MXPA00012387A - Synthesis of benzo[f]quinolinones - Google Patents

Abstract

A process for preparing intermediates and benzoquinolin-3-one pharmaceuticals, such pharmaceuticals are effective in treating conditions consequent on 5&agr;-reductase.

Description

SYNTHESIS OF BENZO [F] QUINOLINONAS Field of Invention The present invention pertains to the fields of organic chemistry, pharmaceutical chemistry and chemical manufacturing, and provides a convenient and economical process for preparing benzo [f] quinolinones which are useful as inhibitors of 5a-reductase and provides intermediates for the preparation of such pharmacists.

Background of the Invention A currently active field of pharmaceutical resources is the inhibition of 5a-reduct asa, the enzyme that converts testosterone to dihydro-testosterone, a more powerful androgen. It has been shown that inhibitors of 5a-reductase can block the formation of dihydrot these terones and improve a number of highly undesirable conditions, including family baldness in men and benign prosthetic hypertrophy. Audia and collaborators, has Ref. 125680 describes a series of Benzo [f] quinolinone compounds which are inhibitors of 5a-reductase. See: U.S. Patents 5,239,075 and ,541,190; I do not. Le t. , 44, 7001 (1993); J. Med. Ch em. , 3 6, 421 (1993); and European Patent Publication 0703221.

Description of the invention.

The present invention provides a novel process for the preparation of benzo [f] quinolinones which are effective inhibitors of 5a-reductase. The present process is more efficient than previous processes and is sensitive to large-scale synthesis. This invention also provides intermediary compounds for the preparation of such pharmaceuticals.

The present invention provides a novel process for preparing benzo [f] quinolinones and provides intermediates useful in the preparation of benzo [f] quinolinones. More specifically, the present invention is directed to a process for preparing a compound of the formula I where R1 represents: 2 - . 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-n-t-ronaphthyl, -n-t-ronaphthyl 2-cyanonaphthyl, -cyanonaphthyl, 2-quinolinyl, 4-quinolinyl, 7- ? uinolini lo, 1-isoquinolinilo, 3-isoquinolinilo, 8 -i soquinolini lo, 2-quinoxalini lo, 2-benzot iazol ilo, 3- lH-inda zoli lo, 2-benzoxa zol ilo, 3- 1, 2-benzoisot ia zolyl, 2-pyridinyl, 4-pyridinyl, 2-pyrazinyl, 2-naphtho [2,3-d] thiazolyl. 2 -na fto [1, 2 -d] t iazoli lo, 9-anthryl, 2-thiazolyl, 2-benzimidazolyl, 1-benz [g] isoqumo inyl, 8 -benz [g] isoquinolinyl, 5-lH-tet razolij -o, 2 -quinazolinyl, 2-t-azolo [4, 5-b] pyridinyl, 4-10H-pyridazino [3,2-b] -2-quinazolinyl, 2-1, -benzodioxinyl, 2-triazine, 2- benzoxazino, 4-benzoxazino, 2-purine or 8-purine; wherein the above R1 groups are substituted or unsubstituted with 1-3 functionalities selected from the group consisting of trifluoromethyl, trifluoroethoxy, C? -C4 alkyl, trifluoromethoxy, hydroxy, C? -C3 alkoxy, nitro, C? -C3 alkylthio, C 1 -C 3 alkanoyl, phenyl, oxo, phenoxy, phenylthio, C 1 -C 3 alkylsulphyl, C 1 -C 3 alkylsulfonyl, cyano, amino, C 1 -C 3 alkylamino, diphenylmet ylamino, t-rifenylmethylamino, benzyloxy, benzylthio, (mono- halo, nitro or CF3) benzyl (oxy or thio), di (C? -C3 alkyl, C3-C6 cycloalkyl, or C-C8 cycloalkylalkyl) amino, (monoC? -C3 alkyl, C1-C3 alkoxy or halo) (phenyl, phenoxy, phenylthio, phenylsul fonyl or phenoxysulfonyl), C2-C6 alkanoylamino, benzoylamino, di phenylmethylamino (C1-C3 alkyl), aminocarbonyl, C1-C3 alkylaminocarbonyl, di (C1-C3 alkyl) aminocarbonyl, halo-alkanoyl Cj C6, aminosul fonilo, alkylaminosul fonilo C1-C3, di (C? -C3 alkyl) aminosulfon, phenyl (oxy or thio) (C1-C3 alkyl), (halo, C1-C3 alkyl, or C1-6 alkoxy) C3) phenyl (oxy or thio) (C 1 -C 3 alkyl), benzoyl, or (amino, C 1 -C 3 alkylamino, or di (C 3) alkyl) amino (C 1 -C 3 alkyl).

