United States Patent 1191
`Bodor et al.
`
`3,966,749
`[111
`[45] June 29, 1976
`
`1541 NOVEL SYNTHESIS OF OPTICALLY ,
`ACTIVE
`M-ACYLOXY-u-[ ( METHYLAMINO)ME
`THYL IBENZYL ALCOHOLS, THE
`PHARMACEUTICALLY ACCEPTABLE
`ACID ADDITION SALTS THEREOF AND
`INTERMEDIATE USEFUL IN THE
`PREPARATION THEREOF
`[75] Inventors: Nicolae S. Bodor; Sun-Shine Yuan,
`both of Lawrence, Kans.
`[73] Assignee: Interx Research Corporation,
`Lawrence, Kans. -
`..
`
`Feb. 10, I975
`[22] , Filed:
`[21] Appl. No.:'548,606
`
`[52] US. Cl. ........................ ..p260/295~'R; 260/5707
`[51] Int. C1.2 ...................................... .. C07D 213/02
`‘[58] Field of Search .................... .. 260/295 R, 570.7
`
`[56}
`
`References Cited
`UNITED STATES PATENTS
`
`3542.874
`260/5707 OH
`1 1/1970 1 Keller ct a1 ..........
`3,641,152
`260/570] OH
`2/1972
`Shave], .11’. C1. a1.
`3,825,583
`7/1974
`Hussain et a1.‘ .... ............. .. 424/311
`FOREIGN PATENTS OR APPLICATIONS
`
`1,178,721
`
`1/1970
`United Kingdom ............ _. 260/5707
`OTHER PUBLICATIONS
`Elderdield, “Heterocyclic Compounds,” vol. 5, p. 391,
`( 1957).
`_
`Morrison et 211., Organic Chemistry, p. 593, (1959).
`
`Primary E.raminer—-N0rman A. Drezin '
`Attorney, Agent, or Firm—Charles N. Blitzer
`
`ABSTRACT
`[57]
`Optically and therapeutically active compounds of the
`formula:
`
`‘I’
`
`Rio
`
`NHCH
`
`wherein R represents a member selected from the
`group Consisting of a straight or branched alkyl group
`of from one to_ twenty carbon atoms (Cl-C; being pre
`ferred), an ethoxycarbonyl group, a benzyloxycarbo
`nyl group, a phenyl group, an
`
`group, wherein R is as de?ned above and R3 is a mem
`ber selected from the group consisting of a hydrogen
`atom, a methyl group and a phenyl group, and a 2-, 3-,
`or 4-pyridyl group, or the HX salts thereof, wherein X
`represents a pharmaceutically acceptable acid addi
`tion salt anion, are prepared using optically active m
`hydroxy-a-l (methylamino )-methyl lbenzyl
`alcohol
`(phenylephrine).
`The ' compounds prepared by the process of this
`invention
`?nd
`therapeutic
`applicaton
`to
`warm-blooded animals (e.g., humans) in
`the
`management of asthma, nasal congestion and as
`decongestants, vasoconstrictors, mydriatic agents, and
`anti-glaucomatous agents in
`the
`practice
`of
`opthalmology.
`'
`these
`Upon administration,
`compounds will
`enzymatically “cleave,” thus releasing optically active
`phenylephrine
`'
`(m-hydroxy-a-l (methylamino)methyl ]benzyl' alcohol,
`the therapeutically active moiety thereof.
`13 Claims, 1 Drawing Figure
`
`Exhibit 1011- Page 1 of 7
`
`

`
`US. Patent June 29,1976
`
`3,966,749
`
`é -\ is G
`
`0%
`
`7v:
`
`09
`
`
`
`22215232 $72 3522
`
`cm
`
`8
`
`m
`
`("1'") NOILVWIG
`
`Exhibit 1011- Page 2 of 7
`
`

`
`1
`
`3,966,749
`
`2
`the optically active form over a racemicmixture con
`taining the same.
`_
`‘These and other obvious objects are achieved via the
`synthesis scheme set out below.
