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Esters of 3-(hydroxy or hydroxymethyl)-4-hydroxyphenyl aminomethyl ketones |
| RE30241 |
Esters of 3-(hydroxy or hydroxymethyl)-4-hydroxyphenyl aminomethyl ketones
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| Patent Drawings: | |
| Inventor: |
Minatoya, et al. |
| Date Issued: |
March 25, 1980 |
| Application: |
05/808,280 |
| Filed: |
June 20, 1977 |
| Inventors: |
Conway; Walter D. (Amherst, NY)
Minatoya; Hiroaki (East Greenbush, NY)
Tullar; Benjamin F. (Laurel Park, NC)
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| Assignee: |
Sterling Drug Inc. (New York, NY) |
| Primary Examiner: |
Killos; Paul J. |
| Assistant Examiner: |
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| Attorney Or Agent: |
Dupont; Paul E.Wyatt; B. Woodrow |
| U.S. Class: |
560/106; 560/107; 560/108; 560/73 |
| Field Of Search: |
560/106; 560/107; 560/108; 560/73 |
| International Class: |
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| U.S Patent Documents: |
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| Foreign Patent Documents: |
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| Other References: |
Bretschneider, H. Monatshefte fur Chemie 78 71-81 (1948)..
H. Bretschneider, Monatshefte fur Chemie 76 368-380 (1947).. |
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| Abstract: |
Mono-, di- and tri-esters of 3-(hydroxy or hydroxymethyl)-4-hydroxy-alpha-(aminomethyl)benzyl alcohols, obtained by methods involving reduction of the corresponding mono- and di-ester ketones, are useful for producing sympathomimetic effects, such as bronchodilation, of long duration with low cardiovascular stimulating effect, in warm-blooded mammals. |
| Claim: |
We claim:
1. A compound of the group consisting of: 3-(Y.sup.1 -O-)-4-(Y-O-)phenyl (R-NH-)(R')methyl ketones having the formula ##STR6## and 3-(Y-O-CH.sub.2 -)-4-(Y.sup.1 -O-)phenyl (R-NH-)(R')methyl ketones having the formula ##STR7## .Iadd.wherein R, in Formula III, is tert-butyl or cycloalkyl having 3-6 carbon atoms; and in Formula IV is hydrogen, alkyl having 1-4 carbon atoms, or cycloalkyl having 3-6 carbon atoms; and .Iaddend.
wherein, in each formula:
.[.R is hydrogen, alkyl having 1-4 carbon atoms, or cycloalkyl having 3-6 carbon atoms;.].
R' is hydrogen or alkyl having 1-3 carbon atoms;
Y' is hydrogen or an acyl member which is alkanoyl having 1-22 carbon atoms, cycloalkyl-C.sub.n H.sub.2n --CO-- having a total of 4-10 carbon atoms of which 3-7 are ring carbon atoms in cycloalkyl and wherein n is zero, one, or two, 1- or2-adamantanecarbonyl, phenoxyacetyl, naphthalenecarbonyl, or Z--C.sub.n H.sub.2n --CO-- wherein n is zero, one or two and Z is phenyl or phenyl substituted by 1-3 members of the group consisting of alkyl having 1-4 carbon atoms, alkoxy having 1-4 carbonatoms, halo, or trifluoromethyl;
Y is one of the acyl members defined by Y.sup.1, at least one of Y and Y.sup.1 being Z--C.sub.n H.sub.2n --CO--; and
.[.wherein in Formula III at least one of Y and Y.sup.1 contains no less than four carbon atoms when R is tert-butyl or cycloalkyl and no less than seven carbon atoms when R is hydrogen or alkyl other than tert-butyl; and in Formula IV at leastone of Y and Y.sup.1 contains no less than four carbon atoms; and.]. acid-addition salts thereof.
2. A 3-(Y.sup.1 -O-)-4-(Y-O)phenyl(R-NH-)(R')methyl ketone according to claim 1.
3. A compound according to claim 2 wherein R' is hydrogen. .[.4. A compound
according to claim 3 wherein R is alkyl..]. 5. A compound according to
claim .[.4.]. .Iadd.3 .Iaddend.wherein R is tert-butyl. 6. A 3-(Y-O-CH.sub.2 -)-4-(Y.sup.1 -O-)phenyl (R-NH-) (R')methyl ketone
according to claim 1. 7. A compound according to claim 6 wherein R' is
hydrogen. 8. A compound according to claim 7 wherein R is alkyl. 9. A
compound according to claim 8 wherein R is tert-butyl. 10. A compound
according to claim 9 wherein one of Y and Y.sup.1 is alkanoyl. 11. A
compound according to claim 9 wherein Y.sup.1 is hydrogen. 12. A compound according to claim 5 wherein each of Y and Y.sup.1 is Z-C.sub.n H.sub.2n
--CO--. 13. A compound according to claim 12 wherein n is zero. 14. A compound according to claim 13 wherein each of Y and Y.sup.1 is
alkylbenzoyl. 15. A compound according to claim 14 wherein each of Y and
Y.sup.1 is toluyl. 16. A compound according to claim 13 wherein each of Y
and Y.sup.1 is anisoyl. 17. A compound according to claim 5 wherein one of
Y and Y.sup.1 is alkanoyl and the other is Z--C.sub.n H --CO--. 18. A
compound according to claim 17 wherein n is zero. 19. A compound according
to claim 18 wherein one of Y and Y.sup.1 is alkylbenzoyl. 20. A compound
according to claim 19 wherein one of Y and Y.sup.1 is toluyl. 21. A compound according to claim 18 wherein one of Y and Y.sup.1 is anisoyl.
A compound according to claim 5 wherein Y.sup.1 is hydrogen. 23. A
compound according to claim 22 wherein n is zero. 24. A compound according
to claim 23 wherein Y is toluyl. 25. A compound according to claim 23
wherein Y is anisoyl. 26. A compound according to claim 9 wherein each of
Y and Y.sup.1 is Z--C.sub.n H.sub.2n --CO--. 27. A compound according to claim 26 wherein n is zero. |
| Description: |
This invention relates to compositions of matter classified in the art ofchemistry as esters of 3-(hydroxy or hydroxymethyl)-4-hydroxy-alpha-(aminomethyl)benzyl alcohols, to a process and intermediates for the preparation of the same, and to a method for producing sympathomimetic effects, for instance, bronchodilation, oflong duration in warm-blooded animals by administering said esters.
The invention sought to be patented resides in one of its composition aspects in the chemical compounds designated as (A) esters of 3,4-dihydroxy-alpha-(amino- and N-substituted amino-methyl)benzyl alcohols which have in the free base formFormula I hereinbelow, and (B) esters of 3-hydroxymethyl-4-hydroxy-alpha-(amino- and N-substituted amino-methyl)benzyl alcohols which have in the free base form Formula II hereinbelow: ##STR1## wherein, in each of Formulas I and II:
R is hydrogen, alkyl having 1-4 carbon atoms or cycloalkyl having 3-6 carbon atoms;
R' is hydrogen or alkyl having 1-3 carbon atoms;
Y is an acyl member which is alkanoyl having 1-22 carbon atoms, alkenoyl having one or two double bonds and having 4-22 carbon atoms, cyclalkyl-C.sub.n H.sub.2n --CO-- having a total of 4-10 carbon atoms of which 3-7 are ring carbon atoms incycloalkyl and wherein n is zero, one or two, 1- or 2-adamantanecarbonyl, phenoxyacetyl, naphthalenecarbonyl, pyridinecarbonyl, or Z--C.sub.n H.sub.2n --CO-- wherein n is zero, one or two and Z is phenyl or phenyl substituted by 1-3 members of the groupconsisting of alkyl having 1-4 carbon atoms, alkoxy having 1-4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2-8 carbon atoms, and alkanoylamino having 1-6 carbon atoms; and
Y.sup.1 and Y.sup.2 are the same or different and are hydrogen or one of the acyl members defined by Y, and
wherein in Formula I at least of Y and Y.sup.1 contains no less than four carbon atoms when R is tert-butyl or cycloalkyl and no less than seven carbon atoms when R is hydrogen or alkyl other than tert-butyl; and in Formula II at least one of Yand Y.sup.1 contains no less than four carbon atoms.
These compounds are useful as long-acting sympathomimetic agents when administered orally, intratracheally, intraduodenally, or intravenously to warm-blooded mammals.
The invention resides in another of its composition aspects in the chemical compounds designated as 3-(Y.sup.1 -O-)-4-(Y-O-)phenyl (R-NH-)(R')methyl ketones having in the free base phenol form the formula ##STR2## and 3-(Y-O-CH.sub.2-)-4-(Y.sup.1 -O-)phenyl (R-NH-) (R')methyl ketones having in the free base phenol form the formula ##STR3## .Iadd. wherein, in Formula III, R is tert-butyl or cycloalkyl having 3-6 carbon atoms; and in Formula IV is hydrogen, alkyl having 1-4 carbonatoms, or cycloalkyl having 3-6 carbon atoms; and .Iaddend.wherein, in each of Formulas III and IV, .[.R,.]. R', Y, and Y.sup.1 have the same significance indicated hereinabove. These ester ketones are useful as intermediates in the preparation of thealcohols of Formulas I and II respectively hereinabove.
The invention sought to be patented resides in one of its process aspects in the chemical process which comprises reducing an ester ketone having in the free base from Formula III or Formula IV hereinabove to produce an ester alcohol having infree base form Formula I or Formula II respectively hereinabove wherein Y.sup.2 is hydrogen.
The invention sought to be patented resides in another of its process aspects in the chemical process which comprises mono- or di-esterifying a 3,4-dihydroxyphenyl (R-NH-) (R')methyl ketone having in the free base form the formula ##STR4## or a3-hydroxymethyl-4-hydroxyphenyl(R-NH-) (R') methyl ketone having in the free base phenol form the formula ##STR5## wherein in each of Formulas V and VI, R and R' have the same significance indicated hereinabove, .Iadd.in Formulas III and IV .Iaddend.toproduce an ester ketone having in the free base form Formula III or Formula IV respectively hereinabove.
The invention sought to be patented, in its method aspect, resides in the method of producing sympathomimetic effects in a warm-blooded mammal which comprises administering to said mammal an effective amount of a compound having in the free baseform Formula I or Formula II hereinabove.
When R in the formulas herein is alkyl having 1-4 carbon atoms, there are included methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and sec-butyl.
When R in the formulas herein is cycloalkyl having 3-6 carbon atoms, there are included cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
When R' in the formulas herein is alkyl having 1-3 carbon atoms, there are included methyl, ethyl, n-propyl, and isopropyl.
When Y, Y.sup.1 or Y.sup.2 in the formulas herein is alkanoyl containing 1-22 carbon atoms, there are included both unbranched and branched alkanoyl, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl,2-methylbutanoyl, pivalyl, 3-methylpentanoyl, 3,3-dimethylbutanoyl, 2,2-dimethylpentanoyl, docosanoyl, and 7,7-dimethyloctanoyl. The branched alkanoyl groups are preferred over the unbranched alkanoyl groups.
When Y, Y.sup.1, or Y.sup.2 in the formulas herein is alkenoyl having one or two double bonds and having 4-22 carbon atoms, there are included, for example, crotonyl, 9-octadecenoyl, 2,5-hexadienoyl, 3,6-octadienoyl, 10,13-octadecadienoyl, and5,13-docosadienoyl.
