United States Patent Office Patented Nov
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3,541,151 United States Patent Office Patented Nov. 17, 1970 1. 2 vated temperatures which may be suitably in the range of 3,541,151 from 60° C. to 220 C, preferably 100° C. to 180° C. PREPARATION OF TERTARY...BUTYLAMNO The reaction is conveniently carried out in the absence of a BENZOPHENONES solvent although inert organic solvents of well known con Robert W. Coombs, Summit, and Goetz E. Hardtmann, Florham Park, N.J., assignors to Sandoz-Wander Inc., ventional types may be employed in practicing the inven Hanover, N.J. tion. The thermal rearrangement yielding the compounds No Drawing. Filed Dec. 26, 1968, Ser. No. 787,256 of Formula I is completed in a relatively short time, typi nt. C. COTd 5 1/34 cally, between about 30 minutes to 6 hours. The reaction U.S. C. 260-570 4 Claims product of Formula I may be recovered in desired form 10 for Subsequent use by conventional procedures. The benzisoxazolines of Formula II are novel com ABSTRACT OF THE DISCLOSURE pounds which are prepared by a two-step procedure iri The invention discloses preparation of 2-tert-butyl volving in a first Step 1 the reaction of a benzisoxazole of amino-benzophenones by thermal rearrangement of a cor Formula III: responding 1-tert-butyl-4-aryl - 2,1 - benzisoxazoline. The 5 N latter compounds are prepared by reduction of a corre 2 sponding 1-tert-butyl-4-aryl - 2,1 - benzisoxazolium salt (R)n which may be prepared by reaction of a corresponding 4 )o aryl-2,1-benzisoxazole with tert.-butanol. The 2-tert-bu tylamino-benzophenones are useful as intermediates in pre. 20 Y paring pharmaceutically useful 1-substituted-4-aryl-2(1H)- quinazolinones. (Y) in III The invention relates to preparation of 2-tert-butyl 25 wherein R, n, Y and n are as defined, with tert-butanol in amino-benzophenones useful as intermediates, and to the presence of a strong inorganic acid to obtain a 1-tert chemical intermediates useful in the preparation of said butyl-4-aryl-2,1-benzisoxazolium quaternary Salt of For 2-tert-butylamino-benzophenones. mula IV: In accordance with the invention it has been found that 2-tert-butylamino-benzophenones of the Formula I: 30 CH-C-CH3(H, CH3 N© CH-C-CH, 2 (R) O 35 Y/ xe 40 wherein R, n, Y and m are as defined, and Xe is the anion wherein of the acid forming said quaternary salt, said benzisoxazo R is halo of atomic weight of from 19 to 80; lower lium salt of Formula IV then being subjected in Step 2 to alkyl, preferably of 1 to 3 carbon atoms, e.g. meth reduction in an inert organic solvent to obtain the 1-tert yl; or lower alkoxy, preferably of 1 to 2 carbon butylamino-4-aryl-2,1-benzisoxazoline of Formula II. atoms; The preparation of compounds IV by the reaction of n is 0 to 2, and when 2 then R is the same or different; Step 1 may be carried out at temperatures in the range of Y is halo of atomic weight of from 19 to 80; lower from 0° C. to 60° C., preferably 10° C. to 35 C., and alkyl, preferably of 1 to 3 carbon atoms; and lower 50 conveniently at about room temperature. A strong inor alkoxy, preferably of 1 to 2 carbon atoms; and ganic acid adapted to form a crystalline quaternary salt is m is 0 to 2, and when 2 then Y is the same or differ required. Acids of this type are known and include by ent; way of illustration perchloric acid and tetrafluoroboric are prepared by subjecting to thermal rearrangement a 1 acid. The reaction is carried out in the presence of organic tert-butylamino-4-aryl-2,1-benzisoxazoline of Formula II: 55 solvent which is inert and adapted to well dissolving the reactants and product compound of Formula IV. Suitable CE solvents are known and available, and include by way of illustration, the nitrated hydrocarbons such as nitrometh CH-)-CH, ane. The resulting reaction product of Formula IV may be 60 isolated from the reaction of Step 1 by working up by con 2\ ventional procedures. (R) - The preparation of compounds II by Step 2 involving the reduction of a compound IV is desirably effected with H^3. 65 a suitable borohydride as reducing agent, desirably an al kali metal borohydride such as sodium borohydride, fol (Y)m lowed by working up in a manner conventional for boro hydride reductions. The reduction may be carried out at II temperatures in the range of 0° C. to 80 C., preferably wherein R, n, Y and m are as above-defined. 