`
`(I)
`
`8 ..
`IN‘
`
`wherein R represents a vmember selected from the
`group consisting of a‘straight or branched alkyl group
`of from one to 20 carbon atoms (Cl-C5 being pre
`ferred), an ethoxycarbonyl group, a benzyloxycarbonyl
`group, a phenyl group, an
`4
`
`35
`
`group, wherein R is de?ned as above and R3 represents
`a member selected from the group consisting of a hy
`drogen atom, a methyl group and a phenyl group, and
`a 2-, 3-, or 4-pyridyl group, orthe HX salts thereof, andv
`wherein X represents a pharmaceutically acceptable
`acid addition salt anion derived from the corresponding
`acid (e.g., chloride, bromide, sulfate, sulfonate, phos
`phate, nitrate, acetate, propionate, succinate, glyco
`late, stearate, lactate, tartrate, citrate, ascorbate, par
`moate, maleate, hydroxymaleate, phenylacetate, gluta
`mate,‘ benzoate, salicylate‘, sulfonilate, fumarate, tolu
`enesulfonate, etc.) are prepared by:
`l. reacting optically active phenylephrine with an
`excess of a carbonyl compound of the formula: R,—
`CO—'R2, wherein R1 and R2 which can be the same or
`different and represent a member selected from the
`group consisting of a hydrogen atom, a C1-C1‘, alkyl
`group, and a di(C,4C2)alkylamino(C,—Cm)alkyl group, '
`or wherein R1 and R2 together with the carbonyl group
`to which they are attached can form a member selected
`from the group consisting of a C5-C1 cycloalkanone
`group (pentanone, hexanone, or heptanone) and a
`substituted or unsubstituted N- or O-heterocyclic(
`45
`C5-C7) alkanone group (e.g., piperidone, pyrrolidone,
`'N-methylpiperidone, or N-methylpyrrolidone, etc.),
`wherein said substituent is a C1-C2 alkyl group, either
`in the presence of a dehydrating agent selected from
`the group consisting of, but not limited to an alkaline
`earth metal carbide (calcium carbide, magnesium car
`bide, etc. ), a molecular sieve of from 4 to 5 A, calcium
`chloride, magnesium sulfate, and sodium sulfate, or in
`the presence of a conventional inert aromatic hydro
`carbon solvent (e.g.j, benzene, toluene, xylene, etc.)
`plus an organic or inorganic acid catalyst (e.g., p-tol
`uenesulfonic acid, sulfoscalicyclic acid, benzenesul
`fonic acid, sulfuric acid, hydrochloric acid, etc.) to
`eliminate the water formed as an. azeotropic mixture,
`said steps being carried out at a temperature of from
`20° to 140° C (preferably, however, at the boiling point
`of .the solvent or solvent mixture employed), standard
`pressure, and for a period of time, ranging from 2 to 48
`hours, whereby intermediate:
`
`NOVEL SYNTHESIS OF OPTICALLY ACTIVE
`M-AcYL0xY-a-uMETuYLAMINmMETIIYu
`BENZYL ALCOHOLS, TIIE PHARMACEUTICALLY
`ACCEPTABLE ACID ADDITIoN sALTs TIIEREoE
`-
`; AND INTERMEDIATE USEFUL IN THE
`PREPARATION THEREOF ,
`BACKGROUND OF ‘Tl-IE INVENTION
`Field of the Invention
`‘
`‘
`,
`, The present invention is directed‘to certainesters of
`‘ m-hydr_oxy-a,-[(methylamino)methyl]benzyl alcohols,
`their pharmaceutically acceptable acid addition salts
`and certain intermediates useful in the preparation
`thereof. Moreparticularly, the instant invention is di
`rected to a novel synthesis for preparing the optically
`active (hereinafter R) or racemate form of the above
`identi?ed compounds.
`7
`Upon administration, these compounds will enzymat
`ically “cleave”'and release optically active rn-hydroxy
`a-[ ( methylamino)methyl ] benzyl alcohol (phenyleph
`rine), the therapeutically active moiety thereof.