When Y, Y.sup.1, or Y.sup.2 in the formulas herein is cycloalkyl-C.sub.n H.sub.2n --CO--, there are included for example the cycloalkanecarbonyl and cycloalkanealkanoyl groups: cyclopropanecarbonyl, 1-methylcyclopropanecarbonyl,cyclopropaneacetyl, alpha-methylcyclopropaneacetyl, 1-methylcyclopropaneacetyl, 2-amylcyclopropaneacetyl, cyclopropanepropionyl, alpha-methylcyclopropanepropionyl, 2-isobutylcyclopropanepropionyl, 2-hexylcyclopropanecarbonyl, cyclobutanepropionyl,2-methylcyclobutanecarbonyl, 1,3-dimethylcyclobutanecarbonyl, 3,3-dimethylcyclobutanecarbonyl, cyclobutaneacetyl, 2,2-dimethyl-3-ethylcyclobutaneacetyl, cyclobutanepropionyl, cyclopentanecarbonyl, 1-methyl-3-isopropylcyclopentanecarbonyl,cyclopentanepropionyl, cyclohexanecarbonyl, cyclohexaneacetyl, 4-methylcyclohexaneacetyl, cycloheptanecarbonyl, 4-methylcycloheptaneacetyl, and cycloheptanepropionyl.
When Y, Y.sup.1, or Y.sup.2 in the formulas herein is (phenyl or substituted phenyl)-C.sub.n H.sub.2n --CO--, there are included for example benzoyl, phenylacetyl, alphaphenylpropionyl, beta-phenylpropionyl, p-tolyl, m-toluyl, o-toluyl,o-ethylbenzoyl, p-tert-butylbenzoyl, 3,4-dimethylbenzoyl, 2-methyl-4-ethylbenzoyl, 2,4,6-trimethylbenzoyl, m-methylphenylacetyl, p-isobutylphenylacetyl, beta-(p-ethylphenyl)propinyl, p-anisoyl, m-anisoyl, o-anisoyl, m-isopropoxybenzoyl,p-n-butoxybenzoyl, 3-methoxy-4-ethoxybenzoyl, 3,4,5-trimethoxybenzoyl, 2,4,6-triethoxybenzoyl, p-methoxyphenylacetyl, m-isobutoxyphenylacetyl, 3,4-diethoxyphenylacetyl, beta-(3,4,5-trimethoxyphenyl)propionyl, o-iodobenzoyl, m-bromobenzoyl,p-chlorobenzoyl, p-fluorobenzoyl, 2-bromo-4-chlorobenzoyl, 2,4,6-trichlorobenzoyl, p-chlorophenylacetyl, alpha-(m-bromophenyl)propionyl, p-trifluoromethylbenzoyl, 2,4-di(trifluoromethyl)benzoyl, m-trifluoromethylphenylacetyl,beta-(p-trifluoromethylphenyl)propionyl, 2-methyl-4-methoxybenzoyl, 3-chloro-4-ethoxybenzoyl, beta-(3-methyl-4-chlorophenyl)propionyl, p-dimethylaminobenzoyl, m-diethylaminobenzoyl, p-dibutylaminobenzoyl, p-(N-methyl-N-ethylamino)benzoyl,o-acetamidobenzoyl, m-propionamidobenzoyl, p-hexanoylaminobenzoyl, 3-chloro-4-acetamidophenylacetyl, and p-acetamidophenylpropionyl.
When Y, Y.sup.1 or Y.sup.2 in the formulas herein is naphthalenecarbonyl, there are included 1-naphthalenecarbonyl and 2-naphthalenecarbonyl.
When Y, Y.sup.1, or Y.sup.2 in the formulas herein is pyridinecarbonyl, there are included picolinoyl (2-pyridinecarbonyl), nicotinoyl (3-pyridinecarbonyl), and isonicotinoyl (4-pyridinecarbonyl).
As provided above, in Formula I when R is tert-butyl or cycloalkyl, no more than one of Y and Y.sup.1 contains less than four carbon atoms; and when R is hydrogen or alkyl other than tert-butyl, no more than one of Y and Y.sup.1 contains lessthan seven carbon atoms. In Formula II at least one of Y and Y.sup.1 contains no less than four carbon atoms.
Due to the presence of the basic amino grouping, the free base forms of the final products represented by Formulas I and II and also of the intermediates represented by Formulas III and IV react with organic and inorganic acids to formacid-addition salts. The acid-addition salt forms are prepared from any organic or inorganic acid. They are obtained in conventional fashion, for instance either by direct mixing of the base with the acid, or, when this is not appropriate, bydissolving either or both of the base and the acid separately in water or an organic solvent and mixing the two solutions, or by dissolving both the base and the acid together in a solvent. The resulting acid-addition salt is isolated by filtration, ifit is insoluble in the reaction medium, or by evaporation of the reaction medium to leave the acid-addition salt as a residue. The acid moieties or anions in these salt forms are in themselves neither novel nor critical and therefore can be any acidanion or acid-like substance capable of salt formation with the base.
Representative acids for the formation of the acid-addition salts include formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tannic acid,glutamic acid, tartaric acid, oxalic acid, pyromucic acid, citric acid, lactic acid, glycolic acid, gluconic acid, saccharic acid, ascorbic acid, penicillin, benzoic acid, phthalic acid, salicylic acid, 3,5-dinitrobenzoic acid, anthranilic acid, cholicacid, 2-pyridinecarboxylic acid, pamoic acid, 3-hydroxy-2-naphtholic acid, picric acid, quinic acid, tropic acid, 3-indoleacetic acid, barbituric acid, sulfamic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid,p-toluenesulfonic acid, butylarsonic acid, methanephosphonic acid, acidic resins, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, arsenic acid, and the like.
All of the acid-addition salts are useful as sources of the free base form, by reaction with an inorganic base. It will thus be appreciated that if one or more of the characteristics, such as solubility, molecular weight, physical appearance,toxicity, or the like of a given base or acid-addition salt thereof render that form unsuitable for the purpose at hand, it can be readily converted to another, more suitable form. For pharmaceutical purposes, acid-addition salts of the compounds ofFormula I and Formula II with relatively non-toxic, pharmaceutically acceptable acid, for example hydrochloric acid, lactic acid, tartaric acid, and the like, are of course employed.
The mono esters of Formulas I and II wherein Y.sup.1 is hydrogen are of course amphoteric, having both free phenol and basic amino groups, and thus form salts with both acids and bases.
The manner and process of making and using the invention, and the best contemplated by the inventors of carrying out this invention, will now be described so as to enable any person skilled in the art to which it pertains to make and use thesame.
The esters of Formula I hereinabove wherein Y.sup.2 is hydrogen are obtained in accordance with the invention by reducing an ester ketone of Formula III. Similarly, the esters of Formula II hereinabove wherein Y.sup.2 is hydrogen are obtained byreducing an ester-ketone of Formula IV. As will of course be appreciated, in effecting reduction of these ester-ketones of Formulas III and IV to the corresponding ester-alcohols, the use of reducing means resulting in reduction of carboxylic estergroupings must be avoided. Ordinarily, it is preferred to effect the desired reduction either by catalytic hydrogenation in the presence of a noble metal catalyst such as platinum or palladium, or by employing an alkali metal borohydride and a loweralkanol. In those instances where one or both of Y and Y.sup.1 in the ester-ketones of Formulas III and IV contain an olefinic double bond, and it is desired to retain this unsaturation in the reduction product (Formula I or II wherein Y.sup.2 ishydrogen), the borohydride method is used since, as is well known, catalytic hydrogenation effects reduction of such double bonds.
The catalytic hydrogenation process is conveniently carried out in a suitable solvent, for example ethyl alcohol, at 20.degree.-60.degree. C. under pressure, for instance on the order of 20-50 pounds of hydrogen pressure per squaare inch, in thepresence of palladium or platinum hydrogenation catalyst. The hydrogenation is continued until the theoretical amount of hydrogen is absorbed as calculated in conventional fashion from drop in hydrogen pressure. A hydrogenation time of 4 hours or lessis generally satisfactory. After removal of the catalyst, the isolation of the ester-alcohol product is effected in conventional manner, as by evaporation of some or all of the solvent from the reaction mixture, collecting the precipitated crudeester-alcohol, and purifying it by recrystallization from a suitable solvent.
In some instances, when applied to the ester ketones of Formula IV, the catalytic hydrogenation method may result in the production of an undesired byproduct by reduction of the 3-(Y-O-CH.sub.2 -) group to a 3-(CH.sub.3 -) group. In such cases,for best results it may be preferable to employ the borohydride reduction method.
The ester-ketones of Formulas III and IV used as starting materials in the reduction process described hereinabove are obtained by mono- or di-esterifying the corresponding known and readily available 3,4-dihydroxyphenyl (R-NH-)(R')-methylketones of Formula V and 3-hydroxymethyl-4-hydroxyphenyl (R-NH-)(R')methyl ketones of Formula VI, respectively. .[.When R is hydrogen, methyl, or ethyl, to prevent undesired N-acylation it is advantageous to N-benzylate (N,N-dibenzylate when R ishydrogen) the ketone of Formula V before the esterification is carried out. These protective N-benzyl groups can of course be readily removed by catalytic hydrogenation either at the ester ketone stage or at the ester alcohol stage (final product), asdesired..].
For the production of the mono-ester ketones of Formula III wherein Y.sup.1 is hydrogen, the starting 3,4-dihydroxyphenyl (R-NH-)(R'-)methyl ketone (Formula V) is treated with one molecular equivalent of an acid anhydride or an acid halide of theappropriate carboxylic acid (Y-OH wherein Y has the significance indicated hereinabove), optionally but preferably in the presence of an acid-absorbing medium, in any suitable manner for the acylation of phenolic hydroxyl. In one preferred procedure,the 3,4-dihydroxyphenyl (R-NH-)(R')methyl ketone (Formula V) is treated with two molecular equivalents of an alkali metal lower alkoxide, for instance sodium methoxide, and the resulting alkali metal phenolate is treated with one molecular equivalent ofthe appropriate acid halide, Y-halogen wherein Y has the same significance indicated hereinabove, for instance the acid chloride, Y-Cl. The 4-hydroxy group in the starting 3,4-dihydroxyphenyl (R-NH-)(R')methyl ketone (Formula V) is more readily acylatedthan the 3-hydroxyl group, and thus the monoacylation produces the desired 3-hydroxyphenyl-4-acyloxyphenyl (R-NH-)(R')methyl ketone (Formula III wherein Y' is hydrogen).
The mono-ester ketones of Formula IV wherein Y.sup.1 is hydrogen are readily obtained either by selectively esterifying the alcoholic hydroxyl without esterifying the phenolic hydroxyl or by selectively mono-deacylating the diester (obtained asindicated hereinbelow) to convert the 4-acyloxy group to 4-hydroxyl while leaving the 3-acyloxymethyl group intact. The selective esterification is conveniently effected by reacting the ketone of Formula VI with one mole equivalent of a mixed anhydrideof the formula Y.sup.1 --CO--O--CO--CF.sub.3, wherein Y.sup.1 has the same significance indicated hereinabove, in trifluoroacetic acid. If desired, it is satisfactory and ordinarily more convenient to form the mixed anhydride in situ by mixing theappropriate acid chloride, Y.sup.1 --Cl, with trifluoroacetic acid. In the selective mono-deacylation method, a diester of Formula IV wherein Y.sup.1 is an acyl group is treated at room temperature with a relatively weak organic base such as benzylamineor 2-phenylcyclopropylamine in N,N-dimethylformamide, dimethylsulfoxide, or similar solvent, whereby there is obtained the desired mono-ester of Formula IV where Y.sup.1 is hydrogen.
