CN1241998A - Synthesis of benzo (F) quinolinones - Google Patents
Synthesis of benzo (F) quinolinones Download PDFInfo
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- CN1241998A CN1241998A CN 97180985 CN97180985A CN1241998A CN 1241998 A CN1241998 A CN 1241998A CN 97180985 CN97180985 CN 97180985 CN 97180985 A CN97180985 A CN 97180985A CN 1241998 A CN1241998 A CN 1241998A
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Abstract
A process for preparing intermediates and benzoquinolin-3-one pharmaceuticals is provided, such pharmaceuticals are effective in treating conditions consequent on 5 alpha -reductase.
Description
The invention belongs to the category of organic chemistry, pharmaceutical chemistry and chemical production, and for preparation provides a kind of convenience, economic method as benzo [f] quinolinone of 5 inhibitor, and provide midbody compound for the preparation of this class medicine.
The active field of pharmacology research at present is the inhibition of 5, and this enzyme is converted into dihydrotestosterone (a kind of male hormone that has more effectiveness) with testosterone.Proved that now the 5 inhibitor can stop the formation of dihydrotestosterone and can improve many very bothersome diseases, comprises male pattern baldness and benign prostatauxe.Audia etc. disclose a series of benzo [f] quinolinone compounds of 5 inhibitor that are.See: U.S. Patent number 5,239,075 and 5,541,190; Tet.Let., 44,7001 (1993); J.Med.Chem., 36,421 (1993) and European Patent Publication No 0703221.
The present invention is that benzo [f] quinolinones compound that is prepared as effective 5 inhibitor provides a kind of new method.Present method has method more efficient more earlier, is suitable for large-scale synthesizing, and has avoided the formation of unwanted by product.The present invention also provides midbody compound for the preparation of this class medicine.
The present invention provides a kind of new method for preparing benzo [f] quinolinone, and the intermediate that is used to prepare benzo [f] quinolinones compound is provided.More particularly, the present invention relates to prepare the method for following formula I compound
R wherein
1Representative: 2-nitrophenyl, the 4-nitrophenyl, the 2-cyano-phenyl, the 4-cyano-phenyl, 2-nitro naphthyl, 4-nitro naphthyl, 2-cyano group naphthyl, 4-cyano group naphthyl, the 2-quinolyl, the 4-quinolyl, the 7-quinolyl, the 1-isoquinolyl, the 3-isoquinolyl, the 8-isoquinolyl, the 2-quinoxalinyl, the 2-[4-morpholinodithio base, the 3-1H-indazolyl, the 2-benzoxazolyl, 3-1,2-benzisothiazole base, the 2-pyridyl, the 4-pyridyl, the 2-pyrazinyl, 2-naphtho-[2,3-d] thiazolyl, 2-naphtho-[1,2-d] thiazolyl, the 9-anthryl, the 2-thiazolyl, the 2-benzimidazolyl-, 1-benzo [g] isoquinolyl, 8-benzo [g] isoquinolyl, the 5-1H-tetrazyl, the 2-quinazolyl, 2-thiazole also [4,5-b] pyridyl, 4-10H-pyridazine also [3,2-b]-the 2-quinazolyl, 2-1,4-benzo two oxine bases (benzodioxinyl), the 2-triazine, the 2-benzoxazine, the 4-benzoxazine, 2-purine or 8-purine; Wherein above-mentioned R
1Group is unsubstituted or replaces with 1-3 functional group that described functional group is selected from trifluoromethyl, trifluoro ethoxy, C
1-C
4Alkyl, trifluoromethoxy, hydroxyl, C
1-C
3Alkoxyl group, nitro, C
1-C
3Alkylthio, C
1-C
6Alkanoyl, phenyl, oxo, phenoxy group, thiophenyl, C
1-C
3Alkyl sulphinyl, C
1-C
3Alkyl sulphonyl, cyano group, amino, C
1-C
3Alkylamino, diphenylmethyl amino, triphenyl methylamino-, benzyloxy, benzylthio-, (list-halo, nitro or CF
3) benzyl (oxygen base or sulfo-), two (C
1-C
3Alkyl, C
3-C
6Cycloalkyl or C
4-C
8Cycloalkylalkyl) amino, (list-C
1-C
3Alkyl, C
1-C
3Alkoxyl group or halo) (phenyl, phenoxy group, thiophenyl, benzenesulfonyl or phenoxy group alkylsulfonyl), C
2-C
6Alkanoyl amido, benzamido, diphenylmethyl amino (C
1-C
3Alkyl), aminocarboxyl, C
1-C
3Alkyl amino-carbonyl, two (C
1-C
3Alkyl) aminocarboxyl, halo-C
1-C
6Alkanoyl, amino-sulfonyl, C
1-C
3Alkylamino alkylsulfonyl, two (C
1-C
3Alkyl) amino-sulfonyl, phenyl (oxygen base or sulfo-) (C
1-C
3Alkyl), (halo, C
1-C
3Alkyl or C
1-C
3Alkoxyl group) phenyl (oxygen base or sulfo-) (C
1-C
3Alkyl), benzoyl or (amino, C
1-C
3Alkylamino or two (C
1-C
3Alkyl) (C amino)
1-C
3Alkyl).
One aspect of the present invention comprises: with the ketone of following formula
Wherein R is a halogen, is preferably bromine or iodine; Be converted into protected ketone acetal, preferably in methylene dichloride, use TMS fluoroform sulfonyl ester and 1,3-pair-trimethyl silicane alcoxyl base propylene glycol; Make described protected ketone acetal and active alkyl lithium compounds (as just-butyllithium) and sulfur transfer additive (as methyl-sulfide) reaction, obtain the methylated ketal compound of S-; And the methylated ketal compound of described S-is gone protection, obtain methyl-sulfo-Tetralone an intermediate of Sertraline compound of formula II
Another aspect of the present invention comprises the compound of preparation formula II
By making the compound of following formula
With the di-isopropyl lithamide, just-reaction of butyllithium and methyl-sulfide, perhaps by compound with formula XI
Be converted into carboxylic acid halides, for example acyl chlorides; Make described acyl chlorides and Lewis acid and ethylene reaction subsequently, obtain the compound of described formula II.
According on the other hand, the present invention includes the compound that the compound of described formula II is converted into described formula I.A kind of like this preferable methods comprise the compound that makes described formula II with (R)-(+)-the phenylethylamine reaction, obtain the compound of following formula III:
Make the compound and strong lithium alkali reaction of described formula III, obtain the lithium enamine compound of following formula I V
The lithium enamine product of described formula IV is methylated becomes the compound of described formula V, for example, by make the reaction of described lithium enamine product and methyl-iodide in ether solvents, prepares the compound of described formula V
Make compound and carboxylic acid halides or the acrylic anhydride reaction of described formula V, prepare the compound of described formula VI
With this reactant of alkaline quench, and mix with suitable silane and trifluoroacetic acid, prepare the compound of described formula VII at the resistates that does not have to contain under the situation of solvent described formula VI compound
Compound and the methyl halogenide (as methyl-iodide) of described formula VII are reacted in containing organic solvent and alkaline reaction mixture, obtain the arylmethyl sulfide of described formula VIII
With the compound oxidation of described formula VIII is the sulfoxide compound of formula IX
Make sulfoxide compound and the acylation reaction of described formula IX, obtain the Pummerer rearrangement product; Make the reaction of described Pummerer rearrangement product and electrophilic reagent, this electrophilic reagent is selected from A-R
1, wherein A is a leavings group, R
1Representative: 2-nitrophenyl, the 4-nitrophenyl, the 2-cyano-phenyl, the 4-cyano-phenyl, 2-nitro naphthyl, 4-nitro naphthyl, 2-cyano group naphthyl, 4-cyano group naphthyl, the 2-quinolyl, the 4-quinolyl, the 7-quinolyl, the 1-isoquinolyl, the 3-isoquinolyl, the 8-isoquinolyl, the 2-quinoxalinyl, the 2-[4-morpholinodithio base, the 3-1H-indazolyl, the 2-benzoxazolyl, 3-1,2-benzisothiazole base, the 2-pyridyl, the 4-pyridyl, the 2-pyrazinyl, 2-naphtho-[2,3-d] thiazolyl, 2-naphtho-[1,2-d] thiazolyl, the 9-anthryl, the 2-thiazolyl, the 2-benzimidazolyl-, 1-benzo [g] isoquinolyl, 8-benzo [g] isoquinolyl, the 5-1H-tetrazyl, the 2-quinazolyl, 2-thiazole also [4,5-b] pyridyl, 4-10H-pyridazine also [3,2-b]-the 2-quinazolyl, 2-1,4-benzo two oxine bases, the 2-triazine, the 2-benzoxazine, the 4-benzoxazine, 2-purine or 8-purine; Wherein above-mentioned R
1Group is unsubstituted or being selected from following group with 1-3 replaces: trifluoromethyl, trifluoro ethoxy, C
1-C
4Alkyl, trifluoromethoxy, hydroxyl, C
1-C
3Alkoxyl group, nitro, C
1-C
3Alkylthio, C
1-C
6Alkanoyl, phenyl, oxo, phenoxy group, thiophenyl, C
1-C
3Alkyl sulphinyl, C
1-C
3Alkyl sulphonyl, cyano group, amino, C
1-C
3Alkylamino, diphenylmethyl amino, triphenyl methylamino-, benzyloxy, benzylthio-, (list-halo, nitro or CF
3) benzyl (oxygen base or sulfenyl), two (C
1-C
3Alkyl, C
3-C
6Cycloalkyl or C
4-C
8Cycloalkylalkyl) amino, (list-C
1-C
3Alkyl, C
1-C
3Alkoxyl group or halo) (phenyl, phenoxy group, thiophenyl, benzenesulfonyl or phenoxy group alkylsulfonyl), C
2-C
6Alkanoyl amido, benzamido, diphenylmethyl amino (C
1-C
3Alkyl), aminocarboxyl, C
1-C
3Alkyl amino-carbonyl, two (C
1-C
3Alkyl) aminocarboxyl, halo-C
1-C
6Alkanoyl, amino-sulfonyl, C
1-C
3Alkylamino alkylsulfonyl, two (C
1-C
3Alkyl) amino-sulfonyl, phenyl (oxygen base or sulfo-) (C
1-C
3Alkyl), (halo, C
1-C
3Alkyl or C
1-C
3Alkoxyl group) phenyl (oxygen base or sulfo-) (C
1-C
3Alkyl), benzoyl or (amino, C
1-C
3Alkylamino or two (C
1-C
3Alkyl) (C amino)
1-C
3Alkyl); In the presence of phase-transfer catalyst, hydride reducer and alkali, the compound of preparation formula I.
According to a further aspect in the invention, the compound of described formula VIII
Preparation by the following method, this method comprises the compound that makes described formula XII
Reaction mixture reaction with containing alkali (as di-isopropyl lithamide or hexamethyl two silicon Lithium Azides) and ether solvents obtains acid amides-enolate solution; Make the reaction of described acid amides-enolate solution and alkyl lithium compounds, obtain the dianion compound of following formula
Make the reaction of described dianion compound and methyl-sulfide, obtain the arylmethyl sulfide of described formula VIII.
