HU189693B - Process for preparing trans-dl-1-alkyl-6-alkoxy-octahydro-quinolines - Google Patents

Abstract

A trans-octahydroquinoline compound of the formula (I) where R and R2 are independently C1-C3 alkyl. - (10pp)

Description

A 4.198.415. U.S. Pat. The compounds described therein exhibit dopamine antagonistic (dopamineergic) activity. One of the most active groups of compounds contains a propyl moiety on the nitrogen atom of quinoline.

In the process for the preparation of these octahydropyrazolo [3,4-g] quinolines, one of the exemplary outer products is traes-dl-1-alidl-6-oxo-decahydroquinoline, one of its stereoisomers (4aa, 8a / 3) being 4198415. U.S. Pat. The same intermediate is used in U.S. Patent No. 4,235,909. U.S. Pat. No. 4,400,123 for the preparation of 4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrrolo [3,4-g] quinolines. The octahydro-2H-pyrrolo [3,4-g] quinolines, like the octahydro-1H (and 2H) -pyrazolo [3,4-g] quinolines, are dopamine antagonist compounds that inhibit prolactin secretion and are thus useful in the treatment of Parkinson's disease.

In the two patents cited above, the process for the preparation of trans-d1-1-alkyl-6-oxo-decahydroquinolines involves five steps using commercially available starting materials. Its production is not high enough to be used to produce a commercial product.

The present invention relates to an improved process for the preparation of trans-d1-1-alkyl-6-oxo-decahydroquinolines, which is more readily accomplished and can be carried out in a better yield than previously known methods.

The present invention relates to a process for the preparation of a novel trans-octahydroquinoline flavor derivative of formula (V) which is a key intermediate for the preparation of trans-d1-1-alkyl-oxo-decahydroquinolines, wherein:

R and R ² are independently C 1-3 alkyl.

The components forming the trans racemic mixture of the compound of formula (V) are given by the formulas (Va) and (Vb) wherein R and R ² are as defined above. According to the invention, the octahydroquinoline compound of formula V is hexahydroquinoline of formula IV wherein R and R ² are as defined above and the dotted line represents the presence of a double bond and MBH 4 or MCNBH of the general formula wherein

M is prepared by reaction of an alkali metal reducing agent in an inert solvent.

The alkali metal in the reducing agent may be sodium, potassium or lithium, preferably sodium. Preferred reducing agents are sodium tetrahydroborate or sodium cyanoborohydride. A crucial feature of the reducing agent is that it is stereoselective. suitable for reduction. Suitable inert solvents for both components are, for example, tetrahydrofuran, dioxane, dimethoxyethane, diglyme or C 1-3 alkanol, such as methanol or ethanol. The reaction is preferably carried out at room temperature, 20-25 ° C]. If desired, a small amount of a mineral acid such as hydrochloric or sulfuric acid or a saturated carboxylic acid having from 1 to 3 carbon atoms may preferably be glacial acetic acid.

A compound of formula (IV) is a mixture of isomers of formula (IVa), (IVb) and (IVc) wherein R and R ² are as defined above.

In the above formulas, R 10 and R ^J are C 1-3 alkyl, such as methyl, ethyl and propyl.

The complete reaction scheme for the preparation of the pharmaceutically active compound from known starting materials via the intermediates of this invention is illustrated in Scheme A) wherein R and R ⁹ are independently selected from C 1-3 alkyl, X is halogen, or pseudohalogen, M is an alkali metal and R ¹ is the same as R or allyl.

According to the flowchart A) (commercially available) 6-alkoxyquinoline, such as

Kvatemerezzük solvent such as acetonitrile of formula R aUáljodiddal inert 6-methoxyquinoline R ^J X alkyl halide or allyl halide or pszeudohalogeniddel, preferably of formula. The term pseudohalogen refers to a mesyloxy group or a tosyloxy group which behaves chemically similar to halogens. The quaternization reaction is conveniently carried out at the boiling point of the solvent used. The quaternary salt of formula II is a crystalline material. In the second step of the synthesis, this salt is hydrogenated under pressure in the presence of a noble metal such as platinum (deposited on a platinum oxide support), palladium, rhodium or the like. The hydrogenation is preferably carried out in an acidic medium such as glacial acetic acid at a high temperature of 60-100 ° C. Both low and high pressure reaction conditions may be employed. Is the pressure a low pressure hydrogenator? 3.5-42 kg / cm ² for high pressure hydrogenation, 70.30 kg / cm ² for hydrogenation. For example, to reduce half a mole of the compound of formula II to the salt of 1-alkyl-6-methoxy-1,2,3,4-tetrahydroquinoline of formula IIa into the hydrochloride iodide at 7025 kg / cm ^{2 in} the presence of platinum oxide in glacial acetic acid a reaction time of about ten hours is required.

