CA1041544A - Optically active 2,3-cis-1,2,3,4-tetrahydro-5-(2-hydroxy-3-(tertbutylamino)-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 addition, pharmaceutical compositions containing said optically active compounds and mixtures and methods for using said compositions as .beta.-blocking and antiarrhythmic agents are described.

Description

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 which 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 useful, 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 effects and a higher ~, . . .
degree of activity; that is, a ~-blocking agent would result having a minimal of antiarrhythmic properties and an antiar-; rhythmic agent would result having a lower order of ~-blocking properties. As stated in the Canadian Patent No. 979,926, it was believed that the two properties were probably related, and thus by resolving the 2,3-cis-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(tert-butylamino)propoxy]-2,3-naphthalenediol into its four possible optical isomers, a separation of activities 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 ~-blocking 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.
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~041S~4 This invention relates to methods for obtaining the four optical isomers and partially resolved mixtures thereof. The four optical isomers, and the various partially resolved mixtures thereof can be obtained ac-cording to the following two reaction schemes.
SCHEME I ---v .

fCH2 1CHCH2NHt-C4Hg ' .
~ OH

~, , dibenzoyl-d-tartaric acid / ~ Mother liquor ':
/ strong base / \ ditoluoyl-l-/ \ tartaric acid ~1 , (d)-l-(tert-Butylamino)-3-[(5,8- (l)-l-(tert-Butylamino) d~lhydro~I~~aphthyl)oxy]-2-propanol. -3-[(5,~=~Thydro-l-naph-dibenzoyl-d-tartaric acid thyl)oxy]-2-propanol.
ditoluoyl-l tart II III
strong base strong base fl, "'~
(d)-l-(tert-Butylamino)-3-[(5,8- (l)-l-(tert-Butylamino) dihydro-l-naphthyl)oxy]-2-propanol. -3-[(5,8-dihydro-1-naph-thyl)oxy]-2-propanol.
IV V
l)AgOAc,HoAc l)AgOAc, I2 and H2O I2 and H2O

2)NaOH, H2O ~ /2)NaOH, H2O
; 5-[d-3-(tert-Butylamino)-2-hydroxy- 5-[1-3-(tert-Butylamino)-propoxy]-1,2,3,4-tetrahydro-dl-cis- 2- ~ydroxy-propoxy]-1,2, i - 2 -, .

. . . . . - ~ . , , ,, ,, . ~ ' . . .

11)4~S~
2,3-naphthalenediol. 3,4-tetrahydro-dl-cls-- 2,3-naphthalenedlol.
:
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-. ~
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 for -~ utilizing said compositions.
: - .
The term "salts" is intended to encompass "acid addition c 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 that may be used for purification such as salts formed with optically active compounds, such as dibenzoyl-d-tartaric acid, and other salts, such as oxalates, etc.
~, The term "quaternary ammonium salts" is intended to en-~` compass the compounds formed when compounds of the formula IV
~ to XI are reacted with alkylating agents of from 1 to 10 ;~ carbon atoms, 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) ; :,., i5~' ' propoxy]-2,3-naphthalenediol, which is reported in Canadian 30 Patent No. 979,926 possesses a high degree of utility as an ..
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.=. ~ .

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11~)41S4~ v 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 No. 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 (_) -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 of the mother liquor with di~oluoyl-l-tartaric acid. These compounds may be converted to other salts for the purpose of further purification or storage, such as the hydrochloride salt, phosphate salt, sulfate salt, acetate salt by treatment with a strong base, such as sodium hydroxide, potassium hydroxide, etc., followed optionally by treatment with an acid.
In order to prepare the pharmacologically active compounds 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 -4- ~ ~ r ~ ' 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. Initially the compounds of formula IV and V are dissolved in the aqueous 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 j an alcoholic or acidic solvent of from one to six carbon s atoms which may or may not contain water. While cata-lysts such as nickel, platinum, etc., may be employed, the preferred catalyst is palladium. The reaction is ~ conducted at about room temperature utilizing hydrogen : 20 at pressures of about 50 pounds per sq. inch.

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` , , ~ - , The "Wet" Prevost Reaction in the case of compound IV gives rise to a mixture of two isomers designated V}, 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 utilizing mixtures of an aromatic hydrocarbon of up to ten carbon atoms such as benzene, toluene, 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 of 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 from the aromatic hydrocarbon of up to ten carbon atoms: low alkylnitrile mixture is also recrystallized from a halogenated hydro-carbon 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 -... . .