`I
`,
`2. Description of the Prior Art '
`l
`‘ U.S. Pat. No. 3,825,583 f l-Iussain‘ and Truelove,
`discloses and claims an ester of m-hydroxy-a-Kme
`thylam_ino)methyl]benzyl alcohol, namely, ‘m(3-)
`pivaloxy-aé [ methylamino ) methyl ] benzyl alcohol.
`A‘review of the manner in which this compound is
`prepared readily reveals that a racemic'_mixture (a
`mixture containing both the biologically active and the
`30
`biologically non-active isomer) is obtained. Since the R
`isomer is the onlyisomer exhibiting therapeutic activ
`ity‘, to date (R)-m-pivaloxy-a-[(methylamino)methyl]
`benzyl alcohol is normally administered in the form of
`a racemic mixture as the means to separate the opti
`cally active form from the racemic mixture is quite time
`consuming and expensive.
`Therefore, a need exists for a means to synthesize the
`optically active form of certain m-aceyloxy-a-[(me-'
`thylamino)methyl]benzyl alcohols of which m
`pivaloxy-a-[ (methylamino )methyl]benzyl alcohol is so
`among and thus avoid the need to '(l) ?rst obtain a
`racemic mixture, and (2) optionally, resolve the race
`mic mixture into the optically active isomer for admin
`istration or administer’the racemic mixture, per se.
`In addition to the foregoing, it is obviously apparent
`that since only the-active isomer of the compounds
`described herein is therapeutically active, the dosage
`amount of a racemic mixture containing the same re
`quired to achieve therapeusis is much greater than that
`which would be. required if-the optically active form
`were administered, per se. Thus,,an ancillary need
`exists for a means to synthesize the optically active
`isomer, per se, for the sake of minimizing the therapeu
`tic dose required as well as to avoid any toxic reactions
`which may occur. \
`
`50
`
`55
`
`I SUMMARY OF THE INVENTION; j
`It is, therefore, the primary object of the present
`invention to synthesize the optically active form of
`certain
`m-acyloxy-a-[(methylamino ) methyl]benzyl
`alcohols as described herein, which’ upon administra
`tion to a warm-blooded animal (e.g.,rhuman) will enzy
`matically “cleave” to release optically active’phenyl
`ephrine, the therapeutically active moiety thereof.
`It is another object of the present invention to synthe
`size the above-described optically active forms so as to
`enable therapeusis to be achieved with a lesser dose of
`
`65
`
`(II)
`
`Exhibit 1011- Page 3 of 7
`
`

`
`3,966,749
`and for a period of time of from 1 to 24 hours, whereby
`the free base of formula (1) is obtained; and
`5. optionally, replacing the catalytic amount of the
`HX acid in step (4) with the stoichiometric amount of
`the same, whereby the HX salt of the free base of the
`compound represented by formula (I) is obtained.
`The compounds prepared by the process of this in
`vention find therapeutic application‘ to warm-blooded
`animals (e.g., humans) in the management of asthma,
`nasal congestion, and as decongestants, vasoconstric
`tors, mydriatic agents, and anti-glaucomatous agents in
`the practice of ophthalmology. Upon administration,
`they will enzymatically “cleave” and release phenyl
`ephrine, the therapeutically active moiety thereof.
`At this juncture, it should be emphasized that the
`intermediate products formed in steps (1 ), (2), and (3)
`are considered novel by the present inventors and spe
`ci?c for the process described and claimed herein, or
`any process equivalent thereto. As such, these interme
`diates vare'considered part and parcel of the overall
`invention described in the instant application.
`In addition, a number of solvents and acid catalysts
`have been described for purposes of exempli?cation.
`However, it is apparent that any solvent or acid catalyst
`not described but serving the same purpose as required
`by the present inventors is included within the scope of -
`the instant invention.
`Finally, it is obvious that the instantly described pro
`cedure can be employed equally as well in the synthesis
`of racemic mixtures containing the above-described
`compound by simply substituting racemic phenyleph
`rine for optically active phenylephrine in step (1). As
`such, the scope of this invention is extended to include
`this feature as well.
