CA1187885A - Trans-d1-1-alkyl-6-oxodecahydroquinolines - Google Patents

Abstract

ABSTRACT OR THE DISCLOSURE

Trans-1-alkyl-6-alkoxy-octahydroquinolines are described herein. These compounds are prepared by reducing 1-alkyl-6-alk oxy-hexahvdroquinolines. The octahydroquinoline compounds are useful as intermediates to make various pharmaceutically active products.

Description

TRANS-dl-l-ALXYL-6- ALKoxyocTAHyDRoQuINoLINEs ITnited States Patent 4,198,415 discloses a group oF octahydropyrazolo~3,4-g]quinolines useful as prolactin inhibitors and in -the treatment of Parkinsonism. ~he compo~lnds disclose~ therein are said to have dopamine agonist ~dopaminergic) activity. One of the more active druos disclosed carries an n-propyl group on the quinoline nitrogen~
A key intermediate in the preparation of these octahydropyrazolo[3,4-glquinolines is a trans-dl-l-alkyl-6-oxodecahvdroquinoline, one of whose stereoisomers [the ~a~, 8a~ compound) is disclosed in VII of column 5 of United States Patent 4,198,415. The same intermediate is used to prepare a related group of compounds, the 4,4a,5,6,7,8,8a,9-octahydro-2~l-pyrrolo[3,4-g]quinolines of United States Patent 4,235,909. The octahydro-2H-pyrrolo[3,4-g]quinolines are similar in activity to the octahydro-lH(and 2~)-pyrazolo[3,4-g]quinolines in that the compounds are dopamine agonists having activity as inhibitors of prolactin secretion and also in experimental models of Parkinson's disease.
The method of synthesizinq the trans-dl-l-alkyl-6-oxodecahydroquinolines as disclosed in the two patents, while operative, involves five steps from a commercially available starting material. Furthermore, yields are not as high as desirable for a commercial process.
This invention concerns an improved method of preparing trans-dl-1-alkyl-6-oxodecahydroquinolines which is easi~r to carry out and which gives higher yiel(1s -than the process previously known.
This invention concerns a key novel intermediate for preparing the trans-dl-l-alkyl-6-oxodecahydroquinolines, namelv a trans-octahydroquinoline compound of the formula R ~ V

\~
R
wherein R and R are independently C1-C3 alkyl.
The trans racemic mixture of the compounds of formula V are shown by the structures below.

R2 ~ ~I R20 ~i ` / \
Va Vb R and R~ are defined as above.
The above octahydroquinoline compounds of formula V are prepared by rPacting a hexahydroquinoline compound of the formula ~, ~
R2~ \T/ \ IV
3\ jo~ ~o 1~ 1 ~ ~ ~7i~

where R and R are defined as before and the dotted line represents the presence of one double bond, with a reducing aqent of the formula MBH4 or MCNBH3 where M
is an alkali metal, in an inert solvent.
Examples of the alkali metal (~) in the reducing agent are sodium, potassium, or lithium, preferably sodium. Preferred reducing agents are sodium borohydride or sodium cyanoborohydride. A critical chracteristic of the reducing aqent is its ability for stereoselective reduction. A mutual inert solvent is used such as tetrahydrofuran, dioxane, di~ethoxyethane, diglyme or a C1-C3 alkanol, especially methanol or ethanol. Particularlv preferred solvents are tetrahydrofuran, methanol, and ethanol. The preferre~
temperature is room temperature, about 20 to 25 C.
Optionally, a small quantity of a mineral acid such as HCl or ~2SO4, or of an Cl-C3 alkanoic acid, preferably glacial acetic acid, may be present.
The isomeric mixture of the compounds of formula IV consists of the following compounds.
H

R 0~ R 0 ~

IVa IVb IVc where R and R are defined as before.

