CA1064965A - Optically active 2,3-cis-1,2,3,4-tetrahydro-5-(2-hydroxy-3-(tert-butylamino)-propoxy)-2,3-naphthalenediols - Google Patents

Abstract

Abstract This invention relates to optically active 2,3-cis-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(tert-butylamino)propoxy]-2,3-naphthalenediols and partially resolved mixtures thereof and their method of preparation. In additlon, pharmaceutical compositions containing said optically active compounds and mixtures and methods for using said compositions as .beta.-blocking and antiarrhythmic agents are described.

Description

~0~i4965 .
Cardiovascular diseases are considered by many to be the greatest health hazard in the United States. This has resulted in an intensive research effort to prepare compounds ~hich could be used in the treatment of cardiovascular diseases. Canadian Patent No. 979,926, issued December 16, 1975, discloses a structure, 2,3-cis-1,2,3,4-tetrahydro-5-~2-hydroxy-3-~tert-butylamino)propoxy]-2,3-naphthalenediol which exhibits considerable ~-blocking and antiarrhythmic activities.
While all of these activities are useul, usually only a single activity is desired in a compound at any instance. In the present case, the ~-blocking activity, if separated from the antiarrhythmic activity, would give rise to agents having significantly fewer undesirable side efects and a higher degree of activity; that is, a ~-blocking agent would result having a minimal o~ antiarrhythmic properties and an antiar-rhythmic agent would result having a lower order of ~-blocking properties. As stated in the Canadian Patent No. 979,~26, it r`
was believed that the two properties were probably related, and thus by resolving the 2,3-cis-1,2,3,4-tetrahydro-5-E~-hyd~oxy-3-~tert-butylamino)propoxy]-2,3-naphthalenediol into , its our possible optical isomersl a separation of ~ctivities could not be obtained. Surprisingly, this is not the case.
Upon obtaining optically active isomers, one finds that only the (-) side chain isomer ~I) retains most of the ~-blocXing activity. Even more surprising is the fact that while the ~-blocking activity is centered in only the (-) side chain isomer, the antiarrhythmic properties are about equally present in all the isomers.

.
.
-1- ~ .' 6496~;
This invention relates to methods for obtaining .
the four optical isomers and partially resolved mixtures thereof. The four optical isomer5, and the various partially resolved mixtures thereof can be obtained ac-cording to the following two reaction schemes.
SCHEME I
.`
OCH IHcH2NHt C4 9 ~11;

dibenzoyl-d-tartaric ~ ~ acid / ~ Mother liquor \
/ strong base / \ ditoluoyl~
~ ~tartaric acid (d)-l-(tert-Butylamino)-3-[(5,8- (l)-l-(tert-Butylamino) dlhydro-l-naphthyl)oxyl-2-propanol. -3-[(5,8-dihydro-1-naph-dibenzoyl-d-tartaric acid thyl)oxy]-2-propanol.
ditoluoyl-l-tartaric acid strong base strong ba~o . ' ~ ~ / `~
(d)~ tert-Butylamino)-3-1(5,8- (l)-l-(tert-Butylamino) dihydro-l-naphthyl)oxy]-2-propanol. -3-[(5,~ hydro-1-naph-thyl)oxy]-2-propanol.

IV V

l)AgOAc,HoAc l)AgOAc, -I2 and H20 2 d H20 ~ ~ 2~NaOH, H20 ~2)NaOH, H~O

5-[d-3-(tert-Butylamino)-2-hydroxy- 5-[1-3-(tert-Butylamino)-propoxy]-1,2,3;4-tetrahydro-dl-cis- 2- hydroxy-propoxyl-1,2, :1~64965

2,3-naphthalenediol. 3,4-tetrahydro-dl-cis-2,3-naphthalenediol.

¦ VI ¦ VII
recrystallization ~ recrystallization . .
isomers VIII (m.p. 124-126) isomers X (m.p. 126-and IX (m.p. 144-145) 130) and XI (m.p. 141-143~) In addition, this invention is intended to encompass the partially or completely resolved isomers shown by the formu-lae II to XI and their salts.
Lastly, this invention is intended to encompass pharma-ceutical compositions containing compounds IV to XI and their acid addition and quaternary ammonium salts and methods fox utilizing said compositions.
The term "salts" is intended to encompass "acid addition salts" and "quarternary ammonium salts".
The term "acid addition salts" is intended to encompass the "pharmaceutically acceptable salts" such as hydrochloride salts, sulfide salts, citrate salts, etc. and other salts 'i that may be used for purification such as salts ~ormed with optically active compounds, such as dibenzoyl-d-tartaric acid, and othex salts, such as oxalates, etc.
The term "quaternary al~onium sal~s" is intended to en-compass the compounds formed when compounds of the formula IV
to XI are reacted with alkylating a~ents of from 1 to 10 car~on atomR, such as methyliodide, dipropylsulfate, benzyl chloride, phenethyl bromide, isobutyl tosylate, etc.
2,3-Cis-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(tert-butylamino) propoxy]-2,3-naphthalenediol, which is reported in Canadian Patent No. 979,926 possesses a high degree or utility as an