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" ' ' ' . . . ' '. ' ' ' ' , ' ' ' ~)41S44 of said halogenated hydrocarbon: hydrocarbon solvent system which is allowed to slowly evaporate giving a gel having a dense white solid which i8 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 recrystallizations (2 to 5) of the material from a mixture of a halogenated hydrocarbon of up to three carbon atoms and a hydrocarbon of from five to ten carbon atoms (about l:l) 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 havo approximately equivalent antiarrythmic activity, they exhibit varying orders of ~-blocking activity, with isomer XI having a range of 2.5 to lO times the activity of the mixture of all four isomers.
Compound X is from 1.6 to 2.3 times, IX is from .l 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 allowlng an alkylating agent such as methyl iodide, benzyl chloride, etc. to react with an . . . . . .. .
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~041~44 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 II
.
OCH2CHCH2NH[C(cH3)3]
HO ~ OH
HO ~ .

I fractional crystallization / \ ,'~
~ / \ `'''' ~`

5-[d-3-(tert-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-~1-3-(tert-Butylamino)-2- and 5-[1-3-(tert-Butylamino)-2-i hydroxypropoxy]-1,2,3,4-tetra- hydroxypropo~T~1,2,3,4-tetra- :
. 20 hydro-d-cis-2,3-naphthalenediol. hydro-1-cis-2,3-naphthalenediol :
(Racemate A) (Racemate B) --~
.. ~,.

. ~ resolution resolution :~ 5-[d-3-(tert -Butylamino)-2-hydroxypropoxy]- . ,.~ , 1,2,3,4-tetrahydro-1-cis-2,3-naphthalenediol(VIII) ~:
:~ + 5-[1-3-(tert-Butylamino)-2-hydroxypropoxy]- ~:::
1,2,3,4-tetrahydro-d-cis-2,3-naphthalenediol(X) \ ~
5-[d-3-(tert-Butylamino-2-hydroxypropoxy] ~.:
-1,2,3,4-tetrahydro-d-cis-2,3-naphthal- . :
enediol(IX) + 5-[1-3-(tert-Butylamino)- :
2-hydroxypropoxy]-1,2,3,4-tetrahydro-1-cis-2,3-naphthalenediol(XI) . .

In addition, this invention is intended to encompaffff the partially resolved isomers termed racemate A and racemate B and their acid addition 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 dibenzoyl-_-tartaric acid and conversion of the salt to the free base by use of strong 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 tartrate salts of Compounds IX and XI by reaction with optically active tartaric acid followed by crystallization !. from a lower alkyl alcohol of up to three carbon atoms.
Compound IX (ring +, side chain +) is obtained by using preferably dibenzoyl-d-tartaric acid and conversion of the salt to the free base by use of a strong aqueous base, and h XI (ring -, side chain -) is isolated ., .

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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 for 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.
The isomers exhibit varying orders of ~-blocking activity with isomer XI having a range of 2.5 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)propoxyl-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 assymetric center 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 warm (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 where a lower alkylnitrile is used, the racemate A crystallizes from ..'-'' -10- ,, ~'''..`',Y." '. :, . ~:

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1041S~4 the cooled extract and the raaemate B is obtained from the material that did 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 salts 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 divided doses of about 2.5 to 25 mg/kg, preferably about 4 to `
10 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 10 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.
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~A118/126 1~41544 rrhe compounds of the present invention may be ad ministered by any convenient route such as orally, intra-peritoneally, subcutaneously, intramuscularly or intravenously.
Injectable com~ositions according to the present in-vention having the desired clarity, stability, and adapt-ability for parenteral use are obtained by. dissolving from 0.10%to 10.0% by weight of active compound in a veh.icle consisting of a polyhydric aliphatic alcohol or mixtures thereof. Especially satisfactory are glycerin, propylene glycol, and the polyethylene glycols. The polyethylene glycols consist of a mixture of non-volatile, normally liquid, polyethylene glycols which are soluble in both water and organic liquids and which have molecular weights of from about 200 to about 1500. Although the amount of active compound dissolved in the above vehicle may vary from 0.10% to 10.0% by weight, it is preferred that the amount of active compound employed be from about 3.0%

to about 9.0% by weight. Although various mixtures of the aforementioned non-volatile polyethylene glycols may be employed, it is preferred to use a mixture having I an average molecular weight of from about 200 to about 400.
', In addition to the active compounds, the parenteral solutions of the present invention may alqo contain various preservatives which may be used to prevent bacterial and fungal contamination. The preservatives which may be i used for such purposes are, for example, benzyl alcohol, . 30 .; ., . ~ , - . . - . . . . ,.. . . . . : ,. . - :. . :~ .