In the above structures, R and R are C1-C3 alkyl such as methyl, ethyl and n-propyl.
The entire reaction sequence starting with a known compound, going through the claimed intermediate, S and forminq the pharmaceu-tically active products is shown in Flow Chart A in which the terms are defined as follows: R and R are independently Cl-C3 alkyl, X
is a halogen or a pseudohalogen, M is an alkali metal, and R is R or allyl.

X-5912 _5_ Flow Chart A

R20l~ ~~ ~ R1X1~~ ~~ H2 o~ ~

5~O/ ~ ~ ~o/ \N~ ~ ~ \N/
II R' X IIIa R HX
¦ [OH ]
R20~/ `f `I R20~, `t' `I R20t~ `~ `t ~ < reducin~ a (Li or Na a 3 ~ agent~ o ~ ~ NH3 ~o/
V R MCNBH3 ~ C2Hs0H III R
¦ H 0+ or MBH4 ~6~ ~0~ dimethylformamide > 0~ /~\ a 0=~ ~ ~ dimethylacetal (CH3)2NHC~ ~
/ R \ potassium R H2NNH2 / \ acetic H o l / \ l anhydride ~ `f `~ -- ~o I ¦
I

/ \ / \ hydrolysls H ~ O/I~R~I HN\ ¦ ~

IXb VIII R

According to Flow Chart A, a 6-alkoxyquinoline such as 6-methoxyquinoline (available commercially), is ~uarternlzed with an alkyl or allyl halide or pseudo halide tR X), preferably an alkyl iodide (RI), in an inert solvent such as acetonitrile. The term "pseudo halide" here refers to such groups as mesvloxy or tosyloxy which behave chemically like a halide. The quarterni~ation reaction is carried out conveniently at the boiling point of the solvent employed. The quarternary salt (II) is a crystalline material. In the second step of the synthetic proce~ure, this salt is hydrogenated under pressure usin~ a noble metal catalyst such as platinum (supplied as PtO2), palladium, rhodium and others. This hydrogenation is preferably carried out in an acidic medium such as glacial acetic acid and at elevated temperatures; i.e., in the range 60-lnO~C. Both low and high pressure reaction conditions are operative, i.e., pressures varying from 3.5 to 4.2 kg./cm.2 ~or low pressure hydrogenation to up to 70.3 kg./cm.2 for 2n high pressure hydrogenation are operative. For example, about ten hours are required to reduce one-half mole of (II) to l-al~yl-~-methoxy-1,2,3,4-tetrahydroquinoline, as the hydrogen iodide salt (IIIa) at 70.3 kg./cm.2 with a PtO2 catalyst in glacial acetic acid.
The free base (III) is prepared from the salt by treatment of an aqueous solution of the salt with base followed by extraction of the base-insoluble tetrahydroquinoline into a water immiscible solvent.
In a second reduction step, the tetrahydroquinoline is reduced under ~irch reduction X-5912 _7_ conditions, using an al~ali metal, such as sodium or lithium dissolved in liquid ammonia. The quinoline is customarily added as a solution in THF to the solution of the alkali metal in liquid NH3. After the reduction mixture is stirred at liquid ammonia temperatures for a suitable period of time, anhvdrous ethanol is added until the blue color is discharged. The reaction mixture is then allowed to warm to room temperature as the NH3 evaporates. The residual THF solution contains a mixture of hexahydroquinolines of formula IV [represented hereinbefore by IVa ~l-alkyl-6-alkoxy-l,2,3,4,4aS,5-hexahydroquinoline~, IVb (l-alkyl-6-alkoxy-l,2,3,4,4aR,5-hexahydroquinoline) and IVc (l-alkyl-6-alkoxy-l,2,3,4,5,8-hexahydroquinoline)]. This mixture of hexahydroquinoline isomers is then stereoselectively reduced using a reducing agent of the formula MBH~ or MCNBH3, where M is an alkali metal, such as sodium borohydride or sodium cyanoborohydride. A solvent such as THF or C1-C3 alkanol is employed in this reaction.
Also, a small quantity of mineral acid such as HCl or H2SO4)or qlacial acetic acidJor of an C1-C3 alkanoic acid may be added, preferably ~lacial acetic acid. The reduction is carried out at room temperature.
The product of the reduction is a racemate of formula V [represented hereinbefore by Va and Vb, where Va is named as a l-alkyl-6-alkoxy-1,2,3,4,4aS,5,8,8aS-octahydroquinoline and Vb is named as a l-alkyl-6 alkoxy-l,2,3,4,4aR,5,8,8aR-octahydroquinoline]. Treatment of this racemate with aqueous acid, preferably HCl/ yields a racemic mixture of trans-dl l-alkyl-6-oxadecahydro-quinolin~s of formula I. The 6-o~o compound of I is reacted with ~imethylformamide dimethylacetal to yield a trans-dl-l-alkyl-6-oxo-7-dimethylaminomethylene-decahydroquinoline(VI). The int~rmediate of formula (VI) can be further reacted in one of the followlng two ways.
Reaction with potassium glycinate followed by acetic anhydride yields trans-dl-2-acetyl-5-alkvl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolol3,4-g]quinoline (VII). The compound of formula VII then undergoes alkaline hydrolysis to vield trans-dl-5-alkyl-4,4a,5,6,7,8~8a,9-octahydropyrrolo[3,4-g]quinolines (VIII), described in U. S. Patent No. 4,235,909.
Secondly, the compound of formula (VI) reacts with hydraæine to yield a tautomeric mixture of trans-dl-15 5-alkyl-4,4a,5,6,7,8,8a,9-octahydro-lH(or 2H)-pyrazolo[3,4-g]quinoline (IXa and IXh), described in U. S. Patent No. 4,198,415.
Preparation of the above compounds is illustrated by the following specific Examples.

