NOVEL PROCESS AND INTERMEDIATES USEFUL IN THE PREPARATION OF SYMPATHOMIMETIC AMINES

Abstract: Novel process and novel intermediates useful in the preparation of sympathomimetic amines. The pharmacologically useful final products, which are acyl derivatives of mono- and dihydroxy aromatic amines (e.g., catechol amines) can be prepared in optically active or racemic form by reacting the corresponding mono- or dihydroxy aromatic amine with a reagent capable of forming the N-tert-butoxycarbonyl derivative thereof; reacting the novel intermediate thus obtained with an acyloxymethyl chloride to afford the corresponding novel mono- or diacylated N-protecting aromatic amine; and removing the N-protecting group therefrom.

Description: NOVEL PROCESS AND INTERMEDIATES USEFUL IN THE PREPARATION OF SYMPATHOMIME IC AMINES TECHNICAL FIELD; The present invention is directed to a novel synthetic process for preparing esters of catechol amines and other sympathomimetic amines in optically active or racemic form, and to novel N-tert-butoxycar- bonyl intermediates useful in the subject process. BACKGROUND ART; United States Patent Nos. 3,809,714, 3,825,583, 3,839,584, 3,868,461, 3,959,485, 3,966,749, 3,908,017, 4,035,405, 4,088,783, 4,145,441 and 4,158,005 disclose a number of sympathomimetic amine derivatives within the general formula (I) set forth hereinbelow, and nontoxic pharmaceutically acceptable acid addition salts thereof. The compounds of formula (I) and their salts are useful in the treatment of conditions responsive to sympathomimetic amines, e.g., glaucoma, asthma and nasal congestion. Prior art methods for the preparation of compounds within the scope of the formula (I) below generally have provided the compound in the form of a racemic mixture, i.e., a mixture containing both the biologically active and the biologically inactive isomer. Normally, the compounds of formula (I) have been administered in the form of a racemic mixture, as the means to separate the optically active, biologi¬ cally active isomers from their racemic mixtures are tedious and expensive. In fact, resolution of the racemic mixtures of many of the compounds of formula (I) has not been reported in the literature. Consequently, it is apparent that a need exists for a means of directly synthesizing the opti¬ cally active, biologically active forms of the com¬ pounds of formula (I), thus avoiding the necessity of first obtaining the racemic mixture and then either resolving the racemic mixture and administering the optically and biologically active isomer thereof, or else, as is more frequently the case, administering the racemic mixture itself. In the latter case, it is apparent that the dosage amount of a racemic mixture which would be required to achieve therapeusis would be much greater than that required if only the optically active, biologically active isomer were administered. DISCLOSURE OF INVENTION; Accordingly, the present invention has as an object a novel process for the preparation of a com¬ pound of the formula wherein R*^ is H or alkyl of 1 to 7 carbon atoms; R 2 is H, alkyl of 1 to 7 carbon atoms, or -alkylene wherein m is zero or one, the alkylene portion contains 1 to 5 carbon atoms, and X is H or -OR' 4 wherein R' 4 is identical to R 4 as defined below; R 3 is H, Cl, -CH 2 OH or -OR" wherein R" 4 is identical to R 4 as defined as below; and R 4 is an acyl radical; or a nontoxic pharmaceutically acceptable acid addition salt thereof; which is characterized by: (a) reacting a compound of the formula wherein R-^ is defined as above; R is H, Cl, -CH 2 OH or -OH; and R 5 is H, alkyl of 1 to 7 carbon atoms, or -alkylene-(0) - 3/ X ' wherein and alkylene are defined as above and X' is H or -OH; with a reagent capable of forming the N-tert-butoxycarbonyl derivative thereof; (b) reacting the resultant N-tert-butoxycar- bonyl compound of the formula wherein R, R-^ and R- are defined as above, with an acyloxymethyl chloride of the formula R 4 0CH 2 C1 ( IV) wherein 4 is an acyl radical, in an organic solvent in the presence of a base, to effect acylation of all phenolic hydroxy groups in said compound of formula (III); and (c) removing the tert-butoxycarbonyl protect¬ ing group from the resultant compound of the formula wherein R*^, R 2 , R3, and R 4 are defined as above. The novel process