~118/126 15~4 myristyl-gamma-picolinium chloride, phenyl mercuric nitrate, ben~alkonium chloride, phenethyl alcohol, p-chlorophenyl-a-glycerol ether, methyl and propyl parabens, and thimerosal. As a practical matter it i~ also conveni~nt to employ antioxidants. Suitable antioxidants include, for example, sodium bisulfite, sodium metabisulfite, and sodium formaldehyde sulfoxylate. Generally, from about 0.05% to about 0.2% concentrations 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 therapeutic administration, the active compounds of this invention may be incorporated 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 between about 5% to about 75% or more of the weight of the unit. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained. Preferred compositions or .: '.

.

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' ' `: -}~118 /126 lV41S44 p~eparations according to the present invention areprepared so that an oral dosage unit form contains between about 2.5 and 100 milligrams of active compound.
The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient 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 of wintergreen, or cherry flavoring.
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, sugar, or both. A syrup or elixir may contain the active com-pounds, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amount employed.

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1~11~126 :~041544 The following examp]es are provided for illustrative purposes 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 other- ~ -wise 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-1-naphthyl)oxyl-2-propanol A mixture of 25 g (0.125 moles) of 1-(2,3- ~ -epoxypropoxy)-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 affords 27.5 g (80%) tan solid, 1- 0 (tert-butylamino)-3-[(5,8-dihydro-1-naphthyl)oxy]-2-propanol.
Recrystallization of a 5.0 g sample from pet ether affords 3.4 g of the pure named compound.

. .

Example 2 (~-l-(tert-ButYlamino)-3-r(5,8-dihydro-1-naphthyl)oxyl-2- ~ ~
ropanol, hydrochloride ; ~ -A mixture of 62.0 g (0.225 M) of the racemic '. . '' ' -15- ~Y -;, .....

1C~4~S44 ; compound prepared in ~xample 1 and 84.7 g (0.225 M) of diberl~oyl-d-tartaric acid in 700 ml methanol is allowed to c--ystalli~e for a few hours at room temperature.
The tartrate is removed by filtration and recrystallized two times from methanol. Small samples (r~500 mg) are removed at each recrystallization, shaken with ether and 10% NaO~. The ether layers are dried (MgSO4) and treated with a few drops of HCl in isopropyl alcohol.

The crystalline hydrochlorides are isolated and dried in vacuo. [a]D first recrystallization +20.8, C=1.0; second recrystallization +23,5C. A third recrystallization of a small portion of the tartrate and conversion to the hydrochloride gives material [a]EtH = + 23.4 (c=1.0).

The tartrate is shaken with ether and excess 2N
NaOH. The ether layer is dried (MgSO4) and the solvent is removed in vacuo to give 23.7 g (76.5%) of oil.
A sample (2.0 g) 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 harvested and recrystallized from isopropyl alcohol-ether to give 1.3 g (58%) of the named compound m.p. 118-1230 [~]EtH + 23 1 (c=l 0) .

~.' ' ", . ~ ' ' ' ' ' lV415~4 Example 3 (tert-Butylamino)-3-[5~8-dihydro-l-naphthyl) .
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 base. A small EtOH
sample is converted to the hydrochloride [a] -19.3, C=l. O.
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 tartr~ate 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 cryst. -22.4 (c=1.0);
D
recrystallized -23.7 (c=1.0). Recrystallization of a ~ -small portion of the tartrate and conversion to the EtOH
. HCl gives material [a] -23.7.
D
~ The tartrate (r-23 g) is shaken with ether and .~ excess 2N NaOH. The ether layer is dried (MgSO4) and the solvent is removed in vacuo to give 10.1 g of oily free base.
.

.. . ....

; ., .
; .