-3 ~649EiS

agent in the treatment of cardiac arrhythmia and as a ~-blocking agent. The reported compound may exist in four isomeric forms and, in fact, the method employed in Canadian Patent ~o. 979,926 gives rise to a mixture of all four possible isomers. The reported activity was obtained from pharmacological tests on the mixtures of isomers. One obtains the individual isomers or pairs of isomers by the following procedure.
dl-l-(tert-Butylamino)-3-[5,8-dihydro-1-naphthyl)oxy~
-2-propanol ~I) is prepared by the reaction of 1-(2,3-epoxy-propoxy)-5,8-dihydronaphthlene with tert-butylamine which is disclosed generically in U.S. Patent 3,354,085. Compound I is resolved into the tartrate salts of Compounds IV (d) and V ~1) by reaction with optically active tartaric acid ~`
followed by recrystallization from a lower alkyl alcohol having up to three carbon atoms. Compound IV is obtained by using dibenzoyl-d-tartaric acid and V is isolated by treatment of the free base o the mother liquor with ditoluoyl~
l-tartaric acid. These compounds may be converted to other salts for the purpose of further puri~ication or storage, such as the hydrochloride salt, phosphate salt, sulfate salt, acetate salt by krea~ment with a s~rong base, such as sodium hydroxide, potassium hydroxide, etc., followed optionally by treatment with an acid.
Tn ordex to prepare the pharmacologically ac~ive com~ounds of this invention, the free bases of the (d) and (1) isomers, that is, compounds IV and V, respectively, are subjected to a "Wet" Prevost Reaction. This reaction is generally conducted under nitrogen with the aid of heat ~ 649~5 HA118/12~ j utilizing the silver salt of a lower alkyl carboxylic acid of from 1 to 8 carbon atoms, said lower alkyl carboxylic acid of from 1 to 8 carbon atoms, iodine and from about 0.5% to about 10~ water, preferably 2~ to 8%.
The temperature range is generally from about 85~ to about 110C. Initial~y the compounds of formula IV and V are dissolved in the a~ueous lower alkyl carboxylic acid, preferably acetic acid and then the solution is treated with the silver salt of a lower alkyl carboxylic acid, preferably silver acetate, iodine and heated under nitrogen.
Then salts and excess acid are removed and the free base liberated.
Next the material is catalytically hydrogenated in an alcoholic or acidic solvent of from one to six carbon atoms which may or may not contain water. While cata-lys~s such as nickel, platinum, etc., may be employed, the preferred catalyst is palladium. The reaction is conducted at about room temperature utilizing hydrogen at pressures of about 50 pounds per sq. inch.

..

S

The "wet" Prevost Reaction in the case of compound IV gives rise to a mixture of two isomers designated VI, while in the case of compound V, a mixture of two isomers designated VII is obtained.
While the isomer pairs VI and VII show approximately equivalent antiarrhythmic activity, isomer pair VII
demonstrates a range of 35 to 200 times the ~-blocking activity than that of isomer pair VI, which exhibits only marginal ~-blocking activity. ~`
The isomer pair VI is further separated by fractional crystallization into compounds VIII and IX utili~ing mixtures of an aromatic hydrocarbon of up to ten carbon atoms such as benzene, tvluene, xylene, and a lower alkyl-nitrile having from two to eight carbon atoms such as acetonitrile, butyronitrile wherein the aromatic hydro-carbon is from 70 to 90 percent o~ the mixture with the remainder being the lower alkylnitrile. The first crop, after numerous recrystallizations from an approximately 1:1 halogenated hydrocarbon of up to three carbon atoms (such as chloroform, methylene dichloride, etc.): hydro-carbon of from five to ten carbon atoms (such as hexane, 2-ethylpentane, etc.) mixture gives pure compound VIII.
The second crop which crystallized ~rom the aromatic hydrocarbon of up to ten carbon atoms: low alkylnitrile -mixture is also recrystallized from a halogenated hydro-car~on of up to three carbon atoms: hydrocarbon of from five to ten carbon atoms (about 3:1) followed by being dissolved in an approximately 1:1 mixture -..

~64~65 of said halogenated hydrocarbon: hydrocarbon solvent system which is allowed to slowly evaporate giving a gel having a dense white solid which is removed and recrystallized from a lower alkyl lower alkanoate having a total of from two to ten carbon atoms to give pure compound IX.
The isomer pair VII is separated into compounds X and XI by slow crystallization from mixture of an aromatic hydrocarbon of up to ten carbon atoms and a lower alkylnitrile having from two to eight carbon atoms wherein said aromatic hydrocarbon is about 65% to about 90% of the solvent mixture. Repeated recrystalli~ations (2 to 5) of the material from a mixture of a halogenated hydrocarbon of up to three carbon atoms and a hydrocarbon of from ive to ten carbon atoms (about 1:1) gives pure compound X.
The aromatic hydrocarbon:lower alkylnitrile solvent mixture which is depleted of X, is evaporated. The residue is crystallized from an aromatic hydrocarbon of up to ten carbon atoms, followed by recrystallization from a low alkyl lower alkanoate having a total of from two to ten carbon atoms, giving pure compound XI.
While the four isomers have approximately equivalent antiarr~thmic activity, they exhibit varying o~ders of ~-blocking activity, wit.h isomer XI having a range of 2.5 to 10 times the activity of the mixture of all four isomers.
Compound X i9 from 1.6 to 2,3 times, IX is from .1 to ~2 times and VIII is from .04 to .13 times as active as a mixture of all four isomers.
Quaternary ammonium salts of the present invention can be prepared by allowing an alkylating agent such as methyl iodide, benzyl chloride, etc. to react with an 49~

amine of structure IV to XI in an organic solvent such as acetonitrile, ether or a lower alcohol at between room temperature and the reflux temperature of the solvent SCHEME I I
]

