FI74459B - 6-OXODEKAHYDROKINOLINDERIVAT ANVAENDBART SOM MELLANPRODUKT VID FRAMSTAELLNING AV TRICYKLISKA DOPAMIN-AGONISTER. - Google Patents

Description

74459 6-Oxodecahydroquinoline derivatives useful as intermediates in the preparation of tricyclic dopamine agonists

Divided by application 792046 5

The invention relates to novel 6-oxodecahydroquinoline derivatives of the formula 0 r1

My 1 R

wherein R is C 1-3 alkyl and R is COOZ ', wherein Z' is C 1-2 alkyl.

Compounds of formula XIII are useful as intermediates in the preparation of tricyclic dopamine agonists. Such tricyclic dopamine agonists are described in FI patent application 792046 and have the formula f yOaA ^ '1' ^ 8a. R1 '20 11 —f-'κι / ήΜτΜ N 2 -} H-N 2 V3ch - Il 4 5 d <\ c3H_1 4 11 5 6 ,,

3εί ^ 4Ά N 3a> r ^ 4a ^ N

R R '25 Ia Ib wherein R' is (C 1 -C 4) alkyl R 1 'is SCH 3.

In the above formulas, the term "C 1-2 alkyl" means methyl and ethyl and the term "C 1-2 alkyl" means methyl, ethyl, n-propyl and isopropyl.

The preparation and use of the intermediates according to the invention are shown in the following reaction scheme.

74459

reaction scheme

Z

0 CO

1! i. OF

5 S \ RNH9_ V V V COOZ 'CH 2 -COOZ 2

1 CH Hal X R

o-co-z 1 10 acid BH. ~ 4

Z

15 CO

H 7 H

HO— N — COOZ '/ EtOH / OH ~ ° Y Y f C00Z'

HCl ^ N

20 XI1 pyridine.HCl 25 CrO3

B

a-y '* y \ __ cooz · 30 \ k)

x * I N

H t

XIII

35 74459

In the above reaction scheme, Z 'has the same meaning as above and Z is C 1-3 alkyl, C 2-3 alkenyl, C 1-4 alkynyl, C 1-4 cycloalkyl, phenyl or substituted-2-ob-substituted phenyl, wherein the substituent may be methyl, methoxy, chlorine or a group thereof at any position on the phenyl ring. Z-CO can be, for example, acetyl, propionyl, butyryl, propiolyl, acrylyl, benzoyl, p-toluyl, o-chlorobenzoyl or m-methoxybenzoyl. Shark is chlorine or bromine.

According to the reaction scheme, 4-acyloxycyclohexanone is reacted with an o-halomethyl acrylate ester, e.g. ethyl ester, and the amine RNH 2, wherein R is C 1-3 alkyl. The product of this reaction is dl-1-substituted-3-ethoxycarbonyl-6-acyloxy-1,2,3,4,5,6,7,8-octahydro-15-quinoline and dl-1-substituted-3-ethoxycarbonyl-6 -acyloxy-1,2,3,4,4a, 5,6,7-octahydroquinoline represented by formula X, wherein the dashed line indicates alternative locations for the double bonds. The hydrochloride salts of these isomers are prepared and the resulting mixture is reduced with sodium cyanoborohydride to give trans-dl-1-substituted-3-ethoxycarbonyl-6-acyloxide decahydroquinoline (XI). Hydrolysis of this diester to give 6-hydroxy-3-carboxylic acid and subsequent re-esterification of the carboxylic acid group with ethanol or another suitable alcohol in the presence of an acid affords trans-dl-1-substituted-3-ethoxycarbonyl-6-hydroxide-dihydroquinoline. (XII). Oxidation of the hydroxy group with Sarett's reagent (pyridine hydrochloride and chromium trioxide) gives the 6-oxo intermediate 30 (XIII) of the invention. Treatment of this 6-oxo derivative as described in FI patent application 792046 provides therapeutically valuable compounds of formulas Ia and Ib.

The following examples illustrate the invention.