The di-ester ketones of Formula III and IV wherein both of Y and Y' are acyl groups are obtained by acylating the 3-hydroxy-4-acyloxyphenyl(R-NH-)(R')methyl ketones (Formula III wherein Y.sup.1 is hydrogen) and the3-(acyloxymethyl)-4-hydroxyphenyl (R-NH-)(R')methyl ketones (Formula IV wherein Y.sup.1 is hydrogen, obtained as above-described, with one molecular equivalent of an acid anhydride or an acid halide of the appropriate carboxylic acid (Y--OH) which iseither different from or the same as the acylating agent used in the first acylation step. As will be appreciated, when it is desired that Y and Y.sup.1 in the di-ester ketone (Formula III and Formula IV) be identical, it is generally more convenient toprepare these products by introducing both acyl groups in a single procedure by employing two molecular equivalents of the acylating agent, and thereby proceed directly to the desired diester ketone without isolation of the intermediately-formedmono-ester ketone. When the alkali metal phenolate method is employed, the starting 3,4-dihydroxyphenyl (R-NH-)(R')-methyl ketones of Formula V are of course reacted with two molecular equivalents of alkali metal lower alkoxide so as to replace both ofthe phenolic hydrogens with the alkali metal, whereas the 3-hydroxymethyl-4-hydroxyphenyl (R-NH-)(R')methyl ketones of formula VI require use of only one molecular equivalent of alkali metal alkoxide.
In the preparation of the di-ester ketones of Formula IV, a procedure alternative to the one above-described comprises forming a 3-(acyloxymethyl)-4-acyloxy-alpha-(R')-acetophenone, brominating to produce a3-(acyloxymethyl)-4-acyloxy-alpha-(R')-alpha-bromoacetophenone, and aminating this product at very low temperature, preferably in the range -20.degree. C. to -60.degree. C. with the appropriate aminating agent having the formula R-NH.sub.2 wherein Rhas the same significance indicated hereinabove. For the preparation of mono-esters of Formula IV wherein Y.sup.1 is hydrogen, this method is readily modified by selective removal of the 4-acyloxy group by treating the3-(acyloxymethyl)-4-acyloxy-alpha-(R')-acetophenone with benzylamine, or the like weak organic base, in N,N-dimethylformamide, dimethyl sulfoxide, or similar solvent, and subjecting the resulting 3-acyloxymethyl-4-hydroxy-alpha-(R')-acetophenone to thebromination and amination steps as indicated. Alternatively, if it is desired to obtain a mixed di-ester of Formula IV wherein Y and Y' are different acyl groups, the 3-acyloxymethyl-4-hydroxy-alpha-(R')-acetophenone is appropriately acylated to yield a3-acyloxymethyl-4-acyloxy-alpha-(R')-acetophenone wherein the acyl groups are different and thereafter subjecting this product to the indicated bromination and amination procedures.
The preparation of the esters of Formula I and Formula II wherein Y.sup.2 is acyl are obtained generally by esterification of the corresponding ester-alcohols of Formula I and Formula II wherein Y.sup.2 is hydrogen. This esterification isconveniently effected by treatment of an acid(strong)-addition salt of the ester-alcohol, for instance a hydrohalide or methanesulfonate salt, with the appropriate acid halide of formula Y-halogen, preferably the acid halide, Y-Cl, wherein Y has the samesignificance indicated hereinabove.
The esters of Formula II wherein Y.sup.1 is hydrogen and Y.sup.2 is acyl are alternatively obtained by preferential hydrolysis of the triesters of Formula II wherein Y Y.sup.1, and Y.sup.2 are each acyl to convert the 4-acyloxy group to 4-hydroxywhile leaving the other two ester groups intact.
The esters of this invention, having as above-indicated in free base form the Formulas I and II, when administered orally, intratracheally, intraduodenally, or intravenously to warm-blooded mammals are useful for producing sympathomimetic effectsof substantially longer duration than the corresponding unesterified sympathomimetic agents.
Generally speaking, the di-esters of Formula I and Formula II (wherein Y.sup.1 is acyl) have longer duration of sympathomimetic action than the corresponding mono-esters of Formula I and Formula II (wherein Y.sup.1 is hydrogen). Particularlypreferred embodiments of this invention are the esters of the sympathomimetic agents, for instance 3,4-dihydroxy-alpha-(isopropylaminomethyl)benzyl alcohol and especially 3,4-dihydroxy-alpha-(tert-butylaminomethyl)benzyl alcohol, which have usefulbronchodilator action. These particularly preferred esters, which are those having Formula I wherein R' is hydrogen and R is isopropyl or tert-butyl, not only have longer duration of bronchodilator action than the corresponding unesterifiedbronchodilator agents, when administered orally, intratracheally, intraduodenally, or intravenously to warm-blooded mammals but also advantageously produce lower cardiovascular effects than the corresponding unesterified compounds. In this group ofpreferred esters the diesters especially those wherein one of Y and Y.sup.1 is benzoyl or substituted benzoyl and the other is benzoyl, substituted benzoyl, or alkanoyl, afford special advantages.
In carrying out the method aspect of this invention, i.e. the method of producing sympathomimetic effects of long duration in warm-blooded mammals which comprise administering to said mammal an effective amount of an ester having in the free baseform Formula I or Formula II hereinabove, the said esters are orally administered in the same manner as the known corresponding unesterified sympathomimetic. Thus, they can be used with any of the pharmaceutically acceptable carriers conventionallyemployed for oral or parenteral administration of such agents. Ordinarily, they are combined with conventional pharmaceutical solid or liquid diluents and carriers in tablets, capsules, syrups, emulsions, solutions, suspensions or the like. Theformulations may contain any of the usual excipients was water, lactose, starch, magnesium stearate, talc, gelatin, calcium carbonate, gums, and the like. An especially preferred method for administering these esters (Formula I and Formula II) is in theform of an aerosol inhalent preparation, for example of the general type conventionally used in aerosol therapy, as in the treatment of bronchospasms, wherein a sympathomimetic agent with effective bronchodilator activity is incorporated with suitablecarriers and an inert propellent in a nebulizing unit. A typical formulation of the aerosol type contains, by weight: 0.25 percent of the ester (Formula I or Formula II) or a suitable pharmaceutically-acceptable salt thereof, 39.75 percent of U.S.P. ethanol, 48 percent of dichlorotetrafluoroethane, and 12.00 percent of dichlorodifluoromethane.
The individual unit dosage can be varied as desired. For general use it is preferred to incorporate, in a solid vehicle, table or capsule, about 0.1 to 100 mg. of the ester (Formula I or Formula II); or in a liquid vehicle, about 0.1 to 100 mg. of the ester (Formula I or Formula II) per teaspoonful or, in an aerosol, 0.02 to 2 mg. per actuation. The effective oral dose for producing bronchodilation is in the approximate range 0.002-2.0 mg./kg.
This invention is illustrated by thefollowing examples without, however, being limited thereto.
EXAMPLE 1
A. A mixture of 25 g. of 3,4-dihydroxyphenyl N-tert-butylaminomethyl ketone hydrochloride, 150 ml. of butyric acid saturated with hydrogen chloride, and 150 ml. of butyryl chloride was stirred on a steam bath until a clear solution was obtained(in about 6 hours) and the solution was heated on the steam bath for one hour. Approximately 50 ml. of solvent was distilled under reduced pressure from the reaction mixture which was then cooled. The mixture was filtered to collect a crystallinesolid product which was washed well with diethyl ether and sucked dry under a rubber dam overnight. There was thus obtained 31 g. of 3,4-bis(-butyryloxy)phenyl N-tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which melted at212.degree.-215.degree. C. (dec.)(uncorr.).
B. A mixture of 30 g. of 3,4-bis(butyryloxy)phenyl N-tert-butylaminomethyl ketone hydrochloride, 200 ml. of 90 percent ethyl alcohol, and 2 g. of 10 percent palladium-on-charcoal hydrogenation catalyst was hydrogenated for 2 hours at 50.degree. C. under an initial hydrogen pressure of 50 pounds per square inch. The hydrogenation mixture was filtered to remove the catalyst. The solvent was evaporated from the filtrate under reduced pressure and the resulting residue was taken up in 50 ml. ofisopropyl alcohol, allowed to stand overnight at 5.degree. C., and filtered to remove 3 g. of solid. The filtrate was evaporated under reduced pressure, the residue thus obtained was dissolved in 50 ml. of isopropyl acetate, and this solution wasfiltered to remove a small amount of insoluble solid. When the filtrate was diluted with anhydrous diethyl ether, a solid separated from solution. This solid was collected on a filter. There was thus obtained 20 g. of crude3,4-bis(butyryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride. This salt was dissolved in water and then ammonium hydroxide was added, resulting in precipitation of the free base, 3,4-bis(butyryloxy)-alpha-(tert-butylaminomethyl)benzylalcohol. This precipitate was collected on a filter and washed well first with water and then with n-hexane. This base, which melted at 97.degree.-99.degree. C. (uncorr.), was dissolved in isopropyl alcohol and this solution was concentrated underreduced pressure. The resulting residue was dissolved in 30 ml. of isopropyl acetate and there was added ethereal hydrogen chloride solution in an amount affording a slight excess of the required amount of hydrogen chloride for conversion of the baseto the hydrochloride. The mixture was cooled and the inside of the container was scratched to induce crystallization. The mixture was diluted with 100 ml. of diethyl ether and the solid precipitate was collected on a filter and washed with anhydrousdiethyl ether and dried at 70.degree. C. There was thus obtained 11 g. of 3,4-bis(butyryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white crystalline solid which melted at 136.degree.-138.degree. C. (uncorr.). This salt wassoluble in water to the extent of at least 20 percent. The pH of a 1 percent aqueous solution of this salt was 6.0; and a precipitate formed when the pH of this solution was raised to 7.0 by addition of N/10 sodium hydroxide solution.
EXAMPLE 2
A. To a mixture of 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of N,N-dimethylformamide under an atmosphere of nitrogen there was added 17 g. of sodium methoxide. By distillation under reduced pressure, 50ml. of liquid was removed and the mixture was then cooled and under an atmosphere of nitrogen 25 g. of isobutyryl chloride was added rapidly at 5.degree.-25.degree. C. The reaction mixture was stirred at 25.degree. C. for 1 hour and then was warmed to70.degree. C. and the solvent was removed by distillation. The resulting residue was slurried in 400 ml. of diethyl ether, and the slurry was filtered to remove about 10 g. of insoluble solid. The ethereal layer in the filtrate was separated, washedwith dilute aqueous sodium hydroxide solution and then with water. There was thus obtained an ether solution of 3,4-bis(isobutyryloxy)phenyl tert-butylaminomethyl ketone. To this solution there was added a solution obtained by adding 4 ml. ofhydrochloric acid to 25 ml. of water, and the resulting mixture was shaken. The crystalline solid which formed was collected on a filter and dried at 70.degree. C. There was thus obtained 8.5 g. of 3,4-bis(isobutyryloxy)phenyl tert-butylaminomethylketone hydrochloride as a white crystalline powder which melted at 221.degree.-223.degree. C. (dec.)(uncorr.).
B. By catalytic hydrogenation of 8.5 g. of 3,4-bis(isobutyryloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of 95 percent ethyl alcohol in the presence of 2 g. of 10 percent palladium-on-charcoal catalyst there was obtained 5.0g. of 3,4-bis(isobutyryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white crystalline powder which melted at 190.degree. C. (uncorr.).