The free base of Formula Cili can be recovered from the salt by reaction of the aqueous solution of the salt with a base, followed by extraction of the insoluble tetrahydroquinoline with a water-immiscible solvent.

In a second reduction step, tetrahydroquinoline is reduced under Birch reduction using an alkali metal such as sodium or lithium dissolved in liquid ammonia. The lanolin is usually added to a solution of the alkali metal in liquid ammonia dissolved in tetrahydrofuran. After stirring the reduction mixture at the temperature of liquid ammonia for an appropriate time, anhydrous ethanol is added until the blue color disappears. The reaction mixture was then allowed to warm to room temperature while the ammonia was evaporated. The resulting tetrahydrofuran solution is hexahydroquinolines of formula IV, 1-alkyl-6-alkoxy-123.4,4aS3-hexahydroquinoline of formula IVa, and 1-alkyl-6- of formula TVb. alkoxy-1 2,3,4,4aR, 5-hexahydroquinoline and a mixture of 1-alkyl-6-alkoxy-1234,5,8-hexahydroquinoline of formula IVc. The mixture of hexahydroquinoline isomers is then

MBH <or MCNBH ₃ , where M is an alkali metal atom, are stereoselectively reduced with reducing agents such as sodium tetrahydroborate or sodium cyanotrihydroborate. The reaction is carried out using tetrahydrofuran or a C 1-3 alkanol solvent. A small amount of a mineral acid such as hydrochloric or sulfuric acid or a saturated aliphatic carboxylic acid having from 1 to 3 carbon atoms, preferably glacial acetic acid, may be added to the reaction mixture. The reaction is carried out at room temperature.

The reaction product is a racemate of formula (V) which is of formula (Va)

-alkyl-6-alkoxy-1,2,3,4,4aS3,6,6aS-octahydroquinoline, and a compound of formula Vb

a mixture of isomers of alkyl-6-alkoxy-1,2,3,4aR5,8,8aR-octahydroquinoline. Reaction of this racemate with an aqueous acid, preferably hydrochloric acid, yields the trans-d1-1-alkyl-6-oxooctahydro-indoline of formula (I). The 6-oxo compound of formula (I) is reacted with dimethylformamide dimethylacetate to produce trans-d1-1-alkyl-74 (dimethylamino) methylene] decahydroquinoline of formula (VI). The intermediate of formula (VI) can be further processed in two ways. Reaction with sodium glycinate followed by acetic anhydride gives the trans-dl-2-acetyl-5-ester-4,4a5,6,7,8,8a, 9-octahydro-2H-pyrrolo [3,4-g] quinoline of formula (VII) live. The compound of formula VII is then subjected to basic hydrolysis to the trans-dl-5-aldl4,4a, 5,6,7,8,8a, 9-octahydro-2H-pyrrolo [3,4-g] of formula VIIIa. quinoline, which is prepared according to the method described in 4.235509. United States Patent No. 4,600,198. On the other hand, the compound of formula (VI) is reacted with hydrazine to form trans-d1-5-alkyl-4,4a, 6,7,83a5-octahydro-1H (or 2H) -pyrazolo of formula IXa and IXb. 4-g] is converted to quinoline, which is disclosed in U.S. Pat. U.S. Pat.

The following examples illustrate the invention.

Preparation of starting materials

1. Production

Propyl-o-methoxyphenyl-iodide kmolinium

400 g of 6-methoxyquinoline are dissolved in 234 acetonitrile containing 854.4 g of propyl iodide and the solution is refluxed under nitrogen for 18 hours. The reaction mixture was cooled and the solvent was evaporated in vacuo. The residue was dissolved in acetone and ether was added until the first precipitate formed. Scratching causes crystallization. It's made like that

1-Propy-6-methoxyquinolinium iodide was filtered off, weighing 5472 g, m.p. 111-115 ° C.

Rf (4: 1 chloroform-methanol, silica gel> 0.58) A further 1362 g of the desired product can be obtained from the filtrate. The NMR spectrum is consistent with the expected structure.