~A118/126 lO9~1S44 A sample (1.7 g) of the free base is dissolved in ether and converted to the hydrochloride by adding a solution of HCl in iso~ropyl alcohol. The cry~talline salt is harvested and recrystallized from isopropyl alcohol-ether to give the named compound 1.1 g (58%), m.p. 119-124C. [~]DtH -24.0 (c=l.0).

Example 4 5-rd-3-(tert-ButYlamino)-2-hYdroxvpropoxvl-1~2~3~4-tetrahydro-~l-c s-2,3-na~hthalenediol A 10.2 g (0.037 moles) of optically pure free base of the compound of Example 2 in a mixture of 200 ml glacial acetic 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) of 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 suctlon. The salts are washed with glacial acetic acid, and the filtrates are 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 15.2 g of a tan foam. This is taken up in 200 ml of ~ , . . . .
', ~ , , , . ~ -1~41S44 : -absolute ethanol, 1.5 g of 5% palladium-on-charcoal i5 added, and the mixture hydrogenat~d at 50 psi for one hour, until hydrogen uptake ceases. The catalyst is filtered and washed with alcohol, and the solution is evaporated to an oil. The oil is taken up in chloroform (200 ml) and washed once thoroughly with 50 ml of 10%
sodium hydroxide. The aqueous layer i 5 reextracted with chloroform, and the combined organics are dried overnight (sodium sulfate). Evaporation affords 12.5 9 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 filtered for analysis. Standing -at 23C for 18 hours and filtering, affords, on drying at 80C and 0.1 mm Hg for 15 hours over paraffin, 4.4 g of 5-~d-3-(tert-butylamino)-2-hydroxypropoxY]-1,2,3,4-tetrahydro- _ -cis-2,3-naphthalenediol, m.p. 114-124C.
. , - -ExamPle 5 5-~L-3-(~rt-Butvlamino)-2-hydrDxyoropoxv~ 2~3~4-tetrahYdro-gL-ci~-2,3-naphthalenediol - -8.3 g (0.030 mole) of the free base of the compound -!. :
prepared in Example 3 in a mixture of 200 ml glacial acetic acid and 10 ml of water is treated with 10.8 g (0.066 mole) of silver acetate, and then 7.7 g (0.030 mole) of iodine i (I2). The slurry is stirred and heated to 95C, and . ~ , . .

.',' ' . .

- ` HA118/126 ~)41S44 held at 95-105C 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 is added, and the mixture hydrogenated at 50 psi for 0.75 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 benzene and allowed to cool o room temperature overnight. The solid is 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 'I drying at 80C and 0.1 mm Hg for 15 hours over paraffin,

3.8 g (41%) of 5-[1-3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-dl-cis-2,3-naphthalenediol, m.p. 114-121C, la] = +23.6, c=1.0, run in 0.1 N HCl in EtOH.

~ . . - -.,: - . - . . ~ .

-:, ~
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~lAll8/l26 ~)41S44 :

Example 6 Separation of 5-~-3-(tert-Butvlamino)-2-hydroxypropoxyl- -1,2,3,4-tetrahYdro-dl-~i~-2,3-na~hthalenediol into :
compounds _III and IX
The compound of Example 4 (15.3 g) iB recrystallized twice from benzene:acetonitrile (9:2) (20 ml/g) by cooling the undisturbed solution for two days and decanting. The mother liquors are scratched to give additional crops of crystals. The first 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 additional crops obtained from benzene-ace-~i tonitrile (5.7 g) are combined and recrystallized twice - ~ -from hexane: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 solid is mechanically separated and recrystallized i three times from ethyl acetate (12,30, and finally 75 ml/g) to give a mixture of fluffy solid and dense granule~
;- which are separated by swirling and decanting. The residual granules are filtered and dried to give 0.12 g (1.6%), m.p. 144-145C, [a]D = +20.0, c=0.5, run in -~
0.1 N HCl in EtOH.
. - ~

: . .

' ' ' 1~41544 _xample_ Sepalation o~ 5-rl-3-(tert-Butylamino)-2-hydroxy~r 1,2,3,4-tetrahvdro-~LL-si~-2,3-naphthalenediol (VII) into Compounds X and XI
The compound of Example V (10.8 g) is recrystallized from a mixture of 180 ml of benzene and 40 ml of ace-tonitrile over a 2 1/2 day period. The mother liquor is decanted and stripped to an oil which gives a second crop of crystals on crystallization from pure 10benzene. The first crop is recrystallized three times from chloroform:hexane 1:1 (100 ml/g) to give 0.67 g (12.4%), m.p. 126-130~C, [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 from ethyl acetate (15, 70, and finally 45 ml/g) to give 0.4 g (7,4%), l m.p. 141-143, [~]D = -19.5, c=0.5, run in 0.1 N HCl in EtOH.