for the preparation of compounds of formula (I) and their nontoxic pharmaceu¬ tically acceptable acid addition salts which is set forth above provides the desired compounds in optically active or in racemic form, depending on the particular starting material employed. Said process further pro¬ vides novel intermediates useful in the preparation of the compounds of formula (I), said novel intermediates having the structural formulas (III) and (V) set forth above. OMP /,. V/IP -S~ DETAILED DESCRIPTION OF THE INVENTION AND BEST MODE FOR CARRYING OUT THE INVENTION: With respect to the various groups encom¬ passed by the generic terms used here and throughout this specification, the following definitions and explanations are applicable: The alkyl groups encompassed by R*^ include straight and branched-chain radicals containing the indicated number of carbon atoms, with methyl and ethyl being preferred. The alkyl groups encompassed by R 2 and R- likewise can be straight or branched-chain containing the indicated number of carbon atoms. In the case of the R and R- substituents, preferred alkyl groups are methyl, isopropyl and tert-butyl. When R 2 is an -alkylene- when R- is an -alkylene-(0) m - θ/ "X group, the a y ene bridge can be a straight or branched-chain group of the type C n H 2n , wherein n is 1 to 5, e.g. ethylene, 1,2- propylene and 1,3-butylene. With respect to the acyl groups represented by the R 4 term, it is to be noted that at each occur¬ rence R 4 preferably represents an acyl radical selected from the group consisting of alkanoyl having 1 to 22 carbon atoms; alkenoyl having one or two double bonds 0 I! and having 4 to 22 carbon atoms; cycloalkyl-C H 2 -C- having a total of 4 to 10 carbon atoms of which 3 to 7 are ring carbon atoms in the cycloalkyl portion and wherein n is zero, one or two; phenoxyacetyl; naphtha- lenecarbonyl; pyridinecarbonyl; and p enyl-C n H 2n -C- wherein n is zero, one or two and phenyl is unsubsti- OMPI Λ -• IPO tuted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, t ifluoromethyl, dialkylamino having 2 to 8 car¬ bon atoms or alkanoyla ino having 1 to 6 atoms. When R 4 is alkanoyl containing 1 to 22 carbon atoms, there are included both unbranched and branched alkanoyl, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, 2-methyl- butanoyl, pivalyl (pivaloyl) , 3-methylpentanoyl, 3,3- dimethylbutanoyl, 2,2-dimeth lpentanoyl, docosanyl and 7,7-dimethyloctanoyl. Branched alkanoyl groups are generally preferred, an especially preferred group being pivaloyl. When R 4 is alkenoyl having one or two double bonds and having 4 to 22 carbon atoms, there are included, for example, crotonyl, 9-octadecenoyl, 2,5- hexadienoyl, 3,6-octadienoyl, 10,13-octadecadienoyl and 5,13-docosadienoyl. 0 1! When R is cycloalkyl-C n H 2n -C-, there are included cycloalkanecarbonyl and cycloalkanealkanoyl groups wherein the cycloalkane portion can optionally bear 1 or 2 alkyl groups as substituents, e.g., cyclo- propanecarbonyl, 1-methylcyclopropanecarbonyl, cyclo- propaneacetyl, alpha-methylcyclopropaneacetyl, 1- methylcyclopropaneacetyl, 2-amylcyclopropaneacetyl, cyclopropanepropionyl, alpha-methylcyclopropanepro- pionyl, 2-isobutylcyclopropanepropionyl, 2-hexylcyclo- propanecarbonyl, cyclobutanepropionyl, 2-methylcyclo- butanecarbonyl, 1,3-dimethylcyclobutanecarbonyl, 3,3- dimethylcyclobutanecarbonyl, cyclobutaneacetyl, 2,2- dimethyl-3-ethylcyclobutaneacetyl, cyclobutanepro¬ pionyl, cyclopentanecarbonyl, l-methyl-3-isoρropyl- cyclopentanecarbonyl, cyclopentanepropionyl, cyclo- hexaπecarbonyl , cyclohexaneacetyl , 4-methylcyclohexane- acetyl , cycloheptanecarbonyl , 4-methylcycloheptane- acetyl , and cycloheptanepropionyl . 