2. Production

1-Propyl-6-methoxyl-1,2,4-tetrahydroquinoline

The 1-propyl-6-methoxy-1-quinolinium iodide produced in Preparation 1 is hydrogenated and 1-propyl-6-methoxy-1, 3,4-tetrahydroquinoline is prepared. The usual procedure is to dissolve 136 g of quatemeric salt in 1917 ml of glacial acetic acid and then add 20 g of platinum oxide. Hydrogenation is carried out at a pressure of 70.3 kg / cm ³ at about 100 ° C. After about 10 hours, the mixture absorbs the theoretical amount of hydrogen. The hydrogenation reaction mixture was filtered, the catalyst was removed and the solvent evaporated in vacuo. The resulting residue was dissolved in water and made basic with a saturated sodium bicarbonate solution. The aqueous phase is extracted with ether. The ethereal phase formed from the reaction, containing 1-propyl-6-methoxy-123,4-tetrahydroquinoline, was washed with water and dried. The ether was evaporated in vacuo to give 92 g (90.6%) of 1-propyl-6-methoxy-1,2,3,4-tetrahydroquinoline.

The above hydrogenation can also be carried out at low pressure, such as 422 kg / cm ³ . Instead of platinum oxide, palladium on activated carbon and rhodium on alumina can be used and the same or better results are obtained.

Alternatively, an alkyl halide such as allyl bromide may be used for quaternization of 6-methoxyquinoline, since hydrogenation of N-allyl-6-methoxyquinolinium bromide in the presence of a noble metal catalyst such as platinum oxide is also mainly 1-propyl-6-methoxy. 1,2,3,4-tetrahydroquinoline.

3. Production

-Propil-6-methoxy-1 23,4,5,8-hexahydro-kmoline,

Preparation of -propyl-6-methoxy-1,2,3,4,4aR3-hexahydro-choline and 1-propyl-6-methoxy-123,4,4aS3-quinoline

Three liters of ammonia were dried over sodium metal for about 1 hour, and 800 ml were distilled into a 3-liter three-necked flask with a gas inlet, a calcium chloride tube, a reflux condenser and a dropping funnel. The ammonia was magnetically stirred and 200 g of dry distilled tetrahydrofuran solution of Preparation 2 containing 1-propyl-6-methoxy-1,2,3,4-tetrahydroquinoline were added. Lithium (10 g) is cut into approximately 1 cm ³ pieces and added in one portion to the ammonia-9-tetrahydro-indnine-tetrahydrofuran mixture. After stirring for 20 minutes, dry ethanol (about 160 mL) was added dropwise over 15 minutes. The resulting solution was stirred under nitrogen overnight without external cooling. During this time, the ammonia evaporates. Water (400 ml) was added and the aqueous solution was extracted with 200 ml portions of dichloromethane. The dichloromethane layers were combined and washed with saturated aqueous sodium chloride solution (250 mL), dried and the solvent evaporated in vacuo. The resulting 1-propyl-6-methoxy-123,43,8-hexafydroquinoline, 1-propyl-6-methoxy-1,2,4,4aR3-hexahydroquinoline and 1-propyl-6-methoxy-12 A mixture of 4.4aS, 5-hexahydroquinoline was distilled off, mp 84-120 ° C (0.03 torr, yield 32.6 g / 803%).

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189 693

Production of the final product

Example 1 Trans-dl-1-Propyl-6-methoxyl-1 (2, 3,4,4a, 8a, 8a-octahydro-quinoline

A solution of 4.4 g of sodium danotrichloroborate in 250 ml of dried distilled tetrahydrofuran was prepared. 14.8 g of 1-propyl-6-methoxy-1β, 20,40,8-hexahydroquinoline prepared according to Preparation 3,

solution of a mixture of -propyl-6-methoxy-1,2,3,4,4aR0-hexahydroquinoline and 1-propyl-6-methoxy-1 (20,4,4aS0-hexahydroquinoline in 100 ml of tetrahydrofuran,

Glacial acetic acid (1.7 ml) was added to the solution. Stirring is continued for 30 minutes and the whole is poured into about 300 mL of water. The aqueous mixture was extracted with dichloromethane (3 x 200 mL), the organic layers were combined with dichloromethane and washed once with an equal volume of water and dried. The solvent was evaporated in vacuo and the residual viscous oil was evaporated. 10 g (66%) of trans-dl-1-propyl-6-methoxy-l 00,4,4a, 5,8,8a-octahydro-quinoline, bp .: 70-140 ^° C (0.15 to 000 tON).

