CA1175840A - Process and intermediates for catecholamines - Google Patents

Abstract

ABSTRACT Novel N-tert.-butoxycarbonyl derivatives of mono-and di-hydroxy aromatic amines of the formula These novel compounds are useful as intermediates in that they can be reacted with an acyloxymethyl chloride to pro-vide the corresponding mono- or di-acylated N-protected aromatic amine from which the N-protecting group can then be removed. The resultant acyl derivatives of mono- and di-hydroxy (e.g., catechol amines) are useful as sympathomine-tic amines.

Description

I ~7~8~

GKG1~0[1ND_ OF _THE :[N ENT.[ON

Field of the Invesltion:

The present invention is directed to a novel synt:he~
tic process Eor preparing esters of ca-techc~l amines and other sympathomimetic amines in optically active or race-mic form, and to novel N-tert-butoxycarbonyl intermediates useful in the subject process.

Description of the Prior Art:
____ _ Vnlted States Patent Nos. 3,809,714, 3,825,583, 3,83~,584, 3,868,~61, 3,959,q~5, 3,966,7~9, 3,908,017, 4,035,405, 4,0~8,783, 4,145,44l and 4,158,005, all in the name of the instant assignee, disclose a number of sympa-thomimetic 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 fo~mula (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, biologically active isomers from their racemic mixtures are tedious and expensive. In fact, resolutLon of the racemic mixtures of many of the compounds of for-mula (I) has not been reported in the literature.

- 2 -~ ~ ~s~

Col~seq~ently, it is ~pvarent t~lat a need e~:i.sts for a means of clirectl~ synthesizing the op-tically ac-tive, bio-logically ~ctive forms of the compounds of form~lla (J), thus avoidin~ th~ necessity of fi.rst obta:ining the racemic mixture and then either resolviny the racemic mi~ture and administering the optically and biologicall.y ac-tive .isomer thereof, or else, as is more frequently the: case, adminis-terinq 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 ac:-tive, biological.ly active isomer we-re administered.

.SUMMARY OE` THE .CNVENT-ION
Accordingly, the present invention has as an object a novel process for the preparation of a compound of the general formula ~4Q ~ } OH ~I) ~3.

wherein Rl is H or alkyl of 1 to 7 carbon atoms; R2 is H, alkyl of 1 to 7 carbon atoms, or -alkylene ~()m ~b~

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 iden-tical to R4 as defined below, R3 is H, Cl, -CH2OH or -OR"4 wherein R"4 is identical to R~ as defined as below; and R~
is an acyl radical; or a nontoxic pharmaceutically accept-able acid addition salt thereof; which comprises:
(a) reacting a compound of the general formula 8 '~ ~

OH ( 11 ) -Rt ~ R5 wherei.n Rl ls deEined as above; R is 1~, Cl, -CE-12OH or --Oll;
and R5 is H, alkyl of :l to 7 c~rbon ~toms, or -alkylene-tO)m ~ X' wherein m and alkylene are de-fined 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~butoxycarbonyl derivat:ive of the formula OH
HO ~
< O ~ _ CHIHRl (:rl~) C=O
OC(CH3)3 wherein R, Rl and R5 are defined as above~ with an acyloxy-methyl chloride of the formula R4ocH2cl (IV) wherein R4 is an acyl radical, in an organic solvent in the presence of a base; and (c) removing the tert-butoxycarbonyl protecting - group from the resultant compound of the formula 4 ~ IHCIH21 (V
C=O
R3 OC(CH3~3 wherein Rl, R2, R3~ and R4 are defined as above.
The novel process for the preparation of compounas of formula (I~ and their nontoxic pharmaceutically accept-able acid addition salts which is set forth above provides ~ J758~

the desired compounds in optic~ active or in r~cemic form, depending on the p~rticular starting material em-ployed. Said process further provides novel intermedlates useful in the preparation or the compounds of formula (I), said novel intermediates having the str~lctural forlllulas (III) and (V) se-t forth above.