One aspect of the invention comprises converting a ketone of the formula wherein R is halogen, preferably bromine; to a protected ether, preferably using trimethyl orthoformate in methanol in the presence of a catalyst acid; reacting the protected ether with an alkyl lithium reactive compound, such as, n-butyllithium and a sulfur transfer reagent, such as dimethyl disulfide, to provide an S-methylated ether compound; and deprotecting the S-methylated ether compound to provide a met ilt iotet ralone compound of the formula II According to another aspect, the invention comprises converting the compound of formula II to a compound of formula I. One such preferred process comprises reacting the compound of formula II with (R) - (+) - phenethylamine to provide a compound of formula III H- reacting the compound of the formula III with a strong lithium base to provide a lithium-enamine compound of the formula IV methylating the resulting lithioanamine of formula IV to a compound of formula V, for example, reacting the resulting lithioenamine with methyl iodide in an ether solvent to prepare the compound of formula V reacting the compound of the formula V with an acyl halide or an acrylic acid anhydride to prepare a compound of the formula VI quenching the reaction with a base, and combining the residue comprising the compound of formula VI with an appropriate silane and trifluoroacetic acid in the absence of a solvent to prepare a compound of formula VII by reacting the compound of the formula VII with a methyl halide, for example, methyl iodide in a reaction mixture comprising an organic solvent and a strong base to provide an arylmethylsulphide compound of the formula VIII oxidizing the compound of the formula VIII for a sulphide compound of the formula IX reacting the sulfoxide compound of formula IX with an acylating agent to provide a Pummerer reconfiguration product; reacting the re-configuration product Pummerer with ur electrophile selected from the group consisting of A-R1 wherein A is a starting group and R1 represents: 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nit ronaphthyl, 4-nitrophthyl, 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1- isoquinol inyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-quinoxalinyl, 2-benzothiazolyl, 3- IH-indazolyl, 2-benzoxazolyl, 3-1,2-benzisothiazolyl, 2-pyridinyl, 4-pyridinyl, -pyrazinyl, 2-naphtho [2,3-d] thiazolyl, 2-naphtho [1,2-d] thiazolyl, 9-anthryl, 2-thiazolyl, 2-benzimide zolyl, 1-benz [g] isoquinolinyl, 8- benz [g] isoquinolinyl, 5-lH-t et razol ilo, 2 -quina zolinilo, 2-t iazolo [4, 5-b] piridinil, 4-10H-piridazino [3,2-b] -2-quinazolinil, 2-1,4-benzodioxinyl, 2-triazine, 2-benzoxazine, 4-benzoxazine, 2-purine or 8-purine; wherein the above R1 groups are substituted or unsubstituted with 1-3 groups selected from the group consisting of trifluoromethyl, tri-f-loredoxy, C1-C-alkyl, trifluoromethoxy, hydroxy, C1-C3-alkoxy, nitro, Cilt-C3 alkylthio , C 1 -C 3 alkanoyl, phenyl, oxo, phenoxy, phenylthio, C 1 -C 3 alkylsulfinyl, C 1 -C 3 alkylsulfonyl, cyano, amino, C 1 -C 3 alkylamino, diphenylmethylamino, triphenylmethylamino, benzyloxy, benzylthio, (mono-halo, nitro or CF 3 ) benzyl (oxy or thio), di (C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, or cycloalkylalkyl C -Clala, (mono-C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or halo) (phenyl, phenoxy, phenylthio , phenylsulfonyl or phenoxysulfonyl), C2-C6 alkanoylamino, benzoylamino, diphenylmetylamino (C1-C3 alkyl), aminocarbonyl, C1-C3 alkylaminocarbonyl, di (C1-C3 alkyl) aminocarbonyl, halo-alkanoyl Ci-Ce, aminosulfonyl, alkylaminosulfonyl C1 -C3, di (C1-C3 alkyl) aminosulfon, phenyl (oxy or thio) (C1-C3 alkyl), (halo, C1-C3 alkyl or C6-C3 alkoxy) phenyl (oxy or thio) ) (C1-C3 alkyl), benzoyl, or (amino, C1-C3 alkylamino or di (C1-C3 alkyl) amino) (C1-C3 alkyl); in the presence of a phase transfer catalyst, a reagent reductive hydride reductant and a base, to prepare a compound of formula I.

Preferred intermediates of the present invention have the formulas: The starting materials for the compounds in the claimed process whether they are commercially available, are known in the art, or can be prepared by methods known in the art, for example, see: Audia et al., In U.S. Pat. 5,239,075, published August 24, 1993 and European Patent Publication 0703221.

Throughout this document, all temperatures are described in degrees centigrade and all expressions of concentration, percentage and proportion are expressed in units of weight, except for solvent mixtures, which are described in units of volume, unless established otherwise.

References to the compounds herein include the pharmaceutically acceptable salts of such compounds, unless stated otherwise.

The different positions in the benzo [f] quinoline ring are indicated below.

The spatial configuration of the group in 10b and the hydrogen atom in 4a is required. The reader should understand that many of the compounds may exist in two or more stereochemical forms, and that all stereochemical forms are included in the present invention. In some of the compounds prepared or described below, simple enantiomers are prepared in pure form and are identified by the (+) or (-) nomenclature. In other cases, the mixture of diastereomers is prepared.

The group S-R1 occupies position 8.

The term "halogen" and "halo" include chlorine, bromine, fluorine and iodine.

Different alkyl groups, such as C 1 -C 4 alkyl and the like include groups such as methyl, ethyl, propyl, isopropyl, t-butyl, n-butyl and isobutyl. The alkenyl and alkylo groups constitute linking groups that are bivalent and bind to two other groups. For example, C2-C4 alkenyl includes ethenyl, 2-propenyl, 3-butenyl and 2-butenyl; and C2-C4 alkynyl includes, for example, ethynyl, 2-propynyl, 2-butynyl, and iso-2-butymyl.