Example 1 A mixture of 10 ml of n-propylamine and 400 ml of toluene was cooled in an ice-water bath. A solution of 16.5 g of ethyl x- (bromomethyl) acrylate in 50 ml of toluene was added dropwise. The resulting mixture was stirred with cooling for about 25 minutes. Next, a solution of 11 g of 4-benzoyl-5-oxycyclohexanone in 75 ml of toluene was added dropwise. This new mixture was heated at reflux for about 23 hours under a nitrogen atmosphere. The reflux condenser was equipped with a Soxhlet extractor with water to remove. 5A filter. The reaction mixture was then cooled and the cooled mixture was filtered. Evaporation of the filtrate to dryness gave a residue containing 1N-propyl-3-ethoxycarbonyl-6-benzoyloxy-1,2,3,4,5,6,7,8-octahydroquinoline and 1N-propyl-3-ethoxycarbonyl-6-benzoyloxy- a mixture of 1,2,3,4, -4a, 5,6,7-octahydroquinoline. The residue was dissolved in an ether-chloroform solvent mixture, and the resulting solution was saturated with hydrogen chloride gas while maintaining the temperature between 0 and 5 ° C. The solvent was decanted apart from the crystalline hydrochloride salts thus formed. The salts were dissolved in 100 ml of methanol. 300 mL of THF was added and the resulting solution was cooled in an ice-water bath. To the stirred and cooled reaction mixture was added portionwise 15 g of sodium cyanoborohydride. At the end of the addition, the reaction mixture was stirred for another 1.25 hours, after which time it was diluted with aqueous sodium hydrogen carbonate solution. The aqueous alkaline mixture was extracted several times with ethyl acetate. The ethyl acetate extracts were combined and the combined extracts were washed with saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent gave trans-dl-1-n-propyl-3-ethoxycarbonyl-306-benzoyloxide decahydroquinoline. The compound was dissolved in a mixture of 400 ml of methanol and 100 ml of 2N aqueous sodium hydroxide solution. This mixture was stirred at ambient temperature under a nitrogen atmosphere for 64 hours, after which time the volatiles were removed by evaporation-35 miles in vacuo. The resulting residue was suspended in 800 ml of ethanol and 15 ml of 12N aqueous hydrochloric acid. The es-74459 sharpening mixture was heated to reflux and about 300 ml of solvent was removed by distillation. An additional 300 mL of ethanol was added and the reaction mixture was heated at reflux for 26 hours in an apparatus equipped with a Sochlet trap with a 3A filter. The reaction mixture was cooled, diluted with aqueous sodium hydrogencarbonate solution, and the alkaline mixture was extracted several times with chloroform. The chloroform extracts were combined, and the combined extracts were washed with saturated aqueous sodium chloride-10 and then dried. Evaporation of chloroform gave 10.3 g of a residue containing trans-dl-1-propyl-3-ethoxycarbonyl-6-hydroxydecahydroquinoline formed by the above hydrolysis after chromatography of the product with 15,150 grams of Florisil using chloroform as eluent. was the increasing amount (2-10%) of methanol.

A solution of 8.8 g of trans-dl-1-n-propyl-3-ethoxycarbonyl-6-hydroxydecahydroquinoline and 400 ml of methylene dichloride was prepared. 4.1 g of sodium acetate were added. Next, 10.8 g of a pyridine hydrochloride-chromium trioxide mixture was added, and the resulting mixture was stirred for about 22 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The obtained concentrate was dissolved in chloroform, and the chloroform solution was chromatographed on 150 g of Florisil using chloroform with an increasing amount (1-2%) of methanol as an eluent. The fractions were found to contain trans-dl-1-n-propyl-3-ethoxycarbonyl-6-oxo-decahydroquinoline using thin layer chromatography. The fractions were combined and the solvent removed to give 3.48 g of the 6-oxo compound.

Use of an intermediate according to the invention

Example I

3.48 g of the 6-oxo compound obtained in Example 1 were dissolved in 100 ml of toluene to which was added 25 ml of dimethyl acetal of di-35 methylformamide. The resulting mixture was heated at reflux under nitrogen for 44 hours and then allowed to stand at room temperature for a further 4 days. The volatiles were removed by evaporation in vacuo and the residue containing trans-dl-1-propyl-5-ethoxycarbonyl-6-oxo-7- (dimethylaminomethylene) decahydroquinoline formed in the above reaction was purified by chromatography on a chloroform solution of the compound using Florisil eluting with Florisil. was the increasing amount (2-5%) of methanol. Fractions shown by TLC to contain 10-10 dimethylaminomethylene were combined and the solvent was evaporated in vacuo.