`Without further elaboration, it is believed that one of
`ordinary skill in the art can, using the preceding de
`scription, utilize the instant invention to its fullest ex
`tent. Consequently, the following preferred speci?c
`embodiments are, therefore, to be construed as merely
`illustrative and not limitative of the remainder of the
`speci?cation and claims in any way whatsoever.
`
`20
`
`25
`
`30
`
`35
`
`3
`wherein Rl and R2 are defined as above is formed: _
`2. reacting with intermediate of step ( l ) with a num
`ber selected from the group consisting of an M-hydrox
`ide, an M-hydride, and an M-alkoxide, wherein M rep
`resents a member selected from the group consisting of
`an alkali metal, an alkaline earth metal, and thallium
`(e.g., NaOH, KOH, Ca(OH)2, Mg(OH )2, Ba(Ol-l)2,
`NaH, CaH2, NaOCH3, NaOC2H5, NaOC3H7, TlOC2l-l5,
`etc.) in the presence of an inert organic solvent se
`lected from the group consisting of an aliphatic hydro
`carbon solvent of from ?ve to 10 carbon atoms (e.g.,
`pentane, hexane, heptane,, octane, decane, etc.), an
`aromatic hydrocarbon solvent (e.g., benzene, toluene,
`xylene, etc.), and CFC,4 aliphatic alcohol (methanol,
`ethanol, propanol, butanol ), a conventional ether (e.g.,
`diethyl ether, tetrahydrofuran, dioxane, etc.) and di
`methylformamide, etc., said step being carried out at
`room temperature, standard pressure, and for a period
`of time ranging from 1 to 24 hours, whereby the inter
`mediate:
`
`(III)
`
`MO
`
`H
`
`">4: 2
`
`CH3
`
`wherein M, R,, and R2 are de?ned above is formed;
`3. reacting the intermediate of step (2) with a stoi
`chiometric amount of an acyl halide of the formula:
`R-CO—Y, wherein R is de?ned as above and Y repre
`sents a halogen atom (chlorine, bromine, iodine) in the
`presence of an inert organic solvent selected from the
`group consisting of an aliphatic hydrocarbon solvent of
`from ?ve to 10 carbon atoms, an aromatic hydrocarbon
`solvent (e.g., benzene, toluene, xylene, etc.), methanol,
`propanol, butanol, a conventional ether (e.g., diethyl
`ether, tetrahydrofuran, dioxane, etc.), or dimethyl-I
`formamid‘e, said step being carried out at room temper
`ature, standard pressure, and for a period of time rang
`ing from 1 to 24 hours, whereby the intermediate:
`
`(IV)
`
`Ri 0
`
`wherein R, R1, and R2 are de?ned as above is formed;
`and
`4. cleaving the R,—CO—R2 moiety of the intermedi
`ate from step (3) in an organic inert solvent selected
`from the group consisting of an aliphatic hydrocarbon
`solvent of from ?ve to 10 carbon atoms, an aromatic
`hydrocarbon solvent (e.g., benzene, toluene, xylene,
`etc.), a C1-C4 aliphatic alcohol, a conventional ether
`(diethyl ether, tetrahydrofuran, dioxane, etc.), and
`dimethylformamide and further in the presence of a
`stoichiometric or excess amount of water and a cata
`lytic amount (normally but not absolutely, 001-] .O%
`of the stoichiometric amount) of an HX acid, wherein
`X is de?ned as above, said step being carried out at a
`temperature of from 20° to 100°C, standard pressure,
`
`45
`
`50
`
`55
`
`60
`
`65
`
`EXAMPLE I
`PREPARATION OF OPTlCALLY ACTIVE
`m-(TRIMETHYLACETOXY)-a-[(ME
`THYLAMINO)METHYL]BENZYL ALCOHOL
`HYDROCHLORIDE
`(R)-phenylephrine (9.0 g, 0.05 mole), acetone (1
`liter) and calcium carbide (4.0 g, 0.06 mole) were
`heated together at re?ux with stirring for 24 hours. The
`solid material formed was ?ltered off and the ?ltrate
`was concentrated in vacuo. The residue was crystal
`lized in an acetone-hexane mixture to give 7.0 g of
`(R)-2,2,3 -trimethyl-5-( m-hydroxyphenyl)-l ,3-oxazoli
`dine, 70% yield. mp ll8°—120° C, c1025": —17.9°
`(CH3OH), ir (KBr); 2980, 2860, 2700, 1600, 1450,
`1260 and l 120 cm“. nmr (CD3COCD3): 8 7.4-6.6 (m,
`4H), 5.2 (b, 1H), 5.0 (t, 1H, J = 7H2), 3.3 (dd, 1H, J
`=7 and 9H2), 2.7 (dd, 1H, J = 7 and 9H2), 2.4 (s, 3H)
`and 1.3 (s, 6H) ppm.