Described preferred intermediate of the present invention has the compound of following formula II, VI and VIII or their salt:
The raw material for preparing the compound in the method for claim both can as known in the art, also can prepare by methods known in the art through commercially available acquisition, as, United States Patent (USP) 5,239,075 (authorizing) and European patent publication 0703221 referring to Audia etc. on August 24th, 1993.
In the text, will represent all temperature with degree centigrade, except as otherwise noted, the phraseology of concentration, percentage and ratio all will be represented with weight unit, and the mixture of solvent will be represented with volume unit.
Except as otherwise noted, the compound of mentioning herein comprises the pharmacy acceptable salt of this compound.
Each position on benzo [f] quinoline ring is expressed as follows:
The sterie configuration and the hydrogen atom on the 4a of the group on the 10b are essential.The reader is appreciated that many described compounds can exist with two or more stereochemical forms, and has comprised all these stereochemical forms in the present invention.In some compounds of preparation or narration, single enantiomer is prepared into pure form below, and by the difference of (+) or (-) nomenclature.In other cases, the mixture that has prepared diastereomer.
S-R
1Group occupies 8.
Term " halogen " and " halo " comprise chlorine, bromine, fluorine and iodine.
Various alkyl are as C
1-C
4Alkyl etc. comprise methyl, ethyl, propyl group, sec.-propyl, tert-butyl, just-butyl and isobutyl-.Alkenyl and alkynyl group are formed linking group, this group be divalence and be connected with two other groups.For example, C
2-C
4Alkenyl comprises vinyl, 2-propenyl, 3-butenyl and crotyl; And C
2-C
4Alkynyl group then comprises, as ethynyl, 2-propynyl, 2-butyne base and different-2-butyne base.
C
1-C
6Alkanoyl comprises as formyl radical, ethanoyl, propionyl, isobutyryl, 2-ethyl propionyl and caproyl.C
3-C
6Cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and C
4-C
8Cycloalkylalkyl comprises as cyclopropyl methyl, cyclohexyl ethyl, cyclobutyl butyl and cyclohexyl methyl.
Term is such as halo-C
1-C
6Alkanoyl, halogenophenyl or C
1-C
3Alkyl phenyl refers to thereon by 1,2 or 3 halo or C
1-C
3The basic group of appointment that alkyl replaces is as described under in particular case.
Present method prepares all formula I compounds with described benzo [f] quinoline ring, and it is on the benzo ring, by cyclic group R
1Replace this R
1Group connects by sulphur and is connected with benzoquinoline.Described R
1Group may be replaced by other organic group, also may have three more than described specified substituting group.A plurality of substituting groups may all be identical, maybe may be different.
Some aspect of present method is preferred, and will mention particularly below.Each all is important to be appreciated that following these aspects, preferred these aspects may combine to obtain further restricted property or more expansion, preferred aspect.
Synthesizing of 6-methylthio group-2-Tetralone an intermediate of Sertraline
The raw material of synthetic 6-methylthio group-2-Tetralone an intermediate of Sertraline is a 4-methylthio phenyl acetate.4-methylthio phenyl acetate can maybe can prepare by method well known to those skilled in the art through commercially available acquisition (Aldrich Catalog Handbook of FineChemicals 1994-5, the 1000th page).For example, can prepare 4-methylthio phenyl acetate by the Kindler modification of Willgerodt reaction.4-methylthio phenyl ethyl ketone and sulphur and primary amine or secondary amine, preferred morpholine combination, effect (flow process I) then is hydrolyzed.Perhaps, can prepare 4-methylthio phenyl acetate (flow process II) with two steps by the hydrolytic action of corresponding nitrile or from benzylalcohol.
Flow process I
Under condition well known by persons skilled in the art,, obtain 4-methylthio group phenyl Acetyl Chloride 98Min. and prepare 6-methylthio group-2-Tetralone an intermediate of Sertraline (flow process III) by making the reaction of 4-methylthio phenyl acetate and thionyl chloride, phosphorus trichloride, oxalyl chloride or phosphorus pentachloride.Preferred thionyl chloride and the N of using, dinethylformamide obtains 4-methylthio group phenyl Acetyl Chloride 98Min..At lewis acid catalyst and inert or basically in the presence of inert solvent or the solvent mixture, by the friedel-crafts acylation reaction of 4-methylthio group phenyl Acetyl Chloride 98Min. and ethylene gas, encircle closure, obtain 2-Tetralone an intermediate of Sertraline II.
Flow process III
Suitable lewis acid catalyst comprises AlBr
3, AlCl
3, AlI
3, GaCl
3, FeCl
3, SbCl
5, ZrCl
4, SnCl
4, BCl
3, BF
3, SbCl
3Deng, preferred AlBr
3The solvent that is used for this reaction comprises dithiocarbonic anhydride, methylene dichloride, Nitromethane 99Min., 1,2-ethylene dichloride, oil of mirbane etc., preferred methylene dichloride.The cyclic action of sulphomethyl Tetralone an intermediate of Sertraline needs stringent condition, and is difficult to separate.At stringent condition and use AlBr
3Under Lewis acid, obtain to improve the 6-methylthio group-2-Tetralone an intermediate of Sertraline of productive rate.℃ to (preferably being lower than 0 ℃) between about 25 ℃ temperature, carry out cyclic action approximately-78.
The adding of ethene causes heat release in fact, so adopt the standard method of cooling to use from approximately-78 ℃ to about 30 ℃ temperature.Between about 5 ℃ to about-15 ℃ temperature, simultaneously 4-methylthio phenyl acetyl halide and ethene are joined methylene dichloride and AlBr
3In, observe 6-methylthio group-2-Tetralone an intermediate of Sertraline output and significantly improve.
Perhaps, also can obtain the preparation of 6-methylthio group-2-Tetralone an intermediate of Sertraline according to following flow process IV.
Flow process IV
Flow process IV
Wherein R is a halogen, preferred bromine.
At first the ketone group protection with described Tetralone an intermediate of Sertraline is ketal.Preferably pass through 1,3-pair-trimethyl silicane alcoxyl base propylene glycol slowly adds in the dichloromethane solution of trifluoromethayl sulfonic acid ester, obtains ketal reaction.Employing standard method of cooling is used from approximately-78 ℃ to-60 ℃ temperature approximately.For example, 6-bromo-2-Tetralone an intermediate of Sertraline is slowly joined 1,3-is two-dichloromethane solution of trimethyl silicane alcoxyl base propylene glycol and trifluoromethayl sulfonic acid ester in, produce the 6-bromo-2-Tetralone an intermediate of Sertraline propylene glycol that contracts.
Then by making described protected ketal and active organolithium compound, preferably just-the butyllithium reaction, obtain halogen-metal exchange.With suitable sulfur transfer additive, make the lithium class alkanisation that is obtained as sulfenyl halides or methyl-sulfide, can obtain 6-methylthio group-2-Tetralone an intermediate of Sertraline propylene glycol compound that contracts.By using aqueous acid, the preferably salt acid treatment obtains the methylate provide protection of going of ketal compound of S-, obtains required 6-methylthio group-2-Tetralone an intermediate of Sertraline compound.
Alkanisation and azepine-annulation
Before according to United States Patent (USP) 5,239,075 and U.S. Patent Application Serial 08/443,994 be attached to herein by reference at this) carry out midbody compound synthetic of described formula VII.European patent publication 0564193 has shown the another kind of synthetic method of described formula VII compound, and it has constituted an improvement in the present invention.The methylthio group group of described formula VII compound is positioned on the 8-position.The preferred process of the preparation formula VII compound of narrating below can need not the purifying of described midbody product or separation and carry out.
Make 6-sulphomethyl-2-Tetralone an intermediate of Sertraline with (R)-(+)-phenylethylamine reaction, to prepare the intermediate of described formula III compound:
At high temperature, especially under the reflux temperature, in the presence of strong acid such as right-toluenesulphonic acids, can in toluene, carry out described reaction easily.Must remove the water that forms in this reaction, the shortage of the water of formation is indicated finishing of this reaction.It is excessive slightly to adopt, as the normal phenylethylamine of about 1.05-1.10.Perhaps, tetrahydrofuran (THF) can be used as solvent, in the case, be particularly suitable for making reaction mixture dehydration, with the molecular sieve of the double weight at least of the water yield that is equivalent to discharge in this process with molecular sieve.
With above-mentioned benzene ethylamino compound use such as just-butyllithium or di-isopropyl lithamide lithiumation (lithiated), obtain formula IV compound.
When carrying out this reaction, as preferably, with the reaction of di-isopropyl lithamide, if this di-isopropyl lithamide in described process with preceding immediately and just by diisopropylamine-butyllithium in generation newly, then will obtain best result.For obtaining best result, should adopt excessive substantially di-isopropyl lithamide, be approximately 15-25%.
At low temperatures, scope is-100 ℃ to about 0 ℃ approximately, in the time of preferred about-78 ℃ to-Yue 10 ℃, makes the di-isopropyl lithamide react best in tetrahydrofuran (THF).Do not need benzene ethylamino compound purifying or separation, but should then residue be dissolved in the tetrahydrofuran (THF) at first with reaction mixture vacuum-evaporation.Preferably benzene ethylamino raw material is joined in the di-isopropyl lithamide solution in cold tetrahydrofuran (THF) with solution; Opposite adding method is feasible, but less output only is provided.In general, this reaction can be finished in one hour.
Be difficult to the compound of separation and purified lithium, so introduce in the inventive method with the lithiation mixture solution.
Alkanisation
The compound of lithium is methylated, for example reacts with methyl-iodide, obtain formula V compound by the enamine lithium (lithioenamine) that makes acquisition:
May use methyl-sulfate, methyl bromide, methyl chloride, methyl-iodide etc. that the enamine lithium is methylated.Advise methyl-iodide, and in solvent, carry out this process, preferably use ether solvents, as ether, methyl-tert-butyl ether or preferred tetrahydrofuran (THF) with about excessive 15-25%.At low temperatures, scope is greatly about-100 ℃ to-50 ℃ approximately, and most preferably approximately-80 ℃ to-Yue 60 ℃ the time, this reaction is very fast.From about several minutes to about one hour reaction times is enough, the preferred 20 minutes reaction times.
If the compound of described lithium is that this reaction mixture contains residual Diisopropylamine so with the form of the reaction mixture of the lithiumation of di-isopropyl lithamide, this amine then must neutralize before methylating.Most convenient ground is that the methyl-iodide mixture is warmed near 0 ℃, the methylsulfonic acid that adds capacity with in and Diisopropylamine.Can use other strong acid, but methylsulfonic acid is to be particularly suitable for because the mesylate of the diisopropylamine that produces only is sl. sol., therefore, may passing through simple filtering or centrifugal with preferred, just can easily be removed.
Azepine-annulation step
The reaction mixture that will contain formula V compound mixes with carboxylic acid halides or acrylic anhydride or acryloyl chloride etc. to cause described azepine-annulation, and this reaction forms formula VI compound:
Be preferably in to use before and react by acrylate chloride and vinylformic acid at once, be applied in triethylamine and stablizer (as quinhydrones and butylated hydroxytoluene) in the tetrahydrofuran (THF), to produce acrylic anhydride, preferred reagent.
