CN85105805A - Produce the novel method of tricyclic quinoline derivatives - Google Patents

Abstract

By reduction corresponding lactam predecessor, preparation has the method for the tricyclic quinoline of Dopamine HCL stimulant performance.

Description

Produce the novel method of tricyclic quinoline derivatives

The present invention relates to a novel method of producing tricyclic quinoline derivatives, and valuable in the method new intermediate.

US Patent specification 4,198,415; The medical chemistry monthly magazine, 23,481(1980) and JPET, and 224,206(1982) the hypotensive performance of Dopamine HCL stimulant and pyrazoles quinoline one class is disclosed, this derivative can prepare by method of the present invention.

According to the present invention, a kind of method for preparing tricyclic quinoline derivatives is provided, the chemical formula of this derivative is:

Wherein

The base representative:

R wherein ₁And R ₂Be independently hydrogen or C _1-3Alkyl; And R is a hydrogen, C _1-3Straight chained alkyl or allyl group; Or its a kind of on pharmacology receivable salt; This method comprises the reduction lactan, and its chemical formula is:

Wherein to close be trans to the loops of non-aromatic ring, and heterocycle is as defined above with R.

Use a kind of chemical reducing agent, for example diborane or Li-Al hydrogen thing carry out reduction reaction.Reaction can be carried out in temperature is 0 to 100 ℃ of scope, and the temperature of preferentially selecting for use is 20-70 ℃.Typical solvent includes has the inert polar organic solvent to proton, for example tetrahydrofuran (THF) and glycol dimethyl ether.

The ketone of chemistry formula II is new, and is to be provided in another field of invention.

The compound of chemistry formula I is the Dopamine HCL stimulant.

Can prepare the pyrazoles intermediate of chemical formula II by following reaction table look-up.For the purpose of illustrating easily,, a kind of enantiomorph is only described here though reaction produces a kind of racemic product:

Wherein R is H, C _1-3Straight chained alkyl or allyl group, ^*CbZ is the CO-O-benzyl; ^*PCC is a Pyridinium chlorochromate on silica gel.

In the superincumbent chemical formula, the X III has illustrated an amine protecting group to XX, BbZ or benzyloxycarbonyl, but clearly, can use other chemical formula CO-ω protecting group, wherein ω is OC _1-3Alkyl or O-phenyl C _1-2Alkyl.

In the superincumbent synthetic route 1, with cis-1,2,3,6-tetrahydrochysene phthalic acid (X) reacts in sodium hydrogen carbonate solution with iodine and KI, gives birth to cis-(±)-5-iodine perhydro-phthalic acid 2, the 4-cyclic lactone.Handle this derivative with three-just-butyl tin hydride and remove iodo (XII).Next step is at the C of XII _-1Free carboxylic acid group go up with DDPA(diphenylphosphoric acid nitrine) carry out curtius' rearrangement.After the reacting by heating mixture, add phenylcarbinol, produce the amino perhydro phenylformic acid 1 of cis-(±)-6-benzyloxycarbonyl, 3-cyclic lactone (X III).Use alkali then, (what preferentially select for use is the methylate that is dissolved in the sodium in the methyl alcohol) opens lactonic ring, forms methyl cis-(±)-6-benzyloxycarbonyl amino-3-hydroxyl hexahydrobenzoic acid salt (X IV).This secondary alcohol and Jones reagent (being dissolved in the chromium trioxide of dilute sulphuric acid) oxidation generates corresponding 3-oxygen derivative (X V).Next is to have protected this ketone group by ketal formation, as when having acid to have (X VI) by the same with 1,2 ethylidene glycol reaction.Then make this ketone acetal carry out isomerization, preferentially select the methylate that is dissolved in the sodium in the methyl alcohol for use, avoid the transesterification problem with alkali, with produce methyl trans-(±)-6-benzyloxycarbonyl amino-3-ethylene ketal cyclohexane carboxylic acid salt (X VII).Become monohydroxy-alcohol (X VIII) with Li-Al hydrogen thing or other reductive agents reduction methyl esters with similar reducing power then.Then this monohydroxy-alcohol is oxidized to corresponding aldehyde (X IX) with Pyridinium chlorochromate on silica gel, this aldehyde conversely with Wittig reagent, methyl (the positive phosphorus subunit of triphenyl) acetate reacts, produce methyl trans-(±)-3-(2-benzyloxycarbonyl amino-5-second=pure ketal) acetate (XX).By a kind of noble metal catalyst, that commonly used is 5%Pd/C, and hydrogenation reduces acrylate alkene; and disconnect carbon benzyloxy protecting group; generate an intermediate, this intermediate is cyclized into trans-(±)-2 automatically, 6-dioxy-6-ethylene ketal+hydrogen quinoline (X XI).Usually use a kind of alkiodide or allyl halide and the alkali that suits such as the hydride of sodium, make azanylization or allylation on the ring, to generate a kind of N-C _1-3Straight chained alkyl or allyl deriv.Remove by acid treatment then ketal protected, and trans-(±)-2.6-dioxy-1-that produces substituted+hydrogen quinoline and three-dimethylamino methane reaction generation 7-dimethylamino methylene derivatives (XX IV).Generate trans-(±)-5-C with hydrazine reaction _1-3Straight chained alkyl or allyl group-6-oxygen-4,4a, 5,6,7,8,8a, 9-octahydro-1H(and 2H) pyrazoles (3,4-g) quinoline (XX V a and XX V b).The reduction reaction of lactone and Li-Al hydrogen thing or similar reductive agent generates the pyrazole derivatives of chemical formula I.