DETAILED DESCRIPTION C)F l`HE IN~7ENTION

With respect to the various groups encompassed by the generic terms used here and throughout this specifi-cation, the followlng definitions and explanat:ions are applicable:
The alkyl groups encompassed by Rl include ~traight and branched-chain radicals containing the indicated num-ber of carbon atoms, with methyl and ethyl being preferred.
The alkyl groups encompassed by R2 and R5 likewise can be straight or branched-chain containing the indicated number of carbon atoms. In the case of the R2 and R5 substituents, preferred alkyl groups are methyl, isopropyl and tert-butyl.
When R2 is an -alkylene-(O) ~ group, or when R5 is an -alkylene-(O) ~ X group, the alkylene bridge can be a straight or branched-chain group of the type CnH2n, 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 R4 term, it is to be noted that at each occurrence R4 pre-ferably represents an acyl radical selected from the group consisting of alkanoyl having 1 to 22 carbon atoms; alke-noyl having one or two double bonds and having 4 to 22 carbon atoms; cycloalkyl-CnH2n-C- having a total of 4 to ' !758'i~

10 carhon ~toms of which 3 to 7 are l-ing car~on ~tolns in the cycloal~yl portion and wherein n is zero, ~n~ or t:wo;
phenoxyacetyl, naphthalenecarbonyl; ~yridinecclrbonyl; and phenyl-CnH2n-C- wherein n is zero, one or t~o and phenyL
is unsubstit~}ted or is su~sti-tuted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 -to 4 carbon atoms, halo, trifluoromethyl, aialkylamino having 2 to 8 car~on atoms or alkanoylamino having 1 to 6 atoms.
When R4 is alXanoyl containing 1 to 22 carbon atoms, there are included both unbranched and branched al~anoyl, ~or example/ Eormyl, acetyl, propionyl, butyryl, isobut~-ryl, valeryl, isovaleryl, 2-methylbutarloyl, plvalyl (piva-loyl), 3-methylpen-tanoyl, 3,3-dime-thylbutanoyl, 2,2-di~
me-thylpentanoyl, docosallyl and 7,7-dimethyloctalloyl~
Branched alkanoyl groups are generally preferred, an es-pecially preferred group being pivaloyl~
When R4 is alkenoyl having one or two double bonds and having 4 to 22 carbon atoms, there are included, ~or example, crotonyl, 9-octadecenoyl, 2,5-hexadienoyl, 3,6-octadienoyl, 10,13-octadecadienoyl and 5,13-docosadienoyl.
When R4 is cycloalkyl-C M2n-C-, there are included cycloalkanecarbonyl and cycloalkanealkanoyl groups wherein the cycloalkane portion can optionally bear 1 or 2 alkyl groups as substituents, e.g., cyclopropanecarbonyl, 1-methylcyclopropanecarbonyl, cyclopropaneacetyl, alpha-methylcyclopropaneacetyl, l-me~hylcyclopropaneacetyl, 2-amylcyclopropaneacetyl, cyclopropanepropionyl, alpha-methylcyclopropanepropionyl, 2-isobutylcyclopropanepropio-nyl, 2-hexylcyclopropanecarbonyl, cyclobutanepropionyl, 2-methylcyclobutanecarbonyl, 1,3-dimethylcyclobutanecarbonyl,