; 30 ' ' . ` ~' " - '. ' '' ~xampLe 8 5-[d-3-(tert-Bu ylamlno)-2-hydroxypropoxy]-1~2~3~-tetra-hydro-l-_is-2,3-naphthalenediol & 5-[l-3-(tert-Butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrah dro-d-cis-2,3-na~hthalenediol (Race~mate A) A 24 g sample of 2,3-cis-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(tert-butylamino)propoxy]-2,3-naphthalenediol which is prepared according to the procedure disclosed in Canadian Patent No. 973,926 is slurried in 400 ml of acetonitrile. - -The slurry is swirled and heated over a steam cone with -immersed thermometer until the temperature reaches 60C. The temperature is maintained at this point for 2 minutes, the supernatant becoming quite clear. Then the suspension is filtered quickly. The filtrate deposits fine needles which are harvested in several crops at roughly 10 minutes, 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 reworked ;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 harvested within 4 hours to prevent small granules of high melting material from forming. After a number of manipulations, 5.7 g, mp 135-139C is obtained. Crystallization of this 5.7 y from 430 ml of acetonitrile affords on drying at 80C for 5 hours over P2O5 and parrafin at 0.1 mm Hg, g.3 g (36%), ~;
mp 137-139C, of Racemate A.

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' - ' . `- , ' . ''.' ' ~ ': ' ." .,'", '" " " '' ' ''"'.,` ' ~ . ' ' '.

11~)41S44 Example 9 5-[d-3-(tert-Butylamino)-2-hydroxypropoxy]-1, 2, 3,4-tetra-hydro-d-cls-2,3-naphthalenediol, and 5-[1-3-($gL~-Butyl-amino)-2-hydroxypropoxy]-l~ 2, 3~4-tetrahydro---cls-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 basis of similar melting range and treated as necessary with a - 10 second portion of 60C acetonitrile. After one treatment, mp 131-142. A second treatment with a ratio of 1 g/50 ml acetonitrile usually gives material mp 140-153. A third treatment gives materials which melt in the range 147-154C, - and when combined total about 5.8g. Recrystallization from 400 ml of acetonitrile gives, after standing overnight

4.5 g (37%), mp 150-152C, of Racemate B.
Example 10 The Resolution of Racemate A
Racemate A (0.2 m) and dibenzoyl-_-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 tartrate is shaken with chloroform and excess 2N
NaOH. The organic layer is dried (MgSO4) and the solvent is removed in vacuo. Benzene is added and Compound VIII
crystallizes over several hours.
The first mother liquor from the mixture of racemic amine and dibenzoyl-_-tartaric acid is taken to dryness and shaken with chloroform and an excess of 2N NaOH. The organic layer is dried (MgSO4) and evaporated ln vacuo leaving 26.8 g of free base.
.
~ ~ -24-''~ ' ' ' " ~ ` ' : !; ~ .

': . ~ . ' ' , : ' .' " . ' .. , ' '' - ' '''~ - ~. ... ' ' :
,, :~ .' . : .
', ',, , ' 11~)41S44 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 (MgSO4) and the solvent is removed in 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 (MgSO4) and the solvent is removed in vacuo, giving the free base as an oil.
Addition of benzene promotes crystallization of Compound IX. " ~ `
The first mother liquor from the mixture of racemic amine and dibenzoyl-_-tartaric acid is taken to dryness and shaken with chloroform and an excess of 2N NaOH. The organic ;layer is dried (MgSO4) and evaporated in vacuo leaving 25.7 ~ `
g of free base.
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 (MgSO4) and the solvent is removed in vacuo to give the free base. Trituration with benzene causes crystallization of Compound XI.
.-.

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~Al]8/126 1~41S44 ~x~)le 12 Preparation of Tablet Formulation Per For 10,000 Ingredient Tablet Tablets (g.) (g.) .. . __ . _ Compound VII 0.0500 500 , Lactose 0.0800 800 - 10 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 (for paste) ~ is suspended in 800 milliliters of water and heated with stirring, to form a paste. This paste is then used to granulate the mixed powders. Additional water is used, if necessary. The wet granules are passed through a No.
8 hand screen and dried at 120F. The dry granules are then passed through a No. 16 screen. The mixture is lubricated with 1% magnesium stearate and compressed into tablets in a suitable tableting machine.