`Anal. Calcd for CmH11NOz: C, 69.6; H, 8.2; N, 6.8.
`Found: C, 70.3; H, 8.4; N, 6.7.
`'
`To a solution of the (R)-2,2,3-trimethyl-5-(m
`hydroxyphenyl)-l,3-oxazolidine previously obtained
`(1.32 g, 6.38 mmole) in 60 ml of ether, there was
`added thallous ethoxide (1.59 g, 6.38 mmole) and the
`mixture was stirred at room temperature for 1 hour.
`
`Exhibit 1011- Page 4 of 7
`
`

`
`3,966,749
`
`5
`.
`Pivalyl chloride (0.79 ml, 6.38 mmole) was then added
`and stirring was maintained for two additional hours.
`The solid material formed in the reaction was ?ltered
`and the ?ltrate (this solution was usually used directly
`in the next reaction without evaporation) was evapo
`rated to dryness to give 1.8 g of an oily product, (R)
`2,2,3-trimethyl-5-( m-trimethylacetoxyphenyl )- l ,3
`oxazolidine, 95% yield. u,,25°
`—1(,).6° <c,n_.,on).
`ir(neat): 2960, 1760, 1610, 1590, 1480, 1450, 1370,
`1360, 1260, 1230, 1140 and 1105 cm". ‘nmr (CCl.,): 8
`7.4—6.8 (m, 4H), 5.0 (t, 1H, J= 7H2), 3.3 (dd, 1H, J =
`7 and 9H2), 2.8 (dd, 1H, .1 = 7 and 9H2), 2.3 (s, 3H),
`1.4 (s, 9H) and 1.3 (s, 6H) ppm.
`The ?ltrate obtained in the previous reaction con
`taining
`(R )-2,2,3-trimethyl-5-( m-t'rimethylacetoxy~
`phenyl)-l ,3-oxazolidine (1.8 g, 6.2 mmole) in 60 ml of
`ether was treated with hydrogen chloride gas until the
`solution was no longer turbid. This mixture was then
`evaporated to dryness and the residue was dissolved in
`a small amount of ethanol and then diluted with hex
`ane. The hydrolysis and crystallization took place in the
`solution to give 1.2 g of the ?nal product, (R)-m
`(trimethylacetoxy)-a-[methylamino)methyl]benzyl
`alcohol hydrochloride, 70% yield. mp 128°—130° C,
`(1,,25 ‘’
`—36.7° (cznsom. ir (KBr): 3370, 2690,
`2795, 2420, 1750, 1610, 1590, 1460, 1240 and 1110
`cm“. nmr (CD3COCD3. D20): 87.5~6.8, (m, 4H), 5.3
`(dd, 1H, .1 = 5 and IOHz), 3.8 (b, 3H), 3.4 (m, 2H), 2.9
`(s, 3H) and 1.4 (s, 9H) ppm.
`Anal. Calcd for CHHnNO3Cl: C, 58.4; H, 7.7; N, 49.
`Found: C, 58.4; H, 7.7; N, 4.6.