When R is H, by the cancellation alkylation and carry out remaining program can from the X XI prepare corresponding tautomerism right-remove with acid ketal protected, with three-dimethylamino methylmethane at C _-7The hydrazine seal ring is used in last reaction, then passes through LiAIH ₄The final generation of lactone carbonyl reduction is trans-(±)-4, and 4a, 5,6,7,8,8a, 9-octahydro 1H(and 2H)-pyrazoles (3,4-g) quinoline, III a and III b are when R is H.This tautomerism has the substituent tautomer of a quinoline ring nitrogen to changing into; That is to say, by the standard alkylation process of use alkali and alkyl or allyl halide, the R=methyl, ethyl, just-propyl group or allyl group; Take care and avoid this severe reaction conditions pyrazoles ring also by alkylation.

Above method produce a kind of trans-(±)-racemoid, this compound is that 439,238 disclosed methods can be dissolved by the U.S. Patent application serial number at Ti Tesi and Kang Feite (Titus and Kornfeld), produces 4aR, 8aR and 4aS, the tautomerism of 8aS is right.But the dioxolane derivative thing, X V a and X V b, or corresponding compounds, wherein R is the tautomer that also can be dissolved in its enantiomorph of H, 4aR, 8aR-6-oxygen-4,4a, 5,6,7,8,8a, 9-octahydro-1H(and 2H)-pyrazoles (3,4-g)-quinoline and corresponding 4aS, the 8aS tautomer.

Same, trans-(±)-2 of dicyclo, 6-dioxy-derivative XX III also can be dissolved in its enantiomorph, 4aR, 8aR-2.6-dioxy-5-C _1-3Straight chained alkyl or allyl group-decahydroquinoline and corresponding 4aS, the 8aS derivative.

What therefore each enantiomorph can be independent reacts XX III → XX IV → XX V a+ XX V b → III a+ III b; That is to say, change into 6-oxygen-octahydro-pyrazoles-quinoline, and pass through LiAIH ₄Reduction is removed the oxygen base and is generated 4aR, 8aR-5-just-propenyl-4,4a, 5,6,7,8,8a, 9-octahydro-1H(and 2H)-pyrazoles (3,4-g)-quinoline or corresponding 4aS, the 8aS enantiomorph depends on the 6-oxygen+hydrogen quinoline that has used the sort of enantiomorph, wherein R be just-propenyl.So method that the invention provides racemoid XX V a ()/() XX V b and prepare these two kinds of racemoids and monomer enantiomorph.

Though the method with synthetic route 1 only is to produce racemic modification material, monomeric enantiomorph, 6-oxygen-octahydro-1H(and 2H)-pyrazoles-(3,4-g)-and quinoline, III a and III b, 6-oxygen-octahydro thiazole (4,5-g)-and quinoline, XXX a and XXX b, 6-oxygen-octahydro-oxazoles (4,5-g) quinoline, XX XII and XX XII b and 7-oxygen-octahydro pyrimidine (4,5-g)-quinoline, XXX V a and XXX V c can prepare by taking racemoid apart.Perhaps, by with (+)-or (-)-2, the ketalization of 3-butyleneglycol, the chromatographic separation of diastereomer, the back is to remove ketal to produce a kind of optically-active ketone, can make trans-(±)-1-commutable-2,6-dioxy+hydrogen quinoline, XXX VII a(4aR is 8aR) with XXX VII b(4aS, 8aS)

Dissolving.So can be with binary acid amides (R=H is XXX VII a or XXX VII b) alkylation or the allylation of enantiomorph, and the tertiary amine that produces is cyclized into pyrazoles, thiazole ， oxazole, or have the pyrimidine of a lactam group, and and use LiAIH ₄Reduction lactan direct production D-2 or D-1 Dopamine HCL stimulant.Perhaps the diamine (R=H) of the enantiomorph in XXX VII a or XXX VII b can increase ring, the compound that reduction lactan and allylation or alkylation obtain is used for producing the 4aR of enantiomorph, 8aR or 5aR, the 4aS of 9aR dopamine D-2 stimulant or a kind of enantiomorph, 8aS or 5aS, 9aS dopamine D-1 stimulant.

Perhaps, by the carboxylicesters X IV that synthetic route 1 obtains, the X V, the X VI, the X VII, or XX can hydrogenation generates corresponding carboxylic acid, and carboxylic acid is produced the diastereomer of available chromatograph-type Crystallization Separation with the alkaline purification of optically-active.Therefore the optically-active ester can very fast regeneration by the ester cracking.Compound X VIII also is a kind of alcohol, and this alcohol can be isolated the diastereomer of generation with an optically-active acid estersization, has obtained optically-active alcohols by hydrolytic action.Similarly, protected alpha-amino group ester X IV, the X V, the X VI, X VII and X VIII can be removed protection, with in the optically-active acid and monoamine, separate the salt of diastereomer, reclaim optically active amine by salt, and newly protect amido with identical or different basic weights.

Perhaps, sour XI or XII can be neutralized again by a kind of amine of optically-active with the isolated salt of recrystallization.Acidifying is to prepare for separating optically-active acid.Consult applied chemistry, English second edition, 23(1), and 67(1984): preparation cis-(±)-1,2,3,5-tetrahydrochysene phthalic acid, half acid esters of monomethyl ester and enantiomer separation is produced a kind of enantiomorph of＞94%.