The C6-C6 alkanoyl group includes such groups as formyl, acetyl, propionyl, isobutyryl, 2-ethylpropionyl and hexanoyl. The C3-C6 cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and the cycloalkylalkyl group C4-Ce includes, for example, cyclopropylmethyl, cyclohexylethyl, cyclobutylbutyl and cyclohexylmethyl.

Terms such as halo -C 1 -C 6 alkanoyl, halophenyl or C 1 -C 3 alkylphenyl refers to the indicated basic group having substitutions in their halo 1, 2 or 3 or C 1 -C 3 alkyl groups as can be described in the individual case.

The present process that prepares compounds of formula I has all the benzo [f] quinoline nuclei, in the benzo ring which is replaced by a cyclic R1 group linked to the benzoquinoline through a sulfur bond. The R1 groups can be substituted with additional organic groups, and can have at most three of said substituent groups. Many of the substituents may be the same or may be different.

Certain aspects of the process are preferred and will be specifically mentioned below. It will be understood that the following aspects are each individually important, and also that the preferred aspects can be combined to create preferred, more limited, more expanded, additional aspects.

Synthesis of 6-met ilt io-2-tetralona.

The starting material for the synthesis of 6-methylthio-2-tetralone is a 4-halophenylacetic acid (bromophenylacetic acid can be used for an example). 4-Bromophenylacetic acid is commercially available (Aldrich Catalog Handbook of Fine Chemicals 1994- 5, page 233) or can be prepared by procedures well known to those skilled in the art. 4-Bromophenylacetic acid is used to prepare 6-bromo-2-tet ralone. 6-bromo-2-ethyl ralone is prepared by reacting 4-bromo-phenylacetic acid with thionyl chloride, phosphorus trichloride, oxalyl chloride, or phosphorus pentachloride, under conditions known to those skilled in the art, to provide 4-bromophenacetyl chloride (Scheme 1). Preferably, thionyl chloride and methylene chloride are used to provide the 4-bromophenacetyl chloride. By means of a Friedel-Craft acylation reaction of 4-bromophenacetyl chloride with ethylene gas in the presence of a Lewis acid catalyst and an inert or substantially inert solvent or a mixture of solvents, ring closure is carried out for provide ß-bromo-2-tetralone.

SCHEME 1 Suitable Lewis acid catalysts include AlBr3, A1C13, A1I3, GaCl3, FeCl3, SbCl5, ZrCl4, SnCl4, BC13, BF3, SbCl3 and the like, preferably AICI3. The solvents used for this reaction include carbon disulfide, methylene chloride, nitromethane, 1,2-dichloroethane, nitrobenzene, and the like, preferably methylene chloride.

The ketone group of 6-bromo-2-tet ralone is protected by reaction with trimethyl orthoformate in a solvent, such as methanol, to provide the corresponding ethers according to the following Scheme 2. Hydrochloric acid, formed in situ by the addition of thionyl chloride acts as a catalyst in this reaction. One skilled in the art will recognize that other acid catalysts may be employed, for example, p-toluenesulfonic acid, phosphoric acid, etc. Temperatures from about 20 ° C to about 65 ° C are employed using standard cooling procedures.

SCHEME 2 The halogen-metal exchange is then provided by reacting the ethers protected by 6-bromo (A and B) with a reactive organolithium compound, preferably n-butylithium.

Alkylation of the resulting lithium species with an appropriate sulfur transfer reagent, for example, a sulfenyl halide or dimethyl disulfide, provides the ether protected by 6-met ilt io-2 -tet ralones. Deprotection is provided by methods known to those skilled in the art. A preferred method of deprotection is treatment with aqueous acid, preferably hydrochloric acid, to provide the desired 6-methylthio-2-tetralone compound (Schemes 3 and 4).

SCHEME 3 SCHEME 4 II All transformations, starting from 4-bromophenylacetic acid to the desired 6-methylthio-2-tetralone, can be carried out conveniently in a simple reaction flask without isolation of the intermediates. This improved process offers better yields, a reaction in a pot, the use of readily available reagents and is appropriate for large-scale production. The desired 6-met ilt io-2-tetralone can be isolated by standard methods, preferably by crystallization from the reaction mixture.

Alkylation and annulation aza.

A preliminary synthesis for the intermediate compound of formula VII is taught in U.S. Pat. 5,239,075 and U.S. Patent Application. Serial Number 08 / 443,994, each of which is incorporated herein by reference. A further synthesis of the compound of the formula VII, of which this invention is an improvement, is shown in European Patent Publication 0564193. The methylitol group of the compound of the formula VII is located in the 8-position. This preferred process for preparing the The compound of the formula VII, described below, can be carried out without purification or isolation of the intermediates.