70 between 15° C. to 30° C. The reaction is carried out in The preparation of compounds I by the process of the an organic solvent of known type, preferably a lower al invention is a thermal rearrangement carried out at ele kanol such as methanol or ethanol, preferably ethanol. 3,541,151 3. 4. The reaction products of Formula II may be isolated from such forms as tablets, capsules, elixirs, suspensions and the reaction mixture of Step 2 by working up by established the like or parenterally in the form of an injectable solu procedures. tion or suspension. The dosage administered will, of The benzisoxazoles of Formula III employed as start course, vary depending upon the compounds used and ing material in Step 1 are either known or can be prepared the mode of administration. However, in general, satis from known materials by established procedures. 5 factory results are obtained when administered at a daily The 2-tert. - butylaminobenzophenones of Formula I dosage of from about .3 milligram to about 100 milli are useful as intermediates for the preparation of a grams per kilogram of body weight, preferably given in pharmaceutically active 1-tert.-butyl - 4 - aryl-2(1H)- divided doses 2 to 4 times a day, or in sustained release quinazolinones. For this purpose it is desirable to first form. For most mammals the administration of from convert the 2-tert-butylaminobenzophenones of Formula IO about 20 milligrams to about 1000 milligrams of the I to the corresponding 2-tert-butylaminobenzophenoni compound per day provides satisfactory results and dos mine of Formula IA: age froms suitable for internal administration comprise from about 5 milligrams to about 500 milligrams of the Cl3 compound in admixture with a solid or liquid pharmaceu CII--Cit. tical carrier or diluent. N The following examples show representative com / pounds encompassed within the scope of this invention (R) and the manner in which such compounds are prepared. 20 However, it is to be understood that the examples are for purposes of illustartion only and are not intended as in any way limiting the scope of the invention. (Y) in EXAMPLE 1. IA 2-tert-butylamino-5-chloro-4-methyl-benzophenone wherein R, In, Y and n are as above-defined. CH3 The conversion of a compound I to a compound IA CH -CH3 is suitably carried out in a Step 3 by subjecting the com N I pound I to reaction with ammonia in a sealed reactor C3 under anhydrous conditions and at elevated tempera tures in the range of 100° C. to 200° C., preferably 110 Cl C. to 150° C. The reaction is preferably carried out in the presence of a catalyst such as a Lewis acid, e.g. zinc chloride. Excess ammonia is conveniently employed as solvent, or a suitable cosolvent may be employed, e.g. dioxane. The reaction product of Formula I may be iso lated for use by Working up in a conventional manner. The 2-tert.-butylaminophenonimine of Formula IA are Step A-Preparation of 1-tert.-butyl-5-chloro-6- well suited for the preparation of pharmaceutically active 40 methyl-4-phenyl-2,1-benzisoxazolium perchlorate 1-tert-butyl - 4 - aryl-2(1H)-quinazolinones of Formula V: To a solution of 9 g. of 5-chloro-6-methyl-4-phenyl-2, 1-benzisoxazole in 500 ml, of nitromethane is added 4 CII ml. of tert-butanol and 7.5 ml. of a 60% aqueous solu tion of perchloric acid. The resulting red/brown solu tion is allowed to stand at room temperature for 60 hours. It is then diluted with 2 liters of anhydrous di (R) ethyl ether. The yellow precipitate obtained is isolated by filtration and redissolved in 100 ml. of acetone. This solution is again diluted with 500 ml. of diethyl ether 50 and the crystalline precipitate formed is isolated by fil tration to yield 1-tert.-butyl - 5 - chloro - 6 - mehyl - 4 (Y) in phenyl - 2, 1 - benzisoxazolium perchlorate, M.P. 183 W 185°. whereiri R, In, Y and in are as defined, by cyclizing said 55 Step B.-Preparation of 1-tert-butyl-5-chloro-6-methyl compound IA in a Step 4 with phosgene in an inert or 4-phenyl-2, 1-benzisoxazoline ganic solvent, To a suspension of 24 g. of 1-tert-butyl-5-chloro-6- The production of compound V by Step 4 involving methyl-4-phenyl-2,1-benzisoxazolium perchlorate in 200 reaction of a compound IA with phosgene may be car ml. of absolute ethanol is added in portions over 15 min ried out at temperatures in the range of 0° C. to 50° C., 60 utes 3.5 g. of sodium borohydride. The suspended solid preferably 10° C. to 30° C. The preferred inert organic slowly goes into solution and some heat is evolved.