The 4aR of chemical formula II, 8aR-6-oxygen pyrazoles (3,4-g)-quinoline is the meta-bolites of corresponding tautomeric 6-dihydro derivative:

Wherein R is a hydrogen, C _1-3Straight chained alkyl (methyl, ethyl, just-and propyl group) or allyl group, and be trans at the steric configuration of 4a and 8a wherein.

In synthetic route 1, X is a meso-form, is not optically-active, because it has a symmetric plane.XI because it does not have symmetrical plane, is optically-active; Be a cis-(±) or racemize type.But, up to the X IX, have only a quilt of the enantiomorph of cis or trans (according to circumstances) to draw at XI and all successive chemical formulas in order to simplify flow process, comprise a kind of racemoid but be actually.In dicyclo X XI, the X XII, the XX III, the XX IV among XX V a ()/() XX V b and III a ()/() III b, except having prepared unique trans-(±) type, is not given outgoing direction, therefore has only by structural formula and represents these patterns.

Example 1

Cis-(±)-5-iodine perhydro-phthalic acid, 2, the preparation of 4-cyclic lactone

By the cis-1,2,3 of dissolving 17.0 grams in 100 milliliters 10% sodium bicarbonate aqueous solution, 6-tetrahydrochysene phthalic acid prepares a kind of solution.Add KI and I ₂The aqueous solution.These two kinds of solution mix fully, then can place 16 hours in room temperature.Thiosulfuric acid salt brine solution with saturated sodium shakes with reaction mixture then, promptly shows by auburn disappearance and has removed superfluous iodine.With the mixture aqueous solution of ether extracting alkali, and separation and dry ether extract.Evaporation ether obtains a kind of pink residue of heavy 22.3 grams.Ethyl acetate with heat is handled residue, and filters the mixture that produces.Release filtrate with the ethane alkene that diploid is long-pending.Be settled out cis-(±)-5-iodine perhydro-phthalic acid, 2, the tenderly white look needle crystal of 4-cyclic lactone is collected fusing point=161-164 ℃ by filtering.Productive rate is 61%.

Analyze: calculate: C, 32.46; H, 3.06; I, 42.86;

Actual measurement: C, 32.19; H, 2.89; I, 42.68;

Infrared spectra: 3190,1763,1724Cm ^-1

UV spectrum: maximum), 250(ε=620) in 207(ε=330.

Example 2

Cis-(±)-perhydro-phthalic acid; 2, the preparation of 4-cyclic lactone

By 200 milliliters 1, in the 2-glycol dimethyl ether dissolving 60 the gram cis-(±)-5-iodine perhydro-phthalic acids, 2,4 cyclic lactones prepare a kind of solution.In this solution, add 70.8 grams, three-just-butyl tin hydride.Reaction mixture kept 3 days in room temperature, poured into then in the aqueous solution of 10% charcoal acid hydrogen sodium.Then with the ether aqueous solution of this mixture of extracting up hill and dale, and ether extract itself is with 10% charcoal acid hydrogen sodium water solution extracting.Charcoal acid hydrogen salt is combined, uses the spirit of salt acidifying then.New acid layer carries out extracting with a kind of 1: 3 isopropanol/chloroform solvent mixture.Evaporate organic extract and carry out drying, getting one heavily is the solid yellow residue of 34.1 grams.Solid gets 18.6 grams for the first time by the ethyl acetate/hexane recrystallization, gets 10.4 gram white crystals cis-(±)-perhydro-phthalic acids for the second time, and 2, the 4-cyclic lactone.

Example 3

Cis-(±)-2-benzyloxycarbonyl aminocyclohexane carboxylic acid, 1, the preparation of 3-cyclic lactone.

By cis-(±)-perhydro-phthalic acid of dissolving 18.6 grams in 235 milliliters tetrahydrofuran (THF), 2, the 4-cyclic lactone prepares a kind of solution.The triethylamine that adds 12.1 grams inwards.Follow method, add the solution of the diphenyl phosphoryl azides that dissolving 31.6 restrains in 50 milliliters tetrahydrofuran (THF) in room temperature to splash into.About 20 minutes to 30 ℃ in reacting by heating mixture, under reflux temperature about 3 hours then.Then reaction mixture is cooled to room temperature, and in stirring at room all night, adds 12.4 milliliters benzylalcohol.Heat this reaction mixture and kept 3 hours, pour in the water then to refluxing.The aqueous solution of mixture is with methylene dichloride extracting (PH of water liquid layer is approximately 7).Dry organic extract removes remaining a kind of heavy 50.6 water white oils that restrain of volatile component.This irreducible oil is dissolved in the ether, and this real ethereal solution is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel.Initial fraction shows it is nonreactive benzylalcohol.Secondly eluted material is cis-(±)-2-benzyloxycarbonyl aminocyclohexane carboxylic acid, 1, and the 3-cyclic lactone.Obtain the white solid product of 9.5 grams.