EXAMPLE 3
A. A mixture of 25 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride, 100 g. of isovaleryl chloride, and 100 g. of isovaleric acid was stirred on a steam bath for 72 hours. The reaction mixture was allowed to stand overnightat room temperature (approximately 25.degree. C.) and then was heated and filtered while hot to remove 18 g. of solid. The filtrate was evaporated to dryness under reduced pressure and the resulting residue was crystallized from isopropyl acetatecontaining a small amount of acetic acid. There was thus obtained 11.2 g. of 3,4-bis(isovaleryloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 220.degree.-222.degree. C. (uncorr.). Afterrecrystallization of a sample of this compound from isopropyl alcohol the melting point was 224.degree.-225.degree. C.
B. By catalytic hydrogenation of 11.2 g. of 3,4-bis(isovaleryloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 250 ml. of 95 percent ethyl alcohol in the presence of 2 g. of 10 percent palladium-on-charcoal catalyst there was obtained3.6 g. of 3,4-bis(isovaleryloxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol hydrochloride as a white crystalline powder which melted at 173.degree. C. (uncorr.). This salt was soluble in water at 25.degree. C. to the extent of at least 20 percent. The pH of a 1 percent aqueous solution was 5.4; and when the pH of this solution was adjusted to 7.0 by addition of N/10 sodium hydroxide solution, a precipitate formed.
EXAMPLE 4
A. A mixture of 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride, 50 g. of 2-methylbutanoyl chloride, 100 g. of 2-methylbutanoic acid, and 0.5 g. of aluminum chloride was heated with vigorous stirring at 120.degree. C. for1 hour. Then, since evolution of hydrogen chloride from the reaction mixture had slowed considerably, the mixture was heated at 145.degree. C. for 2 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue wasslurried in 300 ml. of boiling acetone, and the slurry was filtered. The solid thus collected, which was 3,4-bis(2-methylbutanoyloxy)-phenyl tert-butylaminomethyl ketone hydrochloride, weighed 30 g. and melted at 218.degree.-221.degree. C. (uncorr.).
B. By catalytic hydrogenation of 29.5 g. of 3,4-bis(2-methylbutanoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of 95 percent ethyl alcohol in the presence of 2 g. of 10 percent palladium-on-charcoal catalyst there wasobtained 26 g. of 3,4-bis(2-methylbutanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white crystalline powder which melted at 163.degree.-165.degree. C. (uncorr.). The solubility of this salt in water at 25.degree. C. was atleast 5 percent.
EXAMPLE 5
A. Proceeding in a manner similar to that described in part A of Example 2 above, 17 g. of sodium methoxide was interacted with 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of N,N-dimethylformamide and theresulting sodium phenolate salt was interacted with 24 g. of pivalyl chloride (alternatively designated as trimethylacetyl chloride or 2,2-dimethylpropanoyl chloride). From this acylation reaction there was obtained 3,4-bis(pivalyloxy)phenyltert-butylaminomethyl ketone which was treated with hydrochloric acid to yield 11.5 g. of 3,4-bis(pivalyloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 243.degree.-244.degree. C. (dec.)(uncorr.). Thissalt was soluble in water at 25.degree. C. to the extent of at least 1 percent.
B. By catalytic hydrogenation of 11.7 g. of 3,4-bis-(pivalyloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of 95 percent ethyl alcohol in the presence of 2. g. of 10 percent palladium-on-charcoal catalyst there was obtained8.0 g. of 3,4-bis(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white crystalline powder which melted at 249.degree. C. (uncorr.). This salt was soluble in water at 25.degree. C. to the extent of at least 5 percent.
EXAMPLE 6
A. Proceeding in a manner similar to that described in Example 1A above, 10.4 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride, 24 ml. of 3-methylpentanoyl chloride, and 40 ml. of 3-methylpentanoic acid were interacted toyield 4.5 g. of 3,4-bis(3-methylpentanoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 139.degree.-140.degree. C. (uncorr.).
B. By catalytic hydrogenation of 4.5 g. of 3,4-bis(3-methylpentanoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 100 ml. of anhydrous ethyl alcohol in the presence of 0.5 g. of 10 percent palladium-on-charcoal catalyst there wasobtained 2.7 g. of 3,4-bis(3-methylpentanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white crystalline solid which melted at 139.degree.-140.degree. C. (uncorr.). This salt was soluble in water at 25.degree. C. to the extentof at least 5 percent.
EXAMPLE 7
A. Proceeding in a manner similar to that described in Example 2A above, 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was interacted with 17 g. of sodium methoxide and the resulting sodium phenolate salt was interactedwith 25 g. of 3,3-dimethylbutanoyl chloride to yield 7.0 g. of 3,4-bis(3,3-dimethylbutanoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 225.degree.-228.degree. C. (dec.)(uncorr.).
B. By catalytic hydrogenation of 7.0 g. of 3,4-bis(3,3-dimethylbutanoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of 95 percent ethyl alcohol in the presence of 2 g. of 10 percent palladium-on-charcoal catalyst there wasobtained 6.0 g. of 3,4-bis(3,3-dimethylbutanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white crystalline powder which melted at 226.degree. C. (uncorr.). This salt was soluble in water at 25.degree. C. to the extent of atleast 1 percent.
EXAMPLE 8
A. Proceeding in a manner similar to that described in Example 2A above, 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was interacted with 18 g. of sodium methoxide, and the resulting sodium phenolate salt was interactedwith 30 ml. of 2,2-dimethypentanoyl chloride to yield 17 g. of 3,4-bis(2,2-dimethylpentanoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 183.degree.-185.degree. C. (uncorr.).
B. By catalytic hydrogenation of 15 g. of 3,4-bis(2,2-dimethylpentanoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of 95 percent ethyl alcohol in the presence of 2 g. of 10 percent palladium-on-charcoal catalyst there wasobtained 3,4-bis(2,2-dimethylpentanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride which by treatment with an excess of 10 percent ammonium hydroxide was converted to the free base (11 g.). This base was converted to itsmethanesulfonic acid salt (10 g.), a white crystalline powder which melted at 107.degree.-109.degree. C. (uncorr.). The methanesulfonate was soluble in water at 25.degree. C. to the extent of at least 5 percent.
EXAMPLE 9
Following the procedure described above in Example 2A but using decanoyl chloride instead of isobutyryl chloride there is obtained 3,4-bis(decanoyloxy)-phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acidthere is obtained the hydrochloride salt as a white crystalline solid which decomposed slowly above 235.degree. C. (uncorr.). When this hydrochloride was catalytically hydrogenated, using the procedure described above in Example 2B, there was obtained3,4-bis(decanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride which was converted to the corresponding free base, a crystalline white solid, m.p. 73.degree.-74.degree. C. (uncorr.), and this base was converted to the methanesulfonatesalt, a crystalline white solid, m.p. 45.degree.-48.degree. C. (uncorr.).
EXAMPLE 10
Following the procedure described above in Example 2A but using tetradecanoyl chloride instead of isobutyryl chloride there is obtained 3,4-bis(tetradecanoyloxy)phenyl tert-butylaminomethyl ketone, and by interaction of this base withmethanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated, using the procedure described above in Example 2B, there is obtained3,4-bis(tetradecanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate.
EXAMPLE 11
Following the procedure described above in Example 2A but using octadecanoyl chloride instead of isobutyryl chloride there is obtained 3,4-bis(octadecanoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloricacid there is obtained the hydrochloride salt as a white crystalline solid, m.p. 180.degree.-185.degree. C. (uncorr.). When 14 g. of this hydrochloride was catalytically hydrogenated, using the procedure described above in Example 2B, there wasobtained 3,4-bis(octadecanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white solid which melted at 75.degree.-78.degree. C. (uncorr.). This hydrochloride was converted to the base by treatment with ammonium hydroxide, and thebase was extracted with diethyl ether. The ethereal solution thus obtained was dried over anhydrous calcium sulfate and then treated with 1.5 g. of methanesulfonic acid to yield 6.3 g. of 3,4-bis-(octadecanoyloxy)-alpha-(tert-buylaminomethyl)benzylalcohol methanesulfonate as a white crystalline solid which melted at 105.degree.-108.degree. C. (uncorr.).
EXAMPLE 12
Following the procedure described above in Example 2A but using docosanoyl chloride instead of isobutyryl chloride there is obtained 3,4-bis(docosanoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with methanesulfonicacid there is obtained the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated, using the procedure described above in Example 2B, there is obtained 3,4-bis(docosanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcoholmethanesulfonate.
EXAMPLE 13
A. A mixture of 5.2 g. of 3,4-dihydroxy tert-butylaminomethyl ketone hydrochloride, 10 ml. of 1-methylcyclopropanecarbonyl chloride, and 20 ml. of 1-methylcyclopropanecarboxylic acid was stirred at 120.degree. C. under slight pressure. Afterevolution of hydrogen chloride had slowed considerably, the temperature of the reaction mixture was raised to 140.degree. C. for 30 minutes. Approximately 10 ml. of solvent was distilled from the mixture and the residue, which contained a crystallinesolid, was mixed with anhydrous diethyl ether and filtered. The solid thus collected, which weighed 7.5 g., was slurried in a waterdiethyl ether mixture and the slurry was made basic by addition of ammonium hydroxide. The ether layer was separated,washed with dilute sodium hydroxide solution and then with water, and was shaken with a solution prepared by diluting 3 ml. of concentrated hydrochloric acid to 30 ml. with water. The solid which precipitated was collected on a filter, washed withdiethyl ether, and dried at 70.degree. C. to yield 6.5 g. of 3,4-bis-(1-methylcyclopropanecarbonyloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 253.degree.-255.degree. C. (dec.)(uncorr.).
B. By catalytic hydrogenation of 6.1 g. of 3,4-bis(1-methylcyclopropanecarbonyloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of 90 percent ethyl alcohol in the presence of 2 g. of 10 percent palladium-on-charcoal catalystthere was obtained 2.6 g. of 3,4-bis(1-methylcyclopropanecarbonyloxy)-alpha-(tert-butylaminomethyl)benz yl alcohol hydrochloride as a white crystalline powder which melted at 210.degree.-212.degree. C. (uncorr.).
EXAMPLE 14
When cyclopropanecarbonyl chloride and cyclopropanecarboxylic acid are substituted for the 1-methylcyclopropanecarbonyl chloride and 1-methylcyclopropanecarboxylic acid, respectively, in the procedure described in Example 13A above, the acylationproduct obtained is 3,4-bis(cyclopropanecarbonyloxy)phenyl tert-butylaminomethyl ketone hydrochloride; and when this product is catalytically hydrogenated using the procedure described in Example 13B above, there is obtained3,4-bis(cyclopropanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 15
A. Under an atmosphere of nitrogen, 17.0 g. of sodium methoxide was added to a solution of 26.0 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of N,N-dimethylformamide. During this addition the temperature ofthe mixture rose to 45.degree. C. The mixture was cooled to 0.degree. C. and under an atmosphere of nitrogen 29.1 g. of cyclohexanecarbonyl chloride was added dropwise with stirring at 0.degree.-3.degree. C. The reaction mixture was stirred for 1 hourat room temperature (about 25.degree. C.) and then was poured into a mixture of ice water and diethyl ether. The ether layer was separated, washed successively with water, dilute aqueous sodium hydroxide solution, and water, and dried over anhydrouscalcium sulfate. Ethereal hydrogen chloride solution was added to the dry ether solution and the solid which precipitated was collected on a filter. The product thus collected was recrystallized from 200 ml. of isopropyl alcohol to yield 11 g. of3,4-bis(cyclohexanecarbonyloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 204.degree.-210.degree. C. (dec.) (uncorr.).