3,3-dimethylcyclobutanecarbonyl, cyclobutaneacetyl~ 2,2-dimethyl-3-ethylcyclobutaneacetyl, cyclobutanepropionyl, cyclopentanecarbonyl, l-n!et:hyl-3-isoprop~lcyclo~ent~necar-bonyl, cyclopentanepropion~l, cyclohex~necarbonyl, cyclo-hexaneacetyl, ~-metilylcyclohex~lneacetyl, cycloheptanecar-bonyl, 4~methylcycloheptaneacet~1, and cyc:lohept~n~propiorlyl.
When R4 i5 phenyl-Cn~l~n-C- there are inc.l-lded, for e~ample, benzoyl, phenylace-tyl, alpha-pheny:Lpropionyl, beta-phenylpropionyl, p-toluyl/ m-toluyl, o-toluyl, o-ethylbenzoyl, p-tert-butylbenzoyl, 3,4-dimethylbenzoyl, 2-methyl-4-ethylbenzoyl, 2,4,6-trimethylbenzoyl, m--methyl-phenylacetyl, p-isobutylphenylacetyl, beta-(p-ethylphenyl)-propionyl, p-anisoyl, m-anisoyl, o-anisoyl, m-isop:r.opoxy-benzoyl, p-n-butoxybenzoyl, 3-me-thoxy-4-ethox~benzoy:L, 3,4,5--trime-thoxybenzoyl, 2,~,6-triethoxybenzoyl, p-methoxyphenylacetyl, m-isobutoxyphenylacetyl,~3,q--cli.-ethoxyphenylacetyl, beta-(3,4,5-trimethoxyphenyl)propionyl, o-iodobenzoyl, m-bromobenzoyl, p-chlorobenzoyl, p-fluoro-benzoyl, 2-bromo-4-chlorobenzoyl, 2,4,6-trichlorobenzoyl, p-chlorophenylacetyl, alpha-(m-bromophenyl)propionyl, p-trifluoromethylbenzoyl, 2,4-diltrifluoromethyl)benzoyl, m-trifluoromethylphenylacetyl, beta~Ip-trifluoromethyl-phenyl)propionyl, 2-methyl-4-methoxybenzoyl, 3-chloro-4-ethoxybenzoyl, beta-(3-methyl-4-chlorophenyl)propionyl, p-dimethylaminobenzoyl, m-2iethylaminobenzoyl, p-dibutyl-aminobenzoyl, p-(N-methyl-N-ethylamino)benzoyl, o-aceta-midobenzoyl, m-propionamidobenzoyl, p-hexanoylaminoben-zoyl, 3-chloro-4-acetamidophenylacetyl, and p-acetamido-phenylpropionyl.
When R4 is naphthalenecarbonyl, there are included l-naphthalenecarbonyl and 2-naphthalenecarbonyl.
When R4 is pyridinecarbonyl, there are included picolinoyl (2-pyridinecarbonyl), nicotinoyl (3-pyridine-carbonyl), and isonicotinoyl (4-pyridinecarbonyl).

~ 1 7~

Finally, the ~erm l'nontoxic pharmaceutic~ ccep-table acid addition salt" as used herein generally includes the nontoxic acid additioll salts of selected compounds of formula (I), formed with nontoxic inor~anic or or~al~ic acids. For example, the salts include ~h~se deri~e~ rom inorganic acids such as hydrochloric, hydrobrornic, 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, phenylace-tic, glutamic, ben~oic, salicyclic, sulfanilic, fumaric, sulfonic, toluenes~llfonic, and the like.
By selecting the appropriate reactants for the ul~imate specie desired, the compounds of formula ~I) are convenientlv prepared in accordance with the synthetic scheme of the present invention.
The compounds of formula (I) which are prepared 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 treatment of other conditions respon-sive 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 pre-sent invention provides a novel process and novel inter-mediates to acylated derivatives of such known sympathomi-metic amines as epinephrine, isoproterenol, norepinephrine, phenylephrine, metaraminol, metaproterenol, terbutaline, nordeferin, colterol, deterenol, albuterol and fenotexol, and the nontoxic pharmaceutically acceptable acid addition salts th(~reof. The ins-tant proces5 and interlrlediates are especially preferred ~hen they provi.de acylclted de.rivatives of the aforementioned sympathomlmet.ic am:ines wh~rein the acyl group is ~lkanoyl as hereinbefore def:Lned, mvst esp~-cially when the alkanoyl group is branched~ e.g., pival-oyl. Also, while it is a particular and surprising advan-tage of the present process that the stereochemical inte-grity of the starting material of formula (II) can be maintained throughout the instant reaction scheme, thus affording an attractive synthetic route to the opt.ically and biologically active isomers of :Eormula (I), i.t w:i.ll be apparent to those skilled in the art that the proces~s of the invention can be employed equally as well :i.n the production of racemic mi~-tures as in the preparation of optically active isomers. As such, the scope of -the pre-sent inventio~ 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~butoxycarbonyl deriva-tives 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 pro-.
tect the amino group of amino acids. Typical reagents include t-butylazidoformate, di(t-butyl)dicarbonate and the like, with t-butylazidoformate being a preferred re-agent. Obviously, the choice of solvent and other reac-tion conditions 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 conve-3 ~ 7S8~