At extremely low temperature as under approximately-100 ℃ to-Yue 70 ℃; by adding acrylic anhydride or acryloyl chloride; and make this mixture rise to approximately-20 ℃ to about 0 ℃ very lentamente by stirring, or even high to about 10 ℃ to 20 ℃, described azepine-annulation can carry out preferably.Making the warm rational time of this mixture is 12-15 hour.When this reaction proceeds to as expected reaction and finishes, by adding sodium bicarbonate solid, this reactant of quenching.Preferred about 1.5 to about 4 normal alkali, the most preferably about 2 normal alkali of using.For example, described alkali can be added as the aqueous solution or water-soluble solvent such as water/Dimethylamino pyridine solution, but preferably add with solid form.With described reaction mixture with the of short duration stirring of the alkali of quenching, filter this mixture then, remove volatile matter, and can use ether solvents, the preferred described solvent of substituted ether, pass through then with alkali aqueous solution and aqueous acid washing, and may use purification step again as using this organic solution of saturated salt solution carrying out washing treatment.If adopt this treatment step, then subsequently with this solution dehydrates and vacuum-evaporation, obtain the non--volatility part of this reaction mixture, this part contains the whole intermediate of formula VI.On the other hand, if desired, the residue that derives from the reaction mixture of quenching can be gone on foot under not treated being used for.
Reduction-cleavage step
Cooling derives from the residue of azepine-annulation step, and adds the refrigerative mixture of suitable silane and trifluoroacetic acid.Suitable silane is the silane of solubility, for example, and dialkyl silane or trialkyl silane etc.Should approximately-40 ° under about 0 ° low temperature, add, and without other solvent.Use a large amount of trifluoroacetic acids, in the about normal scope of 10-50,20-30 equivalent most preferably from about.Although also can use trimethyl silane, tripropyl silane etc., preferred trialkyl silane then is triethyl silicane.Adopt excessive basically trialkyl silane, in the about normal scope of 5-20,7-15 equivalent most preferably from about.Stirred the about 10-20 of this mixture hour, allow it slowly to be warmed to about 30 ° therebetween, slowly heat this mixture then, preferred reflux temperature to high temperature, and stirred for several hour under this temperature, as the formation with the compound of formula VII as described in finishing in about 2-6 hour:
Purifying
The residue that will contain the product of described formula VII preferably dissolves in haloalkane such as methylene dichloride, washs with alkali such as sodium bicarbonate aqueous solution, and concentrates under vacuum.This residue can be used such as ether solvents, and preferred ether thoroughly washs, with the compound of the formula VII that obtains purifying.
The N-alkylation process
In synthetic, 4 nitrogen on benzo [f] quinoline ring is methylated.United States Patent (USP) 5,239,075 shows that this alkylating is by in the presence of highly basic such as sodium hydride, takes place with alkyl iodide reaction.In European patent publication 0703221, shown other alkylating.
Described N-methylation is included in and contains organic solvent, as be selected from the solvent and the alkali of tetrahydrofuran (THF), glycol dimethyl ether, diethoxyethane and methyl-tert-butyl ether, in the reaction mixture as sodium hydroxide or aqueous solutions of potassium, the compound of described formula VII and methyl halogenide such as methyl-iodide are reacted, obtain the compound of described formula VIII:
The effectively alkylation under condition gentleness, that be easy to control of this alkylation process, and make described product be easy to separate.
Described alkylation process can carry out in the construction equipment that routinizes, and preferably carries out under normal pressure and moderate temperature.Preferably,, more preferably from about 15 ° to about 25 °, in organic solvent, the raw material of formula VII is made slurry and begin as about 0 ° to about 50 ° near room temperature.Most preferred organic solvent is a tetrahydrofuran (THF), and preferred per kilogram raw material uses about 5-15 to rise solvent; Preferred quantity of solvent is about 10 liters of a per kilogram raw material.Add alkyl iodide with equal pure product liquid then.Preferred use excessive substantially alkyl iodide, as in the about 1.2-1.8 equivalent of raw material, most preferably from about 1.5 equivalents.
Then, still under about room temperature, the amount that rises with the about 1-4 of per kilogram raw material adds sodium hydroxide or aqueous solutions of potassium.The amount of alkali aqueous solution depends on the concentration of used alkali and the selection of sodium hydroxide or potassium a little; When using most preferred alkali to be 50% sodium hydroxide, its most preferred amount is about 2 liters of a per kilogram raw material.Then, make the reaction mixture of forming by the solid matter of pulping in two kinds of liquid phases be warmed to about 25-65 ° of vigorous agitation simultaneously, and make this be reflected at about constant temp constantly to stir and carry out.Preferred temperature of reaction is about 35-40 °.When this reaction proceeds to when finishing, described solid material and alkyl iodide will dissolve and react, thus solid to disappear be the rough indication that reaction is finished.This reaction back is in the enterprising horizontal high voltage liquid chromatography (LC) of C-18 silicagel column, with 1: 1 acetonitrile: and aqueous buffer solution (5% ammonium acetate) wash-out, and monitor in 220 nanometers.
When this reaction proceeds to when complete, cool off described mixture to room temperature, separate and discard water layer.
Preferred purifying and separating step be by the dilute with water organic layer, and with in the inorganic acid aqueous solution with carry out.Distill described solution then, be elevated to about 69-80 °, remove most tetrahydrofuran (THF) up to vapour temperature.Slowly be cooled to about 5 ° with about 1-14 hour, make the product crystallization, it only need wash with water and be dry, with standby as intermediate or medicine.
When operating according to described preferred mode, described alkylation process provides with raw material has product in the identical stereochemical form, and has gratifying purity and be used for pharmaceutical industry, its output 90% or more than.
The thio-alkylation effect
The compound of described formula VIII also can pass through (+)-(4aR)-(10bR)-4-methyl-8-halo-10b-methyl isophthalic acid, and 2,3,4,4a, 5,6, the sulphomethylization of 10b-octahydro benzo [f] quinoline-3-ketone prepares.Preferably, in the preferred tetrahydrofuran (THF), mix (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl isophthalic acid, 2 by at organic solvent, 3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone and lithium salts such as lithium chloride obtains acid amides enolate (amideenolate).Add weak base lentamente, as hexamethyl two silicon Lithium Azides (LiN (TMS)
2), and at room temperature stir this mixture.Add lithium methide to promote hexamethyl two silicon trinitride deprotonations.Described reactant is cooled to-70 ℃ then, and use alkyl lithium compounds as just-butyllithium, to help the formation of dianion.
Acid amides-enolate solution also can pass through (+)-(4aR)-(10bR)-4-methyl-8-halo-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone is used highly basic in proper order, as the di-isopropyl lithamide, in the preferred tetrahydrofuran (THF) of ether solvents, subsequently with aged just-butyllithium, the second month in a season-butyllithium etc. carry out the lithium halogen exchange to be handled and obtains (flow process V).
Make the reaction of described dianion compound and methyl-sulfide then, obtain the arylmethyl sulfide of formula VIII.Can observe methyl-sulfide dianion is had very high chemo-selective.
Flow process V
Wherein R is a halogen, preferred bromine.
Electrophilic coupling
R
1The electrophilic coupling of the methylthio group on substituting group and described benzo [f] the quinolinone ring can obtain according to following flow process VI.
Flow process VI
R wherein
1Be as above-mentioned defined in formula I.
With (+)-(4aR)-(10bR)-4-methyl-8-methylthio group-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-oxidation of ketones is a sulfoxide compound.Between-the chlorine peroxybenzoic acid is preferred oxygenant.As Young etc. at TetrahedronLett.25; described in 1753 (1984), will separate or not separated described sulfoxide compound carries out Pummerer reaction, so that sulfoxide compound and acylating agent; as the trifluoroacetic acid anhydride reactant, obtain trifluoroacetyl oxygen methylene sulfide.Make this trifluoroacetyl oxygen methylene sulfide and electrophilic reagent, hydride reducer (as sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride etc.) and alkali (preferred oxyhydroxide or carbonate, most preferably salt of wormwood) reaction, the compound of preparation formula X.For the purpose of this reaction, suitable acylating agent comprises that acyl halide such as Acetyl Chloride 98Min., sulfonic acid halide, active acid anhydride such as trichlorine acetic anhydride, phosphoric anhydride, sulphonic acid anhydride etc. can produce the reagent of Pummerer rearrangement product.
By method as known in the art, make electrophilic reagent by replacements such as leavings group such as halogen, sulfuric ester, sulphonates.Make the sulphur coupling on this electrophilic reagent and described benzo [f] the quinolinone ring then.Preferred electrophilic reagent is a 2-chloro-4-ethyl benzothiazole, makes the compound coupling of this reagent and described formula X, obtains (+)-(4aR)-(10bR)-4-methyl-8-(4-ethyl-2-[4-morpholinodithio base sulfo-)-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone.
Preferred catalyzer such as the 4-butyl ammonium hydrogen sulfate of using directly makes trifluoroacetyl oxygen methylene sulfide and electrophilic reagent coupling.Found that sodium borohydride induces the reduction of trifluoroacetyl oxygen methylene sulfide.And formaldehyde generation also on the throne, it is an environment and pharmaceutically all unacceptable.Present method is reduced to methyl alcohol with it when formaldehyde forms.And, according to present method, be reduced by the formed disulphide of atmospheric oxidation is also on the throne.This step more makes full use of raw material, and does not need the impurity of deoxygenation more strictly or promotes oxidn effect.Add alkali in the described mixture, to promoting that coupling is not essential.Yet, add alkali and can slow down the decomposition of hydroborate, thereby improve relative coupling speed.
Following preparation process further illustrates method of the present invention.This preparation process does not also mean that in office where face has limited scope of the present invention, and should do not explained like this.
Unless otherwise indicated, otherwise raw material by commercially available acquisition and need not be further purified promptly and to use.Toluene, dimethyl formamide and methylene dichloride are stored through 4 molecular sieves.Distilled tetrahydrofuran from the benzophenone sodium ketyl.Use being reflected under the nitrogen of organometallic reagent to carry out.Use following concrete condition, by high pressure liquid chromatography (HPLC) method monitoring reaction.Adopt silica gel 60 plates and the fluorescent indicator (F of Merck
254) carry out thin-layer chromatography.Unless outside specializing, otherwise at room temperature adopt CDCl
3As solvent, will
1H and
13C NMR spectrum is recorded on General Electric QE or the Bruker 300 MHz spectrophotometers.The nmr chemical displacement is with 1,000,000/(ppm) records as interior target solvent, and with the d scale, and the J value is represented with hertz.IP, UV and mass spectrum (MS) analyses are undertaken by Eli Lilly Physical Chemistry Experiment chamber.The high pressure liquid chromatography (HPLC) condition: Hitachi type L-6200A intelligent pump and D-2500 chromatogram-integration are only.25cm Zorbax RX C-18 post, 60: 40 CH
3CN/H
2O, 1.0ml/ minute, 275nm, injection-10uL.Gas-chromatography (GC) condition: HP 5890A GC and DB1 0.25 μ * 25m post; 300 ℃ of injection temperatures; 300 ℃ of detections (FID); Post is 5 ℃ (5 minutes), 18ml/ minute to 250 ℃ then 250 ℃ continue 20 minutes.The described product spectrum that term " NMR ", " MS ", " IR " and/or " GC " expression are analyzed, and consistent with required structure.
