dissolved in benzene (500 ml.) and the solution is washed with water, saturated NaHCO3 solution and saturated salt brine and dried over anhydrous Mg SO4. The dried solution is again evaporated under reduced pressure and the temperature is finally raised to 140-150C under 65 mm.
pressure to remove unchanged 2-trifluoromethylphenol.
The residue is distilled at 65 mm. after collecting a small fore-run (75~ unchanged starting phenol and 25% product), 2-trifluoromethyl-4-tert-butylphenol (13.6 g) is collected - at 120-132C as a pale pink oil that is 98~ pure by gas liquid chromatography analysis and can be used directly in the next step.
Following the above procedure but using an equiva-lent amount of isopropyl alcohol, sec-butyl alcohol or cyclohexyl alcohol in place of tert-butyl alcohol, there is produced an equivalent amount of 2-trifluoromethyl-4-,~ isopropylphenol, 2-trifluoromethyl-4-sec-butylphenol or 2-trifluoromethyl-4-cyclohexylphenol.

B. Preparation of 2-aminomethyl-4-tert-butyl-6-trifluoro-methylphenol hYdrochloride 2-Trifluoromethyl-4-tert-butylphenol (15.6 g., " - 18 -.. . . . .. . . . . .. .. . .

` 1()39;~10 0.062 mole) is dissolved in a mixture of glacial acetic acid (200 ml.) and 96% sul~uric acid (150 ml.). The mixture is stirred and finely powdered N-hydroxymethyl-2-chloroacetamide (8 9., 0.065 mole) is added in small portions at 20-25C.
Stirring then is continued for 5 hours after which the mixture -is poured into water (3 1.). The 2-(2-chloroacetamidomethyi)-4-tert-butyl-6-trifluoromethylphenol that separates is col-lected and dried by suction to obtain a solid (19 9., m.p.
about 85-100C).
The solid, the 2-chloroacetyl derivative of 2-amino-methyl-4-tert-butyl-6-trifluoromethylphenol hydrochloride, is dissolved in a mixture of ethanol (75 ml.) and 12 N hydro-chloric acid (25 ml.). The mixture is refluxed for 5 hours, cooled to 20C and diluted with 12 N hydrochloric acid (150 ml.). Upon cooling to -20C, the product separates (14 9.).
It is crystallized from ethanol-12 N hydrochloric acid (1:4) to obtain pure 2-aminomethyl-4-tert-butyl-6-trifluoromethylphenol hydrochloride, m.p. 202-204C.
Anal. Calc.: C,50.80 H,6.04 N,4.94 Found: C,50.75 H,6.01 N,4.72 Following the above procedure but using an equiva-lent amount of 2-trifluoromethyl-4-isopropylphenol, 2-tri- -fluoromethyl-4-sec-butylphenol or 2-trifluoromethyl-4-cyclo-hexylphenol in place of 2-trifluoromethyl-4-tert-butylphenol, there is obtained an equivalent amount of 2-aminomethyl-4-isopropyl-6-trifluoromethylphenol hydrochloride, 2-aminomethyl-4-sec-butyl-6-trifluoromethylphenol hydrochloride or 2-amino-methyl-4-cyclohexyl-6-trifluoromethylphenol hydrochloride.

"s ' ~"'' - 19_ ,, .
.... . . . . . . . . . . . ...

:

2 2-Aminomethyl-4-tert-butyl-6-trifluoromethylphenol hydro-- chloride - 3 A. 3-Trifluoromethyl-5-tert-butyl salicylaldehyde 4 0.1 mole of 2-trifluoromethyl-4-tert-butylphenol and 0.1 mole of hexamethylenetretramine is dissolved in 6 trifluoroacetic acid (150 ml.) and the mixture refluxed 7 for 8 hours. After this time, 150 ml. of water and 8 50 ml. of concentrated hydrochloric acid is added. This 9 mixture is then refluxed for l/2 hour. The reaction mixture is cooled and extracted with ether (5 x 50 ml.) ll and the ether extract is dried over magnesium sulfate. The 12 ether is evaporated and the residue is crystallized from 13 ethanol to yield 3-trifluoromethyl-5-t-butyl salicylaldehyde.
- 14 B. 3-Trifluoromethyl-5-tert-butYl salicylaldehYde oxime 0.05 moles of the aldehyde from Step A, 0.12 16 moles of hydroxylamine hydrochloride and sodium acetate 17 (0.12 moles) are dissolved in a mixture of ethanol 18 (100 ml.) and water (30 ml.). The reaction mixture is 19 refluxed for 2 hours, cooled and water added until no more precipitate forms. The solid that separates is , 21 crystallized from ethanol to yield 3-trifluoromethyl-5-22 tert-butyl salicylaldehyde oxime.
23 C. 2-Aminomethyl-4-tert-butyl-6-trifluoromethylphenol hydrochloride .
24 The oxime of Step B (0.02 moles) is dissolved in ethanol (200 ml.) to which concentrated H2SO4 (0.05 moles) 26 is added. To this solution is added 5% Ruthenium on carbon 27 (100 mg.). The mixture is hydrogenated at 40 lbs./sq. in.

28 until the calculated amount of hydrogen is taken up. The 29 catalyst is removed by filtration and the filtrate is .. , .... .. ... , .. _ .. .

,, , , '; 1039~
1 evaporated to dryness, giving the sulfate salt of the title 2 compound. The sulfate is suspended in water and neutralized 3 with 2~ ammonium hydroxide. The free base is taken up 4 in ethanol and an equivalent amount of 6N ethanolic HCl is added. On addition of ether the title product is pre-6 cipitated. The precipitate is collected and crystallized 7 from a mixture of ethanol and concentrated HCl.

.

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Claims (5)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound of the formula Wherein X1 is C1-7 lower alkyl and X2 is trihalomethyl which comprises treating a compound of the formula wherein X1 and X2 are as defined above and R is acyl with an aqueous solution in the presence of mineral acid or analkalimetal.

2. A process for preparing a compound of the formula:

wherein X1 is C1-7 lower alkyl and X2 is trihalomethyl which comprises treating a compound of the formula:

wherein X1 and X2 are as defined above and R is haloacetyl, with an aqueous solution in the presence of a mineral acid.

3. The process of Claim 1, wherein 2-(2-chloro-acetamidomethyl)-4-tert-butyl-6-trifluoromethylphenol is treated with a mineral acid to form the 2-aminomethyl-4-tert-butyl-6-trifluoromethylphenol.

4. A compound of the formula wherein X1 is C1-7 lower alkyl X2 is trihalomethyl and the non-toxic pharmaceutically acceptable salts thereof, when prepared by the process of claims 1 or 2 or by an obvious chemical equivalent.

5. The 2-aminomethyl-4-tert-butyl-6-trifluoro-methylphenol, when prepared by the process of claim 3 or by an obvious chemical equivalent.