~

¦ ractional crystallization /\
/' \ ' 1~ \J
5-[d-3-(ter-t-Butylamino-2- 5-~d-3~~tert-Butylamino-2-hydroxypropoxy]-1,2,3,4-tetra- hydroxypropoxy]-1,2,3,4-tetra-hydro-l-cis-2,3-naphthalenediol, hydro-d-cis-2,3-naphthalenediol, and 5-11-3-(tert-sutylamino)-2- and 5-[1-3-(tert-Butylamino)-2-hydroxypropoxy]-1,2,3,4-tetra- hydroxypropoxy~-1,2,3,4-tetra-hydro-d-cis-2,3-naphthalenediol. hydro-1-cls-2,3-naphthalenediol (Racemate ~) ~Racemate B) . ~ resolution resolution 5-[d-3-~te.rt-~utylamino)-2-hydroxypropoxYl-l~,2r3r~-tetrahydro~l-cis-2~3-naphthalenediol(vIII) -~ 5-~1-3-(tert Butylamlno)-2-hydroxypropoxy]-1,2,3,4-tetral~ydro-d-cis-2,3-naphthalenediol(X) \ f 5-[d-3-ttert-Butylamino-2-hydroxypropoxy]
-1,2,3,~-tetrahydro-d-cis-2,3-naphthal-enediol(IX) ~ 5-[1 3-(tert-Butylamino)-2-hydroxypropoxy]-1,2,3,~-tetrahydro-1-~ cis-2,3-naphthalenediol(XI) .
_~_ ( In addition, thïs invention is intended to encompass the partially resolved isomers termed race~ate A and racemate B and their acid additi.on salts.
Lastly, this invention is intended to encompass pharmacetuical compositions containing racemate A or racemate B and their acid addition and quaternary ammonium salts and methods for utilizing said compositions. One obtains the individual isomers or partially resolved isomers (racemate A or racemate B) by the following procedure.
Racemate A is resolved into the tartrate salts of Compounds VIII and X by reaction with optically active tartaric acid followed by crystallization from a lower alkyl alcohol of up to three carbon atoms. Preferably Compound VIII (ring -, side chain ~) is obtained by using dib~nzoyl-d-tartaric acid and conversion o the salt to the free base by use of strony aqueous base, such as sodium hydroxide, and X
(ring ~, side chain -) is isolated by treatment of the free base of the mother liquor with an optically active tartaric acid, preferably ditoluoyl-l-tartaric acid, and conversion of the purified salt to the free base.
Racemate B is resolved in a similar manner into the tartrake salts of Compounds IX and XI by reaction with optic~lly active tartaria acicl followecl by c~rystallization from a lower alkyl alcohol of up to three carbon atoms.
Compound IX (ring -~, side chain ~) is obtained by using preferably dib~næoyl-d~tartaric acid and conversion of the salt to the free base by use of a strong aqueous base, and XI (ri.ng -, side chain ~) is isolated _g _ ~o6~9i;5 by treatment of the free base of the mother liquor with an optically active tartaric acid, preferably ditoluoyl-l-tartaric acid, and conversion of the purified salt to the free base by the use of strong aqueous base, such as sodium hydroxide.
These materials may be converted to other salts or the purpose of further purification or storage, such as the hydro-chloride salts, phosphate salts, sulfate salts, acetate salts by treatment with the appropriate acid.
L0 The iso~ers exhibit varying orders of ~-blocking activity with isomer XI having a range of ~.5 to 10 times the activity of the mixture of all four isomers. Compound X is from 1.6 to 2.3 times, IX is from .1 to .2 times, and VIII is from .04 to .13 times as active as a mixture of all four isomers.
2,3-Cis-1,2,3,4-tetrahydro-5-~2-hydroxy-3-(tert-butyl-amino)propoxy]-2,3-naphthalenediol, which is prepared accord-ing to the procedure disclosed in Canadian Patent No. 979,926 is separated into racemate A (isomer pair wherein the assy metric center in the ring is (~) and the side chain is (-), and the ring is (-) and the side chain is (~), and racemate B (isomer pair wherein the assyme~ric cen~er in the ring is (+) and the side chain is (+), and the ring is (-) and the side chain is (-), by repeated extractions (2 to 3) with a ~arm (20-60C) solvent, using a lower alkylnitrile of from two to eight carbon atoms, such as acetonitrile or butyronitrile, or a halogenated hydrocarbon of up to three carbon atoms such as chloroform or methylene dichloride. In the instance ~here a lower alkylnitrile is used, the racemate A crystallizes from -10- .