0 II L When R 4 is phenyl-C n H 2n -C- there are included, for example, benzoyl, phenylacetyl, alpha- phenylpropionyl, beta-phenylpropionyl, p-toluyl, m-toluyl, o-toluyl, o-ethylbenzoyl, p-tert-butyl- benzoyl, 3,4-dimethylbenzoyl, 2-methyl-4-ethylbenzoyl, 2,4,6-trimethylbenzoyl, m-methylphenylacetyl, p- isobutylphenylacetyl, beta-(p-ethylphenyl)proρionyl, 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- diethoxyphen lacetyl, 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, -trifluoromethyIphenylacetyl, beta-(p- trifluoromethylphenyl)propionyl, 2-methyl-4- ethoxybenzoyl, 3-chloro-4-ethoxybenzoyl, beta-(3- methyl-4-chlorophenyl)proρionyl, p-dimethyl- aminobenzoyl, m-diethylaminobenzoyl, p-dibutylamino- benzoyl, p-(N-methyl-N-ethylamino)benzoyl, o-acetamido- benzoyl, m-propionamidobenzoyl, p-hexanoylaminobenzoyl, 3-chloro-4-acetamidophenylacetyl, and p-acetamido- phenylpropionyl. When R 4 is naphthalenecarbonyl, there •are included 1-naphthalenecarbonyl and 2-naphthalene- carbonyl. When 4 is pyridinecarbonyl, there are included picolinoyl (2-pyridinecarbonyl) , nicotinoyl (3-pyridinecarbonyl) , and isonicotinoyl (4-pyridine- carbon l) . Finally, the term "nontoxic pharmaceutically acceptable acid addition salt" as used herein generally includes the nontoxic acid addition salts of selected compounds of formula (I), formed with nontoxic inorga¬ nic or organic acids. For example, the salts include those derived from inorganic acids such as hydro¬ chloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycollic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, fumaric, sulfonic, toluenesulfonic, and the like. By selecting the appropriate reactants for the ultimate specie desired, the compounds of formula (I) are conveniently prepared in accordance with the synthetic scheme of the present invention. The compounds of formula (I) which are pre¬ pared by the process of the present invention find therapeutic application in the treatment of warm- blooded animals (e.g., humans) in the management of asthma, as decongestants, vasoconstrictors, mydriatic agents and anti-glaucomatous agents, and in the treat¬ ment of other conditions responsive to sympathomimetic amines. Upon administration, the compounds of formula (I) will enzymatically "cleave" and release the parent phenol, the therapeutically active moiety thereof. Thus, in a preferred embodiment, the present invention provides a novel process and novel intermediates to acylated derivatives of such known sympathomimetic OM ■ WIP amines as epinephrine, isoproterenol, norepinephrine, phenyleprine, metaraminol, metaproterenol, terbutaline, nordeferin, colterol, deterenal, albuterol and feno- terol, and the nontoxic pharmaceutically acceptable acid addition salts thereof. The instant process and intermediates are especially preferred when they pro¬ vide acylated derivatives of the aforementioned sym¬ pathomimetic amines wherein the acyl group is alkanoyl as hereinbefore defined, most especially when the alkanoyl group is branched, e.g., pivaloyl. Also, while it is a particular and surprising advantage of the present process that the stereochemical integrity of the starting material of formula (II) can be main¬ tained throughout the instant reaction scheme, thus affording an attractive synthetic route to the opti¬ cally and biologically active isomers of formula (I), it will be apparent to those skilled in the art that the process of the invention can be employed equally as well in the production of racemic mixtures as in the preparation- of optically active isomers. As such, the scope of the present invention extends to this feature as well. Turning now to the individual steps of the novel process of the present invention, it is noted that step (a), which provides novel N-tert-butoxy- carbonyl derivatives of formula (III) above, proceeds by reacting a starting material of formula (II) with a reagent capable of forming the N-tert-butoxycarbonyl derivative thereof. Such reagents are well-known to those skilled in the art of peptide synthesis, where they are widely used to protect the amino group of a ino acids. Typical reagents include jt_-butylazido- formate, di(_t_-butyl)dicarbonate and the like, with _ -butylazidoformate being a preferred reagent. Obvi- '- ously, the choice of solvent and other reaction condi¬ tions will depend upon the particular reagent employed, suitable solvents and conditions being apparent to those skilled in the art of peptide synthesis. In the case of _t-butylazidoformate, the reaction can be con¬ veniently conducted in pyridine, preferably in the presence of triethylamine, although a dioxane/magnesium oxide solvent system may be employed in place of the pyridine/triethylamine. Time and temperature depend on the particular starting material of formula (II), the particular reagent and the particular solvent system employed. Generally speaking, heating accelerates the reaction, which is typically complete in 16 hours