CA1074320A - 1'-hydroxy-5-lower alkoxy-2-lower alkyl-7,8-cyclopentano (h)-1,2,3,4-tetrahydroisoquinoline - Google Patents

Abstract

Abstract of the Disclosure Novel tetrahydroisoquinolines and their method of preparation by chemically reducing a 5-lower alkoxy-2-lower alkyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinoline-1'-one to a 1'-hydroxy-5-lower alkoxy-2-lower alkyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinoline. The compounds are useful, primarily as intermediates, for the formation of other tetrahydro-isoquinolines used to effect pharmacological activity in animals.

Description

~074320 This invention relates to novel, primarily intermediate, compounds and their production. More particularly, this invention provides tetrahydro-isoquinolines which are useful for effecting desirable pharmacological activ-ity in animals.
This application is divided from Canadian application serial number 223,274 filed on March 27th 1975 to the present applicants, application number 223,274 being directed to the abovementioned tetrahydroisoquinolines and to their method of preparation which is defined as follows:
The process of hydrogenolyzing l'-hydroxy-5-lower alkoxy-2-lower alkyl-7,8-cyclopentano~h]-1,2,3,4-tetrahydroisoquinoline to a 5-lower alkoxy-

2-lower alkyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinoline and then cleaving the ether group of such compound to form a 5-hydroxy-2-lower alkyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinoline.
According to the present invention, there are now provided novel l'-hydroxy-5-lower alkoxy-2-lower alkyl-7,8-cyclopentano[h]-1,2,3,4-tetra-hydroisoquinolines having the formula O -Rl N-R Formula I.

wherein R is a lower alkyl havin~ 1 to 6 carbon atoms such as methyl, ethyl, isopropyl; butyl and n-hexyl, and Rl is a lower alkyl group such as defined for R and acid addition and quaternary ammonium salts thereof.
The compounds of Formula 1 are prepared by chemically reducing 5-alkoxy--2-alkyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinoline-1'-oneS
to l'-hydroxy-5-alkoxy-2-aikyl 7,8-cyclopentano[h]-1,2,3,4-tetrahydroiso-quinolines. This process can be represented as follol~s:
- 1 ~
.. .. .

1~7~3ZO

R > HO~

wherein R has the significance previously assigned and a lower alkyl as de-fined for R.
The present invention will now be further described in more detail.
Some of the 5-alkoxy-2-alkyl-7,8-cyclopentano[h]-1,2,3,4-tetra-hydroisoquinoline-l'-ones which can be used as starting materials in this in-vention are 5-methoxy-2-methyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroiso-quinoline-l'-one, 5-ethoxy-2-ethyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroiso-quinoline-l'-one, 5-propoxy-2-propyl-7J8-cyclopentano[h]-1,2,3,4-tetra-hydroisoquinoline-l'-one and 5-methoxy-2-ethyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinoline-l'-one.
The 5-alkoxy-2-alkyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydro-isoquinoline-l'-ones can be readily reduced by use of lithium aluminum hydride in an inert liquid reaction medium, such as diethyl ether, at an elevated temperature, such as at the reflux temperature. After the reaction is terminated, water can be added to the reaction mixture to decompose any excess hydride. The desired reaction product can be recovered by conventional methods.
Among the l'-hydroxy-S-alkoxy-2-alkyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinolines are l'-hydroxy-5-methoxy-2-methyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, 1'-hydroxy-5-ethoxy-2-ethyl-7,8-cyclopentano [h]-1,2,3,4-tetrahydroisoquinoline and 1'-hydroxy-5-propoxy-2-propyl-7,8-cyclopentano~h]-1,2,3,4-tetrahydroisoquinoline and 1'-hydroxy-5-methoxy-2-propyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinoline.