B. By catalytic hydrogenation of 10.6 g. of 3,4-bis(cyclohexanecarbonyloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 100 ml. of anhydrous ethyl alcohol in the presence of 1.0 g. of 10 percent palladium-on-charcoal catalyst there wasobtained 8.2 g. of 3,4-bis(cyclohexanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white crystalline solid which melted at 212.degree.-213.degree. C. (uncorr.). The solubility of this salt in each of water andpolyethyleneglycol at 25.degree. C. was less than 0.1 percent. When a 1 percent solution of this salt in dimethyl sulfoxide was diluted with three volumes of water, no precipitate formed.
EXAMPLE 16
When cyclobutanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis-(cyclobutanecarbonyloxy)phenyl tert-butylaminomethyl ketone; and whenthis product is catalytically hydrogenated using the procedure described in Example 15B above there is obtained 3,4-bis(cyclobutanecarbonyloxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol.
EXAMPLE 17
When cyclopentanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(cyclopentanecarbonyloxy)phenyl tert-butylaminomethyl ketone; andwhen this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(cyclopentanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
EXAMPLE 18
When cycloheptanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(cycloheptanecarbonyloxy)phenyl tert-butylaminomethyl ketone; andwhen this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(cycloheptanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
EXAMPLE 19
When 2-hexylcyclopropanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(2-hexylcyclopropanecarbonyloxy)phenyl tert-butylaminomethylketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(2-hexylcyclopropanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzy l alcohol.
EXAMPLE 20
When 1-methyl-3-isopropylcyclopentanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is2,4-bis(1-methyl-3-isopropylcyclopentanecarbonyloxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained3,4-bis(1-methyl-3-isopropylcyclopentanecarbonyloxy)-alpha-(tert-butylamin omethyl)benzyl alcohol.
EXAMPLE 21
When 1,3-dimethylcyclobutanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(1,3-dimethylbutanecarbonyloxy)phenyltert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(1,3-dimethylcyclobutanecarbonyloxy)-alpha-(tert-butylaminomethyl)b enzyl alcohol.
EXAMPLE 22
When 2-amylcyclopropaneacetyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(2-amylcyclopropaneacetoxy)phenyl tert-butylaminomethyl ketone;and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(2-amylcyclopropaneacetoxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
EXAMPLE 23
When 2,2-dimethyl-3-ethylcyclobutaneacetyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(2,2-dimethyl-3-ethylcyclobutaneacetoxy)phenyltert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(2,2-dimethyl-3-ethylcyclobutaneacetoxy)-alpha-(tert-butylaminometh yl)benzyl alcohol.
EXAMPLE 24
Following the procedure described above in Example 15A but using cyclohexaneacetyl chloride instead of cyclohexanecarbonyl chloride the acylation product obtained is 3,4-bis(cyclohexaneacetoxy)phenyl tert-butylaminomethyl ketone; and when thisproduct is catalytically hydrogenated, using the procedure described above in Example 15B, there is obtained 3,4-bis(cyclohexaneacetoxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
EXAMPLE 25
When 4-methylcycloheptaneacetyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(4-methylcycloheptaneacetoxy)phenyl tert-butylaminomethylketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(4-methylcycloheptaneacetoxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
EXAMPLE 26
When 2-isobutylcyclopropanepropionyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A, above, the acylation product obtained is 3,4-bis(2-isobutylcyclopropanepropionyloxy)phenyltert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(2-isobutylcyclopropanepropionyloxy)-alpha-(tert-butylaminomethyl)b enzyl alcohol.
EXAMPLE 27
Following the procedure described above in Example 15A but using cycloheptanepropionyl chloride instead of cyclohexanecarbonyl chloride the acylation product obtained is 3,4-bis(cycloheptanepropionyloxy)phenyl tert-butylaminomethyl ketone; andwhen this product is catalytically hydrogenated, using the procedure described above in Example 15B, there is obtained 3,4-bis(cycloheptanepropionyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
EXAMPLE 28
Following the procedure described above in Example 15A but using alpha-methylcyclopropaneacetyl chloride instead of cyclohexanecarbonyl chloride the acylation product obtained is 3,4-bis(alpha-methylcyclopropaneacetoxy)phenyltert-butylaminomethyl ketone; and when this product is catalytically hydrogenated, using the procedure described above in Example 15B, there is obtained 3,4-bis(alphamethylcyclopropaneacetoxy)-alpha-(tert-butylaminomethyl)benzy l alcohol.
EXAMPLE 29
A. To 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of dioxane there was added rapidly 20 g. of potassium hydroxide in 50 ml. of methanol. One-half of the solvent was distilled from the resulting mixtureunder reduced pressure and then 29 g. of benzoyl chloride was dripped in at 5.degree.-10.degree. C. during a period of 30 minutes. The reaction mixture was stirred for another half-hour at 10.degree. C., after which the solvent was distilled off underreduced pressure. The residue thus obtained was slurried with a mixture of 100 ml. and 400 ml. of diethyl ether, and the slurry was filtered to remove 12 g. of insoluble solid. The ether layer in the filtrate was separated, washed with water, diluteaqueous sodium hydroxide solution, and water, and then was shaken with a solution of 7 ml. of concentrated hydrochloric acid in 50 ml. of water. The mixture was cooled in ice and the precipitate which formed was collected on a filter and washed with afew ml. of water and then with diethyl ether, and dried at 70.degree. C. There was thus obtained 11.0 g. of 3,4-bis(benzoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 215.degree.-218.degree. C.(dec.) (uncorr.).
B. By catalytic hydrogenation of 11 g. of 3,4-bis(benzoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of anhydrous ethyl alcohol in the presence of 1.0 g. of 10 percent palladium-on-charcoal catalyst there was obtained 6.0 g.of 3,4-bis(benzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride which crystallized from a diethyl etheracetic acid-isopropyl acetate mixture as a white solid which melted at 214.degree.-216.degree. C. (uncorr.). The solubility of thissalt in each of dimethylsulfoxide and glycerol formal at 25.degree. C. was 1 percent or more; and when a 1 percent solution of this salt in each of these solvents was diluted with three volumes of water, no precipitate formed in either instance.
EXAMPLE 30
A. Under an atmosphere of nitrogen, 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was mixed with 17 g. of sodium methoxide in 200 ml. of N,N-dimethylformamide and 50 ml. of solvent was distilled off below 40.degree. C. under reduced pressure. Then 31 g. of p-toluyl chloride was dripped in at 5.degree.-10.degree. C. The solvent was distilled from the reaction mixture under reduced pressure, the resulting residue was slurried in a mixture of water and diethyl ether,and the slurry was filtered to remove 9.5 g. of insoluble solid. The ether layer in the filtrate, which contained 3,4-bis(p-toluyloxy)phenyl tert-butylaminomethyl ketone, was separated, washed with water and dilute sodium hydroxide, and then was shakenwith a solution obtained by diluting 4 ml. of concentrated hydrochloric acid with water to a volume of 30 ml. After the mixture had stood for 1 hour at room temperature, the precipitate which had formed was collected on a filter, washed with diethylether, and recrystallized from isopropyl alcohol. There was thus obtained 14.0 g. of 3,4-bis(p-toluyloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 221.degree.-224.degree. C. (uncorr.). Thesolubility of this salt in water at 25.degree. C. was less than 0.1 percent.
B. By catalytic hydrogenation of 13.5 g. of 3,4-bis(p-toluyloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 220 ml. of anhydrous ethyl alcohol at room temperature in the presence of 2.0 g. of 10 percent palladium-on-charcoal catalystuntil one mole equivalent of hydrogen was absorbed (about 30 min. required), there was obtained 8.0 g. of crude, 3,4-bis(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a pulvurulent solid which by treatment with an excess of 10percent ammonium hydroxide was converted to the free base, which weighed 4.3 g. and melted at 80.degree.-84.degree. C. This base was converted to its methanesulfonic acid salt (4.3 g.), a white crystalline powder which melted at 170.degree.-172.degree. C. (uncorr.). The methanesulfonate was soluble in dimethyl sulfoxide to the extent of at least 1 percent; and when a 1 percent solution of dimethyl sulfoxide was diluted with three volumes of water, no precipitate formed.
C. To a solution of 1.1 g. of 3,4-bis(p-toluyloxy)phenyl tert-butylaminomethyl ketone methanesulfonate (m.p. 185.degree.-187.degree. C. (uncorr.) obtained by reacting the free base with methanesulfonic acid) in 20 ml. of anhydrous methylalcohol at 5.degree. C. under an atmosphere of nitrogen there was added with stirring 100 mg. of dry sodium borohydride. After 5 minutes the reaction was quenched with about fifteen drops of glacial acetic acid to bring the pH of the mixture toapproximately 6. The mixture was evaporated to dryness, diluted with 200 ml. of diethyl ether, and washed with 100 ml. of 5 percent aqueous sodium bicarbonate solution, followed by washing successively with water and water saturated with sodiumchloride. The aqueous washes were combined and extracted with diethyl ether and this extract was combined with the ethereal solution, dried over sodium sulfate, and evaporated to yield 1 g. of colorless oil. This oil, which was3,4-bis(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol, was diluted with 70 ml. of anhydrous diethyl ether and 0.14 ml. of methanesulfonic acid was added. A white precipitate formed on cooling. The mixture was concentrated to a volume ofabout 25 and filtered. The white crystalline solid thus obtained, which weighted 1.1 g., was 3,4-bis(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate, identical with the product described above in part B. The correspondingacetate salt was a white solid, m.p. 110.degree. C. (uncorr.).
EXAMPLE 31
Following the procedure described above in Example 29A but using p-tert-butylbenzoyl chloride instead of benzoyl chloride there is obtained 3,4-bis(p-tert-butylbenzoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 29B, there is obtained 3,4-bis(p-tert-butylbenzoyloxy)-alpha-(tert-butylaminomethyl)-benzylalcohol hydrochloride.
EXAMPLE 32
Following the procedure described above in Example 29A but using 2-methyl-4-ethylbenzoyl chloride instead of benzoyl chloride there is obtained 3,4-bis(2-methyl-4-ethylbenzoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of thisbase with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 29B, there is obtained,3,4-bis(2-methyl-4-ethylbenzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 33
A. Proceeding in a manner similar to that described in Example 30A above, 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was reacted with 17 g. of sodium methoxide in 200 ml. of N,N-dimethylformamide, and the resultingsodium phenolate salt was interacted with p-anisoyl chloride to yield 12.3 g. of 3,4-bis(p-anisoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a white crystalline solid which melted at 205.degree.-208.degree. C. (uncorr.).
B. By catalytic hydrogenation of 12.0 g. of 3,4-bis(p-anisoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 300 ml. of anhydrous ethyl alcohol in the presence of 2.0 g. of 10 percent palladium-on-charcoal catalyst there was obtained6.2 g. of 3,4-bis(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white crystalline solid which melted at 165.degree. C. (uncorr.). The solubility of this salt in polyethyleneglycol 200 at 25.degree. C. was less than 1percent When 1 percent solutions of this salt in each of dimethyl sulfoxide and glycerol formal were diluted with 3 volumes of water, no precipitate formed.
EXAMPLE 34
Following the procedure described above in Example 30A but using p-ethoxybenzoyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(p-ethoxybenzoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3,4-bis(p-ethoxybenzoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.
EXAMPLE 35
Following the procedure described above in Example 30A but using p-acetamidobenzoyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(p-acetamidobenzoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base withhydrobromic acid there is obtained the hydrobromide salt. When this hydrobromide is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3,4,5-bis(p-acetamidobenzoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrobromide.