` ( ~A11~126 ~06~6S
the cooled extracL and the racemate B is obtained from the material that dia not dissolve initially in the solvent.
The racemate B proved to be about three times as ac-tive as a ~-blocking and antiarrhythmic agent as racemate A.
The compounds of this invention, namely those represen-ted by the structures IV to XI and their partially resolved mixtures and their pharmaceutically acceptable ~alts are use-ful in arresting cardiac arrhythmia in mammals, such as dogs, horses, etc. For this purpose, a compound of formulae IV to XI or racemates A and B or a pharmaceutically acceptable acid addition salt may be incorporated in a conventional dosage form such as a tablet, capsule, elixir, suppository, injectable or the like along with the necessary carrier mater-ial , excipient, lubricant, buffer or the like. Single or divi~ed doses of about 2.5 to 25 mg/kg, preferably about 4 to lO mg/kg, may be administered (one to four times daily) in conventional dosage forms. Thus from about 150 mg to about 2.0 g of active ingredient are administered to a subject of about 70 kg of body weight.
In addition, compounds VII, X and XI and their partially resolved mixtures and their pharmaceutically acceptable salts are useful as ~-blocking agents in mammals, such as dogs, horses, etc. when administered in amounts ranging from about 2.5 mg to about 25 mg per kg. of body weight per day. A
preferred dosage regimen for optimum results would be from about 4 mg. to about lO mg. per kg. of body weight per day, and such dosage units are employed that a total of from about 150 mg. to 2.0 g of active ingredient are administered to a subject of about 70 kg. body weight.

1~6~9~S

The compounds of the present invention m~y b~ ad-ministered by any convenient route such as orally, intra-peritoneally~ subcutaneously, intramuscularly or intravenously .
Injectable compositions according to the present in-vention having the desired clarity, stability, and adapt-ability for parenteral use are obtained by dissolving ~rom 0.10%to 10.0% by weight of active compound in a vehicle consisting of a polyhydric aliphatic alcohol or mixtures thereo~. Especially satisfactory are glycerin, propylene glyco~, and the poLyethylene glycols. The polyethylene glycols consist of a mixture o~ non-volatile, normally liquid, polyethylene glycols which are soluble in both water and oryanic liquids and which have molecular weights of from about 200 to about lS00. Although the amount of active compound dissolved in ~he above vehicle may vary - from 0.10% to 10.0% by weight, it is preferred that the amount of active compound employed be ~rom about 3.0%

to about 9.0% b~ weight. Although various mixtures o the aorementioned non-volatile pol~ethylene glycol~
may be employecl, it is preferred to use a mixture havin~
an average molecular weight of from about 200 to about 400.
In addition to the ~ctive compounds, the parenteral solutions of the present invention may al~o contain various preservatives which may be used to prevent bacterial and fungal contamination. The preservatives which may be used for such purposes are, ~or example, benæyl alcohol, ~12-~64~65 myristyl-gamma-picolinium chloride, phenyl mercuric nitrate, benzalkonium chloride, phenethyl alcohol, p chlorophenyl-~-glycerol ether, methyl and propyl parabens, and thimerosal.
As a practical matter it is also convenient to employ antio~idants. Suitable antioxidants include, for example, sodium bisulfite, sodium metabisulfite, and sodium formaldehyde sulfoxylate. Generally, from about 0.05% to about 0.2~ concentra~ions of antioxidant are employed.
The active compounds of the present invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet~ For oral therapeutia administration, the active compounds of this invention may be incorpor~ted with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like. Such compositions and preparations should contain at least 0.1% of active compound.
The percentage in the compositions and preparations may, of course, be varied and may conveniently be be~ween about 5% to about 75% or more of the weight of the unit. The amount of aative compound in such therapeutically use~ul compositions or preparations is such ~hat a suitable dosage will be obtained. Preferred compositions or ~ 9~5 HA118 /126 preparations accordincJ to the present invention are prepared so that an oral dosacJe unit form contains bet~een about 2.5 and 100 milligrams of active compound.
The tablets, troches, pills, ca~sules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipi~nt such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like, a lubricant such as magnesium stearate and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil o~ wintergreen, or cherry 1avoring.
When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit, for instance, tablets, pills or capsules may be coated with shellac, su~ar, or both~ A syrup or elixir may contain the active com-pounds, sucrose as a sweetenin~ ag~n~, mekhyl and propyl parabens AS pr~servative~, a dye and a ElavorincJ ~uch as cherry or orange flavor. Of course, any material us~d in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amount employed.

~64~6~i;

The following examples are provided for illustrative oses and may include particular features of the invention; however, the examples should not be construed as limiting the invention, many variations of which are possible without departing from the spirit or scope thereof.
Parts are by weight unless otherwise indicated. Examples 1 through 7 refer to Scheme I. Examples 8 through 11 refer to Scheme II.

Example 1 dl-l-(tert-Butylamino)-3-[5,8-dihydro-l~naphthyl)oxy]-2- i propanol A mixture of 25 g (0.125 moles) o 1-(2,3-epoxy-propoxy)-5,8-dihydronaphthalene and 125 ml of tert-butylamine is heated in a stainless steel bomb at 115-120C overnight.
The contents are removed and evaporated in vacuo to an oil which crystallizes on scratching. Trituration with cold pet ether (30-60C) filtration and drying in vacuo aords 27.5 g (80%) tan solid, 1-(tert-butylamino)-3-[~5,8-dihydro-1-naphthyl)oxy]-2-propanol.
Recrystallization o a 5.0 g sample rom pet ether afords 3.4 g of the pure named compound.