The 6-t iomet il-2-tetralone is reacted with (R) - (+) - phenethylamine to prepare the intermediate of formula III The reaction is conveniently carried out at elevated temperature, particularly at reflux temperature, in toluene in the presence of a strong acid such as p-toluenesulfonic acid. The water that forms in this reaction must be removed, and the absence of water formed is an indication that the reaction has been completed. A slight excess of phenethylamine should be used, such as about 1.05-1.10 equivalents. Alternatively, tetrahydrofuran can be used as the solvent, and it is particularly convenient in the case of using molecular sieves for dehydrating the reaction mixture, using at least twice the weight of the molecular sieves compared to the amount of water that is released by the process .

The above phenethylamino compound is made of lithium with, for example, lithium n-butyllithium or diisopropylamide to provide a compound of formula IV When the reaction is carried out, as preferred, with lithium diisopropylamide, the best results are obtained if the lithium diisopropylamide is freshly generated from diisopropylamine and n-butyllithium immediately before being used in the process. A substantial excess, about 15-25%, of lithium diisopropylamide is used for the best results.

The reaction of the lithium diisopropylamide is best carried out in rahydrofuran at a low temperature in the range of about -100 ° to about 0 °, preferably about -78 ° to about -10 °. The phenethylamino compound does not need to be purified or isolated, but the first reaction mixture must be evaporated under vacuum and the residue is taken up in tetrahydrofuran. It is preferred to add the phenethylamino material, in a solution, to a solution of lithium diisopropylamide in cold tetrahydrofuran; the contrary way of adding it is operable but it provides low yields. In general, the reaction can be carried out in less than one hour.

The lithium compound is difficult to isolate and purify, and should be introduced into the process of the present invention as a solution in the lithiation reaction mixture.

Alkylation The lithium compound is methylated, for example by reacting the resulting lithioenamine with methyl iodide to provide the compound of the formula V : "i» v ", Dimethyl sulfate, methyl bromide, methyl chloride, methyl iodide, and the like can be employed to methylate the lithioenamine. It is convenient to use about 15-25% excess of methyl iodide, and to carry out the process in a solvent, preferably an ether solvent, such as diethyl ether, methyl t-butyl ether or, preferably, tetrahydrofuran . The reaction is very rapid at low temperatures in the range of about -100 ° to about -50 °, more preferably, about -80 ° to -60 °. Reaction times in the range from about a few minutes to about an hour are adequate, and a reaction time of 20 minutes is preferred.

If the lithium compound is in the form of the reaction mixture from lithiation with lithium diisopropylamide, and the reaction mixture therefore contains the excess diisopropylamine, the amine must be neutralized before methylation. More conveniently, the mixture of methyl iodide is allowed to warm to a temperature close to 0 °, and a sufficient amount of methanesulfonic acid is added to neutralize the diisopropylamine. Other strong acids can be used, but methanesulfonic acid is particularly convenient and is preferred because the methanesulfonate salt resulting from the diisopropylamine is only slightly soluble and therefore can be easily removed by simple filtration or centrifugation.

Nail override step The reaction mixture comprising the compound of the formula V is combined with an acyl halide or an acrylic acid anhydride or acryloyl chloride, or the like, to initiate the aza nullification reaction forming the compound of formula VI It is better to generate the acrylic anhydride, the preferred reagent, immediately before use by the reaction of acryloyl chloride and acrylic acid, using triethylamine and stabilizers, such as hydroquinone and butylated hydroxytoluene, in tet rahydrofuran.

Aza nullification is carried out by adding the acylic anhydride or acryloyl chloride to a very low temperature, such as from about -100 ° to about -70 °, and allowing the mixture to warm very slowly with stirring to a temperature in the range of about -20 ° to about 0 °, or even to about 10 ° -20 ° C. A period of time of 12-15 hours is reasonable to allow the mixture to warm. has been completed as desired, the reaction is quenched by the addition of solid sodium bicarbonate, use is preferred from about 1.5 to about 4 equivalents of base, more preferably about 2 equivalents. solution, for example, in water or in an aqueous solvent such as water / dimethylaminopyridine, but it is preferred to add the base in solid form.The reaction mixture is stirred with the base turned off for a short period, and then the mixture is filtered, the volatiles are removed, and the solvent can be replaced with an ether solvent, preferably diethyl ether, and the organic solution can then be worked by washing with an aqueous base and aqueous acid, and perhaps with steps of additional purification such as a wash with a saturated saline solution. If such working steps are used, the solution is then dehydrated and evaporated under vacuum to obtain the non-volatile portions of the reaction mixture, containing the final intermediate of formula VI.

On the other hand, the residue of the quenched reaction mixture can be taken out of work, if desired.

Reduction-partition step.

The residue of the aza nulling step is cooled, and a cooled mixture of an appropriate silane and trifluoroacetic acid is added. A suitable silane is a soluble silane, for example a dialkylsilane or tialkylsilane or the like. The addition takes place at a low temperature in the range from about -40 ° to about 0 °, and no other solvent is used. A large amount of trifluoroacetic acid, in the range of about 10-50 equivalents, more preferably about 20-30 equivalents, is used. The preferred trialkylsin is t-riet ilsilane, although trimethsilylsilane, t-isopropylsilane and the like can also be used. A substantial excess of tialkylsilane is used, in the range of about 5-20 equivalent, more preferably about 7-15 equivalents. The mixture is stirred for about 10-20 hours while allowing it to slowly warm to about 30 °, and then the mixture is slowly heated to an elevated temperature, preferably reflux temperature, and stirred at this temperature for a few hours. , such as about 2-6 hours to complete the formation of the compound of formula VII Purification The residue containing the product of formula VII can be dissolved, preferably in a haloalkane such as dichloromethane, washed with a base, such as aqueous sodium bicarbonate, and concentrated under vacuum. The purification is provided by recrystallization from, for example, ethyl acetate and methyl t-butyl ether or acetone or the like.