EXAMPLE 36
When 3,4,5-tributoxybenzoyl chloride is substituted for the p-toluyl chloride in the procedure described in Example 30A above, there is obtained 3,4-bis(3,4,5-tributoxybenzoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of thisbase with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated using the procedure described in Example 30B above, there is obtained3,4-bis(3,4,5-tributoxybenzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 37
Following the procedure described above in Example 30A but using 3,5-dimethoxy-4-ethoxybenzoyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(3,5-dimethoxy-4-ethoxybenzoyloxy)phenyl tert-butylaminomethyl ketone; and byinteraction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained3,4-bis(3,5-dimethoxy-4-ethoxybenzoyloxy)-alpha-(tert-butylaminomethyl)ben zyl alcohol hydrochloride.
EXAMPLE 38
Following the procedure described above in Example 30A but using 2-bromo-5-chlorobenzoyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(2-bromo-5-chlorobenzoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of thisbase with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained3,4-bis(2-bromo-5-chlorobenzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 39
Following the procedure described above in Example 30A but using 2,3,4-trichlorobenzoyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(2,3,4-trichlorobenzoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this basewith methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained3,4-bis(2,3,4-trichlorobenzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate.
EXAMPLE 40
When 2,3,5-trifluorobenzoyl chloride is substituted for the p-toluyl chloride in the procedure described in Example 30A above, the product obtained is 3,4-bis(2,3,5-trifluorobenzoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction ofthis base with hydrochloric acid there is obtained by hydrochloride salt. When this hydrochloride is catalytically hydrogenated using the procedure described in Example 30B above, there is obtained3,4-bis(2,3,5-trifluorobenzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 41
When 3,5-bis(trifluoromethyl)benzoyl chloride is substituted for the p-toluyl chloride in the procedure described in Example 30A above, the product obtained is 3,4-bis[3,5-bis-(trifluoromethyl)benzoyloxy]phenyl tert-butylaminomethyl ketone; andby interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated using the procedure described in Example 30B above, there is obtained3,4-bis[3,5(trifluoromethyl)benzoyloxy]-alpha-(tert-butylaminomethyl)benzy l alcohol hydrochloride.
EXAMPLE 42
Following the procedure described above in Example 30A but using 2-ethoxy-5-fluorobenzoyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(2-ethoxy-5-fluorobenzoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of thisbase with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained3,4-bis(2-ethoxy-5-fluorobenzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 43
Following the procedure described above in Example 30A but using 2,6-dimethyl-4-propoxybenzoyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(2,6-dimethyl-4-propoxybenzoyloxy)phenyl tert-butylaminomethyl ketone; and byinteraction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained3,4-bis(2,6-dimethyl-4-propoxybenzoyloxy)-alpha-(tert-butylaminomethyl)ben zyl alcohol hydrochloride.
EXAMPLE 44
When 2-chloro-3-methoxy-4-methylbenzoyl chloride is substituted for the p-toluyl chloride in the procedure described in Example 30A above, the product obtained is 3,4-bis(2-chloro-3-methoxy-4-methylbenzoyloxy)-phenyl tert-butylaminomethyl ketone;and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated using the procedure described in Example 30B above, there is obtained3,4-bis(2-chloro-3-methoxy-4-methylbenzoyloxy)-alpha-(tert-butylaminomethy l)benzyl alcohol hydrochloride.
EXAMPLE 45
Following the procedure described above in Example 30A but using phenylacetyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(phenylacetoxy)-phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloricacid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3,4-bis(phenylacetoxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 46
Following the procedure described above in Example 30A but using p-ethylphenylacetyl chloride instead of p-tolyl chloride there is obtained 3,4-bis(p-ethylphenylacetoxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3,4-bis(p-ethylphenylacetoxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.
EXAMPLE 47
Following the procedure described above in Example 30A but using 2,5-dimethyl-4-methoxyphenylacetyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(2,5-dimethyl-4-methoxyphenylacetoxy)phenyl tert-butylaminomethyl ketone; and byinteraction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained3,4-bis(2,5-dimethyl-4-methoxyphenylacetoxy)alpha-(tert-butylaminomethyl)b enzyl alcohol hydrochloride.
EXAMPLE 48
Following the procedure described above in Example 30A but using 2-bromo-4,5-diethoxyphenylacetyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(2-bromo-4,5-diethoxyphenylacetoxy)phenyl tert-butylaminomethyl ketone; and byinteraction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained3,4-bis(2-bromo-4,5-diethoxyphenylacetoxy)-alpha-(tert-butylaminomethyl)be nzyl alcohol hydrochloride.
EXAMPLE 49
Following the procedure described above in Example 30A but using .beta.-phenylpropionyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(.beta.-phenylpropionyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this basewith hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained3,4-bis(.beta.-phenylpropionyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 50
Following the procedure described above in Example 30A but using .beta.-(2-bromo-4-methoxyphenyl)propionyl chloride instead of p-toluyl chloride there is obtained 3,4-bis[.beta.-(2-bromo-4-methoxyphenyl)propionyloxy]phenyl tert-butylaminomethylketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained3,4-bis[.beta.-(2-bromo-4-methoxyphenyl)propionyloxy]-alpha-(tert-butylami nomethyl)benzyl alcohol hydrochloride.
EXAMPLE 51
Following the procedure described above in Example 30A but using 2-naphthalenecarbonyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(2-naphthalenecarbonyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this basewith hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained3,4-bis(2-naphthalenecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 52
Following the procedure described above in Example 30A but using phenoxyacetyl chloride instead of p-tolyl chloride there is obtained 3,4-bis(phenoxyacetoxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloricacid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3,4-bis(phenoxyacetoxy)-alpha-(tert-butylaminomethyl)benzyl alcoholhydrochloride.
EXAMPLE 53
Following the procedure described above in Example 30A but using p-diethylaminobenzoyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(p-diethylaminobenzoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this basewith hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained3,4-bis-(p-diethylaminobenzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 54
Following the procedure described above in Example 30A but using nicotinoyl chloride instead of p-toluyl chloride there is obtained 3,4-bis(nicotinoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acidthere is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3,4-bis(nicotinoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 55
Following the procedure described above in Example 2A but using crotonoyl chloride instead of isobutyryl chloride there is obtained 3,4-bis(crotonoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acidthere is obtained the hydrochloride salt. When this hydrochloride is reduced with sodium borohydride, using the procedure described above in Example 30C, there is obtained 3,4-bis(crotonoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 56
Following the procedure described above in Example 2A but using 9-octadecenoyl chloride instead of isobutyryl chloride there is obtained 3,4-bis(9-octadecenoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is reduced with sodium borohydride using the procedure described above in Example 30C, there is obtained 3,4-bis(9-octadecenoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.
EXAMPLE 57
Following the procedure described above in Example 2A but using 5,13-docosadienoyl chloride instead of isobutyryl chloride there is obtained 3,4-bis(5,13-docosadienoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is reduced with sodium borohydride, using the procedure described above in Example 30C, there is obtained3,4-bis(5,13-docosadienoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 58
A. Under an atmosphere of nitrogen, 8.1 g. of sodium methoxide was added to 13 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of dimethylformamide and 50 ml. of solvent was distilled from the reaction mixtureunder reduced pressure. Then under an atmosphere of nitrogen 7.8 g. of isovaleryl chloride was dripped in at 20.degree.-25.degree. C. and the reaction mixture was stirred at 25.degree. C. for 1 hour. The solvent was distilled off under reducedpressure and the resulting residue was taken up in a mixture of 500 ml. of water, 3 ml. of 35 percent aqueous sodium hydroxide solution, and 200 ml. of diethyl ether. The ether layer was separated and discarded. The aqueous layer was acidified withacetic acid and the precipitate which formed was collected on a filter and washed well with water and n-hexane. There was thus obtained 12 g. of 3-hydroxy-4-(isovaleryloxy)phenyl tert-butylaminomethyl ketone. This base was slurried in 500 ml. ofanhydrous ethyl alcohol and with stirring there was added 68 percent methanesulfonic acid in an amount (5 ml.) sufficient to produce a persistent acidic reaction in the slurry, which was then stirred until a heavy precipitate formed. The precipitate wascollected on a filter and washed with ethyl alcohol and diethyl ether. There was thus obtained 8.1 g. of 3-hydroxy-4-(isovaleryloxy)phenyl tert-butylaminomethyl ketone methanesulfonate as a white crystalline solid which melted at 242.degree.-245.degree. C. (dec.)(uncorr.).
B. By catalytic hydrogenation of 8.1 g. of 3-hydroxy-4-(isovaleryloxy)phenyl tert-butylaminomethyl ketone methanesulfonate suspended in 250 ml. of 95 percent ethyl alcohol in the presence of 3.0 g. of 10 percent palladium-on-charcoal catalystthere was obtained 4.8 g. of 3-hydroxy-4-(isovaleryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid which melted at 148.degree.-150.degree. C. (uncorr.). The solubility of this salt in water at 25.degree. C. was at least 5 percent.
EXAMPLE 59
A. Following a procedure similar to that described in Example 58A above, 260 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was reacted with 170 g. of sodium methoxide in 2 kg. of N,N-dimethylformamide, and the resultingsodium phenolate was interacted with 160 g. of pivalyl chloride to yield 250 g. of 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone. The hydrochloride of this base was a white crystalline solid which melted at 268.degree.-270.degree. C.(dec.)(uncorr.), and the methanesulfonate of the base was a white crystalline solid which melted at 260.degree.-263.degree. C. (dec.)(uncorr.).
B. By catalytic hydrogenation of 18 g. of 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone methanesulfonate suspended in one liter of 95 percent ethyl alcohol in the presence of 3 g. of 10 percent palladium-on-charcoal catalyst therewas obtained 10.0 g. of 3-hydroxy-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid which melted at 175.degree.-177.degree. C.-(uncorr.).
EXAMPLE 60
By interacting 13 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride with 8 ml. of 3,3-dimethylbutanoyl chloride in 35 ml. of trifluoroacetic acid at room temperature, there was obtained3-hydroxy-4-(3,3-dimethylbutanoyloxy)phenyl tert-butylaminomethyl ketone trifluoroacetate which was converted to the free base by treatment with ammonium hydroxide; and by interaction of this base with methanesulfonic acid there was obtained themethanesulfonate salt, m.p. 240.degree.-245.degree. C. (dec.). When this methanesulfonate was catalytically hydrogenated, using the procedure described above in Example 58B, there was obtained3-hydroxy-4-(3,3-dimethylbutanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid which melted at 176.degree.-178.degree. C. (uncorr.).
EXAMPLE 61
Following the procedure described above in Example 58A but using 7,7-dimethyloctanoyl chloride instead of isovaleryl chloride there is obtained 3-hydroxy-4-(7,7-dimethyloctanoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of thisbase with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 58B, there is obtained3-hydroxy-4-(7,7-dimethyloctanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 62
When dodecanoyl chloride is substituted for the isovaleryl chloride in the procedure described in Example 58A above, the product obtained is 3-hydroxy-4-(dodecanoyloxy)phenyl tert-butylaminomethyl ketone; by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated using the procedure described in Example 58B above, there is obtained 3-hydroxy-4-(dodecanoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.
EXAMPLE 63
When 2,2,17,17-tetramethyloctadecanoyl chloride is substituted for the isovaleryl chloride in the procedure described in Example 58A above, the product obtained is 3-hydroxy-4-(2,2,17,17-tetramethyloctadecanoyloxy)phenyl tert-butylaminomethylketone hydrochloride; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated using the procedure described in Example 58B above, there is obtained3-hydroxy-4-(2,2,17,17-tetramethyloctadecanoyloxy)-alpha-(tert-butylaminom ethyl)benzyl alcohol hydrochloride.