Preparation 1
The 6-bromo-2-Tetralone an intermediate of Sertraline propylene glycol that contracts.
With 1,3-pair-trimethylsiloxy propylene glycol (38.5g, 175mmol, by 1, ammediol, triethylamine and trimethylchlorosilane prepare in tetrahydrofuran (THF)) slowly join stirring at methylene dichloride (100ml,-70 ℃) in the TMS triflate (0.5ml, 2.6mmol) solution keep temperature of reaction therebetween between-70 ℃ and-60 ℃.At-70 ℃ with described solution stirring 10 minutes.With the 6-bromo-2-Tetralone an intermediate of Sertraline (35.5g, 158mmol) solution that slowly were added in the methylene dichloride (100ml) in 10 minutes.With 15 hours the gained reaction mixture slowly is warmed to 15 ℃, after during this period of time, thin-layer chromatography (55: 45 ether: hexane) and high pressure liquid chromatography (HPLC) show the completely consumed of raw material Tetralone an intermediate of Sertraline.With this reactant of saturated sodium bicarbonate (200ml) quenching, and separate each layer.Water layer extracts with dichloromethane.The blended dichloromethane solution is used dried over sodium sulfate, and under reduced pressure is condensed into golden yellow residue with salt solution (200ml) washing.With this material by 300 gram filtered through silica gel, and with 3: 1 hexane/ethyl acetate wash-outs.Concentrated filtrate under reduced pressure, and from hexane recrystallized product, the 6-bromo-2-Tetralone an intermediate of Sertraline that obtain 33.5 gram (75% productive rate) white crystals contract propylene glycol (NMR, MS).C
13H
15O
2The calculated value of Br: C, 55.14; H, 5.34.Measured value C, 55.05; H, 5.52.
Preparation 2
6-methylthio group-2-Tetralone an intermediate of Sertraline propylene glycol that contracts.
To the 6-bromo-2-Tetralone an intermediate of Sertraline in tetrahydrofuran (THF) (5ml ,-75 ℃) that stirs contract propylene glycol (0.511g, 1.81mmol) drip in the solution 2.5M just-(0.76ml, 1.90mmol), holding temperature is between-73 ℃ and-70 ℃ therebetween for butyllithium.-70 ℃ with gained solution stirring 15 minutes, perhaps up to portion with this reaction mixture of phenyl aldehyde quenching till thin-layer chromatography (70: 30 hexane/ethyl acetate) is not when having tangible raw material.After 15 minutes ,-75 ℃ drip methyl-sulfide (0.18ml, 2.00mmol).-75 ℃ stir 20 minutes after, with ethyl acetate (25ml) diluting reaction thing, and with saturated ammonium chloride (10ml) quenching.Separate organic layer, with salt solution (10ml) washing, through anhydrous sodium sulfate drying, concentrating under reduced pressure is a yellow oil.The crude product product is by through silica gel (50g) flash chromatography purifying, with 3: 1 hexane/ethyl acetate wash-outs, the 6-methylthio group-2-Tetralone an intermediate of Sertraline that obtains 0.39 gram (87%) and be transparent sticking oily matter contract propylene glycol (IR, NMR, MS).C
13H
18O
25Calculated value: C, 67.17; H, 7.25.Measured value C, 67.04; H, 7.20.
Preparation 3
6-methylthio group-2-Tetralone an intermediate of Sertraline.
Propylene glycol (29.7g will contract at the 6-methylthio group-2-Tetralone an intermediate of Sertraline in the tetrahydrofuran (THF) (50ml), 118mmol) solution 6N hydrochloric acid (9ml, 54mmol) handle, and at room temperature stirred 3 hours or till thin-layer chromatography (80: 20 dichloromethane/hexane) shows the raw material completely consumed.Dilute this reactant with ethyl acetate (60ml) and saturated sodium bicarbonate aqueous solution (110ml).Separate organic layer.With ethyl acetate (30ml) extraction waterbearing stratum.The organic solution that merges jolts with salt solution (100ml), uses dried over sodium sulfate, and is evaporated to linen solid.This crude product product is by through silica gel (400g) flash chromatography purifying, and with 5: 1 hexane/ethyl acetate wash-outs, obtain 19.5 restrain 6-methylthio group-2-Tetralone an intermediate of Sertraline that (85%) is white solid (IR, NMR, MS).C
11H
12The calculated value of OS: C, 68.71; H, 6.29.Measured value C, 68.60; H, 6.31.
Preparation 4
6-methylthio group-2-Tetralone an intermediate of Sertraline.
In 35 ℃, will the 4-methylthio phenyl acetate in the methylene dichloride (50ml) (10g, 54.8mmol) and dimethyl formamide (0.1g, 1.37mmol) (4.4ml 60.25mmol) handles solution with thionyl chloride.This solution was kept 30 minutes at 35 ℃, after this removed and desolvate, and substitute with new methylene dichloride (50ml) by underpressure distillation.In-15 to-10 ℃, (4.6g, (36.5g was 137mmol) in the mixture 164mmol) to join the aluminum bromide in methylene dichloride (450ml) that is stirring simultaneously with solution of acid chloride and ethene with 25 minutes.Under-10 to 0 ℃, the gained reaction mixture was stirred 2.5 hours.Slowly add entry (200ml) (temperature≤25 ℃), and separate each layer.With 5% sodium bicarbonate (200ml) and salt solution (200ml) continuous washing organic layer,, be evaporated to and obtain dark oily matter through dried over sodium sulfate.This oily matter is dissolved in the 3A ethanol (12ml), and is used in sodium bisulfite (22.8g) solution-treated in water (40ml) and the 3A ethanol (12ml).20 ℃ 30 minutes and at 0 ℃ after 1 hour, the hydrosulphite addition complex of filtering-depositing is used ether (50ml) washing then with cold 3A ethanol (15ml).With the solid that leaches join ether (100ml) and salt of wormwood (22.7g, in mixture 164mmol), dissolving in water (75ml), and dissolve fully up to this solid 22 ℃ of vigorous stirring.Separate organic layer,, obtain 5.8 grams (48%) for beige solid 6-methylthio group-(high pressure liquid chromatography (HPLC) records purity to the 2-Tetralone an intermediate of Sertraline: 88%) with 1N hydrochloric acid (100ml) water (200ml) washing then, dry and concentrating under reduced pressure on sodium sulfate.
Preparation 5
(+)-(4aR)-(10bR)-8-methylthio group-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone.
To handle with (R)-(+)-phenylethylamine (0.72ml, 5.7mmol, 1.1 equivalents) and p-TsOH (6mg) at the 6-methylthio group-2-Tetralone an intermediate of Sertraline in the dry toluene (18ml) (1g, 5.2mmol, 1 equivalent) solution.With this solution with the slight underpressure/nitrogen degassing 3 times and keep positive nitrogen pressure.Described solution refluxed under the Dean-Stark condition remove water.Detect the progress that imines forms by NMR.After refluxing 2.5 hours, by
1H NMR detects and observes raw ketone.Evaporate toluene with light vacuum and under nitrogen, carefully this mixture is not exposed to air.Remain on and add anhydrous tetrahydro furan (14ml) acquisition lavender solution under-70 ℃ of nitrogen.Under-45 ℃ of nitrogen by will just-the 2.5M hexane solution of butyllithium (2.4ml, 6.0mmol, 1.15 equivalents) is added drop-wise to Diisopropylamine (0.78ml, 6.0mmol, 1.15 equivalents) the solution generation di-isopropyl lithamide in the tetrahydrofuran (THF) (19ml).Temperature remains between-45 ℃ and-30 ℃ during adding.After the adding, this solution was stirred 10 minutes at-45 ℃.Cool off this di-isopropyl lithamide solution to-75 ℃, holding temperature drips imide liquor with 15 fens clock times by conduit between-70 ℃ and-75 ℃.Make the orange-yellow solution of gained be warmed to-20 ℃ with 20 minutes, and then be cooled to-75 ℃.Between-75 ℃ and-72 ℃, add methyl iodide (0.36ml, 5.8mmol, 1.15 equivalents).With 15 minutes with this solution warm (helping) with acetone bath to 0 ℃.Be cooled to-5 ℃ again, between-5 ℃ and 1 ℃, add methylsulfonic acid (0.43ml, 6.6mmol, 1.3 equivalents) with 2 minutes times.At 0 ℃ after 5 minutes, obtain the uneven mixture of grey.This mixture is cooled to-75 ℃ again.The 1.125M tetrahydrofuran solution that adds acrylic anhydride (11ml, 12.5mmol, 2.4 equivalents) fast.This mixture is kept cryostat 15 hours, and this mixture is warmed to 13 ℃ during this period.Make this reactant be warmed to 15 ℃.Add entry (2ml) and during this mixture is warmed to room temperature, stir this mixture.(50ml) dilutes this solution with ether, and with 1N sodium hydroxide (20ml), 1N hydrochloric acid (20ml), water (20ml), saturated sodium bicarbonate aqueous solution (40ml) and salt solution (20ml) continuous washing.Dry, concentrated vitriol sodium solution and through silica gel (120g) flash chromatography, with 70: 30 hexane/ethyl acetate wash-outs, obtain (+)-(10bR)-4-(2-(R)-the styroyl)-8-methylthio group-10b-methyl isophthalic acid of 1.3 grams (69% productive rate), 2,3,4,6, the 10b-hexahydrobenzene is [f] quinoline-3-ketone (NMR) also.Under nitrogen, will be chilled to-15 ℃ triethyl silicane (12ml in advance, 75mmol) and trifluoroacetic acid (14.5ml, mixture 188mmol) joins (+)-(10bR)-4-(2-(R)-the styroyl)-8-methylthio group-10b-methyl isophthalic acid of precooling in-15 ℃ of baths, 2,3,4,6, the 10b-hexahydrobenzene also [f] quinoline-3-ketone (2.76g, 7.6mmol).This mixture was stirred 15 hours, it is warmed to 13 ℃ during this period.Thin-layer chromatography (70: 30 hexane/ethyl acetate) and high pressure liquid chromatography (HPLC) show (+)-(10bR)-4-(2-(R)-styroyl)-8-methylthio group-10b-methyl isophthalic acid, 2,3,4,6, the 10b-hexahydrobenzene is [f] quinoline-3-ketone completely dissolve and new product appearance also, shows and has finished two keys reduction.Then this mixture is refluxed 2 hours to remove chiral adjuvant.After being cooled to room temperature, this mixture of concentrating under reduced pressure.This residue is dissolved in the methylene dichloride (50ml), and with saturated sodium bicarbonate aqueous solution (35ml) and salt solution (50ml) washed twice.Through silica gel (100g) flash chromatography purifying, through dried over sodium sulfate and spissated crude product product, at first use 3: 1 hexane/ethyl acetate wash-outs to remove triethyl silicane, with 14% methanol-eluted fractions in methylene dichloride that contains 1% acetate, obtain the spumescence solid then.By recrystallization in the hot ethyl acetate obtain 1.6 the gram (82%) (+)-(4aR)-(10bR)-8-methylthio group-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone (92%ee, IR, NMR, MS).C
15H
19The calculated value of NOS: C, 68.93; H, 7.33.Measured value C, 69.05; H, 7.44.