or less at a temperature of 40-90°C. The reaction is conveniently conducted at atmosphere pressure, prefer¬ ably under nitrogen. With respect to step (b) of the instant pro¬ cess, i.e. reacting a novel N-tert-butoxycarbonyl derivative of formula (III) with an acyloxymethyl chloride of formula (IV), it is to be noted that this reaction is surprising in two respects, namely: (1) that the phenolic hydroxy group(s) of the compound of formula (III) react to form the corresponding ester group(s), not the acyloxymethyl ether group(s) as would normally be expected; and (2) that the stereochemical integrity of the starting material is maintained during the acylation. The reaction is conducted in an organic solvent in the presence of a base. Suitable base/solvent combinations are those which are known to neutralize phenolic hydroxy groups without causing undesirable side reactions such as oxidation. Choice of particular solvent and base will depend upon the nature of the starting material of formula (III). For example, in the case of catechol amines, e.g. deriva- OMPI v.'IPO tives of epinephrine, a potassium carbonate/acetone combination has been found to be highly desirable. On the other hand, when the starting material of formula (III) is not a catechol, e.g. a 3,5-dihydroxyphenol or a monohydroxyphenol, then a stronger base such as potassium carbonate may be used in an appropriate sol¬ vent, e.g. methanol. Time, temperature and pressure are not critical factors. The reaction is conveniently conducted at atmospheric pressure, under nitrogen. Time and temperature vary with the particular starting materials employed. Typical reaction times are 30 minutes to 4 days, while typical temperatures are from room temperature to reflux. With respect to step (c) of the process of the present invention, i.e. removal -of the amino pro¬ tecting group from the compound of formula (V) , it is to be noted that this reaction is analogous to those well-known in the art to peptide synthesis. Thus, removal of the protecting group can be achieved by any means suitable for removing a tert-butoxycarbonyl group without affecting the remaining portions of the mole¬ cule, for example, by use of trifluoroacetic acid in dichloromethane, or hydrogen chloride in ethyl acetate, at room temperature or, preferably, below room tempera- ture, for a short period of time (e.g. 15 minutes to 2 hours). The use of HCl in ethyl acetate is a preferred means of removing the protecting group, since it affords the compound of formula (I) in the form of its highly desirable hydrochloride salt. However, the salt formed by the acid which is used to remove the protect¬ ing group can be readily neutralized to the free base of formula (I) and then, if desired, reacted with an appropriate acid to form the corresponding nontoxic, pharmaceutically acceptable acid addition salt. Alter- natively, the salt obtained after removal of the pro¬ tecting group, e.g. the hydrochloride, can be subjected to an ion exchange procedure in order to obtain a dif¬ ferent, nontoxic, pharmaceutically acceptable salt of formula (I). Preferred embodiments of the present inven¬ tion as set forth in the "DISCLOSURE OF INVENTION" hereinabove include the process there detailed: (1) when R 4 is one of the preferred acyl radicals recited hereinabove on pages 5-6; (2) when R* j _ is hydrogen; (3) when R and R3 are each hydrogen; (4) when R is -OH and R3 is -OR" 4 ; (5) when R* j _ is methyl or ethyl; (6) when R 2 and R- are each hydrogen; (7) when 2 and R- are each C- j -C alkyl, especially when they are each methyl, isopropyl or tert-butyl; (8) when R 2 and R 5 are -alkylene-(0) m —gr x and -alkylene-(0) m —-@T X ' , respectively, especially when alkylene is ethylene, 1,2-propylene or 1,3-butylene; (9) when the product of formula (I) is an optically and biologically active isomer; (10) when the starting material of formula (II) is selected from the group consisting of epinephrine, isoproterenol, norepinephrine, phenylephrine, metaraminol, metaproterenol, terbutaline, nordeferin, colterol, deterenal, albuterol and fenoterol, especially when the starting material of formula (II) is R-(-)-epinephrine; (11) when the reagent employed in step (a) is _t-butylazidoformate, particularly when the reagent is and the step (a) reaction is conducted in pyridine and/or