N-alkylation process It is necessary in the synthesis to methylate nitrogen in position 4 in the benzo [f] quiniline ring. The U.S. Patent 5,239,075 shows such alkylation by a reaction with alkyl iodide in the presence of a strong base such as sodium hydride. An additional alkylation is shown in EPO publication 0703221.

N-methylation comprises reacting a compound of formula VII with a methyl halide, for example, methyl iodide in a reaction mixture comprising an organic solvent, for example a solvent selected from the group consisting of tetrahydrofuran, dimethoxyethane , diethoxyethane and methyl t-butyl ether, and a base, for example, potassium t-butoxide and tetrahydrofuran, aqueous sodium or potassium hydroxide, to provide a compound of formula VIII This alkylation process allows an effective alkylation, under benign and easily controlled conditions, and allows an easy isolation of the products.

The alkylation process is carried out in a conventional chemical plant equipment, preferably at ambient pressure and at moderate temperatures. Preferably it is made by mixing the starting material of the formula VII in the organic solvent at a temperature close to that of the environment, such as from about 0 ° to about 50 °, more preferably from about 15 ° to about 25 ° . The most preferred organic solvent is tetrahydrofuran, and it is preferred to use about 5-15 liters of the solvent per kilogram of starting material; more preferably, the volume of the solvent is about 10 liters per kilogram. The alkyl iodide is then added as a pure liquid. A substantial excess of alkyl iodide is preferably used, such as about 1.2-1.8 equivalents based on the starting material, more preferably about 1.5 equivalents.

The aqueous sodium or potassium hydroxide is then added, still at room temperature, in an amount of about 1-4 liters per kilogram of the starting material. The amount of aqueous base is somewhat dependent on the concentration of the base and the choice of sodium or potassium hydroxide; when the most preferred base is used, 50% sodium hydroxide, the most preferred amount thereof is about 2 liters per kilogram of starting material. So, the reaction medium, consisting of solid material mixed in two liquid phases, is warmed to about 25-26 ° with vigorous stirring and the reaction is allowed to proceed at about a constant temperature with stirring. The preferred reaction temperature is ci'2 about 35-40 °. As the reaction proceeds almost to completion, the solid starting material and the alkyl iodide dissolve and react, so that the disappearance of the solids is a crude indication that it was completed. The reaction can be followed by high pressure liquid chromatography on a C-18 silica gel column, eluting with acetonitrile: aqueous 1: 1 saline solution (5% ammonium acetate) and observed at 220 nanometers.

When the reaction is desired to be near completion, the mixture is cooled to about room temperature and the aqueous layer is separated and discarded.

A preferred purification and isolation process proceeds by diluting the organic layer with water, and neutralizing it with aqueous mineral acid. Then the solution is distilled until the steam temperature reaches about 69-80 °, removing most of the tetrahydrofuran. Slow cooling to about 5 ° for a period of about 1-14 hours crystallizes the product, which only needs to be washed with water and dried to be ready for use as an intermediary or as a pharmacist. The most preferred isolation and purification is the recrystallization of the residue after removal of the tetrahydrofuran with ethyl acetate.

The alkylation process provides the product in the same stereochemical manner as the starting material, in a satisfactory purity for the pharmaceutical industry, and in yields of up to 90% when operated in accordance with preferred manners.

Electrophilic coupling The electrophilic coupling of the Rl substituent to the sulfur group in the benzo [f] quinolinone ring can be provided in accordance with the following Scheme V.

SCHEME V, VIII IX wherein R1 is as defined above in formula I.

Oxidize (+) - (4aR) - (lObR) - - methyl - 8 - met ilt io - 10b - methyl - l, 2, 3,, 4a, 5, 6, lOb - octahydrobenzo [f] quinolin - 3 ona for a sulfoxide compound. M-chloroperoxybenzoic acid is a preferred oxidizing agent. With or without isolation, the sulfoxide compound is subjected to a Pummerer reaction as taught by Young et al., Te t ra h edron Le t t. 25, 1753 (1984), such that the sulfoxide reacts with an acylating agent, such as trifluoroacetic anhydride, to provide a trifluoroacetyloxymethyl sulfide compound (X). The trifluoroacet-yloxymethyl sulfide compound is reacted with an electrophilic reagent, a hydride-reducing reagent, such as sodium borohydride, potassium borohydride, lithium borohydride or the like, and a base, preferably a hydroxide or carbonate, more preferably , potassium carbonate, to prepare a compound of formula I. For the purpose of this reaction, suitable acylating agents include acyl halides, such as, acetyl chloride, sulfonic acid halides, reactive anhydrides, such as, trichloroacetic anhydride, phosphoric acid anhydride, sulfonic acid anhydride and similar agents capable of yielding a Pummerer reconfiguration product.