Example 2 (d)~ tert-Bu~ylamino)-3-[(5,8-dihydro-1-naphthyl)oxy]-2-propanol, hydrochloride A mixture of 62.0 g (0.225 M) of the racemic ` 106~965 HA118/126 compound prepared in Example 1 and 84.7 g (0. 225 M) of dibenzoyl-d-tartaric acid in 700 ml methanol is allowed to crystallize for a ~ew hours at room temperature.
The tartrate is removed by filtration and recrystallized two times from methanol. Small samples 5~500 mg) are removed at each recrystallization, shaken with ether and 10% ~aOH. The ether layers are dried (~gSO4) and treated With a few drops of HCl in isopropyl alcohol.

The crystalline hydrochlorides are isolated and dried EtOH
in vacuo. ~]D first recrystallization +20.8, C=1.0; second recrystallization +23.5C. A third recrystallization of a small portion of the tartrate and conYersion to the hydrochloride gives materia EtOH
ta]D = ~ 23.4 (c=1.0).
The tartrate is shaken with ether and excess 2N
N~OH. The ether layer is dried (MgSO4) and the solvent is removed in ~acuo to give 23.7 g (76.5~) of oil.
A sample (2.0 ~) of the oil is dissolved in ether and converted to the hydrochloride by the addition of a solution of HCl in isopropyl alcohol. The crystalline salt is harvesked and recrystallized from isopropyl alcohol-ether to give 1.3 g (58~) of the named compound m.p~ 118-123 ~EtOH ~ 23 1 (c=l 0) -~ HA118/126 ~6~965 Example 3 (l)-l-(tert-Butylamino)-3- E 5,8-dihydro-1-naphthyl)oxy]-... _ .. . .. .
2-propanol, hydrochloride The first mother liquor from the mixture of racemic amine and dibenzoyl-d-tartaric acid of Example 2 is taken to dryness and shaken with ether and an excess of 2N NaOH. The ether layer is dried and taken to dryness in vacuo leaving 26.1 g of free baseO A small EtOH
sample is converted to the hydrochloride [~] -19.3, ~-1Ø
This free base (23.1 g, 0.084 M) and 32.4 g (0.084M) of di-p-toluoyl-l-tartaric acid in 250 ml methanol is allowed to crystallize overnight. The tartrate is re-moved by filtration and recrystallized once from methanol.
Small samples (r~ 500 mg) of the crystalline tartrates are shaken with ether and 10% NaOH. The ether layers are dried and treated with a few drops of HCl in isopropyl alcohol. The crystalline hydrochlorides are isolated EtOH
and dried in vacuo [a] first cr~st. -22.4 (c=1.0);
recrys~al]ized -23.7 (c=1.0). Recrystallization of a - small portion of the tartrate and conversion to the EtOH
. HCl gives material ~ 23.7.
D
The tartrate (~,23 g) is shaken with ether and excess 2N NaOH. The ether layer is dried (MgSO~) and the solvent is removed in ~acuo to give 10.1 g of oily free base.

~6~9~S HA118/126 A sample (1.7 g) of the free base is dissolved in ether and converted to the hydrochloride by adding a solution o~ HCl in isopropyl alcohol. The crystalline salt is harvested and recrystallized from isopropyl alcohol ether to give the named compound 1.1 g (58%), m.p. 119-124C.
EtOH
[a]D -24.0 (c=1.0).

Example 4 5-~d-3-(tert-Butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-dl-cis-2,3-naphthalenediol A 10.2 g (0.037 moles) of optically pure ree base of the compound of Example 2 in a mixture of 200 ml glacial a ~ ic acid and 10 ml of water is treated with 12.1 g (0.074 moles) of silver acetate, and then 9.6 g (0.38 moles) o~ iodine (I2). The slurry is stirred and heated to 95C, and held at 95-105C for two hours. The mixture is cooled and filtered (Whatman No. 1) by suction. The salts are washed with glacial acetic acid, and the filtrates are evaporated ln vacuo. The residue is taken up in 600 ml of 95% ethanol, basified with 200 ml of 10~ sodium hydroxide, and stirred at room temperature overnight. The dark turbid mixture i9 distilled at 1 atm. to remove 400 ml of solvent, 200 ml o~ waker added, and distillation continued until the temperature is 100C. The mixture is cooled and extracted twice with ahloroform. The extracts are dried (magnesium sulfate) and evaporated to 15.2 g of a tan foam.
This is taken up in 200 ml o ~- HA118/126 1~6~
absolute ethanol, 1.5 g of 5~ palladiu~-on-charcoal is added, and the mix~ure hydrogenated at 50 psi for one hour, until hydrogen uptake ceases. ~he catalyst is filtered and washed with alcohol, and the solution is evaporated to an oil. The oil is taken up in chloroform t200 ml) and washed once thoroughly with 50 ml of 10% sodium hydroxide. The aqueous layer is reextracted with chloroform and the combined organics are dried overnight tsodium sulfate). Evaporation affords 12.5 g of a tan foam. This was taken up in 200 ml of hot benzene and allowed to cool to room temperature overnight. The solid is filtered, taken up in a hot mixture of 25 ml acetonitrile and 130 ml of benzene, treated with decolorizing carbon, and flltered for analysis. ~tanding at 23C for 18 hours and ~ilter~ng, affords, on drying at 80C and 0.1 mm Hg for 15 hours over para~fin, 4.4 g of 5-~d-3-(tert-butylamino~-2-hydroxypropoxy]-1,2,3,4-tetrahydro-dl-cis-2,3-naphthalenediol, m.p. 114-124C.