`The remaining compounds of formula (I) can be
`' prepared with similar success by substituting the gener
`ically or speci?cally described reactants and/or operat
`ing conditions of this invention for those used in the
`preceding example. Similarly, this process can be used
`to prepare the enantiomeric(S)-isomers or the racemic
`(R,S)-isomers as well.
`
`5
`
`20
`
`25
`
`30
`
`35
`
`45
`
`6
`EXAMPLE III
`MYDRIATIC STUDIES
`Standard doses of 50 p. l of the following isotonic
`solutions were applied onto male and female rabbit
`eyes: 0.15% , of (R)-m-(trimethylacetoxy)-a-[(me
`thylamino)methyl]benzyl alcohol hydrochloride (1
`PPE, this-invention); 0.5% of a racemic mixture of
`m-pivaloxy-a-[(methylamino)methyl]benzyl alcohol
`hydrochloride (d,l-PPE) — US. Pat. No. 3,825,583;
`and 2.5% of (R)-phenyleprhine hydrochloride (l-PE).
`All of the compounds tested elicited the same mydri
`atic response as can be seen from a review of FIG. 1
`accompanying the instant application. Thus, it is
`clearly established that the compounds of this inven
`tion easily elicit a mydriatic response at a much lesser
`dosage rate than that observed for its closest competi
`tors (m-pivaloxy-a-[(methylamino)methyl]benzyl al
`cohol hydrochloride) or phenylephrine hydrochloride,
`per se.
`By following the above procedure, equivalent mydri
`atic responses will be observed for the remaining com
`pounds of formula (1).
`The compounds prepared by the process of the in
`stant inventionican be used by the pharmaceutical
`and/0r veterinary arts for the treatment of glaucoma,
`bronchial asthma, and nasal decongestion associated
`with hay fever 'and allergic rhinitis in warmblooded
`animals (e.g., humans) in a variety of pharmaceutical
`preparations as described in US Pat. No. 3,825,583.
`As for the therapeutic dose required of the com
`pounds prepared or the process of the instant inven
`tion, while dosage limitations will naturally vary with
`the size and needs of the individual treated, normally,
`the dosage range will mimic that described for the
`compound m-pivaloxy-a-[(methylamino)methyl]ben
`zyl alcohol as described in US. Pat. No. 3,825,583.
`From the foregoing description, one of ordinary skill '
`in the art can easily ascertain the essential characteris
`tics of this invention, and without departing from the
`spirit and scope thereof, can make various changes
`and/or modi?cations of the invention to adapt it to
`various usages and conditions. As such, these changes
`and/or modi?cations are properly, equitably, and in
`tended to be, within the full range of equivalence of the
`following claims.
`What we claim is:
`l. A method for preparing an optically and therapeu
`tically active (m-acyloxy-a-[(methylamino)methyl]
`benzyl alcohol of the formula:
`
`EXAMPLE II
`HYDROLYSIS (CLEAVAGE) OF OPTICALLY
`ACTIVE
`m-(TRIMETHYLACETOXY)-a-[(ME
`THYLAMINO)METHYL]BENZYL ALCOHOL
`HYDROCHLORIDE TO OPTICALLY ACTIVE
`PHENYLEPHRINE
`
`‘
`
`(m-HYDROXY-a-[(METHYLAMINO)METHYL]
`BENZYL ALCOHOL)
`The following study clearly evidences the fact that
`the compounds of the instant invention hydrolytically
`“cleave,” thus releasing (R)-phenylephrine hydrochlo
`ride, the therapeutic moiety of the initial compound.
`(R )-m-( trimethylacetoxy )-a-[ (methylamino )me
`thyl]benzyl alcohol hydrochloride obtained from Ex
`ample I (1.0 g) was dissolved in 10 ml of methanol
`containing 1 ml of concentrated hydrochloric acid. The
`resulting solution was then re?uxed for 24 hours, and
`subsequently, the solvent was then removed in vacuo to
`give 0.7 g (90% yield) of (R)-phenylephrine as. deter
`mined by conventional optical activity determination
`procedures. a,,25° =47.0° (Lit. a,,25° =—46.2, Dic
`tionary of Organic Compounds. 4th Ed. Oxford Univer
`sity Press, 1965).