Example 2 trans-dl-1-Propyl-6-methoxy-100,4,4a-0,8,8a-octahydroquinolir

The procedure of Example 1 was repeated with 10 g of 1-propyl-6-methoxy-1,2,4,4,8,8-hexahydroquinoline, 1-propyl-6-methoxy-1 hexahydroquinoline mixture in 140 ml of ethanol using 2.19 g of sodium cyanotrihydroborate and 2 ml of hydrochloric acid. 95% yield of trans-dl-1-propyl-6-methoxy-10,3,4,4a0,8,8a-octahydroquinoline is obtained as a product which boils within the same temperature range as the product of Example 1.

Example 3 trans-dl-1-Propyl-6-methoxy-10,4,4a, 5,8,8a-octahydro-lanolin 40 g of 1-propyl-6-methoxy-100,40,8-octahydro-quinoline To a solution of a mixture of 1-propyl-6-methoxy-1,2,4,4aR0-hexahydroquinoline and 1-propyl-6-methoxy-100,4,4aS0-hexahydroquinoline in 140 ml ethanol, 20 ml glacial acetic acid After addition of 102 g of sodium tetrahydroborate, previously dissolved in ⁴⁰ ethanol, was added dropwise. The reaction mixture was cooled and stirred under nitrogen for 16 hours. Trans-dl-1-propyl-6-methoxy-100,4,4a0,8,8a-octaleidroquinoline is

Isolated according to the procedure of Example 1. The product is identical to gn

Yield 82%.

Example 4 Trans-dl-1-Propyl-6-methoxy-10,4,4a -0,8,8a-octahydroquinoline 55

The procedure of Example 3 was followed except that 140 mL of isopropanol was used in place of ethanol. Trans-dl-1-propyl-6-methoxy-10,4,4,4a0.8 in 52% yield,

8a-octahydroquinoline is obtained, which is the same as that obtained in Example 1.

Example 5 trans-dl-1-Propyl-6-methoxyl-100,4,4a, 000a-octahydroquinoline

The procedure of Example 3 is repeated except that 140 ml of methanol are used instead of ethanol. 92% yield of trans-dl-1-propyl-6-methoxy-100,4,4a00,8a-octahydroquinoline is obtained, which is the same as that obtained in Example 1.

Example 6 trans -dl-1-Propyl-6-methoxy-10 -0,4,4a0,8,8a-octahydroquinoline

In the same manner as in Example 3, 40 ml of ethanol were used to dissolve the sodium tetrahydroborate and 100 ml of 20 methanol were used instead of 140 ml of ethanol. 98% yield of trans-dl-1-propyl-6-methoxy-100), 4a, 8,8, 8a-octahydroquinol is obtained which is the same as in Example 1.

_Λ Example 7 trans-dl-1-Propyl-6-methoxy-10 -0,4,4a0,8,8a-octahydroquinoline

The procedure of Example 6 was followed with -θ omitting glacial acetic acid. ^Ου obtained trans-dl-1-propyl-6-methoxy-l-00,4,4a0,8,8a oktalúdro quinoline 89% yield, which is identical with the product prepared in Example 1.

EXAMPLE 8 Trans-dl-1-Propyl-6-methoxy-10-0,4,4a0,80a-octahydroquinoline

According to the procedure of Example 3, a mixture of 10 g of l-propu-6-methoxyhexahydroquinoline, 1.07 g of sodium tetrahydroborate in 40 ml of ethanol, 100 ml of methanol and 20 ml of glacial acetic acid. 99% yield of trans-dl-1-propyl-6-methoxy-100,4,4a0,8,8a-octahydroquinoline is obtained, which is the same as that obtained in Example 1.

Preparation of the active product Example A Preparation of trans-dl-1-propyl-6-oxo-10,4,4a, 5,6,7,8,8a-decahydroquinoline

3.1 g of trans-dl-1-propyl-6-methoxy-100,4,4a, 5,8,8a-octahydroquinoline prepared in Example 1 are dissolved in 25 ml of tetrahydrofuran and 4 ml of 10% aqueous sulfuric acid is added. The resulting biphasic mixture was refluxed for 17 hours, then cooled and extracted with dichloromethane, the dichloromethane extract dried and the solvent evaporated in vacuo. Approximately 2.8 g of residual oil containing t-trans-dl-1-propyl-6-oxo-decahydroquinoline is distilled within 63 to 87 ^{d of} C / 0.1 torr. Thin-41

189,693 chromatography indicated that the product contained more than 90% trans-dl-1-propyl-6-oxodecahydro-4-indine.