Example 5 5-ll-3-(tert-Butylamino)-2-hydroxypropoxy]-l~2~3~4-tetra hydro-dl-cls-2,3-naphthalenediol 8.3 g ~0.030 mole) of the ~ree base o~ the compound prepaxed in E~ample 3 ln a mi~ture of 200 ml glaciA1 acetic acid and 10 ml o water is treated with 10.8 g (0.066 mole) of silver acetate, and then 7.7 g (0.030 mole) of iodine ~I2). The slurry is ~tirred and heated to 95C, and ~ ~. .118/126 1~6~9~i;5 held at 95-105DC for two hours. The mixture is cooled somewhat and filtered (Whatman No. 1) by suction. The salts are washed with glacial acetic acid, and the filtrates evaporated in vacuo. The residue is taken up in 600 ml of 95% ethanol, basified with 200 ml of 10%
sodium hydroxide, and stirred at room temperature overnight. The dark turbid mixture is distilled at 1 atm. to remove 400 ml of solvent, 200 ml of water added/
and distillation continued until the temperature is 100C.
The mixture is cooled and extracted twice with chloroform.
The extracts are dried (magnesium sulfate) and evaporated to 13 g of a tan foam. This is taken up in 200 ml of abs.
ethanol, 1.8 g of 5~ palladium-on-charcoal i5 added, and the mixture hydrogenated at 50 psi for 0.7S hour, until hydrogen uptake ceases. The catalyst is filtered and washed with alcohol, and the solution is evaporated to an oil. This is taken up in chloroform ~200 ml) and washed twice with 10% sodium hydroxide. The aqueous layer is reextracted with chloroform, and the combined organics are dried overnight (sodium sulfate). Evapora-tion affords 12 g of a tan foam. This is taken up in 125 ml of hot ben~ene and allowed to cool to room temperature overnight. ~h~ ~olid iæ filtered and recrystallized from 100 ml of a 9:2 benzene:acetonitrile mixture for analysis.
Standing at 23C for two days and filtering, affords on drying at 80C and 0.1 mm Hg for 15 hours over paraffin, 3.8 g (41~3 of 5-[1-3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro- _-cis-2,3-naphthalenediol, m.p. 114-121C, [a] = ~23.6, c=1.0, run in 0.1 N HCl in BtOH.

1~6~g65 HAl 18/126 Example 6 Separation of 5-rd-3-~t~rt~B~ amino)-2-hydroxyprQPO
1,2,3,4-tetrahydro-dl-ci~-2,3-naphthalenediol into compounds VIII and IX
The compound of Example 4 (15.3 g) is recrystallized twice from benzene:acetonitrile (9:2) (20 ml/g) by cooling the undisturbed solution ~or two days and decanting. The mother liquors are scratched to give additional crops of crystals. The firsk crop is recrystallized five times from chloroform:hexane (1:1) (100 ml/g) to give 1.2 g (15.7%), m.p. 124-126C, [a~D = -~8.0; c=1.0, run in 0.1 N HCl in EtOH.
The aclditional crops obtainea from benzene-ace-tonitrile (5.7 g) are combined and recrystallized kwice from hex~ne:chloroform (3:1) (80 and 200 ml/g); then from hexane:chloroform (1:1) (50 ml/g) by slow evaporation over ~ a 3 day period to give a dense solid dispersed in a gel.
The dense ~olid i~ mechanically separated and recr~talliza~
three tim~s from ethyl acetate (12,30, and Einally 75 ml/~) -to give a mixture oE fluffy solid and dense granules which are separated by swirling and decanting. Tl.e r~sidual granules are filtered and dried to give 0~12 g (1.6%), m.p, 144-145C, [a]D - ~20.0O, c=0.5, run in 0.1 N HCl in EtOH.

~L~64965 r,~am~ e 7 ~eparatiOn o~ 5-tL-3-(te.rt-sutylamino -2=hvdroxypropoxy~-1,2,3,4-tetrahydro-dl-~i~.-Z,3-naphthalenediol (VII) into Cotnpounds X_and Xl The compo~lnd of Example V (10.8 g) is recrystallized rom a mixture of 180 ml of benzene and 40 ml of ace-toni.trile over a 2 ~/2 day period. The mother liquor is decanted and stripped to an oil which gives a second crop of crystals on crystallization from pure benzene~ The first crop is recr~stallized three t.imes from chloroform:hexane 1:1 (100 ml/g) to give 0~67 ~
(12.~%), m.p. 126-130C, ~a~D = -4.1C, c=0.5, run in 0.1 N HCl in EtOII.
The second crop of crystals from benzene~acetonitrile (2.7 g) is recrystallized from ethyl acetate:hexane (1:3) (300 ml/g) and then three times ~rom ethyL acetate (15, 70, and finally 45 rnl/g) to give 0,4 g (7.4%), rn.p. 1~1-143, ~]D = -19.5, c=0.5, run in 0.1 N llCl in E-tOH.