Preparation of starting materials Preparation 1 Preparation of l-n-propyl 6-methoxyquinolinium iodide Four hundred grams of 6-methoxyquinoline were dissolved in 2.5 1. of acetonitrile containing R54.4 g.
of n-propyl iodide. The resulting solution was heated to reflux for about 18 hours under a nitrogen blanket. The reaction mixture was cooled and the so~vent removed by evaporation in vacuo. The residue was dissolved in acetone and ether was added to the point of incipient precipitation. Crystals were produced by scratchlng.
Crystalline l-n-propyl-6-methoxyquinolinium iodide thu~
prepared was isolated by ~iltration; weiqht = 547.2 g.;
melting point = 111-115C. Rf (4:i chloroform:methanol, silica) = .580 An additional 136.2 g. of desired product were obtained from the filtrate. ~R was compatible with the proposed structure.
Preparation 2 Preparation of l-n-Propyl-6-methoxy-1,2,3,4-tetrahydroquinoline l-n-Propyl-6-methoxyquinolinium iodide, from Preparation 1, was hydrogenated to yield l-n-propyl-25 6-methoxy-1,2;3,4-tetrahydroquinoline. In a typical run, 163 g. of the quarternary salt were dissolved in 1917 ml.
of glacial acetic acid to which were added 20 g. of platinium oxide. Hydrogenation was carried ou-t at 70.3 kg./cm.~ at a temperature of about 100C. After about ten hours, the theoretical amount O r hydrogen had been X-5 _ lO-absorbed. The hydroqenation mixture was then filtered to remove the catalyst and the solvent then removed from the filtrate by evaporation in vacuo. The resulting residue was dissolved in water and the aqueous solution made basic by the addition of saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ether.
The ether extracts containin~ l-n-propyl-6-methoxy-1,2,3,4-tetrahydroquinoline formed in the above reaction were washed with water and then dried. The ether was removed by evaporation in vacuo. Ninety-two qrams of l-n-propyl-6-methoxy-1,2,3,4-tetrahydroquinoline were obtained; yield = 90.6~.
The above hydrogenation can also be carried out at a low pressure such as 4.22 ka./cm. . In addition, in place of PtO2, Pd-on C or Rh on Al2O3 can also be used with equal or superior results.
Alternatively, an alkyl halide such as allyl bromide can be used to quarternize the 6-methoxyquinoline since hydrogenation of the N-allyl-6-methoxyquinolinium bromide with a noble metal catalyst such as PtO2 will ultimately yield the identical l-n-propyl-6-methoxy-1,2,3,4-tetrahydroquinoline.
Pre~aration 3 Preparation of l-n-Propyl-6-methoxy-1,2,3,-25 4,5,8-hexahydroquinoline, l-n-Propyl-6-methoxy-1,2,3,-4,4aR,5-hexahydroquinoline and l-n-Propyl-6-methoxy-1,2,3,4,4aS,5-hexahydroquinoline Three liters of ammonium were dried over sodium metal for about one hour. 800 ml. of ammonia thus dried were then distilled into a 3 l. three-neck flask equipped with gas inlet tube, condenser with drying tube attached and addi-tion funnel. The ammonia was stirred with a magnetic stirrer. A solution containing 40 g. of l-n-propyl-6-methoxy-1,2,3,4-tetrahydroquinoline, prepared as Preparation 2, in 200 ml. of THF (dry, distilled) were added. Ten g. of lithium metal were cut into chunks of about 1 cm.3 size and these chunks were added in a single batch to the liquid ammonia-tetrahydroquinoline-THF solution. The reaction mixture was stirred for about 20 minutes. Anhydrous ethanol (about 160 ml.) was added in dropwise fashion over a 15 minute period. The resulting mixture was allowed to stir overnight under a nitrogen atmosphere without external coollnq. During this time, the ammonia evaporated.
Four-hundred ml. of water were then added. The aqueous mixture was extracted with three 200 ml. portions of dichloromethane. The dichloromethane layers were com~ined and the combined layers washed with 250 ml. of saturated aqueous sodium chloride. The dichloromethane layers were then dried and the solvent removed by evaporation in vacuo. The mixture of l-n-propyl-6-methoxv-1,2,3,4,5,8-hexahydroquinoline, 1-n-propyl-6-methoxy-1,2,3,4,4aR,5-hexahydroquinoline and l-n-propyl-6-methoxy-1,2,3,4,4aS,5-hexahydroquinoline 25 thus produced distilled in the ranae 84-120C. at a pressure of 0.03 Torr; yield = 32.6 q. (80.5%).