niently concluc.ed in pyricli~e, preferclbly in the presence of triethylamine, althoush a dioxane/m~(3~esium c).~:ide sol-vent system may be employed in place of the pyridlne/tri-ethylamine. rim~ ana temperarure depend on the partic~llar starting material of formula (II) t -the particular reagent and the particular solvent system employed. Generally speaking, heating accelerates the reaction, which is typi-cally complete in 16 hours or less at a temperature of 40-90C. The reaction is conveniently conducted at at-mospheric pressure, preferably under nitrogen.
With respect to step (b) of the instant pro~essr i.e., reacting a novel M-tert-butoxycarbonyl derivatLve of formul~ (III) with an acyloxymethyl chloricle of forrnula (IV), it is to ~e noted -that this reaction is surprising in two respec-ts, namely: (1) that the phenolic hydroxy group(s) of the compound of formula (III) ~eact 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 con-ducted 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 caus-ing undesirable side reactions such as oxidation. Choice of partlcular 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., derivatives 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 cate~

chol, e.g., a 3,5-dihydroxyphenol or a monohydroxyphènol, then a stronger base such as potassium carbonate may be 3 1758~in used in an appropriate solven~, e.g., Ine-thanol. Time, tem-perature and pressure are not cri~ical factors. The re-action is conveniently conducted at atmospheric pLessure, under ni-trogen. Time and ~emperature vary with the parti-cular starting materials employed. Typical reaction times are 30 min~ltes to 4 days r while typical tempera~ures are from room -temperature to reflux.
With respect to step (c) of the process of the present invention, i.e., removal of the amino protecting group from the compound of formula (V), it is to be noted that this reaction is analogous to those well-known in the art of peptide synthesis. Thus, removal of the protec-ting group can be achieved by any means suitable for removin~3 a tert-butoxycarbonyl group without affecting the remairl-ing portions of the molecule, for example, by use of tri-fluoroacetic acid in dichloromethane, or hydrogen chloride in ethyl acetate, at room temperature or, preferably, be-low room temperature, 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 group7 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 protecting group can be readily neutralized to the free base of for-mula (I) and then, if desired, reacted with an appropriate acid to form the corresponding nontoxic, pharmaceutically acceptable acid addition salt. Alternatively, the salt obtained after removal of the protecting group, e.g., the hydrochloride, can be subjected to an ion exchange proce-dure in order to obtain a different, nontoxic, pharmaceu-tically acceptable salt of formula (I).

~7~8~

Without urther elaboration, it is ~elieved that one of ordinary skill in the art can, using the prece~iny description, utilize the present .inV~ntiOIl to its rllllest e~te~t. Co~seq-~ently, the followin~ preferred speci-~ic embodiments are to he cons-trued as rnerely illustrative and no-t limitative of the remainder of the specification and claims in any way whatsoever.