the step (a) reaction is conducted in the presence of triethylamine and/or the step (a) reaction is conducted at a temperature of from about 40 to about 90°C; (12) when the acyloxymethyl chloride employed in step (b) is an alkanoyloxymethyl chloride wherein the alkanoyl group OM V /-. ip contains 1 to 22 carbon atoms, especially when the acyloxymethyl chloride employed in step (b) is chloromethyl pivalate and/or when the organic solvent employed in step (b) is acetone and/or when the base employed in step (b) is potassium carbonate; (13) when in step (c) the tert-butoxycarbonyl protecting group is removed by use of a reagent which affords the desired compound of formula (I) in the form of a non-toxic, pharmaceutically acceptable acid addition salt; (14) when, in step (c) the tert-butoxycarbonyl protecting group is removed by use of hydrogen chloride in ethyl acetate; and, especially, (15) when the acyloxymethyl chloride of formula (IV) is chloromethyl -pivalate and the starting material of formula (II) is epinephrine, most especially when the latter is R-(-)-epinephrine. A preferred aspect of the present invention is step (b) of the process set forth in the "DISCLOSURE OF INVENTION" hereinabove. Preferred embodiments of the one-step process (b) include that process when the structural variables and/or reaction conditions are as set forth in (1), (2), (3), (4), (5), (6), (7), (8) or (12) in the preceding paragraph, or when the starting material of formula (III) is selected from the group consisting of the N-tert-butoxycarbonyl derivatives of epinephrine, isoproterenol, norepinephrine, phenyl- ephrine, metaraminol, metaproterenol, terbutaline, nordeferin, colterol, deterenal, albuterol and fenoterol, especially when the formula (III) starting material is the N-tert-butoxycarbonyl derivative of R-(-)-epinephrine and/or the acyloxymethyl chloride is chloromethyl pivalate. In yet another preferred aspect, the present invention provides novel intermediates of formulas (III) and (V) as set forth hereinabove. Preferred compounds of formula (III) include those wherein R is hydrogen or -OH; and/or wherein R-^ is hydrogen, methyl or ethyl; and/or wherein R- is hydrogen, alkyl of 1-7 carbon atoms (especially methyl, isopropyl or tert- butyl) ( es P eciall Y when alky ¬ lene is ethylene, 1,2-propylene or 1,3-butylene) . Particularly preferred compounds of formula (III) are the N-tert-butoxycarbonyl derivatives of epinephrine, isoproterenol, norepinephrine, phenylephrine, meta- raminol, metaproterenol and terbutyline. An especially preferred species of formula (III) is R-3,4-dihydroxy-α-[(N-methyl-N-tert-butoxycarbonyl)- aminometh 1]benzyl alcohol. Insofar as concerns the novel intermediates of formula (V) , preferred compounds include those wherein R-*. is hydrogen, methyl or ethyl; and/or wherein R 2 is hydrogen, alkyl of 1 to 7 carbon atoms ethylene, 1,2-propylene or 1,3-butylene) ; and/or wherein R 3 is hydrogen or -OR" 4 ; and/or wherein R 4 is an acyl radical selected from the group consisting of (1) alkanoyl having 1 to 22 carbon atoms, (2) alkenoyl having one or two double bonds and having 4 to 22 car- bon atoms, (3) cycloalkyl-C n H 2n -C- having a total of 4 to 10 carbon atoms of which 3 to 7 are ring carbon atoms in the cycloalkyl portion and wherein n is zero, one or two, (4) phenoxyacetyl, (5) naphthalenecarbonyl, 0 II (6) pyridinecarbonyl, and (7) ρhenyl-C n H 2n -C- wherein n s zero, one or two and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, tri- fluoromethyl, dialkyla ino having 2 to 8 carbon atoms- or alkanoylamino having 1 to 6 carbon atoms. Among the preferred acyl radicals encompassed by R 4 in formula (V) as defined in the preceding sentence, particularly preferred are the C* j _-C 22 alkanoyl radicals, especially those wherein the alkanoyl group is branched-chain, and most especially when the branched-chain group is pivaloyl. Preferred species of formula (V) include the N-tert-butoxycarbonyl 3,4-dipivalate derivatives of epinephrine, isoproterenol and norepinephrine; the N- tert-butoxycarbonyl 3-pivalate derivatives of phenylephrine and metaraminol; and the N-tert- butoxycarbonyl 3,5-diρivalate derivatives of metaproterenol and terbutaline. An especially preferred species of formula (V) is R-α-[(N-methyl-N- tert-butoxycarbonyl)a inomethyl] enzyl