By the methods known in the art, the electrophilic reagent is replaced with a partition group, such as halogen, sulfate, sulfonate or the like. The electrophilic reagent is then coupled to the sulfur in the benzo [f] quinolinone ring. The preferred electrophilic reagent is 2-chloro-4-ethylbenzothiazole and this reagent is coupled with the compound of formula X to provide the (+) - (4aR) - (lObR) -4-methyl-8- (4-ethyl) -2-benzothiazolium) -lOb-methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one.

Preferably a catalyst, for example tetrabutylammonium hydrogen sulfate, is used to direct the coupling of the trifluoroacetyl yloxymethyl sulfide with the electrophilic reagent. Sodium borohydride has been found to induce the reduction of trifluoroacetylloxymethyl sulfide compound. Also, formaldehyde is generated if it is environmentally and pharmaceutically unacceptable. The present process reduces formaldehyde as it is formed for methanol. Also, in accordance with the present process, disulfides formed from oxidation to air are reduced in s i t u. This step of the process allows the starting materials to use more completely and rigorously exclude oxygen, or impurities that promote oxidation, if they are unnecessary. The addition of the base to the mixture is not essential to promote the coupling. However, the decomposition of borohydride is slow, and the relative coupling ratio is accelerated, adding a base.

The following preparations further illustrate the present inventive process. The preparations are not intended to limit the scope of the invention in any way and are not constructive.

Unless otherwise noted, the starting materials are obtained from commercial suppliers and used without further purification. Toluene, dimethylformamide, and methylene chloride are stored on 4Á molecular sieves. The reactions use organometallic reagents where they run under nitrogen. The reactions are observed by high pressure liquid chromatography using the conditions specified below. Thin layer chromatography is given using Merck Silica Gel 60 trays with a fluoiscent indicator (F254). The 1H and 13C NMR spectra are recorded on a General Electric QE or Bruker 300 MHz spectrophotometer at room temperature using CDC13 as solvent unless otherwise specified. The chemical changes of NMR were recorded in ppm with a solvent as the internal standard in the scale d and the J values are in Hertz. The IR, UV, and Mass Spectrometry (MS) analyzes are given by the Eli Lilly Physical Chemistry Laboratory. The conditions of high pressure liquid chromatography are: Intelligent pump model L-6200A of Hitachi with a chromatointegrator D-2500. Column RX C-18 Zorban of 25 cm, 60:40 of CH3CN / H20, 1.0 mL / minute, 275 nm, Injection - 10 uL. Gas chromatography (GC) conditions: HP 5890A GC with DB1 column 0.25 μ x 25 m; injection temperature 300 ° C; 300 ° C detection (FID); column at 5 ° C (5 minutes), 18 mL / minute up to 250 ° C and then at 250 ° C for 20 minutes. The terms "NMR", "MS", "IR" and / or "GC" indicate that the spectrum of the product was analyzed and is consistent with the desired structure.

Preparation 1 The 6-bromo-2-methyl yl ethers (A and B) 6-methylthio-2-methyl ethers (C and D) and 6-met ilt io-2-tetralone (11). The trimethyl ilortoformate (26.7 mL, 0.24 mol) and thionyl chloride (260 mg, 2.2 mol) are added to a thick mixture of 6-bromo-2-tetralone (50 g, 0.22 mol) in methanol (500 mL) under an atmosphere of nitrogen. After stirring 3-5 hours at room temperature, the solvent was removed under reduced pressure. The heptane (500 mL) was added to the residue and the solvent was removed again under reduced pressure to yield a residual oil.

The residual oil was dissolved in tetrahydrofuran (400 mL) and cooled to -78 ° C under a nitrogen atmosphere. The n-butyllithium (1.3 M in hexanes, 190 mL, 0.24 mol) was added to the solution after 15 minutes later by the slow addition of methyl disulfide (23.8 mL, 0.26 mol). The mixture was stirred 10 minutes at -78 ° C and then allowed to warm at 10 ° C for 45 minutes. After the addition of IN hydrochloric acid (200 mL) the mixture was concentrated under reduced pressure in a rotary evaporator (bath temperature 45 ° C) for 1 hour. The additional tetrahydrofuran (50 mL) was added to the mixture and the concentration was continued until the hydrolysis of the enol ether intermediate was completed in accordance with the GLC. The mixture was then extracted with ethyl acetate (2 x 100 mL). The ethyl acetate layers were dried over Na 2 SO 4 and concentrated under reduced pressure to a volume of 50 mL. The heptane was added slowly to the concentrated ethyl acetate and the resulting crystals were stirred 1 hour at 0 ° C, filtered, and dried to afford 30.6 g of 6-methylthio-2-tet ralone (72% yield), mp 57-58 ° C GLC 99.5%.

Preparation 2a (+) - (4aR) - (10bR) -8-met ilt io-lOb-met il- 1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one.

A solution of 6-met ilt io-2-tet ralone (1 gram, 5.2 mmol, 1 equivalent) in dry toluene (18 mL) was treated with (R) - (+) -fenet-ilamine (0.72 mL, 5.7 mmol, 1.1 equivalent) and p-TsOH (6 mg).