C
30 A -2~-~118/126 _ ample13 Preparation of oral sYrup formulation _ n~redient 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 ingredient is suspended therein. The saccharin, sodium benzoate, flavor and dye are added and dissolved in the above solution. The volume is adjusted to 100 milliliters with distilled water.
Other ingredients may replace t~lose listed in the above formulation. For example, a suspending agent such as bentonite magma, tragacanth, carboxymethylcellulose, or methylcellulose may be used. Phosphates, citrate$
or tartrates may be added as buffers. Preservatives may include the parabens, sorbic acid and the like and other flavors and dyes may be used in place of those lis-ted above.

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Claims (12)

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

1. A process for the isolation of 5-[d-3-(tert-butyl-amino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-1-cis-2,3-naphthal-enediol from 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-hydroxypropoxy]-1,2,3,4-tetrahydro-d-cis-2,3-naphthalenediol and their salts, which comprises reacting said racemate with an optically active tartaric acid in a lower alkyl alcohol of up to three carbon atoms, allowing the formed tartrate salt to crystallize, filtering the formed crystals and converting to the free base by the addition of a base.

2. A process for the isolation of 5-[1-3-(tert-butyl-amino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-d-cis-2,3-naphthal-enediol from 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-hydroxypropoxy]-1,2,3,4-tetrahydro-d-cis-2,3-naphthalenediol and their salts, which comprises reacting said racemate with an optically active tartaric acid in a lower alkyl alcohol of up to three carbon atoms, allowing the formed tartrate salt to crystallize, removing the formed crystals, converting the mother liquor to the free base by the addition of a base, reacting the liberated free base with a second optically active tartaric acid in a lower alkyl alcohol of up to three carbon atoms, allowing the formed tartrate salt to crystallize, filtering the formed crystals and converting to the free base.

3. A process for the isolation of 5-[d-3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-d-cis-2,3-naphthalenediol from 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-hydroxypropoxy]-1,2,3,4-tetrahydro-1-cis-2,3-naphthalenediol and their salts, which comprises reacting said racemate with an optically active tartaric acid in a lower alkyl alcohol of up to three carbon atoms, allowing the formed tartrate salt to crystallize, filtering the formed crystals, and converting to the free base by the addition of a base.

4. The process of claim 1 wherein the tartaric acid is dibenzoyl-d-tartaric acid and the alcohol is methanol.

5. The process of claim 3 wherein the tartaric acid is dibenzoyl-d-tartaric acid and the alcohol is methanol.

6. A process for the isolation of 5-[1-3-tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-1-cis-2,3-naphthalenediol from 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-hydroxypropoxy]-1,2,3,4-tetrahydro-1-cis-2,3-naphthalenediol and their salts, which comprises reacting said racemate with an optically active tartaric acid in a lower alkyl alcohol of up to three carbon atoms, allowing the formed tartrate salt to crystallize, removing the crystals, converting the mother liquor to the free base by the addition of aqueous base, reacting the free base with a second optically active tartaric acid in a lower alkyl alcohol of up to three carbon atoms, allowing the formed tartrate salt to crystallize, filtering the formed crystals, and converting to the free base.

7. The process of claim 2 wherein the first optically active tartaric acid is dibenzoyl-d-tartaric acid, the second optically active tartaric acid is ditoluoyl-1-tartaric acid and the alcohol is methanol.

8. The process of claim 6 wherein the first optically active tartaric acid is dibenzoyl-d-tartaric acid, the second optically active tartaric acid is ditoluoyl-1-tartaric acid and the alcohol is methanol.

9. 5-[d-3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-1-cis-2,3-naphthalenediol, whenever prepared by the process of claim 1 or 4.

10. 5-[1-3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-d-cis-2,3-naphthalenediol, whenever prepared by the process of claim 2 or 7.

11. 5-[d-3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-d-cis-2,3-naphthalenediol, whenever prepared by the process of claim 3 or 5.

12. 5-[1-3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydro-1-cis-2,3-naphthalenediol, whenever prepared by the process of claim 6 or 8.