Preparation of R-3,4-Dihydroxy-~-[(N-methyl-N-tel-t-bu-toxy-carbonyl)aminometh~}benzyl alcohol _____ 18.3 G (0.l0 mole) o~ R-~-)-ep:inephrine and .~4.3 g.
(0.10 mole) of t-butylazidoormate EL.A. Carpino, et al., Organic Synthesis, Collective Vol. 5, H.E. Baumgarten, ed., John Wiley and Sons, Ne~ York, p. 157 (1973)] were combined with 13.9 ml (0.1 mole) of triethylamine in 25 ml of pyri-dine. The reaction mixture was stirred under nitrogen at 60C. for approximately 16 hours. The solven-t was evapo-rated 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 eva-porated to give 14.6 g of a reddish brown glass.
IR (CHC13): 3540 ~free OH), 3360 (OH), 1660 cm (-N- -O-). NMR (CDCL3TMS): ~ 1.40 (s, 9H~ C(CH3)3), 2.73 ts, 3H, NC_3), 3.33 (broad s, 2H, -CH2N), 4.70 (broad s, lH, CH-OH), 6.70 (broad s, 2H, aromatic), 6.80 (broad s, lH~ aromatic).
Similarly prepared from dl-epinephrine, dl-iso-proterenol, l-isoproterenol, l-norepinephrine, l-phenyl-ephrine, l-~neta~ inol, cll-~netaprotererlol and ~ tcrib~tA-line are the t-buto~ycarbonyl derivatives thereof, n~lmely dl-3,4-dihydroxy-~-[(N-methyl-N-tert-butoxycarbonyl)amino-methyl]benzyl alcohol; dl-3,4-dihydroxy-~-[(N-isopropyl-N-tert-butoxycarbonyl)aminomethyl]benzyl alcohol; 1-3,4-di-hydroxy-~-l(N-isopropyl-N-tert-bu~oxycarbonyl)aminomethyl]-benzyl alcohol; l-~-[(N-tert-butoxycarbony:L)aminomethyl]-3,4-dihydroxybenzyl alcohol; l-m-hydroxy-~--[(N-methyl-N-tert-butoxycarbonyl)aminomethyl]benzyl alcohol; 1-~-[1-(N-tert-butoxycarbonyl)aminoethyl]-m-hydroxybenzyl alco-hol; dl-3,5-dihydroxy-~-[(N-isopropyl-N-tert-butoxycar-bonyl)aminomethyl]benzyl alcohol; and dl-~-[[N-tert-butyl-N-tert-butoxycarbonyl)aminomethyl]-3,5-dihydroxyben-zyl alcohol, respect:ively.

Preparation of R-~-[(N-Methyl-N-tert-butoxycarbonyl)amino-methyl]benzyl alcohol 3,4-dipivalate To 100 ml of dry acetone were added 2.6 g (.0095 mole) of R-3,4-dihydroxy-~-[(N-methyl-N-tert-butoxycarbo-nyl)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 dissolved in a small amount of petroleum ether (b.p. 30-60C). That solution was then chromatographed on a silica gel column. Elution with 2 column volumes of petroleum ether (b.p. 30-60C) 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 3 ~ 7 ~