Preparation 6
(+)-(4aR)-(10bR)-4-methyl-8-methylthio group-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone.
In about 0 ℃, will be in dimethyl formamide (1.6ml), (+)-(4aR)-(10bR)-8-methylthio group-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone (0.423g, 1.62mmol, 1.0 equivalent) handle with uncle-butanols potassium (the 1.0M solution of 1.86ml in tetrahydrofuran (THF), 1.15 equivalents).Stir after 5 minutes, add methyl-iodide (0.116ml, 1.15 equivalents), and this mixture was stirred 2 hours in 0 ℃.Then with this mixture with about 100mg acetic acid treatment, and in nitrogen gas stream, remove and desolvate.Solid is dissolved in about 50ml methylene dichloride, and washes with water twice.Go up and filter with described extract drying (4 molecular sieve) and through silica gel (2g is with the ethyl acetate washing that contains 2% methyl alcohol).Will be by solid chromatography on silica gel of dichloromethane extract evaporation, with methylene dichloride, ethyl acetate and methyl alcohol (50: 50: 1) as eluent.(GC)。
Preparation 7
(+)-(4aR)-(10bR)-4-methyl-8-methylthio group-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone.
In 20 ℃, with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone (20.0g, 64.9mmol, in the 150ml tetrahydrofuran (THF)) join in the di-isopropyl lithamide solution in the 500ml tetrahydrofuran (THF) of prepared fresh.In ice bath, place after 90 minutes, gained acid amides-enolate solution is cooled to-70 ℃, and in-72 to-75 ℃ with 10 minutes through conduit join in the 300ml tetrahydrofuran (THF) of fresh mix just-butyllithium (60.0ml=is 2.54M in hexane, 152mmol, 2.34 equivalents) solution.Approximately-75 ℃ should uniform solution stirring 45 minutes, and approximately-75 ℃ with methyl-sulfide (11.0ml, 123mmol, 1.9 equivalents) quenching.At-75 ℃ after 30 minutes, described mixture is handled with acetate (18ml), and under vacuum, removed all volatile matters.The gained white solid with 300ml heptane-water (1: 1, v/v) handle and with 1N sulfuric acid adjustment pH to 3.Filter this two-phase mixture, and wash wet filter cake with 1% sodium bicarbonate aqueous solution (2 * 50ml part) and water (200ml).Dry this material obtains (+)-(4aR)-(10bR)-4-methyl-8-methylthio group-10b-methyl isophthalic acid under 50 ℃ of vacuum, and 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone (IR, NMR, MS).C
16H
21The calculated value of NOS: C, 69.77; H, 7.69; N, 5.09.Measured value C, 69.70; H, 7.62; N, 5.06.
Preparation 8
(+)-(4aR)-(10bR)-4-methyl-8-methylthio group-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone.
With lithium chloride (1.80g, 2.46mmol; 10 equivalents) rapid weighing and place the 500ml flask that mechanical stirring, pressure equalization feed hopper, thermopair, injection septum and nitrogen inlet device are housed.Add (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone (13.09g, 2.46mmol; 1.0 equivalent) and 100ml anhydrous tetrahydro furan and stirring up to dissolving (10-15 minute).(1 degree heat release) adds the hexamethyl two silicon Lithium Azides (LiN (TMS) of 46.71ml in tetrahydrofuran (THF) through syringe to use 40 minutes then
2, 46.71mmol; 1.1 equivalent).Obtain clear yellow solution, and stirring at room 1 hour.(1.4M is in ether to drip lithium methide with 50 minutes through syringe; 33.36ml; 46.71mmol; 1.1 equivalent).Observe gas generation and this exothermic heat of reaction 23 to 26 degree.Control this thermopositive reaction with standard method.In room temperature described reaction mixture was stirred 45 minutes, be cooled to-70 ℃ then.Through syringe with just adding in 25 minutes-(1.6M is in hexane for butyllithium; 29.2ml; 46.71mmol; 1.1 equivalent), during this period this temperature of reaction is maintained-71/-70 ℃.The yellow solution that stays is maintained-70 ℃ and stirred 35 minutes.High pressure liquid chromatography (HPLC) shows that dianion almost completely forms after 15 minutes.With methyl-sulfide (4.00g; 42.46mmol; 1.0 equivalent) be dissolved in the 25ml tetrahydrofuran (THF), and added with 50 minutes.This mixture is stirred 30 minutes (70 ℃).High pressure liquid chromatography (HPLC) shows that described reaction finishes after 10 minutes.With 1N hydrochloric acid (100ml ,-70 ℃) this mixture of quenching.Described reaction is warmed to room temperature and extracts the waterbearing stratum with 200ml methyl-tert-butyl ether.Merge organic layer and use the water washing of 50ml salt.This organic layer is through dried over mgso, filters and concentrating in 35 ℃ and vacuum chamber on the rotovapTM.When reducing, volume forms white solid.This organism is concentrated to the white soup compound of about 30-40ml by 550ml.With this soup compound stirred for several hour, the methyl-tert-butyl ether with small portion filters colourless up to washings subsequently in room temperature.Dry this white solid also obtains (+)-(4aR)-(the 10bR)-4-methyl-8-methylthio group-10b-methyl isophthalic acid of 7.73 grams (66%), and 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone.
Preparation 9
(+)-(4aR)-(10bR)-4-methyl-8-(4-ethyl-2-[4-morpholinodithio base sulfo-)-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone.
0 to-1 ℃, with about 1 hour with metachloroperbenzoic acid (about 56% usefulness, 6.32g the solution in methylene dichloride) join (+)-(4aR)-(10bR)-4-methyl-8-methylthio group-10b-methyl isophthalic acid, 2,3,4,4a, 5,6, in the mixture of 10b-octahydro benzo [f] quinoline-3-ketone (5.50g is in the methylene dichloride of 110ml) and sodium bicarbonate aqueous solution (9.4g is in the water of 110ml).After 8 hours, separate each layer and with this organic extraction with 1% sodium bicarbonate aqueous solution washed twice, drying (4 molecular sieve) and be evaporated to 5.90 the gram total amounts.Should be unpurified in 5-10 ℃ at 10ml toluene-d
8In the part (2.91g) of sulfoxide handle with the 2.20ml trifluoroacetic anhydride.After 30 minutes, to the 0.50ml sample
1H NMR analyzes and shows there is not initial sulfoxide (ArSOCH
3Lack unimodal at d=2.25 ppm place) and and get rid of Pummerer product (ArSCH
2OCOCF
3, unimodal at d=5.31 ppm place) formation.Make this reaction mixture experience vacuum (5-10 holder) 30 minutes, after this, in the mixture of 5-10 ℃ of water-soluble boron hydride (12% (weight) of the sodium borohydride in 14N sodium hydroxide) with the water (20ml) that this inclusion was joined in 20 minutes stirring, four-just-butyl monoammonium sulfate (0.1g) and 7.1ml.After another 20 minutes, add 2-chloro-4-ethyl benzothiazole (toluene-d of 3.00g and other 9.5ml
8) and four-just-butyl monoammonium sulfate (0.50g) of another part.Stir this reactant at 37-39 ℃, take out four parts of 0.25ml samples during this period and directly carry out
1H NMR measures and high pressure liquid chromatography (HPLC) transforms and the products distribution situation to analyze.After 26 hours, the top layer that separates this three-phase mixture (contains (+)-(4aR)-(10bR)-4-methyl-8-(4-ethyl-2-[4-morpholinodithio base sulfo-)-10b-methyl isophthalic acid, 2,3,4,4a, 5,6, the toluene liquid of 10b-octahydro benzo [f] quinoline-3-ketone and excessive 2-chloro-4-ethyl benzothiazole), with the dilution of 25ml methylene dichloride.This organic layer washs with 1N aqueous sulfuric acid, 5% sodium bicarbonate aqueous solution, with 4 molecular sieve dryings, and vacuum concentration to 5.24 gram.Resulting solid digests with hot methyl tert-butyl ether (30ml), and after this vacuum concentration is cooled to 0 ℃ then to 20ml.Filter this mixture and dry white solid, obtain (+)-(4aR)-(10bR)-4-methyl-8-(4-ethyl-2-[4-morpholinodithio base the sulfo-)-10b-methyl isophthalic acid of 2.92 grams, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone (IR, NMR, MS).C
24H
26N
2OS
2Calculated value: C, 67.93; H, 6.16; N, 6.83; S, 15.08.Measured value C, 68.21; H, 6.20; N, 6.63; S, 15.17.
Preparation 10
(+)-(4aR)-(10bR)-4-methyl-8-(4-ethyl-2-[4-morpholinodithio base sulfo-)-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone.
In-2 to 0 ℃, with 1 hour inclined to one side chlorine peroxybenzoic acid (35.2mmol is in the 100ml methylene dichloride) is joined (+)-(4aR)-(10bR)-methyl-8-methylthio group-10b-methyl isophthalic acid in the two-phase mixture of methylene dichloride (200ml) and sodium bicarbonate aqueous solution (in the water of 8.90g at 89ml), 2,3,4,4a, 5,6, (10.0g is through weighting standard potency assay 98% purity, 35.6mmol) for 10b-octahydro benzo [f] quinoline-3-ketone.Separate each layer and dichloromethane layer is used sodium metabisulfite (1.00g among the 25ml) washing once, with sodium bicarbonate (1.00g among the 100ml) washing three times.Exsiccant (4 molecular sieve) dichloromethane extract is concentrated into about 20ml, and uses the 100ml dilution with toluene.Under 30-35 ℃ of vacuum, concentrate this mixture then.(every part of 100ml) repeats this process twice with fresh toluene, after this uses toluene (100ml) dilution sulfoxide (being generally crystallization).Handle this mixture above 10 minutes at 0 to 10 ℃ with trifluoroacetic anhydride (7.30ml) then.At 0 ℃ after 30 minutes, make this solution experience vacuum (＜10 holder) 30 minutes, and in the 0-5 ℃ of mixture with the salt of wormwood that joined the degassing (nitrogen) in 30 minutes (41g), sodium borohydride (2.88g), four-just-butyl monoammonium sulfate (2.00g) and 2-chloro-4-ethyl benzothiazole (8.20g is dissolved in the toluene of 5ml with 96.5% purity) and water (87ml).Be warmed to 40 ℃ with 1 hour this mixture, stirred 26 hours at 40 ℃ then.Separation of methylbenzene layer (when warm) and with the water washing of 3 * 100-ml part.Dilute this toluene layer with the 125ml ethyl acetate, use 0.25N hydrochloric acid, 100ml 1% sodium bicarbonate and the 100ml saturated sodium-chloride water solution continuous washing of 3 * 200ml part then.Dry (10g 4 molecular sieves) organic layer, be concentrated into the volume of 25ml altogether and handle and (refluxed 30 minutes with 100ml methyl-tert-butyl ether, then 0 ℃ 1 hour), obtain (+)-(4aR)-(10bR)-4-methyl-8-(4-ethyl-2-[4-morpholinodithio base sulfo-)-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone.
Preparation 11
(+)-(4aR)-(10bR)-4-methyl-8-(4-ethyl-2-[4-morpholinodithio base sulfo-)-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone.