~4965 E~am~le_8 5-[d-3-(tert-Butylamino)-2-hydro~ypropoxy]-1,2,3,q-tetra-hydro-=1-cis-2,3-naphthalenediol & 5-[1-3-(tert-Butyl~mino)-2-hydroxypropoxy]-l~2~3~4-te-trahydro-~-c~s-2~3-naphthalenedi (Racemate A) A 24 g sample of 2,3-cis-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(tert-butylamino)propoxy]-2,3-naph~halenediol which is prepared according to the procedure disclosed in Canadian Patent No. 979,926 is slurried in 400 ml of acetonitrile.
The slurry is swirled and heated over a steam cone with immersed thermomeL-er until the temperature reaches 60C. The temperature is maintained at this point for 2 mînutes, the supernatant becoming quite clear. Then the suspension is filtered quickly. The filtrate deposits ~ine needles which are harvested in several crops at roughly 10 mi~utes, 1 hour, 2 hours, 18 hours. The first two crops melt in a range of 130-134C, the later crops contain other high melting material which alters the appearance of the solid and broadens the range`to 130-145C. The later crops and the solids obtained on evaporation of the mother liquors are re~orked as above with the same proportions of acetonitrile. Solids in the range 130-134C are combined and recrystallized, 2 g/100 ml of acetonitrile. This material is necessarily harvestPd within 4 hours to prevent small granules of high melting material from forminy. After a number or manipulations, 5.7 g, mp 135-139C is obtained. Crystallization of this 5.7 g from 430 ml of acetonitrile affords on drying at 80C for 5 hours over P2O5 and parrafin at 0.1 mm Hg, a.3 g ~36~), mp 137-139C, of Racemate A.

~)64~65 Example 9 5-[d-3-~tert-Butylamino)-2-hydro~ypropo~]-1,2,3,4-tetra-. _ . , ,3-naphthalenediol, and 5-[1~3~ QX~-Bu yl-anlino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-1-cis-2,3-naphthalenediol ~Racemate B) . _ All the materials of Example 8 which are not dissolved in 60C acetonitrile in 2 minutes are combined on the basls of similar melting range and treated a.s necessary with a second portion of 60C acetonitri.le. After one treatment, mp 131-142. A second treatment with a ratio of 1 g/50 ml acetonitrile usually gives materia.L mp 140-153. A third treatment gives materials which melt in the ran~e 147-154~C, and when combined total about S.8g. Recrystclllizati.on fro~l 400 ml of acetonitrile gives, after 5tanding ovexnigh~

4.5 g (37%) ~ mP 150-152C, OL Racemate B.
Example 10 ._ The Resolution of Racemate A
_ Racemate A (0.2 m) and dibenzoyl-d-tartaric acid (0.2 m~ are dissolved in methanol (700 m1) and allow~d to crystallize for a ~ew hours at room temperature. Th~ tartrate.
is remov~d by ~iltration and recr~stallized -two times ~rom methanol~
The tartrate is shaken with chloro~orm and excess 2N
NaOH. The organic layer is dried (MgSO4) and the solvent is .removed in vacuo. Benzene is added and Co~p~und VITI
crystallizes over sev~ral hours.
The first mother liquor from the mi~tu.re of rac2mic amine and dibenzoyl--d-tartaric acid is taken to dryness and shaken ~ith chloro~orm and an e~cess of 2N NaOI1. The orc~anic layer is dried (McJSO4) and evaporated in vacuo leaving 26.8 - of frce base.

-2~-~ HA118/126 ~6~965 This free base and di-p-toluoyl-l-tartaric acid (0.09 m) in 250 ml methanol is allowed to crystallize overnight. The tartrate is removed by filtration and recrystallized once from methanol.
The tartrate is shaken with chloroform and excess 2N
NaOH. The organic layer is dried (MgS04) and the solvent is removed _ vacuo. Benzene is added to afford the crystalline free base, Compound X.
Example 11 The Resolution of Racemate B
Racemate B (0.2 m) and dibenzoyl-d-tartaric acid (0.2 m~
are dissolved in methanol (700 ml) and allowed to crystallize for a few hours at room temperature. The tartrate is removed by filtration and recrystallized two times from methanol.
The purified tartrate is shaken with chloroform and excess 2N NaOH. The organic layer is dried (MgS04) and the solvent is removed ln vacuo, giving the free base as an oil.
Addition of benzene promote~s crystallization of Compound IX.
The first mo~her liquor from the mixture of racemic amine and dibenæoyl-d-tartaric acid i9 taken to dryness and shaken with chlor,oform"an~ an excess of 2N NaOH. The organic layer 1~ dried (MgS04) and evaporated in vacuo leaving 25.7 of ~r b g ee ase.
This free base and di-p-toluoyl-l-tartaric acid (0.09 m) in 250 ml methanol is allowed to crystallize overnight. The tartrate is removed by filtration and recrystallized once from methanol.
The purified tartrate is shaken with chloroform and excess 2N NaOH. The organic layer is dried (MgS04) and the solvent is removed ln vacuo to give the free base. Tri-turation with benzene causes crystallization of Compound XI.