c~ le matt~ri~ as rcchI(,m~ltogra~hcd on c~ilica 9~l ~nd eluted with cllloroform to gi~e a pale yellow oll wh:ich crystallized upon standing. Tllat sol..id was recrys-tallized from petroleum ether (b.p. 30-60C) to give 1.9 g o~ pro-duct, mp 103-105~C. Analysis: Cal'd for C24H37NO7:
C, 63.83; H, 8.~6; N, 3.10. Found: C, 63.95; 1-l, 8.50;
N, 2.99.
In a similar manner, the t-butoxycarbonyl deriva-tives of dl-epinephrine, dl-isoproterenol, l-isoprotere-nol, l-norepinephrine, l-phenylephrine, l-metaraminol, dl-metaproterenol and dl-t~rbuta:L;.ne ar~ reac-ted w.ith chloromethyl plvalate to afford the correspond:ing t-bu-toxycarbonyl pivalates and dip.i.valates, i.e., dl-~-[(N-methyl N-tert-butoxycarbonyl)aminomethyl]be~n~yl alcohol 3,4-dipivalate; dl-~-[(N-isopropyl-N-tert-butoxycarbonyl)-aminomethyl]benzyl alcohol 3,4-dipivalate; l-~-[(N-iso-propyl-N-tert-butoxycarbonyl)aminomethyl]benzyl alcohol 3,4-dipivalate; l-a-[(N-tert-butoxycarbonyl)aminomethyl]-benzyl alcohol 3,4-dipivalate; l-a-[(N-methyl-N-tert-butoxycarbonyl)aminomethyl]benzyl alcohol 3-pivalate; 1- .
~-[l-(N-tert-butoxycarbonyl)aminoethyl]ben:7.yl alcohol 3-pivalate; dl-~-[(N-isopropyl-N-tert-butoxycarbonyl~amino-methyl]benzyl alcohol 3,5-dipivalate; and dl-a-~(N~tert-butyl-N-tert-butoxycarbonyl)aminomethyl]benzyl alcohol 3,5-dipivalate, respectively.

Preparation of R-(-)-~-[(Methylamino)methyl]benzyl alco-hol 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 eth~l acet~te was cooled to 4C in ~n ice bath and dry nitro~en was bubbled into -the solution. After cooling, hydrogen chloride gas was bubbled into the solu-tion until thin layer chromatography indicatecl that no un-reacted startiny material remained (appro~imately 1 hour) .
Solvent was removed from the reaction mixt~lre -to give a white ~oam. That residue was crystallized from a 1:1 mix-ture of acetone and hexane to afford 300 mg of white cry-stals, m.p. 155-157C, [~ID = -27.4 ~C = 1.25, H2O).
Analysis: Cal'd for ClgH3~ClNO5: C, 58.83; H, 7.80; N, 3.61. FOUnd: C, 58.50; H, 7.95; N, 3.36.
In a similar manner, substitution of the prod~lcts named in the second paragraph of Example 2 in khe proce--dure detailed above, or its obvious chemical equivalent affords the following products: dl-a-[(methylamino)-methyl]benzyl alcohol 3,~-dipivalate hydrochloride; dl-~-~(isopropylamino)methyllbenzyl alcohol 3,4-dipivalate hydrochloride; l-a-[~isopropylamino)methyllbenzyl alcohol 3,4- dipivalate hydrochloride; l-a-(aminomethyl)benzyl alcohol 3,4-dipivalate hydrochloride; l-a-[(methylamino)-methyl]benzyl alcohol 3-pivalate hydrochloride; l-a-(l-aminoethyl)benzyl alcohol 3-pivalate; dl-a-[(isopropyl-amino)methyl]benzyl alcohol 3,5-dipivalate; and dl-a-[(tert-butylamino)methyl]benzyl alcohol 3,5-dipivalate, respectively.

While the invention has been described in terms of various preferred embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions and additions may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the following claims.

Claims (54)

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

1. A process for the preparation of a compound of the general formula:

wherein R1 is H or alkyl of 1 to 7 carbon atoms; R2 is H, alkyl of 1 to 7 carbon atoms, or wherein m is zero or one, the alkylene portion contains 1 to 5 carbon atoms, and X is H or -OR? wherein R? is identical to R4; R3 is H, Cl, -CH2OH or -OR? wherein R? is identical to R4; and R4 is an acyl radical which comprises reacting an N-tert-butoxycarbonyl derivative of the formula:

wherein R1 is defined as above; R is H, Cl, -CH2OH or -OH;
and R5 is H, alkyl of 1 to 7 carbon atoms, or wherein m and alkylene are de-fined as above and X' is H or -OH; with an acyloxymethyl chloride of the formula:
R4OCH2Cl wherein R4 is an acyl radical, in an organic solvent and in the presence of a base.