0-5 ℃ in 20 minutes (dissolving take place) be treated to the dry sulfoxide IX (survey 96% purity, 8.90g, 29.4mmol is gauged) of the suspension in toluene (89ml) by gas chromatography with trifluoroacetic anhydride (5.2ml) dropping.After 30 minutes, approximately 5-15 ℃, with the mixture that this solution was joined in 30 minutes salt of wormwood (32g), water (45ml), 4-butyl ammonium hydrogen sulfate (2.25g), sodium borohydride (1.0g), 2-chloro-4-ethyl benzothiazole (7.07g surveys about 96.5% purity by gas chromatography) and toluene (10ml) in.Stir this two-phase mixture 20 hours at 43 ℃ then, after this from this reaction mixture, filter out a spot of solid.Warm toluene layer with 400ml water (45 ℃) washing once, vaporising under vacuum produces 13.86 grams mainly by (+)-(4aR)-(10bR)-4-methyl-8-(4-ethyl-2-[4-morpholinodithio base sulfo-)-10b-methyl isophthalic acid then, 2,3,4,4a, 5,6, the white solid that 10b-octahydro benzo [f] quinoline-3-ketone and 2-chloro-4-ethyl benzothiazole are formed.This mixture of 13.0 grams is handled (50ml with methyl-tert-butyl ether, in reflux down then in 0 ℃ 2 hours) obtain (+)-(4aR)-(10bR)-4-methyl-8-(4-ethyl-2-[4-morpholinodithio base the sulfo-)-10b-methyl isophthalic acids of 11.05 grams, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone (IR, NMR, MS).Calculated value C, 68.21; H, 6.20; N, 6.63.Measured value C, 68.29; H, 6.15; N, 6.67.
Preparation 12
(+)-(4aR)-(10bR)-4-methyl-8-(4-ethyl-2-[4-morpholinodithio base sulfo-)-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone.
At 0 ℃ with metachloroperbenzoic acid (about 92g, about 50% usefulness is in the methylene dichloride of 1.0L) join (+)-(4aR)-(the 10bR)-4-methyl-8-methylthio group-10b-methyl isophthalic acid in methylene dichloride (2.2L), 2,3,4,4a, 5,6, (79.5g, 92.9% usefulness is 0.269mol) in the solution for 10b-octahydro benzo [f] quinoline-3-ketone.By usefulness high pressure liquid chromatography (HPLC) (240nm) monitoring (+)-(4aR)-(10bR)-4-methyl-8-methylthio group-10b-methyl isophthalic acid, 2,3,4,4a, 5,6, the oxidizing reaction of 10b-octahydro benzo [f] quinoline-3-ketone advances to area and is less than 0.3% level.This organic solution stirs with sodium sulfite solution (75g is in the 1L deionized water).Separate organic layer, and (3 * 1L) wash with 6% sodium hydrogen carbonate solution.This organic layer is through dried over sodium sulfate and concentrated.Join toluene (1L) in the described intermediate sulfoxide and concentrated this solution under vacuum.Repeat this process twice with fresh toluene (each 1.1L), after this sulfoxide is dissolved in the toluene of 1.1L and in ice bath, cools off.Trifluoroacetic anhydride (51ml) is added drop-wise in the sulfoxide with 15 minutes at 0 ℃.0 ℃ stir 30 minutes after, at 10 ℃ with Pummerer product (ArSCH
2OCOCF
3) join in the mixture of well-beaten deionized water (414ml), salt of wormwood (319g), sodium borohydride (15.2g), 2-chloro-4-ethyl benzothiazole (65.7g, about 96.5% purity), 4-butyl ammonium hydrogen sulfate (21.6g) and toluene (170ml) through conduit.This reactant slowly is heated to 42 ℃, simultaneously through high pressure liquid chromatography (HPLC) monitoring reaction process.After 18 hours, add the toluene (1.0L) of another part, and wash this toluene layer with deionized water (3 * 1L, 45 ℃).(1L) joins this organic layer with ethyl acetate, use then the 0.25M hydrochloric acid soln (3 * 1L), (3 * 1L), 6% sodium hydrogen carbonate solution (1.5L) and saturated nacl aqueous solution (2L) wash this organic layer to the 1N sulphuric acid soln.Go up dry organic extraction at 4 molecular sieves (500g), concentrate then.Add methyl-tert-butyl ether (400ml) and this mixture heating up is refluxed.Under refluxing, stir after 30 minutes, cool off this mixture to 5 ℃.Filtering suspension liquid is also used methyl-tert-butyl ether (100ml) washing.Filter this solution and under 50 ℃ of about 5mm dry described product 18 hours, obtain (+)-(4aR)-(10bR)-4-methyl-8-(4-ethyl-2-[4-morpholinodithio base the sulfo-)-10b-methyl isophthalic acid of 90.1 grams (80%), 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone.
Claims (26)
1. the method for preparation I compound
R wherein
1Representative: 2-nitrophenyl, the 4-nitrophenyl, the 2-cyano-phenyl, the 4-cyano-phenyl, 2-nitro naphthyl, 4-nitro naphthyl, 2-cyano group naphthyl, 4-cyano group naphthyl, the 2-quinolyl, the 4-quinolyl, the 7-quinolyl, the 1-isoquinolyl, the 3-isoquinolyl, the 8-isoquinolyl, the 2-quinoxalinyl, the 2-[4-morpholinodithio base, the 3-1H-indazolyl, the 2-benzoxazolyl, 3-1,2-benzisothiazole base, the 2-pyridyl, the 4-pyridyl, the 2-pyrazinyl, 2-naphtho-[2,3-d] thiazolyl, 2-naphtho-[1,2-d] thiazolyl, the 9-anthryl, the 2-thiazolyl, the 2-benzimidazolyl-, 1-benzo [g] isoquinolyl, 8-benzo [g] isoquinolyl, the 5-1H-tetrazyl, the 2-quinazolyl, 2-thiazole also [4,5-b] pyridyl, 4-10H-pyridazine also [3,2-b]-the 2-quinazolyl, 2-1,4-benzo two oxine bases (benzodioxinyl), the 2-triazine, the 2-benzoxazine, the 4-benzoxazine, 2-purine or 8-purine; Wherein above-mentioned R
1Group is unsubstituted or replaces with 1-3 group that described group is selected from trifluoromethyl, trifluoro ethoxy, C
1-C
4Alkyl, trifluoromethoxy, hydroxyl, C
1-C
3Alkoxyl group, nitro, C
1-C
3Alkylthio, C
1-C
6Alkanoyl, phenyl, oxo, phenoxy group, thiophenyl, C
1-C
3Alkyl sulphinyl, C
1-C
3Alkyl sulphonyl, cyano group, amino, C
1-C
3Alkylamino, diphenylmethyl amino, triphenyl methylamino-, benzyloxy, benzylthio-, (list-halo, nitro or CF
3) benzyl (oxygen base or sulfo-), two (C
1-C
3Alkyl, C
3-C
6Cycloalkyl or C
4-C
8Cycloalkylalkyl) amino, (list-C
1-C
3Alkyl, C
1-C
3Alkoxyl group or halo) (phenyl, phenoxy group, thiophenyl, benzenesulfonyl or phenoxy group alkylsulfonyl), C
2-C
6Alkanoyl amido, benzamido, diphenylmethyl amino (C
1-C
3Alkyl), aminocarboxyl, C
1-C
3Alkyl amino-carbonyl, two (C
1-C
3Alkyl) aminocarboxyl, halo-C
1-C
6Alkanoyl, amino-sulfonyl, C
1-C
3Alkylamino alkylsulfonyl, two (C
1-C
3Alkyl) amino-sulfonyl, phenyl (oxygen base or sulfo-) (C
1-C
3Alkyl), (halo, C
1-C
3Alkyl or C
1-C
3Alkoxyl group) phenyl (oxygen base or sulfo-) (C
1-C
3Alkyl), benzoyl or (amino, C
1-C
3Alkylamino or two (C
1-C
3Alkyl) (C amino)
1-C
3Alkyl); This method comprises: with the ketone of following formula
Wherein R is a halogen; Be converted into protected ketone acetal; Make the reaction of described protected ketone acetal and active alkyl lithium compounds and sulfur transfer additive, obtain the methylated ketal compound of S-; The methylated ketal compound of described S-is gone protection, obtain methyl-sulfo-Tetralone an intermediate of Sertraline compound of formula II
Make the compound of described formula II with (R)-(+)-phenylethylamine reaction, obtain the compound of formula III:
Make the compound and strong lithium alkali reaction of described formula III, obtain the lithium enamine compound of formula IV
The lithium enamine product of described formula IV is methylated become the compound of formula V
Make compound and carboxylic acid halides or the acrylic anhydride reaction of described formula V, the compound of preparation formula VI
With this reactant of alkaline quench, and mix the compound of preparation formula VIII with suitable silane and trifluoroacetic acid at the resistates that does not have to contain under the situation of solvent formula VI compound
Compound and the methyl halogenide of formula VII are reacted in containing organic solvent and alkaline reaction mixture, obtain the arylmethyl sulfide of formula VIII
With the compound oxidation of formula VIII is the sulfoxide compound of formula IX
Make sulfoxide compound and the acylation reaction of described formula IX, obtain the Pummerer rearrangement product; In the presence of phase-transfer catalyst, hydride reducer and alkali, make with described Pummerer rearrangement product be selected from A-R
1Electrophilic reagent reaction, wherein A is a leavings group, prepares the compound of described formula I.
2. the method for preparation formula II compound
This method comprises: with the ketone of following formula
Wherein R is a halogen; Be converted into protected ketone acetal; Make the reaction of described protected ketone acetal and active alkyl lithium compounds and sulfur transfer additive, obtain the methylated ketal compound of S-; The methylated ketal compound of described S-is gone protection, obtain methyl-sulfo-Tetralone an intermediate of Sertraline compound of formula II.
3. the method for claim 2, wherein said sulfur transfer additive is a methyl-sulfide, and described protected ketone acetal is
4. the method for preparation formula II compound
This method comprises: the compound that makes following formula
With the di-isopropyl lithamide, just-reaction of butyllithium and methyl-sulfide.
5. the method for preparation formula II compound
This method comprises: with the compound of described formula XI
Be converted into acyl halide; Make described acyl halide and Lewis acid and ethylene reaction, obtain the compound of formula II.
6. the method for claim 5 is wherein used the dimethyl formamide of methylene dichloride, thionyl chloride and catalytic amount, obtaining described acyl halide, and with aluminum bromide as Lewis acid.