alcohol 3,4- dipivalate. Without further elaboration, it is believed that one of ordinary skill in the art can, using the preceding description, utilize the present invention to its fullest extent. Consequently, the following pre¬ ferred specific embodiments are to be construed as merely illustrative and not limitative, as various modifications, substitutions, omissions and additions may be made without departing from the spirit of the invention. EXAMPLE 1 Preparation of R-3,4-Dihydroxy-α-[(N-methyl-N-tert- butoxycarbonyl)aminomethyl]benzyl alcohol 18.3 G (0.10 mole) of R-(-)-epinephrine (also known as 1-eρinephrine) and 14.3 g (0.10 mole) of t- -£URE-A OMPI V.'IPO - ' butylazidofor ate [L.A. Carpino et al, -Organic Synthe-. sis. Collective Vol. 5, H.E. Baumgarten, ed., John Wiley and Sons, New York, p. 157 (1973)] were combined with 13.9 ml (0.1 mole) of triethylamine in 25 ml of pyridine. The reaction mixture was stirred under nitrogen at 60°C. for approximately 16 hours. The solvent was evaporated from the resultant solution and the residue was taken up in 200 ml of ether. The ether solution was washed successively with 10% hydrochloric acid, saturated sodium bicarbonate solution, water, and saturated sodium chloride solution, then was dried over magnesium sulfate and evaporated to give 14.6 g of a reddish brown glass. IR (CHCI3): 3540 (free OH), 3360 O (OH), 1660 cm "1 (-N-C-0-). NMR (CDCL3TMS): δl.40 (s, 9H, C(CH3) 3 ), 2.73 (s, 3H, NCH3) , 3.33 (broad s, 2H, -CH^N), 4.70 (broad s, 1H, CH_-OH) , 6.70 (broad s, 2H, aromatic), 6.80 (broad s, 1H, aromatic). Similarly prepared from dl-epinephrine, dl- isoproterenol, ^-isoproterenol, _l_-norepineρhrine, 1^- phenylephrine, _l_-metaraminol, dl-metaproterenol and dl- terbutaline are the -butoxycarbonyl derivatives there¬ of, namely dl-3,4-dihydroxy- -[(N-methyl-N-tert- butoxycarbonyl)aminomethyl]benzyl alcohol; dl-3,4-dihy- droxy- -[(N-isopropyl-N-tert-butoxycarbonyl)amino- methyl]benzyl alcohol; l_-3 , -dihγάroxγ- α-[(N-iso- propyl-N-tert-butoxycarbonyl)aminomethyl]benzyl alco¬ hol; 1_~ α-[(N-tert-butoxycarbonyl)aminomethyl]-3,4- dihydroxybenzyl alcohol; _lr m ~kvci rc - x Y~ α-[(N-methyl-N- tert-butoxycarbonyl)aminomethyl]benzyl alcohol; _l_~ α -*-1.L- (N-tert-butoxycarbonyl)aminoethyl]-m-hydroxybenzyl alcohol; dl-3,5-dihydroxy- -[(N-isopropyl-N-tert- butoxycarbonyl)aminomethyl]benzyl alchol; and dl-α-[(N~ "& SRE OMPI , . IPO tert-butyl-N-tert-butoxycarbonyl)aminomethyl]-3,5- dihydroxybenzyl alcohol, respectively. EXAMPLE 2 Preparation of R- g-[(N-Methyl-N-tert-butoxycarbo- nyl)aminomethyl]benzyl alcohol 3,4-dipivalate To 100 ml of dry acetone were added 2.6 g (.0095 mole) of R-3,4-dihγdroxy- α-[(N-methyl-N-tert- butoxycarbonyl)aminomethyl]benzyl alcohol, 14.3 g (.095 mole) of chloromethyl pivalate, and 2.6 g (.0095 mole) of potassium carbonate. The reaction mixture was stirred overnight, then filtered. The filtrate was evaporated to dryness and the resulting oil was dis¬ solved in a small amount of petroleum ether [b.p. 30- 60°C). That solution was then chromatographed on a silica gel column. Elution with 2 column volumes of petroleum ether (b.p. 30-60°C) gave 7.0 g of recovered chloromethyl pivalate. The desired crude product was obtained by elution with 2 column volumes of ethyl acetate, followed by evaporation of solvent. The crude material was rechromatographed on silica gel and eluted with chloroform to give a pale yellow oil which crystallized upon standing. That solid was recrystal- lized from petroleum ether [b.p. 30-60°C) to give 1.9 g of product, mp 103-105°C. Analysis: Cal'd for C 24 H 37 N0 7 : C, 63.83; H, 8.26; N, 3.10. Found: C, 63.95; H, 8.50; N, 2.99. In a similar manner, the _t-butoxycarbonyl derivatives of dl-epinephrine, dl-isoproterenol, 1- isoproterenol, j^-norepinephrine, _l_-phenylephrine, _1_- metaraminol, dl-metaproterenol and dl-terbutaline are reacted with chloromethyl pivalate to afford the cor- responding _t_-butoxycarbony1 pivalatcs and dipivalates, i.e., dl-r α-[(N-methyl-N-tert-butoxycarbonyl)amino- methyl]benzyl alcohol 3,4-dipivalate; dl- α -[(N-iso- propyl-N-tert-butoxycarbonyl)aminomethyl]benzyl alcohol 3,4-dipivalate; _1_- a-[(N-isopropyl-N-tert-butoxycar- bonyl)aminomethyl]benzyl alcohol 3,4-dipivalate; _l_-α- [(N-tert-butoxycarbonyl)aminomethyl]benzyl alcohol 3,4- dipivalate; 