`
`50
`
`3
`
`wherein R represents a member selected from the
`group consisting of a straight or branched alkyl group
`or from one to twenty carbon atoms, an ethoxycarbo
`nyl group, a benzyloxycarbonyl group, a phenyl group,
`an
`
`60
`
`65
`
`Exhibit 1011- Page 5 of 7
`
`

`
`group, wherein R is as defined above and R3 is a mem
`ber “selected from the group consisting of a hydrogen
`atom, a methyl- group and a phenyl group, and a 2-, 3-,
`or 4-pyridyl group, or the HX salts thereof, wherein X
`represents a pharmaceutically acceptable acid addition
`salt anion which consists essentially of
`l. reacting optically active phenylephrine ,with an
`excess of a carbonyl compound of the formula:
`R1—CO——R2, wherein R1 and R2 which can be the
`same or different and represent a member selected
`from the group consisting of a hydrogen atom, a
`' ‘Cl-CH, alkyl group, and a di(C,—C2)alkylamino(,C
`,-C“,)alkyI group, or wherein R, and R2 together
`with the carbonyl group to which they are attached
`can form a member selected from the group con
`sisting of a C5-C7 cycloalkanone group and'a sub
`stituted or unsubstituted N- or O-heterocyclic
`(C5-C1) alkanone group, wherein said substituent
`is a C1-C2 alkyl group, either in the presence of a
`' dehydrating agent selected from the group consist
`ing of an alkaline earth metal carbide, a molecular
`sieve of from 4 to 5 A, vcalcium chloride, magne
`sium sulfate, and sodium sulfate, or in the presence
`of a conventional inert aromatic‘ hydrocarbon sol
`vent plus an organic or inorganic acid catalyst to
`eliminate the water formed as an azeotropic mix
`ture, said step being carried out at a temperature of
`from 20° to 140° C, standard pressure, and for a
`period of time ranging from 2° to 2 to 48 hours,
`whereby the intermediate;
`
`_
`
`(II)
`
`35
`
`40
`
`wherein R1 and R2 are de?ned as above is formed;
`2. reacting the intermediate of step (1 ) with a mem
`ber selected from the group consisting of an M
`hydroxide, an M-hydride, and an M-alkoxide,
`wherein M represents a member selected from the
`group consisting of an alkali earth metal, an alka
`line earth metal and thallium in the presence of an
`inert organic solvent selected from the group con
`sisting of an aliphatic hydrocarbon solvent or from
`?ve to 10 carbon atoms, an aromatic hydrocarbon
`solvent, and C,—C4 aliphatic alcohol, a conven
`tional ether and dimethylformamide, said step
`being carried out at room temperature, standard
`pressure, and for a period of time ranging from 1
`to 24 hours, whereby the intermediate:
`
`45
`
`50
`
`(I'II)
`
`MO
`
`55
`
`60
`
`wherein M, R1, and R2 are de?ned above is formed;
`3. reacting the intermediate of step (2) with a stoi
`chiometric amount of an acyl halide of the formula:
`65
`R—CO——Y, wherein R is de?ned as above and Y
`represents a halogen atom in the presence of an
`inert organic solvent selected from the group con- '
`sisting of an aliphatic hydrocarbon solvent of from
`
`3,966,749
`
`8
`?ve to 10 carbon atoms, an aromatic hydrocarbon
`solvent, methanol, propanol, butanol, a conven
`tional ether, and dimethylformamide, said step
`being carried out at room temperature, standard
`pressure, and for a period of time ranging from 1 to
`24 hours, whereby the intermediate:
`
`15
`
`20
`
`25
`
`30
`
`wherein R, R,, and R2 are de?ned as above is
`formed; and
`4. cleaving the R,—CO—R2 moiety of the intermedi
`ate from step (3) in an organic inert solvent se
`lected from the group consisting of an aliphatic
`hydrocarbon solvent of from ?ve to ten carbon
`atoms, an aromatic hydrocarbon solvent, a CFC4
`aliphatic alcohol, a conventional ether, and di
`methyl fonnamide and further in the presence of a
`stoichiometric or excess amount of water and a
`catalytic amount of an HX acid, wherein X is de
`?ned as above, said step being carried out at a
`temperature of from 20° to 100° C, standard pres
`sure, and for a period of time of from 1 to 24 hours,
`whereby the free base of formula (I) is obtained.