7. claim 2,3,4,5 or 6 any one method further comprise the compound with formula II
Be converted into the compound of formula I
R wherein
1Representative: 2-nitrophenyl, the 4-nitrophenyl, the 2-cyano-phenyl, the 4-cyano-phenyl, 2-nitro naphthyl, 4-nitro naphthyl, 2-cyano group naphthyl, 4-cyano group naphthyl, the 2-quinolyl, the 4-quinolyl, the 7-quinolyl, the 1-isoquinolyl, the 3-isoquinolyl, the 8-isoquinolyl, the 2-quinoxalinyl, the 2-[4-morpholinodithio base, the 3-1H-indazolyl, the 2-benzoxazolyl, 3-1,2-benzisothiazole base, the 2-pyridyl, the 4-pyridyl, the 2-pyrazinyl, 2-naphtho-[2,3-d] thiazolyl, 2-naphtho-[1,2-d] thiazolyl, the 9-anthryl, the 2-thiazolyl, the 2-benzimidazolyl-, 1-benzo [g] isoquinolyl, 8-benzo [g] isoquinolyl, the 5-1H-tetrazyl, the 2-quinazolyl, 2-thiazole also [4,5-b] pyridyl, 4-10H-pyridazine also [3,2-b]-the 2-quinazolyl, 2-1,4-benzo two oxine bases, the 2-triazine, the 2-benzoxazine, the 4-benzoxazine, 2-purine or 8-purine; Wherein above-mentioned R
1Group is unsubstituted or replaces with 1-3 group that described group is selected from trifluoromethyl, trifluoro ethoxy, C
1-C
4Alkyl, trifluoromethoxy, hydroxyl, C
1-C
3Alkoxyl group, nitro, C
1-C
3Alkylthio, C
1-C
6Alkanoyl, phenyl, oxo, phenoxy group, thiophenyl, C
1-C
3Alkyl sulphinyl, C
1-C
3Alkyl sulphonyl, cyano group, amino, C
1-C
3Alkylamino, diphenylmethyl amino, triphenyl methylamino-, benzyloxy, benzylthio-, (list-halo, nitro or CF
3) benzyl (oxygen base or sulfo-), two (C
1-C
3Alkyl, C
3-C
6Cycloalkyl or C
4-C
8Cycloalkylalkyl) amino, (list-C
1-C
3Alkyl, C
1-C
3Alkoxyl group or halo) (phenyl, phenoxy group, thiophenyl, benzenesulfonyl or phenoxy group alkylsulfonyl), C
2-C
6Alkanoyl amido, benzamido, diphenylmethyl amino (C
1-C
3Alkyl), aminocarboxyl, C
1-C
3Alkyl amino-carbonyl, two (C
1-C
3Alkyl) aminocarboxyl, halo-C
1-C
6Alkanoyl, amino-sulfonyl, C
1-C
3Alkylamino alkylsulfonyl, two (C
1-C
3Alkyl) amino-sulfonyl, phenyl (oxygen base or sulfo-) (C
1-C
3Alkyl), (halo, C
1-C
3Alkyl or C
1-C
3Alkoxyl group) phenyl (oxygen base or sulfo-) (C
1-C
3Alkyl), benzoyl or (amino, C
1-C
3Alkylamino or two (C
1-C
3Alkyl) (C amino)
1-C
3Alkyl).
8. claim 2,3,4,5 or 6 each method, it further comprises the compound with described formula II
Be converted into (+)-(4aR)-(10bR)-4-methyl-8-(4-ethyl-2-[4-morpholinodithio base sulfo-)-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone.
9. each method in the claim 2,3,4,5 or 6, it further comprises: the compound that makes described formula II
With (R)-(+)-phenylethylamine reaction, obtain the compound of formula III:
Make the compound and strong lithium alkali reaction of formula III, obtain the lithium enamine compound of formula IV
The lithium enamine product of formula IV methylated becomes the compound of described formula V
Make compound and acyl halide or the acrylic anhydride reaction of formula V, the compound of preparation formula VI
With this reactant of alkaline quench, and mix the compound of preparation formula VII with suitable silane and trifluoroacetic acid at the resistates that does not have will to contain under the situation of solvent formula VI compound:
10. the method for claim 9, it further comprises: the compound of formula VII and methyl halogenide are reacted in containing organic solvent and alkaline reaction mixture, obtain the arylmethyl sulfide of formula VIII
With the compound oxidation of formula VIII is the sulfoxide compound of formula IX
Make sulfoxide compound and the acylation reaction of formula IX, obtain the Pummerer rearrangement product; Make described Pummerer rearrangement product and be selected from A-R
1Electrophilic reagent reaction, wherein A is a leavings group, R
1Representative: 2-nitrophenyl, the 4-nitrophenyl, the 2-cyano-phenyl, the 4-cyano-phenyl, 2-nitro naphthyl, 4-nitro naphthyl, 2-cyano group naphthyl, 4-cyano group naphthyl, the 2-quinolyl, the 4-quinolyl, the 7-quinolyl, the 1-isoquinolyl, the 3-isoquinolyl, the 8-isoquinolyl, the 2-quinoxalinyl, the 2-[4-morpholinodithio base, the 3-1H-indazolyl, the 2-benzoxazolyl, 3-1,2-benzisothiazole base, the 2-pyridyl, the 4-pyridyl, the 2-pyrazinyl, 2-naphtho-[2,3-d] thiazolyl, 2-naphtho-[1,2-d] thiazolyl, the 9-anthryl, the 2-thiazolyl, the 2-benzimidazolyl-, 1-benzo [g] isoquinolyl, 8-benzo [g] isoquinolyl, the 5-1H-tetrazyl, the 2-quinazolyl, 2-thiazole also [4,5-b] pyridyl, 4-10H-pyridazine also [3,2-b]-the 2-quinazolyl, 2-1,4-benzo two oxine bases, the 2-triazine, the 2-benzoxazine, the 4-benzoxazine, 2-purine or 8-purine; Wherein above-mentioned R
1Group is unsubstituted or replaces with 1-3 group that described group is selected from trifluoromethyl, trifluoro ethoxy, C
1-C
4Alkyl, trifluoromethoxy, hydroxyl, C
1-C
3Alkoxyl group, nitro, C
1-C
3Alkylthio, C
1-C
6Alkanoyl, phenyl, oxo, phenoxy group, thiophenyl, C
1-C
3Alkyl sulphinyl, C
1-C
3Alkyl sulphonyl, cyano group, amino, C
1-C
3Alkylamino, diphenylmethyl amino, triphenyl methylamino-, benzyloxy, benzylthio-, (list-halo, nitro or CF
3) benzyl (oxygen base or sulfenyl), two (C
1-C
3Alkyl, C
3-C
6Cycloalkyl or C
4-C
8Cycloalkylalkyl) amino, (list-C
1-C
3Alkyl, C
1-C
3Alkoxyl group or halo) (phenyl, phenoxy group, thiophenyl, benzenesulfonyl or phenoxy group alkylsulfonyl), C
2-C
6Alkanoyl amido, benzamido, diphenylmethyl amino (C
1-C
3Alkyl), aminocarboxyl, C
1-C
3Alkyl amino-carbonyl, two (C
1-C
3Alkyl) aminocarboxyl, halo-C
1-C
6Alkane acyl, amino-sulfonyl, C
1-C
3Alkylamino alkylsulfonyl, two (C
1-C
3Alkyl) amino-sulfonyl, phenyl (oxygen base or sulfo-) (C
1-C
3Alkyl), (halo, C
1-C
3Alkyl or C
1-C
3Alkoxyl group) phenyl (oxygen base or sulfo-) (C
1-C
3Alkyl), benzoyl or (amino, C
1-C
3Alkylamino or two (C
1-C
3Alkyl) (C amino)
1-C
3Alkyl); In the presence of phase-transfer catalyst, hydride reducer and alkali, the compound of preparation formula I:
11. the method for the compound of preparation following formula
R wherein
1Representative: 2-nitrophenyl, the 4-nitrophenyl, the 2-cyano-phenyl, the 4-cyano-phenyl, 2-nitro naphthyl, 4-nitro naphthyl, 2-cyano group naphthyl, 4-cyano group naphthyl, the 2-quinolyl, the 4-quinolyl, the 7-quinolyl, the 1-isoquinolyl, the 3-isoquinolyl, the 8-isoquinolyl, the 2-quinoxalinyl, the 2-[4-morpholinodithio base, the 3-1H-indazolyl, the 2-benzoxazolyl, 3-1,2-benzisothiazole base, the 2-pyridyl, the 4-pyridyl, the 2-pyrazinyl, 2-naphtho-[2,3-d] thiazolyl, 2-naphtho-[1,2-d] thiazolyl, the 9-anthryl, the 2-thiazolyl, the 2-benzimidazolyl-, 1-benzo [g] isoquinolyl, 8-benzo [g] isoquinolyl, the 5-1H-tetrazyl, the 2-quinazolyl, 2-thiazole also [4,5-b] pyridyl, 4-10H-pyridazine also [3,2-b]-the 2-quinazolyl, 2-1,4-benzo two oxine bases, the 2-triazine, the 2-benzoxazine, the 4-benzoxazine, 2-purine or 8-purine; Wherein above-mentioned R
1Group is unsubstituted or replaces with 1-3 group that described group is selected from trifluoromethyl, trifluoro ethoxy, C
1-C
4Alkyl, trifluoromethoxy, hydroxyl, C
1-C
3Alkoxyl group, nitro, C
1-C
3Alkylthio, C
1-C
6Alkanoyl, phenyl, oxo, phenoxy group, thiophenyl, C
1-C
3Alkyl sulphinyl, C
1-C
3Alkyl sulphonyl, cyano group, amino, C
1-C
3Alkylamino, diphenylmethyl amino, triphenyl methylamino-, benzyloxy, benzylthio-, (list-halo, nitro or CF
3) benzyl (oxygen base or sulfenyl), two (C
1-C
3Alkyl, C
3-C
6Cycloalkyl or C
4-C
8Cycloalkylalkyl) amino, (list-C
1-C
3Alkyl, C
1-C
3Alkoxyl group or halo) (phenyl, phenoxy group, thiophenyl, benzenesulfonyl or phenoxy group alkylsulfonyl), C
2-C
6Alkanoyl amido, benzamido, diphenylmethyl amino (C
1-C
3Alkyl), aminocarboxyl, C
1-C
3Alkyl amino-carbonyl, two (C
1-C
3Alkyl) aminocarboxyl, halo-C
1-C
6Alkanoyl, amino-sulfonyl, C
1-C
3Alkylamino alkylsulfonyl, two (C
1-C
3Alkyl) amino-sulfonyl, phenyl (oxygen base or sulfo-) (C
1-C
3Alkyl), (halo, C
1-C
3Alkyl or C
1-C
3Alkoxyl group) phenyl (oxygen base or sulfo-) (C
1-C
3Alkyl), benzoyl or (amino, C
1-C
3Alkylamino or two (C
1-C
3Alkyl) (C amino)
1-C
3Alkyl); This method comprises the arylmethyl sulfide with formula VIII
Be oxidized to the sulfoxide compound of formula IX
Make sulfoxide compound and the acylation reaction of formula IX, obtain the Pummerer rearrangement product; In the presence of phase-transfer catalyst, hydride reducer and alkali, make described Pummerer rearrangement product and be selected from A-R
1Electrophilic reagent reaction, wherein A is a leavings group, the compound of preparation formula I.
12. the method for claim 11, wherein said acylating agent is a trifluoroacetic anhydride, the trifluoroacetyl oxygen methylene sulfide that described Pummerer rearrangement product is formula X
13. preparation (+)-(4aR)-(10bR)-4-methyl-8-(4-ethyl-2-[4-morpholinodithio base sulfo-)-10b-methyl isophthalic acid, 2,3,4,4a, 5,6, the method of 10b-octahydro benzo [f] quinoline-3-ketone, this method comprises: in the presence of phase-transfer catalyst, hydride reducer and alkali, make the trifluoroacetyl oxygen methylene sulfide of formula X
With 2-halo-4-ethyl benzothiazole reaction.