~ '7 Preparation of Final Products Example l Preparation of trans-dl-l-n-Propyl~6-methoxy-1,213,4,4a,5,8,8a-octahydroquinoline A solution was p~epared containing 4.4 g. o~
sodium cyanoborohydride in 250 ml. of dried, distilled THF. 14.8 g. of a mixture of l-n-propyl-6-methoxy-1,2,3,4,5,8-hexahydroquinoline, l-n-propyl-6-methoxy-1,2,3,4,~aR,S-hexahvdroquinoline and l-n-propyl-10 6-methoxy-1,2,3,4,4aS,5-hexahydroquinoline, prepared in Preparation 3, in lO0 ml. of THF were then added, followed by 1.7 ml. of glacial acetic acid. The reaction mixture was stirred at ambient temperature for about 1.25 hours, at which time another 1.7 ml. of glacial acetic acid were added. Stirring was continued for an additional 30 minutes. The entire reaction mixture was then poured into about 300 ml. of water. The aqueous mixture was extracted three times with 200 ml. of portions of dichloromethane. The organic layers were combined, the combined layers were washed once with an equal volume of water and were then dried. The solvent was removed by evaporation ln vacuo and the residual yellow viscous oil was distilled. Trans-dl-l-n-propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline thus 25 prepared distilled in the range 70-140C. at 0.15-0.20 Torr. givinq a total weight of lO g. (66% yield).