~0743ZO

As previously stated, the l'-hydroxy-5-alkoxy-2-alkyl-7,8-cyclo-pentano[h]-1,2,3,4-tetrahydroisoquinolines, are useful intermediates which may be subjected to hydrogenolysis in a concentrated aqueous acid solution;
such as concentrated hydrochloric acid, by contact with hydrogen at a moder-ately elevated pressure, such as in the range of 40 to 100 psig, in the presence of a suitable catalyst, such as palladium. Following termination of the reaction, sodium hydroxide or some other suitable base can be added to the reaction mixture until it is basic, after which the product can be extracted by use of a water insoluble solvent such as diethyl ether. The product can be separated from the solvent by evaporation of the solvent.
Representative of the 5-alkoxy-2-alkyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinolines which can be thus produced are 5-methoxy-2-methyl-7, 8-cyclopentano[h'J-1,2,3,4-tetrahydroisoquinoline, 5-ethoxy-2-ethyl-7,8-cyclo-pentano[h]-1,2,3,4-tetrahydroisoquinoline, 5-propoxy-2-propyl-7,8-cyclopentano [h]-1,2,3,4-tetrahydroisoquinoline and 5-methoxy-2-propyl-7,8-cyclopentano[h'J-1,2,3,4-tetrahydroisoquinoline.
Conversion of the 5-alkoxy-2-alkyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinolines to the corresponding 5-hydroxy compounds may be ef-fected by cleavage of the ether group using concentrated aqueous hydrobromic acid or hydriodic acid at reflux temperature. Following the reaction the de-sired product can be recovered by standard isolation techniques.
Some of the 5-hydroxy-2-alkyl-7,8-cyclopentano[h]-1,2,3,4-tetra-hydroisoquinolines which are obtained as just described from the appropriate starting material are 5-hydroxy-2-methyl-7,8-cyclopentano[h]-1,2,3,4-tetra-hydroisoquinoline, 5-hydroxy-2-ethyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydro-isoquinoline, 5-hydroxy-2-propyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroiso-quinoline, and 5-hydroxy-2-butyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroquinoline.
Esterification of the 5-hydroxy-2-alkyl-7,8-cyclopentano[h~-1,2,3,4-lQ7~320 tetrahydroisoquinolines can be effected by contacting the hydroxy-containing compound with an alkanoic acid, benzoic acid or an aralkanoic acid in a suit-able liquid reaction medium in the presence of N,N-carbonyldiimidazole. The reaction proceeds quickly at reflux temperature. Following termination of the reaction the product can be separated by standard procedures.
Some of the esters which can be produced, by use of the appropriate acid, are 5-(D,L-~ -methylbutyryloxy)-2-methyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, 5-formyloxy-2-methyl-7,8-cyclopentano~h]-1,2,3,4-tetrahydroisoquinoline, 5-acetoxy-2-ethyl-7,8-cyclopentano[h]-1,2,3,4-tetra-hydroisoquinoline, 5-propionyloxy-2-propyl-7,8-cyclopentano[h]-1,2,3,4-tetra-hydroisoquinoline, 5-benzoyloxy-2-methyl-7,8-cyclopentano~h]-1,2,3,4-tetra-hydroisoquinoline and 5-phenylacetoxy-2-ethyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinoline.
Esters of the l'-hydroxy compounds of Formula 1 can be readily pre-pared by esterification of the 5-alkoxy-2-alkyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinolines using the procedures just previously described for making estcrs. Some of the novel esters which can be produced from the ap-propriatc acids and l'-hydroxy compounds are l'-~D,L-~ -methylbutyryloxy)-5-methoxy-2-methyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, 1'-formyloxy-5-methoxy-2-methyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquino-line, l'-acetoxy-5-ethoxy-2-ethyl-7,8-cyclopentano[h]-1,2,3,4-~etrahydroiso-quinoline, l'-propionyloxy-5-propoxy-2-propyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, l'-benzoyloxy-5-methoxy-2-methyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinoline and 1'-phenylacetoxy-5-ethoxy-2-ethyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinoline.
The compounds of this invention, being tertiary amines, can be con-verted to acid addition salts by contacting the amines with a suitable in-organic acid such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid or an organic acid such as citric acid, acetic acid, formic acid, malic acid, fumaric acid, succinic acid, benzoic acid and tartaric acid.
Quaternary ammonium salts of the compounds are readily prepared by contacting the compounds with an alkyl halide, alkyl sulfate, aralkyl halide or aralkyl sulfate such as methyl chloride, ethyl bromide, propyl iodide, benzyl chloride, benzyl sulfate and methyl sulfate as well as other compounds known to form quaternary ammonium salts with tertiary amines.
Since the compounds provided by this invention are amines they are useful as neutralizing agents since they form salts with acids. The amines can also be used in the isolation and purification of penicillin with which they form salts.
The compounds of this invention, particularly in the form of the free bases and the nontoxic acid addition salts, are also useful pharmaceuti-cally. These compounds when administered to animals intraperitoneally or orally exert an anti-hypertensive effect. The compounds thus can be used to reduce blood pressure.
~ ydroxy-5-methoxy-2-methyl-7,8-cyclopentano[h]-1,2,3,4-tetra-hydroisoquinoline has an ALD50 in mice of 16 mg./kg. i.p. when administered in solution prepared with the acid of dilute acid. When administered as the base at 4 mg./kg. i.p. in solution, prepared with the aid of dilute acid, to hypertensive rats the following percent change in systolic blood pressure was observed:
1 Hour -3.1 + 1.0 2 Hours -2.3 + 1.2 4 Hours -4.9 + 1.4 24 Hours -0.4 + 1.4 The amount of active ingredient administered may be varied; however, it is necessary that the amount of active ingredient be such that a suitable dosage is given. The selected dosage depends upon the desired therapeutic effect and on the duration of treatment. Dosages of from 0.1 to 25 mg./kg.
of body weight daily, preferably in divided doses, i.e., three to four times daily, can be administered.
The active agents of this invention can be administered to animals, including humans, as pure compounds. It is advisable, however, to first com-bine one or more of the compounds with a suitable pharmaceutical carrier to attain a satisfactory size to dosage relationship and thereby obtain a pharma-ceutical composition.
Pharmaceutical carriers which are liquid or solid can be used.
Solid carriers such as starch, sugar, talc and the like can be used to form powders The powders can be used for direct administration or they may be used to make tablets or to fill gelatin capsules. Suitable lubricants like magnesium stearate, binders such as gelatin, and disintegrating agents like sodium carbonate in combination with citric acid can be used to form tablets.
Sweetening and flavoring agents can also be included.
Unit dosage forms such as tablets and capsules can contain any suit-able prc~etermined amount of one or more of the active agents, and they may be administered one or more at a time at regular intervals. Such unit dosage forms, however, should generally contain a concentration of 0.1 to 50 percent by weight of one or more of the active compounds. Unit dosage forms, such as tablets and capsules, can contain about 2 to 300 mg. of active agent.
Since the compounds exhibit both oral and parenteral activity they can be formulated in dosage forms for either oral or parenteral administra-tion to a patient.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, granules and the like.
Liquid dosage forms for oral administration include emulsions, solu-tions, suspensions, syrups and the like, containing diluents commonly used 1~743ZO