1_- α-[(N-methyl-N-tert-butoxycar- bonyl)aminomethyl]benzyl alcohol 3-ρivalate; _1_- - - [1- (N-tert-butoxycarbonyl)aminoethyl]benzyl alcohol 3- pivalate; dl- α-[(N-isopropyl-N-tert-butoxycarbo- nyl)aminomethyl]benzyl alcohol 3,5-dipivalate; and dl- α-[(N-tert-butyl-N-tert-butoxycarbonyl)aminomethyl]- benzyl alcohol 3,5-dipivalate, respectively. EXAMPLE 3 Preparation of R-(-)- α-[(Methylamino)methyl]benzyl alcohol 3,4-dipivalate hydrochloride A solution of 400 mg of R- < ~ -[(N-methyl-N- tert-butoxycarbonyl)aminomethyl]benzyl alcohol 3,4- dipivalate in 10 ml of ethyl acetate was cooled to 4°C in an ice bath and dry nitrogen was bubbled into the solution. After cooling, hydrogen chloride gas was bubbled into the solution until thin layer chromatography indicated that no unreacted starting material remained (approximately 1 hour) . Solvent was removed from the reaction mixture to give a white foam. That residue was crystallized from a 1:1 mixture of acetone and hexane to afford 300 mg of white crystals, .p. 155-157°C, [ α ] D 25 = -27.4 (C = 1.25, H 2 0). Analysis: Cal'd for C 19 H 30 Cl O 5 : C, 58.83: H, 7.80; N, 3.61. Found: C, 58.50; H, 7.95; N, 3\36. The product is also known as _lr DPE hydrochloride or _ - dipivalylepinephrine hydrochloride. In a similar manner, substitution of the products named in the second paragraph of Example 2 in the procedure detailed above, or its obvious chemical equivalent, affords the following products: dl- α - [( ethylamino)methyl]benzyl alcohol 3,4-dipivalate hydrochloride; dl- α -[ (isopropylamino) ethyl]benzyl alcohol 3,4-dipivalate hydrochloride; _1_- α [(isopropyl- amino)methyl]benzyl alcohol 3,4-dipivalate hydro¬ chloride; _1_- α -(aminomethyl)benzyl alcohol 3,4-dipi- valate hydrochloride; _1_- α -[(methylamino)methyl]benzyl alcohol 3-pivalate hydrochloride; _1_- α-(J-_-aminoethyl)- benzyl alcohol 3-pivalate hydrochloride; dl-g - [(isopropylamino)methyl]benzyl alcohol 3,5-dipivalate hydrochloride; and dl- -[(tert- butylamino)methyl]benzyl alcohol 3,5-dipivalate hydrochloride, respectively. Industrial Applicability: The invention provides a novel direct synthe¬ tic route to the optically active, biologically active forms of the acyl derivatives of mono- and dihydroxy aromatic amines of formula (I) above, e.g. R-(-)-α-[Cmsthylamino)methyl]benzyl alcohol 3,4- dipivalate hydrochloride, which avoids the necessity of first obtaining the racemic mixture of both the biologically active and the biologically inactive isomer. The compounds of formula (I) are used therapeutically in the treatment of conditions responsive to sympathomimetic amines, e.g. glaucoma.

Claims: WHAT IS CLAIMED IS: 1. A process for the preparation of a com¬ pound of the formula wherein R^ is H or alkyl of 1 to 7 carbon atoms; R 2 is H, alkyl of 1 to 7 carbon atoms, or -alkylene-(0) m —θ) X wherein m is zero or one, the alkylene portion contains 1 to 5 carbon atoms, and X is H or -0R' 4 wherein R' 4 is identical to as defined below; R3 is H, Cl, -CH 2 OH or -0R" 4 wherein R" 4 is identical to R 4 as defined below; and R is an acyl radical; or a nontoxic pharmaceutically acceptable acid addition salt thereof; which is characterized by: (a) reacting a compound of the formula wherein R-, is defined as above; R is R, Cl, -CH 2 OH or -OH; and R 5 is H, alkyl of 1 to 7 carbon atoms, or -alkylene-(0) - θT X wherein m and alkylene are defined as above and X' is H or -OH; with a reagent capable of forming the N-tert-butoxycarbonyl derivative thereof; (b) reacting the resultant N-tert-butoxy- carbonyl compound of the formula wherein R, R-*_ and R 5 are defined as above, with an acyloxymethyl chloride of the formula R 4 0CH 2 C1 (IV) wherein R is an acyl radical, in an organic solvent in the presence of a base, to effect acylation of all phenolic hydroxy groups in said compound of formula (III); and (c) removing the tert-butoxycarbonyl protec¬ ting group from the resultant compound of the formula wherein R*^, 2 , R and R 4 are defined as above. 