Example 2 Preparation of trans-dl-l-n-Propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline When the procedure of Example 1 was repeated using 10 g. of a mixture of l~n-propyl-6-methoxy-1,2,3,4,5,8-hexahydroquinoline, 1-n-propyl-6-methoxy-1,2,3,4,4aR,5--hexahydroquinoline, and 1-n-propyl-6-methoxy-1,2,3,4,4aS,5-hexahydroquinoline in 140 ml. of ethanol, 2.19 g. of sodium cyanoborohydride and 2 ml. of HCl, there was obtained trans-dl-l-n-propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline (95~ yield) having the same boiling point range as Example 1.
Example 3 Preparation of trans-dl-l-n-Propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline To a solution of 10 g. of a mixture o~
l-n-propyl-6-methoxy-1,2,3,4,5,8-hexahydroquinoline, l-n-propyl-6-methoxy-1,2,3,4,4aR,5-hexahydroquinoline, and l-n-propyl-6-methoxy-1,2,3,4,4aS,5-hexahydroquinoline in 140 ml. of ethanol was added, at one time, 2.5 ml. of glacial acetic acid. A solution of 1.32 g. of sodium borohydride in ethanol was prepared and added portionwise to the first solution. The reaction mixture was cooled and stirred under nitrogen about 16 hours. The product, trans-dl-1-n-propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline, was isolated according to the proceduxe of Example 1 and was identical to the product of Example 1. ~82~ yield) B~

X-591? -14~

Example 4 Preparation of trans-dl-l-n-Propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline When the procedure of Example 3 was repea-ted usinq l40 ml. of isopropanol ~or the ethanol, there was obtained trans-dl-l-n-propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline ~52~ yield) identical to the product of Example 1.
Example 5 Preparation of trans-dl-l-n-Propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline When the procedure of Example 3 was repeated using 140 ml. of methanol for the ethanol, there was obtained trans-dl-l-n-propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroqu~noline ~92~ yield) identical to the product of Example 1.
Example 6 Preparation of trans-dl-l-n-propyl-6-methoxy 1,2,3,4,4a,5,8,8a-octahydroquinoline When the procedure of Example 3 was repeated using 40 ml. of ethanol ~o dissolve the sodium borohydride and 100 ml. of me-thanol for the 140 ml. of ethanol, there was obtained trans-dl-l-n-propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline ~g8~ yield) identical with the product of Example 1.

Example 7 Preparation of trans-dl-l-n-Propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline When the procedure of Example 6 was repeated omitting the glacial acetic acid, there was obtained trans-dl-l-n-propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline (89~ yield) identical with the product of Example 1.
Example 8 Preparation of trans-dl-l-n-Propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline When the procedure of Example 3 was repeated using 10 g. of the mixture of 1-n-propyl-6-methoxy-hexahvdroquinolines, 1.07 q. of sodium borohydride in 40 ml. of ethanol, 100 ml. of methanol, and 2.8 ml. of glacial acetic acid, there was obtained trans-dl-l-n-propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline (99~ yield~ identical to the product of Example 1.