The solution was degassed 3 times with light vacuum / nitrogen and a positive nitrogen pressure was maintained. The solution went to t * «^,,", - ^^, ".a-_, A -».,.

Reflux temperature under Dean-Stark conditions to remove water. The progress of imine formation was monitored by NMR. After 2.5 hours of reflux temperature, no starting ketone could be detected by 1R NMR. The toluene was completely distilled with a light vacuum and under nitrogen carefully not exposing the mixture to the air. Dry tetahydrofuran (14 mL) was added to obtain a light purple solution which was maintained at -70 ° C under nitrogen. The lithium diisopropylamide was generated by the dropwise addition of 2.5 M hexanes in a solution of n-butyllithium (2.4 mL, 6.0 mmol, 1.15 equivalent) to a solution of diisopropylamine (0.78 mL, 6.0 mmol, 1.15 equivalent) in tetrahydrofuran. (19 mL) at -45 ° C under nitrogen. The temperature was maintained between -45 ° C and -30 ° C during the addition. After addition, the solution was stirred for 10 minutes at -45 ° C. During the cooling of the lithium diisopropylamide solution at -75 ° C, the imine solution was added dropwise for 15 minutes through cannula while maintaining the temperature between -70 ° C and -75 ° C. The resulting orange-yellow lent solution was allowed to warm to -20 ° C for 20 minutes and then cooled again to -75 ° C. Iodomethane (0.36 ml, 5.8 mmol, 1.15 equivalent) was added between -75 ° C and -72 ° C. The solution was warmed (with the aid of an acetone bath) for 15 minutes at 0 ° C. During re-cooling at -5 ° C, methane sulphonic acid (0.43 mL, 6.6 mmol, 1.3 equivalent) was added for 2 minutes between -5 ° C and 1 ° C. After 5 minutes at 0 ° C, a gray heterogeneous mixture resulted. The mixture was re-cooled to -75 ° C. A 1.125M tetrahydrofuran solution of acrylic anhydride (11 mL, 12.5 mmol, 2.4 equivalents) was added rapidly. The mixture was kept in the cooling bath for 15 hours, during which time it was heated to 13 ° C. The reaction was allowed to warm to 15 ° C. Water (2 mL) was added and the mixture was stirred while the mixture was warmed to room temperature. The solution was diluted with diethyl ether (50 mL) and washed successively with IN sodium hydroxide (20 mL), IN hydrochloric acid (20 mL), water (20 mL), saturated aqueous sodium bicarbonate (40 mL), and brine (20 mL). The sodium sulfate solution was dried, concentrated and flash chromatographed on silica gel (120 grams), eluting with 70:30 ethyl acetate / hexanes) to obtain 1.3 grams of (69% yield) of (+ ) - (lObR) -4 - (2- (R) -phenethyl) -8-methylthio-10b-methyl-1,2,3,6,9-hexahydrobenzo [f] quinolin-3-one (RMN). A mixture of triethylsilane (12 mL, 75 mmol) and trifluoroacetic acid (14.5 mL, 188 mmol) previously cooled to -15 ° C under nitrogen was added to (+) - (10bR) -4- (2- (R) - phenethyl) -8-met ilt io-lOb-met il-1, 2, 3, 4, 6, lOb-texahydrobenzo [f] quinolin-3-one (2.76 grams, 7.6 mmol) previously cooled in a -15 bath ° C. The mixture was stirred for 15 hours during which time it was warmed to 13 ° C. Thin layer chromatography (70:30 ethyl acetate / hexanes) and high pressure liquid chromatography showed complete disappearance of (+) - (10bR) -4- (2- (R) -phenethyl) -8- meti 11i-1 Ob-meti 1-1, 2, 3, 4, 6, lOb-hexahydrobenzo [f] -quinolin-3-one and the appearance of a new product, indicating the reduction of double complete binding. The mixture was then refluxed for 2 hours to remove the auxiliary chiral. During cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was taken up in methylene chloride (50 mL) and washed twice with saturated aqueous sodium bicarbonate (35 L) and brine (50 mL). The sodium sulfate was dried and the crude crude product was purified by flash chromatography on silica gel (100 grams), eluting first with 3: 1 ethyl acetate / hexanes to remove triethylsilane and then with 14% methanol in chloride of methylene with 1% acetic acid to obtain a foamy solid. Recrystallization from hot ethyl acetate gave 1.6 grams (82%) of (+) - (4aR) - (10-R) -8-met-ilthio-O-methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one (92% ee, IR, NMR, MS). Calculated for C15H19N0S; C, 68.93; H, 7.33. Found C, 69.05; H, 7.44.

Preparation 2b (+) - (4aR) - (10bR) -8-methylthio-lOb-methyl-1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [f] quinolin-3-one.