14. the method for claim 11 or 12, wherein single peroxide phthalic acid or 3-chloroperoxybenzoic acid are described oxygenants, and 2-halo-4-ethyl benzothiazole is described electrophilic reagent, salt of wormwood is described alkali, sodium borohydride is described reductive agent, and the compound of preparation is (+)-(4aR)-(10bR)-4-methyl-8-(4-ethyl-2-[4-morpholinodithio base sulfo-)-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone.
15. the method for preparation formula VIII compound
This method comprises the compound that makes described formula XII
Reaction mixture reaction with containing alkali and ether solvents obtains acid amides-enolate solution; Make the reaction of described acid amides-enolate solution and alkyl lithium compounds, obtain the dianion compound of following formula
Make the reaction of described dianion compound and methyl-sulfide, obtain the arylmethyl sulfide of formula VIII.
16. the method for claim 15, wherein said alkali are the di-isopropyl lithamides.
17. the method for claim 15, wherein said alkali are hexamethyl two silicon Lithium Azides.
18. the method for claim 16 or claim 17, it further comprises adding lithium salts and lithium methide.
19. claim 15,16, each method of 17 or 18, it further comprises the compound that the compound of formula VIII is converted into formula I
R wherein
1Representative: 2-nitrophenyl, the 4-nitrophenyl, the 2-cyano-phenyl, the 4-cyano-phenyl, 2-nitro naphthyl, 4-nitro naphthyl, 2-cyano group naphthyl, 4-cyano group naphthyl, the 2-quinolyl, the 4-quinolyl, the 7-quinolyl, the 1-isoquinolyl, the 3-isoquinolyl, the 8-isoquinolyl, the 2-quinoxalinyl, the 2-[4-morpholinodithio base, the 3-1H-indazolyl, the 2-benzoxazolyl, 3-1,2-benzisothiazole base, the 2-pyridyl, the 4-pyridyl, the 2-pyrazinyl, 2-naphtho-[2,3-d] thiazolyl, 2-naphtho-[1,2-d] thiazolyl, the 9-anthryl, the 2-thiazolyl, the 2-benzimidazolyl-, 1-benzo [g] isoquinolyl, 8-benzo [g] isoquinolyl, the 5-1H-tetrazyl, the 2-quinazolyl, 2-thiazole also [4,5-b] pyridyl, 4-10H-pyridazine also [3,2-b]-the 2-quinazolyl, 2-1,4-benzo two oxine bases, the 2-triazine, the 2-benzoxazine, the 4-benzoxazine, 2-purine or 8-purine; Wherein above-mentioned R
1Group is unsubstituted or replaces with 1-3 group that described group is selected from trifluoromethyl, trifluoro ethoxy, C
1-C
4Alkyl, trifluoromethoxy, hydroxyl, C
1-C
3Alkoxyl group, nitro, C
1-C
3Alkylthio, C
1-C
6Alkanoyl, phenyl, oxo, phenoxy group, thiophenyl, C
1-C
3Alkyl sulphinyl, C
1-C
3Alkyl sulphonyl, cyano group, amino, C
1-C
3Alkylamino, diphenylmethyl amino, triphenyl methylamino-, benzyloxy, benzylthio-, (list-halo, nitro or CF
3) benzyl (oxygen base or sulfenyl), two (C
1-C
3Alkyl, C
3-C
6Cycloalkyl or C
4-C
8Cycloalkylalkyl) amino, (list-C
1-C
3Alkyl, C
1-C
3Alkoxyl group or halo) (phenyl, phenoxy group, thiophenyl, benzenesulfonyl or phenoxy group alkylsulfonyl), C
2-C
6Alkanoyl amido, benzamido, diphenylmethyl amino (C
1-C
3Alkyl), aminocarboxyl, C
1-C
3Alkyl amino-carbonyl, two (C
1-C
3Alkyl) aminocarboxyl, halo-C
1-C
6Alkanoyl, amino-sulfonyl, C
1-C
3Alkylamino alkylsulfonyl, two (C
1-C
3Alkyl) amino-sulfonyl, phenyl (oxygen base or sulfo-) (C
1-C
3Alkyl), (halo, C
1-C
3Alkyl or C
1-C
3Alkoxyl group) phenyl (oxygen base or sulfo-) (C
1-C
3Alkyl), benzoyl or (amino, C
1-C
3Alkylamino or two (C
1-C
3Alkyl) (C amino)
1-C
3Alkyl).
20. claim 15,16,17 or 18 each method, it further comprises the compound with described formula VIII
Be oxidized to the sulfoxide compound of formula IX
Make sulfoxide compound and the acylation reaction of described formula IX, obtain the Pummerer rearrangement product; Make described Pummerer rearrangement product and be selected from A-R
1Electrophilic reagent reaction, wherein A is a leavings group, R
1Representative: 2-nitrophenyl, the 4-nitrophenyl, the 2-cyano-phenyl, the 4-cyano-phenyl, 2-nitro naphthyl, 4-nitro naphthyl, 2-cyano group naphthyl, 4-cyano group naphthyl, the 2-quinolyl, the 4-quinolyl, the 7-quinolyl, the 1-isoquinolyl, the 3-isoquinolyl, the 8-isoquinolyl, the 2-quinoxalinyl, the 2-[4-morpholinodithio base, the 3-1H-indazolyl, the 2-benzoxazolyl, 3-1,2-benzisothiazole base, the 2-pyridyl, the 4-pyridyl, the 2-pyrazinyl, 2-naphtho-[2,3-d] thiazolyl, 2-naphtho-[1,2-d] thiazolyl, the 9-anthryl, the 2-thiazolyl, the 2-benzimidazolyl-, 1-benzo [g] isoquinolyl, 8-benzo [g] isoquinolyl, the 5-1H-tetrazyl, the 2-quinazolyl, 2-thiazole also [4,5-b] pyridyl, 4-10H-pyridazine also [3,2-b]-the 2-quinazolyl, 2-1,4-benzo two oxine bases, the 2-triazine, the 2-benzoxazine, the 4-benzoxazine, 2-purine or 8-purine; Wherein above-mentioned R
1Group is unsubstituted or replaces with 1-3 group that described group is selected from trifluoromethyl, trifluoro ethoxy, C
1-C
4Alkyl, trifluoromethoxy, hydroxyl, C
1-C
3Alkoxyl group, nitro, C
1-C
3Alkylthio, C
1-C
6Alkanoyl, phenyl, oxo, phenoxy group, thiophenyl, C
1-C
3Alkyl sulphinyl, C
1-C
3Alkyl sulphonyl, cyano group, amino, C
1-C
3Alkylamino, diphenylmethyl amino, triphenyl methylamino-, benzyloxy, benzylthio-, (list-halo, nitro or CF
3) benzyl (oxygen base or sulfo-), two (C
1-C
3Alkyl, C
3-C
6Cycloalkyl or C
4-C
8Cycloalkylalkyl) amino, (list-C
1-C
3Alkyl, C
1-C
3Alkoxyl group or halo) (phenyl, phenoxy group, thiophenyl, benzenesulfonyl or phenoxy group alkylsulfonyl), C
2-C
6Alkanoyl amido, benzamido, diphenylmethyl amino (C
1-C
3Alkyl), aminocarboxyl, C
1-C
3Alkyl amino-carbonyl, two (C
1-C
3Alkyl) aminocarboxyl, halo-C
1-C
6Alkanoyl, amino-sulfonyl, C
1-C
3Alkylamino alkylsulfonyl, two (C
1-C
3Alkyl) amino-sulfonyl, phenyl (oxygen base or sulfo-) (C
1-C
3Alkyl), (halo, C
1-C
3Alkyl or C
1-C
3Alkoxyl group) phenyl (oxygen base or sulfo-) (C
1-C
3Alkyl), benzoyl or (amino, C
1-C
3Alkylamino or two (C
1-C
3Alkyl) (C amino)
1-C
3Alkyl); In the presence of phase-transfer catalyst, hydride reducer and alkali, the compound of preparation formula I:
21. preparation (+)-(4aR)-(10bR)-4-methyl-8-(4-ethyl-2-[4-morpholinodithio base sulfo-)-10b-methyl isophthalic acid, 2,3,4,4a, 5,6, the method for 10b-octahydro benzo [f] quinoline-3-ketone, this method comprises: the compound that makes formula II
With (R)-(+)-phenylethylamine reaction, obtain the compound of described formula III:
Make the compound and strong lithium alkali reaction of formula III, obtain the lithium enamine compound of formula IV
The lithium enamine product of described formula IV methylated becomes the compound of formula V
Make compound and acyl halide or the acrylic anhydride reaction of formula V, the compound of preparation formula VI
With this reactant of alkaline quench, and mix the compound of preparation formula VII with suitable silane and trifluoroacetic acid at the resistates that does not have will to contain under the situation of solvent formula VI compound:
Compound and the methyl halide of formula VII are reacted in containing organic solvent and alkaline reaction mixture, obtain the arylmethyl sulfide of formula VIII:
With the compound oxidation of described formula VIII is the sulfoxide compound of formula IX:
Make sulfoxide compound and the trifluoroacetic acid anhydride reactant of described formula IX, obtain the trifluoroacetyl oxygen methylene sulfide compound of formula X:
In the presence of phase-transfer catalyst, sodium borohydride and alkali, make described trifluoroacetyl oxygen methylene sulfide compound and 2-halo-4-ethyl benzothiazole reaction, preparation (+)-(4aR)-(10bR)-4-methyl-8-(4-ethyl-2-[4-morpholinodithio base sulfo-)-10b-methyl isophthalic acid, 2,3,4,4a, 5,6,10b-octahydro benzo [f] quinoline-3-ketone.
22. basically as preparation (+)-(4aR)-(10bR)-4-methyl-8-(4-ethyl-2-[4-morpholinodithio base the sulfo-)-10b-methyl isophthalic acid described in any one embodiment, 2,3,4,4a, 5,6, the method for 10b-octahydro benzo [f] quinoline-3-ketone.
23. the compound of formula II
24. as the method for the preparation formula II compound described in any one embodiment:
25. the compound or its salt of formula VI:
26. the compound or its salt of formula VIII:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 97180985 CN1241998A (en) | 1996-10-30 | 1997-10-27 | Synthesis of benzo (F) quinolinones |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/027,868 | 1996-10-30 | ||
| CN 97180985 CN1241998A (en) | 1996-10-30 | 1997-10-27 | Synthesis of benzo (F) quinolinones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1241998A true CN1241998A (en) | 2000-01-19 |
Family
ID=5178011
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 97180985 Pending CN1241998A (en) | 1996-10-30 | 1997-10-27 | Synthesis of benzo (F) quinolinones |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1241998A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107253956A (en) * | 2007-08-31 | 2017-10-17 | H.隆德贝克有限公司 | Catecholamine derivatives for treating parkinsonism and preparation method thereof |
-
1997
- 1997-10-27 CN CN 97180985 patent/CN1241998A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107253956A (en) * | 2007-08-31 | 2017-10-17 | H.隆德贝克有限公司 | Catecholamine derivatives for treating parkinsonism and preparation method thereof |
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