2. The process according to claim 1 wherein R1 is hydrogen.

3. The process according to claim 1 wherein R1 is methyl or ethyl.

4. The process according to claim 1 wherein R2 is hydrogen.

5. The process according to claim 1 wherein R2 is alkyl of 1 to 7 carbon atoms.

6. The process according to claim 1 wherein R2 is methyl, isopropyl or tert-butyl.

7. The process according to claim 1 wherein R2 is wherein alkylene, m and X are as defined in claim 1.

8. The process according to claim 7 wherein alkylene is ethylene, 1,2-propylene or 1,3-butylene.

9. The process according to claim 1 wherein R3 is hydrogen.

10. The process according to claim 1 wherein R3 is -OR? wherein R? is as defined in claim 1.

11. The process according to claim 1 wherein R4 is an acyl radical selected from the group consisting of alka-noyl having 1 to 22 carbon atoms; alkenoyl having one or two double bonds and having 4 to 22 carbon atoms; cycloalkyl -CnH2n-?- 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; naphthalene-carbonyl; pyridinecarbonyl; and phenyl-CnH2n-?- wherein n is zero, one or two and phenyl is unsubstituted or is substi-tuted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo, trifluoromethyl, dialkyl-amino having 2 to 8 carbon atoms or alkanoylamino having 1 to 6 carbon atoms.

12. The process according to claim 11 wherein R4 is alkanoyl having 1 to 22 carbon atoms.

13. The process according to claim 11 wherein R4 is a branched-chain alkanoyl radical.

14. The process according to claim 11 wherein R4 is pivaloyl.

15. The process according to claim 1 when the compound thus prepared is selected from the group consisting of the N-tert-butoxycarbonyl 3,4-dipivalate derivatives of epine-phrine, isoproterenol and norepinephrine.

16. The process according to claim 1 wherein the com-pound thus prepared is R-.alpha.-(N-methyl-N-tert-butoxycarbonyl)-aminomethyl]benzyl alcohol 3,4-dipivalate.

17. The process according to claim 1 wherein the çom-pound thus prepared is selected from the group consisting of the N-tert-butoxycarbonyl 3-pivalate derivatives of phenyl-ephrine and metaraminol.

18. The process according to claim l wherein the com-pound thus prepared is selected from the group consisting of the N-tert-butoxycarbonyl 3,5-dipivalate derivatives of metaproterenol and terbutaline.

19. The process according to claim 1 wherein the starting material is selected from the group consisting of the N-tert-butoxycarbonyl derivatives of epinephrine, ISO-Proterenol, norepinephrine, phenylephrine, metaraminol, metaproterenol, terbutaline, nordeferin, colterol, deterenol, albuterol and fenoterol.

20. The process according to claim 1 wherein the starting material is the N-tert-butoxycarbonyl derivative of R-(-)-epinephrine.

21. The process according to claim 1 wherein the acyloxymethyl chloride is chloromethyl pivalate.

22. The process accorc1ing to claim 1 wherein the or-ganic solvent employed is acetone.

23. The process according to claim 11 wherein the or-ganic solvent employed is acetone.

24. The process according to claim 1 wherein the base is potassium carbonate.

25. The process according to claim 11 wherein the base is potassium carbonate.

26. The process according to claim 1 wherein the base is potassium carbonate and the solvent is acetone.

27. The process according to claim 11 wherein the base is potassium carbonate and the solvent is acetone.

28. A compound of the general formula wherein R1 is H or alkyl of 1 to 7 carbon atoms; R2 is H, alkyl of 1 to 7 carbon atoms, or wherein m is zero or one, the alkylene portion contains 1 to 5 carbon atoms, and X is H or -OR? wherein R? is identical to R4; R3 is H, Cl, -CH2OH or -OR? wherein R? is identical to R4; and R4 is an acyl radical, when prepared by the pro-cess of claim 1.