EXAMPLE 64
Following the procedure described above in Example 58A but using 1-methylcyclopropanecarbonyl chloride instead of isovaleryl chloride there is obtained 3-hydroxy-4-(1-methylcyclopropanecarbonyloxy)phenyl tert-butylaminomethyl ketone; and byinteraction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 58B, there is obtained3-hydroxy-4-(1-methylcyclopropanecarbonyloxy)-alpha-(tert-butylaminomethyl )benzyl alcohol hydrochloride.
EXAMPLE 65
Following the procedure described above in Example 58A but using cycloheptanecarbonyl chloride instead of isovaleryl chloride there is obtained 3-hydroxy-4-(cycloheptanecarbonyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of thisbase with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 58B, there is obtained3-hydroxy-4-(cycloheptanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 66
Following the procedure described above in Example 58A but using cyclohexaneacetyl chloride instead of isovaleryl chloride there is obtained 3-hydroxy-4-(cyclohexaneacetoxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 58B, there is obtained 3-hydroxy-4-(cyclohexaneacetoxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.
EXAMPLE 67
Following the procedure described above in Example 58A but using cyclopentanepropionyl chloride instead of isovaleryl chloride there is obtained 3-hydroxy-4-(cyclopentanepropionyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of thisbase with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 58B, there is obtained3-hydroxy-4-(cyclopentanepropionyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 68
Following the procedure described above in Example 58A but using nicotinoyl chloride instead of isovaleryl chloride there is obtained 3-hydroxy-4-(nicotinoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 58B, there is obtained 3-hydroxy-4-(nicotinoyloxy)-alpha-(tert-butylaminomethyl)benzylalcohol hydrochloride.
EXAMPLE 69
A. Following a procedure similar to that described in Example 58A above, 13 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was reacted with 8.1 g. of sodium methoxide in 200 ml. of N,N-dimethylformamide, and the resultingsodium phenolate was interacted with 8.5 g. of p-toluyl chloride to yield 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone. This base was converted to the methanesulfonate by treatment, in 200 ml. of warm N,N-dimethylformamide, withmethanesulfonic acid. The 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone methanesulfonate thus obtained was a white crystalline solid which weighed 12 g. and melted at 265.degree. C. (dec.)(uncorr.).
B. By catalytic hydrogenation of 12 g. of 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone methanesulfonate in 1 liter of 95 percent ethyl alcohol in the presence of 4 g. of palladium-on-charcoal catalyst there was obtained 7.4 g. of3-hydroxy-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline powder which melted at 203.degree.-205.degree. C. (uncorr.). The solubility of this salt in water at 25.degree. C. was at least 5 percent.
EXAMPLE 70
Following the procedure described above in Example 58A but using 2,3,4-trichlorobenzoyl chloride instead of isovaleryl chloride there is obtained 3-hydroxy-4-(2,3,4-trichlorobenzoyloxy)phenyl tert-butylaminomethyl ketone; and by interaction ofthis base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 58B, there is obtained3-hydroxy-4-(2,3,4-trichlorobenzoyloxy)-alpha-(tert-butylaminomethyl)benzy l alcohol hydrochloride.
EXAMPLE 71
A. Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted withisovaleryl chloride there is obtained 3-(isovaleryloxy)-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone, which reacts with hydrochloric acid to yield the hydrochloride salt as a white crystalline solid, m.p. 216.degree.-220.degree. C. (uncorr.).
B. By catalytic hydrogenation of 7.7 g. of 3-(isovaleryloxy)-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone hydrochloride in 200 ml. of 95 percent ethyl alcohol in the presence of 2.0 g. of 10 percent palladium-on-charcoal catalyst there wasobtained 6.1 g. of 3-(isovaleryloxy)-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride as a white crystalline solid which melted at 202.degree.-204.degree. C. (uncorr.). The solubility of this salt in water at 25.degree. C. wasat least 5 percent.
EXAMPLE 72
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted withpivalyl chloride there is obtained 3,4-bis(pivalyloxy)phenyl tert-butylaminomethyl ketone, which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above inExample 2B, there is obtained 3,4-bis(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride. The ketone intermediate and the alcohol product obtained in this manner are identical with the ketone and the alcohol described above in Example5A and 5B, respectively.
EXAMPLE 73
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted withdecanoyl chloride there is obtained 3-(decanoyloxy)-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the proceduredescribed above in Example 2B, there is obtained 3-(decanoyloxy)-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 74
Following a procedure similar to that described in Example 30A above, when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted witho-toluyl chloride there is obtained 3-(o-toluyloxy)-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the proceduredescribed above in Example 30B, there is obtained 3-(o-toluyloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 75
Following a procedure similar to that described in Example 30A above, when 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with3,4,5-trimethoxybenzoyl chloride there is obtained 3-(3,4,5-trimethoxybenzoyloxy)-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalyticallyhydrogenated, using the procedure described above in Example 30B, there is obtained 3-(3,4,5-trimethoxybenzoyloxy)-4-(pivalyloxy)-alpha-(tert-butylaminomethyl )benzyl alcohol hydrochloride.
EXAMPLE 76
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted withisovaleryl chloride there is obtained 3-(isovaleryloxy)-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the proceduredescribed above in Example 2B, there is obtained 3-(isovaleryloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 77
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is interactedwith 3,3-dimethylbutanecarbonyl chloride there is obtained 3-(3,3-dimethylbutanecarbonyloxy)-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalyticallyhydrogenated, using the procedure described above in Example 2B, there is obtained 3-(3,3-dimethylbutanecarbonyloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminome thyl)benzyl alcohol hydrochloride.
EXAMPLE 78
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted withdocosanoyl chloride there is obtained 3-(docosanoyloxy)-4-(p-tolulyloxy)phenyl tert-butylaminomethyl ketone which reacts with methanesulfonic acid to yield the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated, using theprocedure described above in Example 2B, there is obtained 3-(docosanoyloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate.
EXAMPLE 79
Following a procedure similar to that described in Example 30A above, when 3-hydroxy-4-(7,7-dimethyloctanoyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt isreacted with p-isopropoxyphenylacetyl chloride there is obtained 3-(p-isopropoxyphenylacetoxy)-4-(7,7-dimethyloctanoyloxy)phenyl tert-butylaminomethyl ketone which reacts with methanesulfonic acid to yield the methanesulfonate salt. When thismethanesulfonate is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3-(p-isopropoxyphenylacetoxy)-4-(7,7-dimethyloctanoyloxy)-alpha-(tert-buty laminomethyl)benzyl alcohol methanesulfonate.
EXAMPLE 80
Following a procedure similar to that described above in Example 30A, when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone is interacted with nicotinolyl chloride, there is obtained 3-(nicotinoyloxy)-4-(p-toluyloxy)phenyltert-butylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained3-nicotinoyloxy-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 81
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(nicotinoyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with9-octadecenoyl chloride there is obtained 3-(9-octadecenoyloxy)-4-(nicotinoyloxy)phenyl tert-butylaminomethyl ketone which reacts with methanesulfonic acid to yield the methanesulfonate salt. When this methanesulfonate is reduced with sodium borohydrideusing the procedure described above in Example 30C, there is obtained 3-(9-octadecenoyloxy)-4-(nicotinoyloxy)-alpha-(tert-butylaminomethyl)benzy l alcohol methanesulfonate.
EXAMPLE 82
Following a procedure similar to that described in Example 13A above, when 3-hydroxy-4-(isovaleryloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reactedwith 1,3-dimethylcyclobutanecarbonyl chloride there is obtained 3-(1,3-dimethylcyclobutanecarbonyloxy)-4-(isovaleryloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride iscatalytically hydrogenated, using the procedure described above in Example 13B, there is obtained 3-(1,3-dimethylcyclobutanecarbonyloxy)-4-(isovaleryloxy)-alpha-(tert-butyl aminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 83
A. Under an atmosphere of nitrogen, 8.4 g. of sodium methoxide is added with vigorous stirring to 16.8 g. of 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride suspended in 200 ml. of N,N-dimethylformamide. About 20 ml. of solventis distilled from the reaction mixture under reduced pressure to remove methyl alcohol. Then, under an atmosphere of nitrogen, 16 g. of 2,2-dimethylpentanoyl chloride is dripped in slowly at 5.degree. C. with vigorous stirring, and stirring iscontinued for one hour after all of the acid chloride has been added. The solvent is distilled off under reduced pressure and the resulting residue is partitioned between water and diethyl ether. The ether layer is separated and washed with water, andthe ether is distilled off to yield 3,4-bis(2,2-dimethylpentanoyloxy)phenyl isopropylaminomethyl ketone. This product is treated with hydrochloric acid in isopropyl alcohol, and the solvent is evaporated to yield 3,4-bis(2,2-dimethylpentanoyloxy)phenylisopropylaminomethyl ketone hydrochloride.
B. A solution of 3,4-bis(2,2-dimethylpentanoyloxy)-phenyl isopropylaminomethyl ketone hydrochloride in anhydrous ethyl alcohol is hydrogenated in the presence of 10 percent palladium-on-charcoal hydrogenation catalyst until one mole equivalent ofhydrogen has been absorbed. The hydrogenation mixture is filtered to remove the catalyst, the solvent is evaporated from the filtrate, and isopropyl acetate is added to the residue and then distilled off. The residue thus obtained is dissolved inboiling isopropyl acetate and the solution thus obtained is cooled. The precipitate which forms is collected on a filter, washed with isopropyl acetate and with diethyl ether, and dried at 70.degree. C. There is thus obtained3,4-bis(2,2-dimethylpentanoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride as a white crystalline powder.
EXAMPLE 84
When 7,7-dimethyloctanoyl chloride is substituted for the isobutyryl chloride in the procedure described in Example 2A above, the product obtained is 3,4-bis(7,7-dimethyloctanoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of thisbase with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated using the procedure described in Example 2B above, there is obtained3,4-bis(7,7-dimethyloctanoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol methanesulfonate.
EXAMPLE 85
When hexadecanoyl chloride is substituted for the isobutyryl chloride in the procedure described in Example 2A above, the product obtained is 3,4-bis(hexadecanoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base withmethanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated using the procedure described in Example 2B above, there is obtained 3,4-bis(hexadecanoyloxy)-alpha-(isopropylaminomethyl)benzylalcohol methanesulfonate.
EXAMPLE 86
When docosanoyl chloride is substituted for the isobutyryl chloride in the procedure described in Example 2A above, the product obtained is 3,4-bis(docosanoyloxy)phenyl isopropylaminomethyl ketone; and by interaction with methanesulfonic acidthere is obtained the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated using a procedure similar to that described in Example 2B above, there is obtained 3,4-bis-(docosanoyloxy)-alpha-(isopropylaminomethyl)benzyl alcoholmethanesulfonate.