Example 4

The preparation of methyl cis-(±)-2-benzyloxycarbonyl amino-5-hydroxyl hexahydrobenzoic acid salt

Sodium kind by dissolving 1.19 grams in 250 milliliters MeOH is equipped with a kind of solution.The second kind of solution that constitutes in the methylene dichloride of 50 milliliters MeOH and 25 milliliters is dissolved in adding by cyclic lactone 14.2 gram of example 3.After dissolving fully, mixture is injected the aqueous solution of the charcoal acid hydrogen sodium of dilution, and with the new mixture of spirit of salt acidifying that waters down.This tart mixture aqueous solution carries out extracting with methylene dichloride, dry extract.Evaporating solvent produces the water white oil that contains methyl cis-(±)-2-benzyloxycarbonyl amino-5-hydroxyl hexahydrobenzoic acid salt of 15.9 grams; Productive rate=about 100%.Nucleus magnetic resonance is consistent with the structure of proposition.

Example 5

The preparation of methyl cis-(±)-2-benzyloxycarbonyl amino-5-oxygen hexahydrobenzoic acid salt

Alcohol by the 15.8 gram examples 4 of dissolving in 400 milliliters acetone prepares a kind of solution.Solution is chilled to about 0 ℃, and in 30 minutes, asks the Jones reagent that wherein adds 12 milliliters with the method for dripping.Thin-layer chromatography shows that the dibasic alcohol complete oxidation generates methyl cis-(±)-2-benzyloxycarbonyl amino-5-oxygen perhydro-benzoate.Isolate established green solid by decant by supernatant liquor.With in the aqueous solution of charcoal acid hydrogen sodium and supernatant liquor material and washes.Neutral solution is crossed diatomite filtration all, and concentrated filtrate.Enriched material is injected water, and with the mixture of the methylene dichloride extracting aqueous solution.Isolate extract, and carry out drying, remove its solvent.Obtain the light color oil (productive rate 100%) that about 15.9 grams contain methyl cis-(±)-2-benzyloxycarbonyl amino-5-oxygen perhydro-benzoate.Nucleus magnetic resonance is consistent with the putative structure of 5-oxygen derivative.

Example 6

The preparation of methyl cis-(±)-2-benzyloxycarbonyl amino-5-ethylene ketal cyclohexane carboxylic acid salt.

Methyl cis-(±)-2-benzyloxycarbonyl amino-5-oxygen hexahydrobenzoic acid salt by 51.5 millimoles, 6.4 the ethylene glycol of gram, a kind of reaction mixture of 100 milligrams right-toluenesulphonic acids-hydrate and the preparation of 250 milliliters benzene, in the equipment that Dean one Rodney Stark steam trap is housed, be heated to and refluxed about 3 hours, collect the water that forms by product as reaction.After having collected the theoretical quantity of water, make reaction mixture reduce to room temperature, keep a night.Then reaction mixture is injected rare charcoal acid hydrogen sodium water solution, and use ether earlier, use methylene dichloride extracting charcoal acid hydrogen sodium layer then.Chemical combination and dry extract, evaporating solvent obtain a kind of desired ketal resistates that contains, weight=17.32 grams.By silica gel chromatography separation and purification ketal, the solvent mixture that uses a kind of 2: 1 ether/hexane is as elutriant.Early stage fraction is 14.61 grams.The pink oil of methyl cis-(±) of the containing purifying-2-benzyloxycarbonyl amino-5-ethylene ketal cyclohexane carboxylic acid salt a little less than a kind of, its productive rate is 81.5%.

Example 7

Methyl cis-(±)-2-benzyloxycarbonyl amino-5-ethylene ketal hexahydrobenzoic acid salt isomerization generates trans accordingly-(±) derivative

Sodium by 960 milligrams of addings in 200 milliliters methyl alcohol is prepared a kind of sodium methoxide solution in methyl alcohol.Add 14.5 methyl cis-(±)-2-benzyloxy amino-5-ethylene ketal perhydro-benzoates that restrain, and mixture was refluxed 2 3/4 hours.Thin-layer chromatographic analysis has shown the equilibrium mixture of a kind of cis and trans racemic modification.This reaction mixture is injected in rare spirit of salt, with this acidic mixture of methylene dichloride extracting.Isolate organic extract, and carry out drying.Evaporating solvent obtains a kind of irreducible oil, weight=14.8 grams.Ether/hexane with 2: 1 is made elutriant, makes oil carry out chromatographic separation through silica gel.Early stage fraction shows, is the mixture of 5: 2 trans and cis-isomeride.Concentrating the fraction of back is near pure trans racemic modification by the thin-film chromatography analysis revealed, weight=8.4 grams.

Example 8

The preparation of trans-(±)-2-benzyloxy amino-5-ethylene ketal hexahydrobenzyl alcohol

To in 75 milliliters of ethers, contain 8.4 gram methyl trans-(±)-2-benzyloxycarbonyl amino-a kind of solution of 5-ethylene ketal cyclohexane carboxylic acid salt is added in 225 milliliters of ethers and contains 910 milligrams LiAIH ₄Solution in.At the stirring at room reaction mixture about 10 minutes, show at thin-layer chromatographic analysis during this period of time not stay hyle.By the water by 0.9 milliliter of the adding of order, the water of 0.9 milliliter 15% sodium hydroxide and 2.7 milliliters makes reaction decomposes.The reaction of decomposing is crossed and is filtered to remove inorganic salts.Concentrate organic layer in the air at it.Obtain a kind of yellow oil of 4.47 grams.Make elutriant with ether and oil carried out chromatographic separation, obtain containing the 2.39(31% of trans-(±)-2-benzyloxycarbonyl amino-5-ethylene ketal hexahydrobenzyl alcohol of purifying through silica gel) water white oil.