A solution of 2.24 g of trans-dl-1-n-propyl-3-ethoxycarbonyl-6-oxo-7-dimethylaminomethylene decahydroquinoline and 150 ml of ethanol was prepared. 0.45 ml of hydrazine hydrate was added and the resulting mixture was stirred at ambient temperature for about 17 hours. The reaction mixture was evaporated to dryness in vacuo. Residue containing trans-dl-5-n-propyl-7-ethoxycarbonyl-4,4a, 5,6, -7,8,8a, 9-octahydro-2H-pyrazolo [3,4-g] quinoline and trans -20 dl-5-n-propyl-7-ethoxycarbonyl-4,4a, 5,6,7,8,8,8a, 9-octahydro-1H-pyrazolo [3,4-g] quinoline, dissolved in chloroform and the resulting solution chromatographed on 35 grams of Florisil using chloroform with 2% methanol as eluent. Fractions shown by TLC to contain the desired pyrazoloquinoline were combined and the solvent was evaporated in vacuo. Recrystallization from the filtrate of ether and hexane gave trans-dl-5-n-propyl-7-ethoxycarbonyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo [3,4-g] - 30 quinoline and its 1H tautomer, m.p. 125-127 ° C.

Analysis calculated: C, 65.95; H, 8.65; N, 14.42; Found: C, 65.75; H, 8.42; N, 14.16.

Mixture of trans-dl-5-n-propyl-7-ethoxycarbon-35-carbonyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo / 3,4-g7-quinoline dihydrochloride and the dihydrochloride disalt salt of the 1H tautomer (3.7 mmol) were suspended in 200 mL of THF.

74459

1 g of lithium aluminum hydride was added portionwise. The resulting reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for about 16 hours and then cooled. Ethyl acetate and 5% aqueous sodium hydride were added successively to react with any excess lithium aluminum hydride and to decompose the organometallic compounds present.

The reaction mixture thus treated was then diluted with water, and the aqueous mixture was extracted several times with a chloroform-10 isopropanol solvent mixture. The organic layers were separated and combined. The combined layers were washed with saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent gave trans-dl-5-n-propyl-7-hydroxymethyl-4,4a, 5,6,7,8,8a, 9-15 octahydro-2H-pyrazolo [3f 4-g] quinoline and its 1H-disease. -mer mixture. The residue was dissolved in ethanol, to which was added 0.2 ml of 12N aqueous hydrochloric acid. Evaporation of the volatiles gave a residue containing trans-dl-5-n-propyl-7-hydroxymethyl-4,4a, 5, -20, 6,7,8,8a, 9-octahydro-2H- and 1H-pyrazolo / 3,4-g7quinoline dihydrochlorides. The residue was dissolved in a mixture of methanol and acetone to give crystals which melted at 270-275 ° C with decomposition; yield 350 mg.

The reaction described above was repeated by reduction of 1.55 g of trans-dl-5-n-propyl-7-ethoxycarbonyl-4,4a, - · 5,6,7,8,8a, 9-octahydro-2H-pyrazolo / 3,4-g7-quinoline in THF with excess lithium aluminum hydride. The reaction product, trans-dl-5-n-propyl-7-hydroxymethyl-4,4a-15,6,7,3,8a, 9-octahydro-1H and 2H-pyrazolo [3,4-g] -30-quinoline, was crystallized from chloroform and from a mixture of ethanol to give a crystalline substance melting at 167-169 ° C.

Analysis calculated: C, 67.43; H, 9.30; N, 16.85; Found: C, 67.21; H, 9.13; N, 16.62.

A suspension of 1 mmol of 35 trans-dl-5-n-propyl-7-hydroxymethyl-4,4a, 5,6,7,8,8a, 9-octahydro-ΙΗ and 2H-pyrazolo [3,4- g / quinoline in 100 ml of pyridine. 1 ml of methanesulfonyl chloride (mes-74459 ethyl chloride) was added and the resulting mixture was allowed to stand overnight at ambient temperature. The mixture was diluted with dilute aqueous ammonium hydroxide solution, and the resulting alkaline layer was extracted several times with chloroform.