Alternatively, 5.0 g of trans-dl-1-propyl-6-methoxy-123.4,4a3,8,8a-octahydrotonoline are dissolved in 50 ml of tetrahydrofuran and 25 ml of aqueous hydrochloric acid 1 N are added and the mixture is stirred under nitrogen at 13 ° C. stir. The reaction mixture was then basified with 14N aqueous ammonium hydroxide solution and the basic mixture was extracted three times with dichloromethane. The organic extracts were combined, dried and the solvent evaporated in vacuo. 43 g of an orange transparent oil are obtained. Thin-layer tomography analysis showed a spotted material, Rf '= 0.67, with little before and after contamination. Distillation (94%) of trans-dl-1-propyl-6-oxo-decahydro-quinoline, 4.39 g, bp .: 77-87 C ⁶ / / 0.025 ton.

As described above, the trans-dl-1-alpha-6-oxo-decahydroquinolines (I) can be reacted with dimethylformamide dimethyl acetate and the trans-dl-1-alpha-7-oxo-7 - [ (dimethylamine o) -methyl] -decahydrotonolines can be prepared. Reaction of this intermediate with sodium glucinate followed by acetic anhydride gives the trans-dl-2-acetyl-5-alpha-4,4a3,6,7,8,8a 9-octahldro-2H-pyrrolo [3,4] -g] quinoline as product. Alkaline hydrolysis of this acetyl derivative leads to the trans-dl-5-alkyl, 4a, 5,6,7,8,8a, 9-octahydropyrrolo [3,4-g] quinolines of formula VIII, which are dopamine antagonists. A compound having a potent activity in the treatment of Parkinson's disease or inhibiting excessive prolactin secretion, and which is disclosed in U.S. Patent No. 4,235,909. U.S. Pat. Alternatively, the 7 - [(dimethylamino) methylene] compound of formula (VI) is reacted with hydrazine and the trans-dl-5-alpha-4,4 to 3,6,7 of formula (Ka and Xb) A mixture of 8,8a-octahydro-1H-pyrazolo [3,4-g] quinoline and its 2H tautomeric isomer, which is also useful as a dopamine antagonist and is described in U.S. Patent No. 4,198,415.

Claims (9)

A process for the preparation of the trans-octahydroquinolines of formula V wherein: R and R ^s are independently selected from the group consisting of C 1 -C 3 alkyl, characterized in that the hexahydrothonoline of formula (TV) wherein R and R ¹ are as defined above, the dotted line is a double bond, MCNBH 3 or MBH 4 agent where M is an alkali metal, reacted in an inert solvent. 2. The method of claim 1, wherein characterized in that sodium (tetrahydroborate) is used as the reducing agent. The method of claim 2, wherein characterized in that methanol or ethanol is used as the inert solvent. 4. A process according to claim 1 wherein the reducing agent is sodium cyanotrihydroborate. 5. A process according to claim 4 wherein the inert solvent is tetrahydrofuran. 6. A process according to any one of claims 1 to 3, characterized in that a mineral acid is present in the reaction mixture. 7. The process of claim 1 wherein glacial acetic acid is present in the reaction mixture. 8. A process according to claim 1 for the preparation of trans-dl-1-propyl-6-methoxy-1,3,4,4a3,8,8a-octahydrotonoline, characterized in that: 1-propyl-6-methoxy-1,2,3,4,8,8-hexahydrotonoline, 1-propyl-6-methoxy-1, 2,3,4,4aR, 5-hexahydroquinoline and A mixture of 1-propyl-6-methoxy-1,2,3,4,4aS3-hexahydroquinoline isomers were reacted with sodium cyano trihydroborate and glacial acetic acid. 9. The process of claim 1 for the preparation of trans-dl-1-propyl-6-methoxy-1,2,3,4,4a, 3,3,8a-octahydrotonoline, characterized in that: 1-propyl-6-methoxy-1,2,4,3,8-hexahydrotonoline, 1-Propyl-6-methoxy-1-2,3,4,4aR 3 -hexahydro-tonolone and A mixture of 1-propyl-6-methoxy-1,2,3,4,4aS3-hexahydroquinoline isomers was reacted with sodium tetrahydroborate and glacial acetic acid.