Example 9

The preparation of trans-(±)-2-benzyloxycarbonyl amino-5-ethylene ketal cyclohexyl aldehyde

Make a kind of solution by dissolving in 150 milliliters methylene dichloride by the methyl alcohol thing that example 8 makes.Add 10 gram Pyridinium chlorochromate on silica gel, and at the violent stirred reaction mixture of room temperature about 2 hours.The ether that adds equal volume.Isolate the supernatant liquor of generation, and separate through a silicagel column flash chromatography.With the solid residue several that ether and dichloromethane rinse obtain from reaction, this rinsing is also by quick silicagel column.Concentrate eluant gets a resistates; All bonded resistates=about 2.1 restrain desirable trans-(±)-2-benzyloxy carboxyamino-5-ethylene ketal cyclohexyl aldehyde of (productive rate 88%).

Example 10

Trans-(±)-2,6-dioxy+hydrogen quinoline, the preparation of 6-ethylene ketal

Produce a kind of reaction mixture by 1.6 grams of dissolving in 40 milliliters of benzene by aldehyde and 2.5 methyl (the positive phosphorus Ji Yaji of the triphenyl) acetates that restrain that example 9 makes.Heat this reaction mixture about 19 hours, concentrate in a vacuum then to reflux temperature.Show the resistates that does not have aldehyde by thin-layer chromatography, make elutriant with ether and carry out chromatographic separation through silica gel that first product that comes out from pillar is desirable acrylate, this acrylate is a kind of colourless oil, weight=1.3 grams.(70% productive rate).

Prepare a kind of solution by the acrylate above 1.30 grams of dissolving in 100 milliliters MeOH.Add 135 milligrams 5%Pd/C, and under the atmosphere of hydrogen, make hydrogenation mixture by violent slurry.After half an hour, add 250 milligrams of catalyzer, under there is situation in hydrogen, make mixture add one hour slurry.Thin-layer chromatography shows when the material that does not begin exists, and filters to isolate catalyzer, and concentrated filtrate gets a kind of muddy oil, the curing when storage of this oil.The mixture of thin-layer chromatography has shown a kind of+hydrogen quinoline, the product of cyclisation and the compound of non-cyclisation, methyl is trans-(±)-3-(2-amino-5-ethylene ketal cyclohexyl) propionic salt.Product is dissolved in 200 milliliters the tetrahydrofuran (THF), and heated solution was to reflux temperature 2 hours.Solvent evaporates in a vacuum, and resistates is made elutriant with tetrahydrofuran (THF), carries out chromatographic separation through silica gel.Trans-(±)-2 of containing purifying that fraction 6-13 output is 429 milligrams, the white solid of 6-2 oxygen-6-ethylene ketal+hydrogen quinoline.

Example 11

Trans-(±)-2, the preparation of 6-dioxy+hydrogen quinoline

A kind of solution of making of ketal of 40 milligrams of examples 10 of dissolving in 5 milliliters formic acid, in stirring at room about 30 minutes.At this moment, thin-layer chromatography shows that the ketal effect virtually completely disappears.Therefore concentrated reaction mixture gets 35 milligrams white solid in a vacuum.With this solid on silica gel with 1: 19MeOH/CH ₂CI ₂Elutriant to start with is then with 1: 9MeOH/CH ₂Cl ₂Elutriant carries out chromatographic separation.The fraction of second kind of elutriant of the usefulness of back (fraction 6-15) produces 33 milligrams trans-(±)-2,6-dioxy+hydrogen quinoline.This compound has following physicals: mass spectrum: ion is 167,111, and 110,97,84 and 56.Infrared spectra (CHCI ₃): 3400,1716,1661Cm ^-1

Example 12

Trans-(±)-6-oxygen-4,4a, 5,6,7,8,8a, 9-octahydro-1H(and 2H)-preparation of pyrazoles (3,4-g) quinoline

In 10 milliliters of warm toluene, dissolve 168 milligrams trans-(±)-2,6-dioxy+hydrogen quinoline is prepared a kind of solution, three (dimethylamino) methane that adds 0.4 milliliter, and the reacting by heating mixture is to reflux 2.5 hours (beginning to occur a kind of white solid 1.5 hours the time).Reaction mixture is cooled to room temperature, filters then.Collect trans-(±)-2,148 milligrams of 6-dioxies-7-dimethylamino methylene+hydrogen quinoline.

Derivative above three milligrams is dissolved in 0.5 milliliter and contains among the MeOH that adds an anhydrous hydrazine.At the stirring at room reaction mixture about 2 hours, water watered down then.Water is by CH ₂CI ₂Extracting, and dry extract.Removing solvent gets 2 milligrams and contains in the above trans-(±)-6-oxygen-4 that generate in the reaction, 4a, 5,6,7,8,8a, 9-octahydro-1N-(and 2H)-white solid of pyrazoles (3,4-) quinoline.The nucleus magnetic resonance of product is consistent with the structure of proposition.

This compound can be used LiAIH ₄Reduction produces tautomerism right, trans-(±)-4,4a, 5,6,7,8,8a, 9-octahydro-1H(and 2H)-pyrazoles (3,4-g) quinoline, a kind ofly prepare the anti-depressant useful as intermediates of dopamine D-2 by alkylation or allylation to quinoline ring nitrogen with standard method.