The chloroform extracts were combined, and the combined extracts were washed with saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent gave a solid residue. The chloroform solution of the residue was chromatographed on 30 grams of Florisil using chloroform with an increasing amount (1-2%) of methanol as eluent. Fractions shown by TLC to contain trans-dl-2-methanesulfonyl-5-n-propyl-7-mesyloxymethyl-4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrazolo / 3,4-J7-quinoline, was combined and the solvent was removed by evaporation. After recrystallization from ether, trans-dl-2-methanesulfonyl-5-n-propyl-7-mesyloxymethyl-4,4a, 5,6, -7,8,8a, 9-octahydro-2H-pyrazolo [3,4] 2 2_ / quinoline melted at 152-154 ° C.

Analysis calculated: C, 47.39; H, 6.71; N, 10.36; S 15.81; Found: C, 47.60; H, 6.71; N, 10.32; S 15.69.

Chromatography gave a second fraction which was shown by NMR to be a 2: 1 mixture of trans-dl-5-n-propyl-7-mesyloxymethyl-2-2 5 methanesulfonyl-4,4a, 5,6,7, 8,8,8a, 9-octahydro-2H-pyrazolo [2,3 ", 4-c [7-quinoline and its 1-methanesulfonyl-1H-isomer.

1 g of methyl mercaptan was dissolved in 40 ml of dimethylformamide. The solution was cooled in an ice-water bath.

About 1 g of sodium hydride (as a 50% mineral oil suspension) was added portionwise. The cooling bath was removed and a solution of 0.4 g of the trans-dl-2-methanesulfonyl-5-n-propyl-7-mesyloxymethyl-4,4a, 5,6,7,8,8a, 9-octahydroxy 2H-pyraz-35 Solo [3,4-g] quinoline, which included slightly trans-dl-1-methanesulfonyl-5-n-propyl-7-mesyloxymethyl-74459 4,4a, 5,6,7,8,8a, 9-octahydro-1H-pyrazolo [5,4-c] quinoline in 10 ml of DMF. The reaction mixture was stirred at ambient temperature for about 5 hours and then diluted with water. The aqueous mixture was extracted several times with ethyl acetate. The ethyl acetate extracts were separated and combined. The combined extracts were washed with water and saturated aqueous sodium chloride solution, and then dried. Evaporation of the solvent gave an oily residue containing trans-dl-5-n-propyl-7-methyl-10-limercaptomethyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H and 2H-pyrazolo / 3,4- ^ j7kinoliinia; yield 0.17 g. The residue was dissolved in ethanol and attempts were made to prepare both the hydrochloride and oxalate salts. At first, both salts appeared non-crystallized. The free bases from the non-crystallized oxa-15 plate were then recovered by dissolving the oxalate in water, adding the base and extracting the mixture with ether. The trans-dl-5-n-propyl-7-methylmercaptomethyl-4,4a, 5,6,7,8,8a, 9-octahydro-ja- and 2H-pyrazolo [3,4-g] quinoline thus purified crystallized 20 on evaporation of the ether melting point 175-177 ° C; yield 40 mg.

Analysis calculated: C, 64.47; H, 9.02; N, 15.04; S, 11.47; Found: C, 64.47; H, 8.96; N, 16.09; S, 11.29.

The free base-tautomer mixture purified above was dissolved in ethanol and an excess of 12-norm was added. hydrochloric acid. The volatiles were removed by evaporation and the resulting residue containing the corresponding dihydrochloride salts crystallized from acetone-methanol.

Analysis calculated for C, 51.13; H, 7.72; N, 11.93; 30 Cl, 20.10; S, 10, Found: C, 50.89; H, 7.57; N, 12.15;

Cl, 20.18; S, 9.31.

Claims (2)

A 7-oxodecahydroquinoline-5 derivative useful as an intermediate in the preparation of tricyclic dopamine agonists, characterized in that it has the formula R XIII R where R is C 1-6 alkyl and R "*" is COOZ ', wherein Z' is C 1-2 alkyl. The 6-oxo-decahydroquinoline derivative is a side-by-side product with a tricyclic dopamine agonist, 5 turns having the following formula: alkyl.