in the art, such as water Besides inert diluents, such preparations can also include adjuvants such as wetting agents, emulsifying and suspending agents and sweetening, flavoring and perfuming agents.
Preparations for parenteral administration include sterile aqueous or non-aqueous solutions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. The parenteral preparations are sterilized by conventional methods.
The 5-alkoxy-2-alkyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquino-line-l'-ones used as starting materials in this invention can be produced by converting a 5-alkoxy-2-alkyl-1,2,3,4-tetrahydroisoquinoline by means of a Friedel-Crafts reaction to a 5-alkoxy-2-alkyl-1,2,3,4-tetrahydroisoquinoline-8-carboxaldehyde, reacting the aldehyde with malonic acid to form a ~-(5-alkoxy-2-alkyl-1,2,3,4-tetrahydroisoquinoline-8)propanoic acid, catalytically reducing the propanoic acid compound to form the ~-~5-alkoxy-2-alkyl-ls2,3,4-tetrahydroisoquinoline-8)propanoic acid and then effecting ring closure of such compound, such as by means of polyphosphoric acid. This process can be represented as follows:

OR4 pR4 N-R > ~ ~ -R

CHO

N-R > ~ ~ -R

CH ' OR4 CH2/
"1 ~
" 1 N-R

I_ wherein R and R4 are the same or different lower alkyl groups having 1 to 6 carbon atoms. Durand et al., _11. Soc. Chem. France, 270 ~1961) discloses the preparation of 5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline. Other such compounds can be prepared by the same process from the appropriate re-actants. In addition, the preparation of the starting materials is well with-in the ordinary skill of an organic chemist.
A particular intermediate of the present invention is produced by the following method, given by way of example only.
l'-Hydroxy-5-methoxy-2-methyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinoline Into a flask (1 liter) equipped with a mechanical stirrer, an equi-librium addition funnel (500 ml.), and a condenser fitted with a calcium chlo-ride drying tube was placed lithium aluminum hydride (0.72 g., 0.0190 mole) which was covered with anhydrous diethyl ether (150 ml.). The contents of the flask were cooled to 0C. and stirred while an anhydrous diethyl ether solution (300 ml.) of 5-methoxy-2-methyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquino-line-l'-one (2.20 g., 0.0095 mole) was added dropwise rapidly. When the addi-tion was complete, the reaction mixture was allowed to warm to room tempera-turc, then refluxed for 5 hrs. To destroy excess hydride,the following steps were taken: the contents of the flask were cooled to 0C., diatomaceous earth filter-aid (1.5 g.) was added, and ice cold water was added very slowly until the reaction mixture lost its gray color. The ether solution was then de-canted and dried over sodium sulfate. Removal of the ether afforded the crude product l'-hydroxy-5-methoxy-2-methyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydro-isoquinoline which was recrystallized from diethyl ether, m.p. 112.5-113.5 C
(1.95 g., 84%).
The following Examples illustrate specifically the preparation of one starting material.