Example 13

Trans-(±)-1-just-propyl group-2, the preparation of 6-dioxy+hydrogen quinoline

By trans-(±)-2 of 390 milligrams of examples 10 of dissolving in 15 milliliters tetrahydrofuran (THF), 6-dioxy-6-ethylene ketal+hydrogen quinoline prepares a kind of solution.This solution joined in 150 milligrams the suspension of sodium hydride in 5 milliliters tetrahydrofuran (THF).Stirring at room reaction mixture 1 hour, add simultaneously 2 milliliters of dimethyl formamides and 0.9 milliliter just-propyl iodide.This new reaction mixture of stirring at room 22 hours, this moment, thin-layer chromatography showed reaction completely dissolve in fact.Reaction mixture is injected water, with 1: 3 aqueous mixture of isopropanol/chloroform extracting.Isolate extract, remove the yellow oil that its solvent obtains 575 milligrams.Oil as elutriant, obtains following result with 5: 4 tetrahydrofuran (THF)/pentanes through the chromatographic separation of silica gel: trans-(±)-1-that early stage fraction (3-5) must 461 milligrams (productive rates 86%) just-propyl group-2,6-dioxy-6-ethylene ketal+hydrogen quinoline.By the method for example 11, remove ketal group with formic acid, produce trans-(±)-1-just-propyl group-2,6-dioxy+hydrogen quinoline.Obtain the productive rate of dioxolane derivative thing 91%.Compound has following physicals: mass spectrum: ion is 209,180, and 152,139,124,110.

With methyl-iodide or iodoethane, or chlorallylene replace to go up in the example just-propyl iodide, produce trans accordingly-(±)-5-methyl at last, ethyl or allyl group-2,6-dioxy+hydrogen quinoline.

Example 14

Trans-(±)-5-just-propyl group-6-oxygen-4,4a, 5,6,7,8,8a, 9-octahydro-1H(and 2H)-preparation of pyrazoles (3,4-g)-quinoline

The then method of example 12, trans-(±)-1-just-propyl group-2,6-dioxy+hydrogen quinoline and three (dimethylamino) methane reaction generates corresponding 7-dimethylamino methylene derivatives.This compound and anhydrous hydrazine react successively, generate trans-(±)-5-just-propyl group-6-oxygen-4,4a, 5,6,7,8,8a, 9-octahydro-1H(and 2H)-pyrazoles (3,4-g)-quinoline, overall yield is 70%.Trans-(±)-1-just-propyl group-6-oxygen-7-dimethylamino methylene+hydrogen quinoline has following physicals:

Mass spectrum: ion is 264,219, and 152,150,125,112,110,82.Infrared spectra: 3465,1624Cm ^-1

Top 6-oxygen derivative and LiAIH ₄Reductive action generate trans-(±)-5-just-propyl group-4,4a, 5,6,7,8,8a, 9-octahydro-1H(and 2H)-pyrazoles (3,4-g)-quinoline.

Though top synthetic method produce trans-(±)-5-just-propyl group-6-oxygen-4,4a, 5,6,7,8,8a, 9-octahydro-1H(and 2H)-pyrazoles (3,4-g) quinoline finishes, the intermediate of example 13 is trans-(±)-1-just-propyl group (or methyl, ethyl or allyl group)-2,6-dioxy+hydrogen-quinoline, or the 1-of corresponding example 11 can not generate with bromine reaction-the 7-br-derivatives by the metathetical derivative, and the sort of intermediate and chemical formula are

Isothiourea reaction, R wherein ¹And R ²Each base is respectively a hydrogen, methyl, ethyl or just-propyl group.

The product of this reaction be one racemic trans-(±)-7-amino (NR ¹R ²)-5-is commutable-6-oxygen-4, and 4a, 5,6,7,8,8a, 9-octahydro-thiazole (4,5-)-quinoline is made up of following enantiomorph XXX a and XXX b, or generates or XXX a or XXX b with a kind of beginning thing of enantiomorph

R wherein ¹And R ²Have the implication before their, and R is H, methyl, ethyl, just-propyl group or allyl group.

Therefore 6-oxygen base can with chemical reducing agent LiAIH for example ₄The reduction generation is disclosed in Titus and KornfeId goes up (U.S. Patent application serial number 604,687) racemic or enantiomorphous dopamine D-2 stimulant, the commutable octahydro thiazole (4 of trans-(±)-2-amino-5-, 5-g)-quinoline XX XI a(4aR, 8aR) with XX XI b(4aS, 8aS).

In XX XI a and XX XI b,, quinoline azanylization or allylation could must be got Dopamine HCL stimulant (D-1 or D-2) if R is H.Since obtaining the cyclic action of thiazole ring carries out on 6-bromo-5 oxygen+hydrogen quinoline, since handling also, bromination can react with a kind of 1-allyl deriv, produce this allylic cpd, just would rather select for use bromine to handle trans-(±)-1-unsubstituted 2,6-dioxy+hydrogen quinoline, produce 6-oxygen thiazole (4,5-g)-quinoline with different stream urea cyclisation bromo derivative, use LiAIH ₄Remove 6 oxo bases, on N-5, carry out allylation then, get N-allyl group Dopamine HCL stimulant.Perhaps, LiAIH ₄Reduction and the order of N-5 alkylation step be reversible.