`2. The process of claim 1, wherein in step (4), a
`stoichiometric amount of said HX acid is employed to
`obtain the pharmaceutically acceptable acid addition
`salt of the compound of formula (I).
`3. The method of claim 1, wherein in step (4), said
`catalytic amount of said HX acid is in the range of from
`0.01 to l.0% of the stoichiometric amount.
`4. The amount of claim 1, wherein in step (1), said
`step is carried out at a temperature equivalent to the
`boiling point of the solvent or solvent mixture em
`ployed.
`5. The method of claim 1, wherein in step (1), said
`carbonyl compound is a member selected from the
`group consisting of pentanone, hexanone, heptanone,
`piperidone, pyrrolidone, N-methylpiperidone, and N
`methylpyrrolidone.
`6. The method of claim 1, wherein in step (1), said
`aromatic hydrocarbon solvent is a member selected
`from the group consisting of benzene, toluene, and
`xylene.
`7. The method of claim 1, wherein in step (1), said
`acid catalyst is a member selected from the group con
`sisting of p-toluene-sulfonic acid, sulfosalicylic acid,
`benzenesulfonic acid, sulfuric acid, and hydrochloric
`acid.
`8. The method of claim 1, wherein in step (2), said
`metal hydroxide, metal hydride, or metal alkoxide is a
`member selected from the group consisting of sodium
`hydroxide, potassium hydroxide, calcium hydroxide,
`magnesium hydroxide, barium hydroxide, sodium hy
`dride, calcium hydride, sodium methoxide, sodium
`ethoxide, sodium propoxide, and thallous ethoxide.
`9. The method of claim 1, wherein in step (2), said
`inert organic solvent is a member selected from the
`group consisting of pentane, hexane, heptane, octane,
`nonane, decane, benzene, toluene, xylene, methanol,
`ethanol, butanol, propanol, diethyl ether, tetrahydrofu
`ran, dioxane and dimethylformamide.
`
`Exhibit 1011- Page 6 of 7
`
`

`
`3,966,749
`10. The method of claim 1, wherein in step (3), said
`inert organic solvent is a member selected from the
`group consisting of pentane, hexane, heptane, octane,
`nonane, decane, benzene, toluene, xylene, methanol,
`propanol, butanol, diethyl ether, tetrahydrofuran, diox
`ane, and dimethylformamide.
`'
`11. The method of claim 1, wherein in step (4), said
`HX acid is a member selected from the group consist
`ing of hydrochloric acid, hydrobromic acid, sulfuric
`acid, sulfamic acid, phosphoric acid, nitric acid, acetic
`acid, propionic acid, succinic acid, glycollic acid, ste
`aric acid, lactic acid, malic acid, tartaric acid, citric
`
`10
`acid, ascorbic acid, pamoic acid, maleic acid, hydrox
`ymaleic acid, phenylacetic acid, glutamic acid, benzoic
`acid, salicylic acid, sulfonilic acid, fumaric acid and
`toluenesulfonic acid.
`12. The method of claim 1, wherein in fonnula (l), R
`represents a straight or branched alkyl group of from
`one to ?ve carbon atoms.
`13. The method of claim 1, wherein in step (I), opti
`cally active phenylephrine is replaced with racemic
`phenylephrine, thus yielding racemic m-acyloxy-a
`[(methylamino)methyl]benzyl alcohol.
`
`*
`
`* * * *
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`Exhibit 1011- Page 7 of 7