EXAMPLE 87
Following the procedure described above in Example 2A but using 4-methylcyclohexaneacetyl chloride instead of isobutyryl chloride there is obtained 3,4-bis(4-methylcyclohexaneacetoxy)phenyl isopropylaminomethyl ketone; and by interaction of thisbase with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained3,4-bis(4-methylcyclohexaneacetoxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 88
When cycloheptanecarbonyl chloride is substituted for the isobutyryl chloride in the procedure described in Example 2A above, the product obtained is 3,4-bis(cycloheptanecarbonyloxy)phenyl isopropylaminomethyl ketone; and by interaction of thisbase with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated using a procedure similar to that described in Example 2B above, there is obtained3,4-bis(cycloheptanecarbonyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 89
When p-toluyl chloride is substituted for the isobutyryl chloride in the procedure described in Example 2A above, the acylation product obtained is 3,4-bis-(p-toluyloxy)phenyl isopropylaminomethyl ketone, m.p. 82.degree.-85.degree. C.(uncorr.). This base was treated with trifluoroacetic acid to yield the trifluoroacetate salt as a white crystalline solid which melted at 193.degree.-195.degree. C. (uncorr.) When 24 g. of this trifluoroacetate was catalytically hydrogenated using aprocedure similar to that described in Example 2B above there was obtained 19.5 g. of 3,4-bis(p-toluyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol trifluoroacetate, m.p. 115.degree.-117.degree. C. (uncorr.). A 15 g. portion of this salt wasconverted to the free base which was then treated with methanesulfonic acid to yield 10.5 g. of the methanesulfonate salt as a white crystalline solid which melted at 114.degree.-116.degree. C. (uncorr.).
EXAMPLE 90
When phenylacetyl chloride is substituted for the isobutyryl chloride in the procedure described in Example 2A above, the product obtained is 3,4-bis(phenylacetoxy)phenyl isopropylaminomethyl ketone; and by interaction of this base withhydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated using a procedure similar to that described in Example 2B above, there is obtained3,4-bis(phenylacetoxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 91
Following the procedure described above in Example 2A but using 3,7-dimethyl-3,6-octadienoyl chloride instead of isobutyryl chloride there is obtained 3,4-bis(3,7-dimethyl-3,6-octadienoyloxy)phenyl isopropylaminomethyl ketone; and by interactionof this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this base is reduced with sodium borohydride, using a procedure similar to that described above in Example 30C, there is obtained3,4-bis(3,7-dimethyl-3,6-octadienoyloxy)-alpha-(isopropylaminomethyl)benzy l alcohol. By catalytically hydrogenating 3,4-bis)3,7-dimethyl-3,6-octadienoyloxy)phenyl isopropylaminomethyl ketone methanesulfonate, using a procedure similar to that describedabove in Example 30B, there is obtained 3,4-bis(3,7-dimethyloctadecanoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol methanesulfonate.
EXAMPLE 92
When isonicotinoyl chloride is substituted for the isobutyryl chloride in the procedure described in Example 2A above, the product obtained is 3,4-bis(isonicotinoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base withmethanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated using a procedure similar to that described in Example 2B above, there is obtained3,4-bis(isonicotinoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol methanesulfonate.
EXAMPLE 93
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert.-butylaminomethyl ketone hydrochloride and octanoyl chloride instead of isovalerylchloride, there is obtained 3-hydroxy-4-(octanoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using aprocedure similar to that described above in Example 2b, there is obtained 3-hydroxy-4-(octanoyloxy)-alpha-(isopropylaminomethyl)-benzyl alcohol hydrochloride.
EXAMPLE 94
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 3,3-dimethylcyclobutanecarbonyl chlorideinstead of isovalery chloride, there is obtained 3-hydroxy-4-(3,3-dimethylcyclobutanecarbonyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochlorideis catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(3,3-dimethylcyclobutanecarbonyloxy)-alpha-(isopropylaminometh yl)benzyl alcohol hydrochloride.
EXAMPLE 95
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert.-butylaminomethyl ketone hydrochloride and phenoxyacetyl chloride instead ofisovaleryl chloride, there is obtained 3-hydroxy-4-(phenoxyacetoxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is catalyticallyhydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(phenoxyacetoxy)-alpha-(isopropylaminomethyl)benzyl alcohol methanesulfonate.
EXAMPLE 96
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 1-naphthalenecarbonyl chloride instead ofisovaleryl chloride, there is obtained 3-hydroxy-4-(1-naphthalenecarbonyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalyticallyhydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(1-naphthalenecarbonyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 97
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and p-toluyl chloride instead of isovalerylchloride, there is obtained 3-hydroxy-4-(p-toluyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using aprocedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(p-toluyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 98
Following a procedure similar to that described above in Example 58A but using 3,4-dihydroxyphenyl isopropylamino-methyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride, and nicotinoyl chlorideinstead of isovaleryl chloride, there is obtained 3-hydroxy-4-(nicotinoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalyticallyhydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(nicotinoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 99
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 2,3,4-trimethylbenzoyl chloride insteadof isovaleryl chloride, there is obtained 3-hydroxy-4-(2,3,4-trimethylbenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride iscatalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(2,3,4-trimethylbenzoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 100
Following the procedure described above in Example 58A, but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and m-dimethylaminobenzoyl chloride insteadof isovaleryl chloride, there is obtained 3-hydroxy-4-(m-dimethylaminobenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride iscatalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(m-dimethylaminobenzoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 101
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and o-propionamidobenzoyl chloride instead ofisovaleryl chloride, there is obtained 3-hydroxy-4-(o-propionamidobenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate iscatalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(o-propionamidobenzoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol and methanesulfonate.
EXAMPLE 102
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 2-chloro-3-methoxy-4-methylbenzoylchloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When thishydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)-alpha-(isopropylaminom ethyl)benzyl alcohol hydrochloride.
EXAMPLE 103
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 10,13-octadecadienoyl chloride instead ofisovaleryl chloride, there is obtained 3-hydroxy-4-(10,13-octadec a dienoyloxy) phenyl isopropylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesuflonate isreduced with sodium borohydride, using a procedure similar to that described above in Example 30C, there is obtained 3-hydroxy-4-(10,13-octadecadienoyloxy)-alpha-(isopropylaminomethy l)benzyl alcohol methanesulfonate. By catalytic hydrogenation of3-hydroxy-4-(10,13-octadienoyloxy)phenyl isopropylaminomethyl ketone methanesulfonate, using a procedure similar to that described above in Example 30B, there is obtained 3-hydroxy-4-(octadecanoyloxy)-alpha-(isopropylaminomethyl)benzyl methanesulfonate.
EXAMPLE 104
Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with3,3-dimethylpentanoyl chloride there is obtained 3-(3,3-dimethylpentanoyloxy)-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochlorideis catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-(3,3-dimethylpentanoyloxy)-4-(isovaleryloxy)-alpha-(isopropylaminomethyl )benzyl alcohol hydrochloride.
EXAMPLE 105
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride there is obtained3-hydroxy-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone.
Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted withp-toluyl chloride there is obtained 3-(p-toluyloxy)-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalyticallyhydrogenerated, using a procedure similar to that described above in Example 2B, there is produced 3-(p-toluyloxy)-4-(isovaleryloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 106
Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(p-toluyloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted withpicolinoyl chloride, there is obtained 3-(picolinoyloxy)-4-(p-toluyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalyticallyhydrogenated, usign a procedure similar to that described above in Example 2B, there is obtained 3-(picolinoyloxy)-4-(p-toluyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 107
Following a procedure similar to that described in Example 2A above, when 3-hydroxy- 4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodiumphenolate salt is reacted with isovaleryl chloride there is obtained 3-(isovaleryloxy)-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloridesalt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-(isovaleryloxy)-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)-alpha-(isoprop ylaminomethyl)benzyl alcoholhydrochloride.
EXAMPLE 108
Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(phenoxyacetoxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted withcyclohexanecarbonyl chloride there is obtained 3-(cyclohexanecarbonyloxy)-4-(phenoxyacetoxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride iscatalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-(cyclohexanecarbonyloxy)-4-(phenoxyacetoxy)-alpha-(isopropylaminomethyl) -benzyl alcohol hydrochloride.
EXAMPLE 109
Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodiumphenolate is reacted with 3,3-dimethylheptadecanoyl chloride there is obtained 3-(3,3-dimethylheptadecanoyloxy)-4-(2-chloro-3-methoxy-4-methylbenzoyloxy) phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there isobtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-(3,3-dimethylheptadecanoyloxy-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 110
Following a procedure similar to that described in Example 2A above when 3-hydroxy- 4-(3,3-dimethylcyclobutanecarbonyloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolatesalt is reacted with 2,5-hexadienoyl chloride there is obtained 3-(2,5-hexadienoyloxy)-4-(3,3-dimethylcyclobutanecarbonyloxy)phenyl isopropylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochlorideis reduced with sodium borohydride, using a procedure similar to that described above in Example 30C, there is obtained 3-(2,5-hexadienoyloxy)-4-(3,3-dimethylcyclobutanecarbonyloxy)-alpha-(isopr opylaminomethyl)benzyl alcohol hydrochloride.
EXAMPLE 111
A mixture of 13 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride, 25 m. of o-toluyl chloride, and 35 ml. of trifluoroacetic acid was heated for 30 minutes on a steam bath. The reaction mixture was concentrated under reducedpressure, and the resulting residue crystallized. This solid, which was crude 3,4-bis(o-toluyloxy)phenyl tert-butylaminomethyl ketone trifluoroacetate, was slurried in anhydrous ethyl ether and the slurry was made basic by treatment with ammoniumhydroxide. The ether layer was separated and washed first with dilute aqueous sodium hydroxide solution and then with water. The ether solution was filtered and the filtrate was slurried with 4.5 g. of methanesulfonic acid in 50 ml. of isopropylalcohol. The crystalline solid which precipitated was collected on a filter and recrystallized from 100 ml. of isopropyl alcohol and dried at 70.degree. C. There was thus obtained 15.8 g. of 3,4-bis(o-toluyloxy)phenyl tert-butylaminomethyl ketonemethanesulfonate as a white crystalline solid which melted at 134.degree.-137.degree. C. (dec.)(uncorr.). When this methanesulfonate (15.5 g.) was catalytically hydrogenated, using a procedure similar to that described above in Example 30B, there wasobtained 12.8 g. of 3,4-bis(o-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid which melted at 151.degree.-153.degree. C. (uncorr.).
EXAMPLE 112
Following a procedure similar to that described above in Example 111 but using m-toluyl chloride instead of o-toluyl chloride, there was obtained 14 g. of 3,4-bis(m-toluyloxy)phenyl tert-butylaminomethyl ketone hydrochloride as a whitecrystalline solid which melted at 215.degree.-218.degree. C. When 19 g. of this hydrochloride (5 g. of which was obtained from a second run) was catalytically hydrogenated, using a procedure similar to that described above in Example 30B, there wasobtained 3,4-bis(m-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride which was converted to the free base and then to the methanesulfonate, a white crystalline solid which weighed 12.0 g. and melted at 135.degree. C. (uncorr.).
EXAMPLE 113
Following a procedure similar to that described above in Example 111, 14 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was reacted with 27 g. of 2,3-dimethylbenzoyl chloride in 50 ml. of trifluoroacetic acid to yield3,4-bis(2,4-dimethylbenzoyloxy)phenyl tert-butylaminomethyl ketone trifluoroacetate. This salt was converted to the free base by treatment with sodium hydroxide solution and the free base was interacted with methanesulfonic acid to yield 22 g. of3,4-bis(2,4-dimethylbenzoyloxy)phenyl tert-butylaminomethyl ketone methanesulfonate as a white crystalline solid which melted at 120.degree.-123.degree. C. (dec.)(uncorr.). This salt (20 g.) was catalytically hydrogenated in N,N-dimethylformamide usinga procedure similar to that described above in Example 30B, to yield 18 g. of 3,4-bis(2,4-dimethylbenzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid which melted at 170.degree.-172.degree. C. (uncorr.).
EXAMPLE 114
Following a procedure similar to that described above in Example 111, 20 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was reacted with 37 g. of 2,5-di | | | |