Same, trans-(±)-1-is commutable-2,6-dioxy-7-bromo+hydrogen quinoline or its 4aR, and 8aR or 4aS, the enantiomorph of 8aS and chemical formula are

The reaction of isourea produce a kind of racemic trans-(±)-2-amino-S-is commutable-6-oxygen-4,4a, 5,6,7,8,8a, 9-octahydro (4,5-g)-and quinoline, structural formula is XX XII a(4aR, 8aR) and XX XII b(4aS, 8aS) or its independent enantiomorph.

Racemic modification or at will that enantiomorph and chemical reducing agent, for example LiAIH ₄Reduction generate+Qing oxazoles (4,5-g)-quinoline that 2-amino-5-of U.S. Patent application serial number 637,232 replaces, structural formula is XXX III a(4aR, 8aR) or XXX III b(4aS, 8aS)

Wherein R is H, C _1-3Straight chained alkyl or allyl group.

Situation as thiazole, when R is allyl group, according to the preparation of XXX III a or XXX III b compound preferably by allylation 2-amino-6-oxygen-octahydro-oxazoles (4,5-g)-quinoline (XX XII a and XX XII b) carries out, reduce N-allyl group lactan or then by the final De oxazole (4 of allylation, 5-g)-quinoline (XXX III a and XXX III b are when R is H).

Racemic modification (making by synthetic route 1) or its enantiomorph and guanidine or monobasic guanidine (

) to generate chemical formula be XXX V a(5aR in reaction, 9aR) and XXX V a(5aS, the commutable octahydro pyrimidine of 7-oxygen-6-9aS) (4,5-g)-quinoline

Wherein R is H, C _1-3Straight chained alkyl or allyl group, R ₁And R ₂Have their implications in the past.With chemical reducing agent LiAIH for example ₄The reduction lactan, when R is H, the back connects alkylation or allylation arbitrarily, generate effective dopamine D-2 stimulant, racemic modification and 5aR, 9aR enantiomorph, XXX VI a and D-1 stimulant, enantiomorph XXX VI b(is in D-1 and D-2 stimulant, and R is not H) be described in the GB Patent Application No. 8421160.

Example 15

Trans-(±)-5-just-propyl group-4,4a, 5,6,7,8,8a, 9-octahydro-1H(and 2H)-preparation of pyrazoles (3,4-g)-quinoline

To be dissolved in the tetrahydrofuran (THF) (2.5 milliliters) trans-(±)-5-just-propyl group-6-oxygen-4,4a, 5,6,7,8,8a, 9-octahydro-1H(and 2H)-pyrazoles (3,4-g)-quinoline (17 milligrams) is added in the suspension of Li-Al hydrogen thing (19 milligrams) in tetrahydrofuran (THF) (5.0 milliliters).Stirring at room reaction mixture 3 hours, make its quenching by adding 15% NaOH solution.The vigorous agitation reaction mixture is 18 hours then, and filtering and concentrating gets 13 milligrams of water white oils.This material is being used the CH that contains 15% methyl alcohol on the silicagel column fast ₂CI ₃And ammonium hydroxide (vestige) carries out chromatographic separation as solvent.The isolating material of chromatogram is being identified aspect being necessary with reliable guinpirole.

Example 16

To-Diaion Hp-20 pillar injection monkey urine, dosage is 5 milligrams/kilogram (or 20 milligrams/kilogram) ¹⁴C-4aR, 8aR-5-just-propyl group-4,4a, 5,6,7,8,8a, 9-octahydro-1H(and 2H)-pyrazoles (3,4-g)-quinoline, wash pillar with water till in elutriant, finding radioactivity.Use methanol-eluted fractions radioactivity (average out to 94%) then.Then evaporating the methyl alcohol fraction stays radioactivity in the remaining fraction and selectively dissolves in (methyl alcohol in the minimum volume of different solvents, ethanol, and ethanol, this processing of ethyl acetic acid salt (2: 1) causes the precipitating action of endogenous substance, and radioactivity is concentrated in the methyl alcohol of a small volume to be suitable for doing thin-layer chromatography separation (chloroform/methanol/15N sodium hydroxide (50: 45: 5)) on the silica gel sheet.The radio-autograph of the thin slice chromatogram sheet that flushes out looks like to demonstrate 5 broadbands.From the zone that sheet is scraped the corresponding band of collection, collect thing elution radioactivity metabolite with methyl alcohol by scraping, and eluant vapourisation under reduced pressure drying.

Will be by thin-layer chromatography band (R _f=0.58-0.85) radioactive substance of elution is dissolved in the deionized water, and pH is transferred to about 12 with the 0.01N NaOH aqueous solution.The extracting of desirable radioactivity metabolite is become ethyl acetic acid salt.Evaporation bonded ethyl acetic acid salt extract generates a kind of resistates that dissolves in 0.001NHCI.

With the acid water layer of ethyl acetic acid salt extracting, and abandon ethyl acetic acid salt extract, with 5N NaOH the PH of water layer is transferred to then about 12, and the extracting of radioactivity metabolite in ethyl acetic acid salt.Dry this ethyl acetic acid salt extract of vapourisation under reduced pressure, the resistates of generation dissolves in the deionized water.High efficiency liquid chromatography solvent systems below this water layer injected: 100% water-5 minute; 0-100% methyl alcohol-37.5 minute, flow velocity is that 2 ml/min are (with a general C ₈, 10 μ pillars).It is right that this method produces tautomerism, 4aR, 8aR-6-oxygen-4,4a, 5,6,7,8,8a, 9-octahydro-1H(and 2H)-pyrazoles (3,4-g)-quinoline, be essentially pure material.To use that identical solvent systems is graceful with a kind of watt, crust is loved and respect one's elder brother western 5 by high efficiency liquid chromatography, ODS-3, and the RAC post is further purified product.