~al 649giiS HAll~ /126 ~,xample 12 P_aration of Tab.~et Fo.rmulation PerFor 10,000 Ingredient Tablet Tablets (g . ) (g. ) .

Compound VII 0.0500 500 Lactose 0.0800 800 Corn Starch (for mix) 0.0150 150 Corn Starch (for paste) 0.0100 100 0.1550 1,550 Magnesium Stearate (1%) 0.0013 12.5 0.1563 1,562.5 _. .

The active ingredient, lactose and corn starch (for mix) are blended together. The corn starch (~or paste) is suspended in 800 milliliters o~ water and haa~ed with stirring, to Eo~m a paste~ This paste is th~n used to c3ranulate the mixed powders. ~ditional water is used, if necessary. The wet granules are passed through a No.
8 hanrl screerL and dried at 120F. The dry granules are then pass~d thro~lyh a No. 16 screen. The mixture is lubricated witll 1% magnesium stearate and compressed into tablets in a sui table tableting machine.

.30 1~6496S ~118/126 _ample13 Preparal:ion oE oral syru~ ~ormulation n~rcdient Amount Compound VI . . ~ . . . . . . . . . . . . 5000 mg.
Sorbitol solution (70% N.F.). . . . . . . 40 ml.
Sodium benzoate . . ~ . . . . . . . . ~ . 150 mg.
Saccharin . . . . . . . . . . . . . . . 20 mg.
Red Dye (F.D. & C. No 2). . . . . . . . . 10 mg.

Cherry flavor . . . . . . . . . . ~ . . . 50 mg.
1~
Distilled water . . . . qs to . . . . . . 100 ml.

The sorbitol solution is added to 40 milliliters of distilled water and the active ingredlent is suspended thexein. The saccharin, sodium benzoa~e, 1avor and dye are added and dissolved in the above solution. The volume i5 adju3ted to 10~ milliliters with distilled water.
Other ingredients may replace those listed in the above formulation. For example, a su~pending agent such as b~ntonit~ mayma, kragacanth, carbox~methylcellulose, ~0 or meth~lcellulose may be used. Phosphates, citrate~
or tartrates rna~ be added as bu~fers~ Preservatives may include the parabens, sorbic acid and the like ancl other flavors and dyes ma~ b~ used in place of those listed above.

Claims (6)

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 the racemates comprising 5-[d-3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-1-cis-2,3-naphthalenediol, and 5-[1-3-(tert-butylamino)-2-hydroxy-propoxy]-1,2,3,4-tetrahydro-d-cis-2,3-naphthalenediol and their salts, and comprising 5-[d-3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-d-cis-2,3-naphthalenediol, and 5[1-3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4,-tetrahydro-1-cis-2,3-naphthalenediol and their salts from 2,3-cis-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(tert-butylamino)propoxy]-2,3-naphthalenediol which comprises slurrying 2,3-cis-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(tert-butylamino)propoxy]-2,3-naphthalenediol in a lower alkyl-nitrile of from two to eight carbon atoms at a temperature of about 60° for more than two minutes, filtering off the nondissolved materials and recrystallizing said nondissolved material.

2. A process for the preparation of the racemate comprising 5-[d-3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-1-cis-2,3-naphthalenediol, and 5-[1-3-(tert-butylamino)-2-hydroxy-propoxy]-1,2,3,4-tetrahydro-d-cis-2,3-naphthalenediol and their salts from 2,3-cis-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(tert-butylamino)propoxy]-2,3-naphthalenediol which comprises slurrying in a lower alkylnitrile of from two to eight carbon atoms at a temperature of about 60° for about two minutes, filtering, cooling and filtering to remove the product.

3. A process for the preparation of the racemate comprising 5-[d-3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-d-cis-2,3-naphthalenediol, and 5-[1-3-(tert-butylamino)-2-hydroxy-propoxy]-1,2,3,4-tetrahydro-1-cis-2,3-naphthalenediol and their salts from 2,3-cis-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(tert-butyl-amino)propoxy]-2,3-naphthalenediol which comprises slurrying 2, 3-cis-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(tert-butylamino)propoxy]-2,3-naphthalenediol in a lower alkylnitrile of from two to eight carbon atoms at a temperature of about 60° for more than two minutes, filtering off the nondissolved materials and recrystallizing said nondissolved material.

4. The process of claim 2 or 3 wherein said lower alkylnitrile is acetonitrile.

5. The racemate comprising 5-[d-3-(tert-butylamino)-2-hydroxy-propoxy]-1,2,3,4-tetrahydro-1-cis-2,3-naphthalenediol, and 5-[1-3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-d-cis-2,3-naphthalenediol and their salts, whenever prepared according to the process of claim 2.

6. The racemate comprising 5-[d-3-(tert-butylamino)-2-hydroxy-propoxy]-1,2,3,4-tetrahydro-d-cis-2,3-naphthalenediol, and 5-[1-3-(tert-butylamino)-2 hydroxypropoxy]-1,2,3,4-tetrahydro-1-cis-2,3-naphthalenediol and their salts, whenever prepared according to the process of claim 3.