Preparation o Active Products Example A
Preparation of trans-dl-l-n-Propyl-6-oxo-1,2,3,4,4a,5,6/7,8,8a-decahydroquinoline A solution was prepared from 3.1 g. of trans-dl-l-n~propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline in 25 ml. of THF, from Example 1.
Four ml. of 10% aqueous sulfuric acid were added. The resulting two-phase mixture was heated at refluxing temperature for about 17 hours after which time it was poured into dilute aqueous sodium hydroxide. The al~aline aqueous mixture was extracted with dichloromethane. The dichloromethane extract was dried and the solvent removed n vacuo. A residual oil weighing about 2.8 g. comprising trans-dl-l-n-propyl-6-oxodecahydroquinoline distilled in the range 63-87C.
at 0.1 Torr. TLC indicated that the combined fractions contained in excess of 90~ trans-dl-1-n-propyl-6-oxodecahvdroquinoline.
Alternately, 5.0 g. of trans-dl-1-n-propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline were dissolved in 50 ml. of T~F. Twenty-five ml. of lN
aqueous hydrochloric acid were added and the mixture stirred for one-half hour under a nitrogen atmosphere.
The reaction mixture was then made hasic with 14N aqueous ammonium hydroxide and the alkaline mixture extracted three times with dichloromethane. The organic extracts were combined, dried and the solvent removed in vacuo.
Ll . ~ g. of an orange transparent oil remained as a residue. TLC indicated a single spot at Rf = .67 with X-59l2 -17-slight leading and trailing spots as impurities.
Distillation yielded trans-dl-l-n-propyl-6-oxodecahydroquinoline boiling at 77-87C. at 0.025 ~orr.
total yield = 4.39 g. (9~.1~).
As previously stated, the trans-dl-1-alkyl-6-oxodecahydroquinolines (I~, can be reacted with dimethylformamide dimethylacetal to yield a trans-dl-l-alkyl-6-oxo-7-dimethylaminomethylene decahydroquinoline (VI). Reaction of this intermediate with potassium glycinate followed by treatment with acetic anhydride yields a trans-dl-2-acetyl-5-alkyl-4,4a,5,6,7,8,8a,9-octahydro-2~-pyrrolo[3,4-g]quinoline (VII). Alkaline hydrolysis of the acetyl derivative yields trans-dl-5-alkyl-15 4,4a,5,6,7,8,8a,9-octahydropyrrolo[3,4- g]quinoline (VIII), a dopamine agonist useful in treating Parkinsonism or excessive prolactin secretion ~see U.S.
Patent 4,235,909). Alternatively, the 7-dimethylaminomethylene compound (VI) reacts with hydrazine to yield a tautomeric mixture consisting of trans-dl-5-alkyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pvrazolo-[3,4-g]quinoline and the corresponding 2H compound (IXa and IXb), useful also as dopamine agonists. (See U. S.
Patent 4,198,415).

Claims (11)

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

1, A process for preparing a trans-octahydroquinoline compound of the formula V

wherein R and R2 are independently Cl-C3 alkyl, which comprises reacting a hexahydroquinoline compound of the formula IV

wherein R and R2 are defined as before and the dotted line represents the presence of one double bond with a reducing agent of the formula MCNBH3 or MBH4 where M
is an alkali metal, in an inert solvent.

2. The process of claim l wherein the reducing agent is sodium cyanoborohydride.

3. The process of claim 2 wherein the inert solvent is tetrahydrofuran.

4. The process of claim l wherein the reducing agent is sodium borohydride.

5. The process of claim 4 wherein the inert solvent is methanol or ethanol.

6. The process of claim 1 wherein a mineral acid is present.

7. The process of claim 1 wherein glacial acetic acid is present.

8. A trans-octahydroquinoline compound of the formula V

wherein R and R2 are independently Cl-C3 alkyl, whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.

9. The process of claim 1 for preparing trans-dl-l-n-propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline which comprises reacting a mixture of l-n-propyl-6-methoxy-1,2,3,4,5,8-hexahydroquinolinne, l-n-propyl-6-methoxv-1,2,3,4,4aR,5-hexahydroquinolline and l-n-propyl-6-methoxy-1,2,3,4,4aS,5-hexahydroquinolline with sodium cyanoborohydride and glacial acetic acid.

10. The process of claim 1 for preparing trans-dl-l-n-propyl-6-methoxy-1,2,3,4,4a,5,8,8a-octahydroquinoline which comprises reacting a mixture of l-n-propyl-6-methoxy-1,2,3,4,5,8-hexahydroquinoline, l-n-propyl-6-methoxy-1,2,3,4,4aR,5-hexahydroquinoline and l-n-propyl-6-methoxy-1,2,3,4,4aS,5-hexahydroquinoline with sodium borohydride, and glacial acetic acid.

11. Trans-dl-l-n-propyl-6-methoxy-1,2,3,4,4a,-5,8,8a-octahydroquinoline whenever prepared by the process of claim 9 or 10 or an obvious chemical equivalent thereof.