2. A process for the preparation of a com¬ pound of the formula wherein -^ is H or alkyl of 1 to 7 carbon atoms; R 2 is H, alkyl of 1 to 7 carbon atoms, or -alkylene-(O)πr(θ/ wherein m is zero or one, the alkylene portion contains 1 to 5 carbon atoms, and X is H or -0R* 4 wherein R' 4 is identical to R 4 as defined below; R 3 is H, Cl, -CH 2 0H or -OR" 4 wherein R" 4 is identical to R 4 as defined below; and R 4 is an acyl radical; which is charac¬ terized by reacting an N-tert-butoxycarbonyl compound of the formula wherein R*^ is defined as above; R is H, Cl, -CH 2 0H or to 7 carbon atoms, or m and alkylene are defined with an acyloxymethyl chloride of the formula R 4 0CH 2 C1 (IV) wherein R 4 is an acyl radical, in an organic solvent, in the presence of a base, to effect acylation of all phenolic hydroxy groups in said compound of formula (III). 3. A process according to Claim 1 or 2 wherein R 4 is an acyl radical selected from the group consisting of alkanoyl having 1 to 22 carbon atoms; alkenoyl having one or two double bonds and having 4 to O 22 carbon atoms; cycloalkyl-C n H 2n -C- having a total of 4 to 10 carbon atoms of which 3 to 7 are ring carbon atoms in the cycloalkyl portion and wherein n is zero, one or two; phenoxyacetyl; 1-naphthalenecarbonyl; 2— naphthalenecarbonyl; 2-pyridinecarbonyl; 3-pyridinecar- O bonyl; 4-pyridιnecarbonyl; and phenyl-C n H 2n -C- wherein n is zero, one or two and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, tri- fluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 1 to 6 carbon atoms. 4. A process according to Claim 1 or 2 wherein R 4 is alkanoyl having 1 to 22 carbon atoms. 5. A process according to Claim 1 or 2 wherein the compound of formula (III) is selected from the group consisting of the N-tert-butoxycarbonyl deri¬ vatives of epinephrine, isoproterenol, norepinephrine, phenylephrine, metara inol, metaproterenol, terbuta- line, nordeferin, colterol-, deterenal, albuter.ol and fenoterol. 6. A process according to Claim 1 or 2 wherein the compound of formula (III) is the N-tert- butoxycarbonyl derivative of R-(-)-epinephrine. 7. A process according to Claim 1 or 2 wherein the acyloxymethyl chloride is chloromethyl pivalate. 8. A process according to Claim 6 wherein the acyloxymethyl chloride is chloromethyl pivalate. 9. A compound of the formula wherein R is H, Cl, -CH 2 0H or -OH; R- j _ is H or alkyl of zero or one, t e a y ene port on conta ns to 5 carbon atoms, and X' is H or -OH. 10. A compound of Claim 9 which is selected from the group consisting of the N-tert-butoxycarbonyl derivatives of epinephrine, isoproterenol, norepine¬ phrine, phenylephrine, metaraminol, metaproterenol and • terbutaline. 11. A compound of Claim 9 which is R-3,4- dihydroxy- α -[(N-methyl-N-tert_-butoxycarbonyl)amino¬ methyl]benzyl alcohol. 12. A compound of the formula wherein R j is H or alkyl of 1 to 7 carbon atoms; R 2 is H, alkyl of 1 to 7 carbon atoms, or alkylene portion contains 1 to 5 carbon atoms, and X is H or -OR' 4 wherein R' is identical to R as defined below; R3 is H, Cl, -CH 2 OH or -OR" 4 wherein R" 4 is identical to R 4 as defined below; and R 4 is an acyl radical. 13. A compound of Claim 12 wherein R is an acyl radical selected from the group consisting of alkanoyl having 1 to 22 carbon atoms; alkenoyl having one or two double bonds and having 4 to 22 carbon atoms; cycloalkyl -C n H 2n - ?C- having a total of 4 to 10 carbon atoms of which 3 to 7 are ring carbon atoms in the cycloalkyl portion and wherein n is zero, one or two; phenoxyacetyl; 1-naphthalenecarbonyl; 2- _O ?I . -f -y W/IIPCOT * N* ' *- naphthalenecarbonyl; 2-ρyridinecarbonyl; 3- pyridinecarbonyl; 4-pyridinecarbonyl; and 0 II phenyl-C n H 2n -C- wherein n is zero, one or two and phenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms or alkanoylamino having 1 to 6 carbon atoms. 14. A compound of Claim 12 wherein 4 is alkanoyl having 1 to 22 carbon atoms. 15. A compound of Claim 14 wherein the alka¬ noyl radical is pivaloyl. 16. A compound of Claim 12 which is selected from the group consisting of the N-tert-butoxycarbonyl 3 ,4-dipivalate derivatives of epinephrine, isoprotere¬ nol and norepinephrine; the N-tert-butoxycarbonyl 3- pivalate derivatives of phenylephrine and metaraminol; and the N-tert-butoxycarbonyl 3,5-dipivalate deriva¬ tives of metaproterenol and terbutaline. - 17. A compound of Claim 12 which is R- - [ (N-methyl-N-tert-butoxycarbonyl)aminomethyl] benzyl alcohol 3 ,4-dipivalate. OMPI IPO

Inventors: ZUPAN J
Applicants: INTERX RESEARCH CORP, INTERX RES CORP
Application year: 1980
Main classification: C07D307
IPC codes: C07C67, C07C239, C07C271, C07C309