29. A compound as defined in claim 28 wherein R1 is hydrogen, when prepared by the process of claim 2.

30. A compound as defined in claim 28 wherein R1 is methyl or ethyl, when prepared by the process of claim 3.

31. A compound as defined in claim 28 wherein R2 is hydrogen, when prepared by the process of claim 4.

32. A compound as defined in claim 28 wherein R2 is alkyl of 1 to 7 carbon atoms, when prepared by the process of claim 5.

33. A compound as defined in claim 28 wherein R2 is methyl, isopropyl or tert-butyl, when prepared by the pro-cess of claim 6.

34. A compound as defined in claim 28 wherein R2 is wherein Alkylene, m and X are as defined in claim 28, when prepared by the process of claim 7.

35. A compound as defined in claim 28 wherein R2 is wherein m and X are defiIned as in claim 28 and alkylene is ethylene, 1,2-propylene or 1,3-butylene, when prepared by the process of claim 8.

36. A compound as defined in claim 28 wherein R3 is hydrogen, when prepared by the process of claim 9.

37. A compound as defined in claim 28 wherein R3 is -OR? wherein R? is as defined in claim 28, when prepared by the process of claim 10.

38. A compound as defined in claim 28 wherein R4 is an acyl radical selected from the group consisting of alka-noyl having 1 to 22 carbon atoms; alkenoyl having one or two double bonds and having 4 to 22 carbon atoms; cycloalkyl -CnH2n-?- 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; naphthalene-carbonyl; pyridinecarbonyl; and phenyl-CnH2n-?- wherein n is zero, one or two and phenyl is unsubstituted or is sub-stituted 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, when prepared by the process of claim 11.

39. A compound as aefined in claim 28 wherein R4 is alkanoyl having 1 to 22 carbon atoms, when prepared by the process of claim 12.

40. A compound as defined in claim 28 wherein R4 is a branched-chain alkanoyl radical, when prepared by the pro-cess of claim 13.

41. A compound as defined in claim 28 wherein R4 is pivaloyl, when prepared by the process of claim 14.

42. A compound as defined in claim 28 which is selected from the group consisting of the N-tert-butoxycar-bonyl 3,4-dipivalate derivatives of epinephrine, isoprote-renol and norepinephrine, when prepared by the process of claim 15.

43. A compound as defined in claim 28 which is R-.alpha.-[(N-methyl-N-tert-butoxycarbonyl)aminomethyl]benzyl alco-hol 3,4-dipivalate, when prepared by the process of claim 16.

44. A compound as defined in claim 28 which is selected from the group consisting of the N-tert-butoxycar-bonyl 3-pivalate derivatives of phenylephrine and metara-minol, when prepared by the process of claim 17.

45. A compound as defined in claim 28 which is selected from the group consisting of the N-tert-butoxycar-bonyl 3,5-dipivalate derivatives of metaproterenol and terbutaline, when prepared by the process of claim 18.

46. A compound as defined in claim 28 wherein the compound thus prepared is selected from the group consist-ing of the N-tert-butoxycarbonyl derivatives of epinephrine, isoproterenol, norepinephrine, phenylephrine, metaraminol, metaproterenol, terbutaline, nordeferin, colterol, deternol, albuterol and fenoterol, when prepared by the process of claim 19.

47. A compound as defined in claim 28 wherein the compound thus prepared is the N-tert-butoxycarbonyl derivative of R-(-)epinephrine, when prepared by the process of claim 20.

48. A compound as defined in claim 28 whexein R4 is pivalyl, when prepared by the process of claim 21.

49. A compound as defined in claim 28, when prepared by the process of claim 22.

50. A compound as defined in claim 28, when prepared by the process of claim 23.

51. A compound as defined in claim 28, when prepared by the process of claim 24.

52. A compound as defined in claim 28, when prepared by the process of claim 25.

53. A compound as defined in claim 28, when prepared by the process of claim 26.

54. A compound as defined in claim 28, when prepared by the process of claim 27.

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