The compound of purifying has following physicals like this:

Mass spectrum: (field desorption(FD)); Molion is 191; (high resolving power electronic impact) 191(molion), 119.94

Infrared spectra: (CHCI ₃) 1660Cm ^-1(lactan carbonyl)

Nucleus magnetic resonance (CDCI ₃) δ is at 7.34(H ₃) ,～2.5(H4aX), 2.89(N4eq), 3.41(H4a)～2.5(H7aX)～2.6(H7eq), 1.70(H8aX), 2.05(H8eq), 1.90(H8a) ,～2.4(H9aX), 2.99(H9eq).

Use identical as top (R _f=0.58-0.85) thin-film chromatography is dissolved in radioactive substance in the NaOH aqueous solution of 0.1N, and the radioactive substance extracting in ethyl acetic acid salt.With 0.001NHCI washing ethyl acetic acid salt extract.The NaOH aqueous solution with 1N is transferred to neutrality to the PH of acid water layer.The aqueous solution of extract is injected in the following high efficiency liquid chromatography system: 100% water 5 minutes; The methyl alcohol of 0-100% 37.5 minutes, flow velocity are 2 ml/min (watt is graceful, crust is loved and respect one's elder brother west 5, ODS-3, RAC pillar).This method is produced tautomerism to 4aR, 8aR-5-just-propyl group-6-oxygen-4,4a, 5,6,7,8,8a, 9-octahydro-1H(and 2H)-pyrazoles (3,4-g)-quinoline.

Solution system below using, but identical pillar are further purified product by high efficiency liquid chromatography: 100% water-7 minute, and the methyl alcohol of 0-60%-20 minute, flow velocity is 2 ml/min.The compound of purifying has following physicals like this:

Mass spectrum (field desorption(FD)): molion is 233, (high resolving power electronic impact) 233(molion), 204,190,176,119,94.

Infrared spectra (CHCI ₃): 1626Cm ^-1(lactan carbonyl)

Nucleus magnetic resonance (CDCI ₃): δ is at 7.37(H ₃) 3.21(H4Gq), 2.39(H4eX), 3.34(H4a), 2.56(7eq), 2.48(H7aX), 1.94(H8eq), 1.63(H8aX), 1.94(H8a), 2.97(H9eq), 2.48(H9aX), 3.75 and 3.23(H10), 1.71 and 1.50(H11), 0.92(H12).

Example 17

Trans-(±)-2-amino-7-oxygen-5,5a, 6,7,8,9,9a, the preparation of 10-octahydro pyrimidine (4,5-g)-quinoline

Trans-(±)-2,6-dioxy-7-dimethylamino methylene+hydrogen quinoline (28 milligrams) is dissolved in the ethanol (6 milliliters), and adds 120 milligrams of guanidine charcoal hydrochlorates).Heat this mixture to refluxing 1 1/3 hours,,, and filter this subject purpose compound (22 milligrams) of producing a kind of white powder then with the reaction mixture cool to room temperature so generate a kind of throw out.

Mass spectrum m/e218(100), 219(30).

Example 18

Trans-(±)-2-amino-5,5a, 6,7,8,9,9a, the preparation of 10-octahydro pyrimidine (4,5-g)-quinoline

With trans-(±)-2-amino-7-oxygen-5,5a, 6,7,8,9,9a, 10-octahydro pyrimidine (4,5-g)-quinoline is suspended in (7 milliliters) in the tetrahydrofuran (THF), and is heated to backflow.Li-Al hydrogen thing (9 milligrams) is added in the suspension, with reaction mixture refluxed heating 3 hours.Make the stopping of reaction by the NaOH solution that adds 2 15%, the vigorous stirring reaction mixture is 17 hours then.Filter reaction mixture, the solid that leaches is handled with 1: 1 methanol of boiling.Leach this mixture, spissated chemical combination filtrate produces a kind of this subject purpose crude product (8 milligrams) of white solid.

On quick silicagel column, with containing vestige NH ₄The methyl alcohol of OH carries out chromatographic separation as elutriant to the part of crude product.The fraction that contains desirable pure substance carries out chemical combination, obtains a kind of white solid (1 milligram).

m/e204（100），205（15）。

Example 19

Use these example 17 described above and 18 similar methods, can prepare trans-2-amino-6-just-propyl group-5,5a, 6,7,8,9,9a, 10-octahydro pyrimidine (4,5-g)-quinoline.

Claims (3)

1, the preparation chemical formula is

A kind of tricyclic quinoline derivatives:

Wherein

The base representative:

R wherein ₁And R ₂Be independently hydrogen or C _1-3Alkyl; And R is a hydrogen, C _1-3Straight chained alkyl or allyl group; Or its a kind of on pharmacology receivable salt, this method comprise the reduction chemical formula be

Lactan, it is trans that the loops of non-aromatic ring closes.

2, according to the process of claim 1 wherein

Representative

And R is hydrogen or C _1-3Straight chained alkyl.

3, according to the method for claim 1 or 2, wherein carry out reductive action with the Li-Al hydrogen thing.