~074320 Example 1 S-Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-8-carboxaldehyde Into a flask equipped with a mechanical stirrer, an equilibrium addition funnel, and a condenser fitted with a calcium chloride drying tube, were placed methylene chloride (150 ml.) and 5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (15.0 g., 0.085 mole). The solution was cooled to 0C. and stirred. Titanium te~rachloride (51.6 g., 0.272 mole) was added gradually, followed by the rapid dropwise addition of ~ dichloromethyl methyl ether (9.8 g., 0.085 mole). After the reaction mixture was allowed to warm to room temperature, it was refluxed for 7 hrs. The titanium chlo-ride complex of the product was decomposed with water and ice, and the result-ing solution kept cool as it was made basic with excess sodium hydroxide (20%).
The resulting suspension was extracted with chloroform. The extract was dried over sodium sulfate and the solvent removed, affording the crude product which was vacuum distilled (b.p. 122C./0.1 mm.) to yield 13.0 g. (74%) of 5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-8-carboxaldehyde. The hydro-chloride salt melted at 244-245C. after recrystallization from absolute othanol.
Example 2 ~-(5-Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-8) propanoic acid hydrochloride Into a flask (100 ml.) were placed malonic acid (12.0 g., 0.116 mole) and dry pyridine (25 ml.). The contents of the flask were heated until solution occurred. After the solution had cooled to room temperature, 5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-8-carboxaldehyde ~12.0 g., 0.058 mole) was added. Piperidine (25 drops) was added as a catalyst. The reaction mixture was warmed for 30 min. at 80 C. followed by a 2 1~2 hr. re-fluxing. After the solution had cooled, it was poured into cold water (200 ml.) and the precipitate was collected by filtration and dried (4 hrs., . _ _ g 110C.); it was then ground and further dried (2 hrs., 110C.) in a vacuum oven. The filtrate was successively concentrated and cooled until no addi-tional product precipitated. The ~-~5-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinoline-8)propanoic acid hydrochloride, m.p. 260-265C. (11.5 g., 70%) was not purified.
Example 3 ~-(5-Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-8) propanoic acid hydrochloride Into a hydrogenation bottle (500 ml.) were placed 5% palladium on charcoal (0.5 g.) and a suspension of ~-(5-methoxy-2-methyl-1,2,3,4-tetra-hydroisoquinoline-8~propanoic acid HCl (5.7 g., 0.028 mole) in dilute (1%) hydrochloric acid (250 ml.). The compound was reduced with hydrogen durin~
a 20 hr. period in a low pressure hydrogenation apparatus. After removal of the catalyst by filtration, the filtrate was successively concentrated and cooled until no further product precipitated. The portions of the product ~-(5-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-8)propanoic acid hydro-chloride were col]ected by filtration and dried (4 hrs., 110C.) in a vacuum oven. If the dry product (4.8 g., 84%) had a melting point less than 210 C., it was recrystallized from water tm.p. 212C.).
Example 4 S-Methoxy-2-methyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydro-isoquinoline-l'-one Into a flask (500 ml.) which was heated to 55C. with an oil bath and equipped with a mechanical stirrer, calcium chloride drying tube, and a thermometer, were placed preheated ~steam bath) polyphosphoric acid (PPA) (100 g.) and ~-(5-methoxy-2-methyl-i,2J3,4-tetrahydro isoquinoline-8)propanoic acid (7.4 g., 0.026 mole). The mixture was stirred as the temperatu~e of the oil bath was gradually raised. At an internal temperature of 60C. the re-action commenced, as evidenced by a light green color. The internal tempera-ture was raised to 78C. over a 15 min. period and maintained there for a ~074320 further 20 min. The reaction mixture became dark green during this time.
The PPA complex formed was then decomposed with ice and water after the con-tents of the flask had cooled to room temperature. The solution was kept at room temperature or cooler during basification with sodium hydroxide (20%) by the addition of large amounts of ice. The resulting suspension was ex-tracted with diethyl ether and the extract was dried over sodium sulfate.
Removal of the ether afforded the crude product 5-methoxy-2-methyl-7,8-cyclo-pentano[h]-1,2,3,4-tetrahydroisoquinoline-1'-one which was recrystallized ~m.p. 151-152C.) from diethyl ether (3.9 g., 65%).
The foregoing detailed description has been given for clearness of understanding only, and no unnecessary limitations should be understood there-from, as modifications will be obvious to those skilled in the art.

Claims (4)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. The process of chemically reducing 5-lower alkoxy-2-lower alkyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinoline-1'-one to 1'-hydroxy-5-lower alkoxy-2-lower alkyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinoline.

2. The process of chemically reducing 5-methoxy-2-methyl-7,8-cyclo-pentano[h]-1,2,3,4-tetrahydroisoquinoline-1'-one to 1'-hydroxy-5-methoxy-2-methyl-7,8-cyclopentano[h]-1,2,3,4-tetrahydroisoquinoline.

3. 1'-hydroxy-5-lower alkoxy-2-lower alkyl-7,8-cyclopentano[h]-1,2, 3,4-tetrahydroisoquinoline when produced according to the process of claim 1.

4. 1'-hydroxy-5-methoxy-2-methyl-7,8-cyclopentano[h]-1,2,3,4-tetra-hydroisoquinoline when produced by the process of claim 2.