A solution of the compound 6-met ilt io-2-tetralona (9.6 g, 50 mmol), p-toluenesulfonic acid monohydrate (40 mg, 0.2 mmol) and R - (+) - a-met i lben zylamine (6.64 g) , 55 mmol) in toluene (150 mL) was heated to reflux temperature. The water generated during the reaction was removed through a Dean-Stark network. The progress of the reaction was monitored by NMR (300 mHz, CDC13) which indicated 100% conversion after 2 hours of reflux temperature. The enamine solution was concentrated to a volume of 30 mL by atmospheric distillation. The enamine solution was then cooled to -78 ° C, diluted with tetrahydrofuran (100 mL) and added via canula to a solution of lithium diisopropyl amide (2.0 M in heptane / THF) (28.7 mL, 57.5 mmoles) and tetrahydrofuran (130 mL). After stirring for 30 minutes at 78 ° C, iodomethane (3.6 mL, 57.5 mmol) was introduced and stirring continued for another 30 minutes at -78 ° C. The methanesulfonic acid (4.05 mL, 62.5 mmol) was added followed by a warming of the reaction mixture at 0 ° C. In a separate vessel, acrylic acid (6.6 g, 91.5 mmol) was added slowly to a solution of triethylamine (9.25 g, 91.5 mmol), hydroquinone (0.11 g) and 2,6-di-tert-butyl-4-methylphenol (0.11 g) in tetrahydrofuran ( 100 mL) a -10 ° C to -15 ° C. Trimethylacetyl chloride (11.0 g, 91.5 mmol) was added slowly, maintaining the temperature at less than -5 ° C. The reaction mixture was stirred 2 hours at -10 ° C, then filtered and the filtered solids were washed with 20 L of tetrahydrofuran. The filtrate and sodium bicarbonate (NaHCO3) (9.2 g, 110 mmol) were added to the enamine solution and the resulting mixture was stirred at 0 ° C for 4 hours. Deionized water (190 mL) was added and stirring continued for 0.5 hours at 0 ° C. the solvent was then removed by vacuum distillation (temperature < 30 ° C). Methylene chloride was added (90 mL) and the layers separated. The methylene chloride layer was washed sequentially with a solution of IN NaOH (4 x 25 mL), an IN hydrochloric acid solution (20 mL) and a saturated sodium bicarbonate solution (20 mL). The solvent was then removed from the reaction mixture by vacuum distillation (temperature < 30 ° C). Triethyl-silane (80 mL, 500 mmol) and trifluoroacetic acid (100 mL, 1.3 mol) were added and the resulting mixture was stirred at 27-32 ° C for 12 hours followed by 6 hours at reflux temperature. The progress of the reaction was monitored by HPLC (such as 25 cm of Supelcosil LC-ABZ, 40% isocratic deionized water / 60% acetonitrile, 220 nm, 2 mL / minute) which indicated a> 95% conversion The reaction mixture was then concentrated by vacuum distillation to about 70 mL and diluted by the addition of acetonitrile (70 mL). The acetonitrile solution was washed with heptane (6 x 25 mL). The acetonitrile was removed by vacuum distillation and the residue was dissolved in methylene chloride (50 mL). A saturated solution of sodium bicarbonate (150 L) was added slowly and the layers separated. The methylene chloride layer was washed with a solution of sodium bicarbonate (150 mL) and the solvent was removed by vacuum distillation. The residue was diluted with ethyl acetate (40 mL) and the resulting mixture was stirred at -30 ° C for 1 hour. The mixture was filtered and the filter cake was washed with cold ethyl acetate (-30 ° C) (10 mL) followed by drying at 50 ° C to give 6.22 g (49%) of (+) - (4aR) - (lObR) -8-methylthio-10b-methyl-l, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [f] quinolin-3-one (GLC purity 99.5%).

Preparation 3 (+) - (4aR) - (lObR) -4-methyl-8-methylthio-10b-methyl-l, 2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3- ona (+) - (4aR) - (lObR) -8 -methylthio-1 Ob-met i 1-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one (0.423 grams, 1.62 mmol, 1.0 equivalents) was treated with potassium t-butoxide (1.86 mL as a 1.0 M solution in tetrahydrofuran), 1.15 equivalents) in dimethylformamide (1.6 mL) at about 0 ° C. After stirring 5 minutes, methyl iodide (0.116 mL, 1.15 equivalents) was added and the mixture was allowed to stir for 2 hours at 0 ° C. The mixture was then treated with about 100 mg of acetic acid and the solvents were removed in a stream of nitrogen. The solid was dissolved in about 50 mL of methylene chloride and washed twice with water. The extracts were dried (molecular sieves 4) and filtered on silica gel (2 grams, washed with ethyl acetate containing 2% methanol). The solid from the evaporation of the methylene chloride extracts was chromatographed on silica gel with methylene chloride, ethyl acetate and methanol (50: 50: 1) as the eluent. (GC).

Preparation 4 (+) - (4aR) - (lObR) - -methyl- 8- (4-ethyl-2-benzothiazolylthio) -10b-methi 1-1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [ f] quinolin-3-one.

A solution of meta-chloroperoxybenzoic acid (about 56% strength, 6.32 grams as a methylene chloride solution) was added to the mixture of (+) - (4aR) - (1 ObR) -8-methylthio-10b-methyl-1,3, 4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one. (5.50 grams in 110 mL of methylene chloride) and aqueous sodium bicarbonate (9.4 grams in 110 mL of water) at 0 to 1 ° C for about one hour. After 8 horde, the layers were separated and the organic extracts were washed twice with 1% aqueous sodium bicarbonate, dried (Molecular sieves 4Á) and evaporated to a total weight of 5.90 grams. A portion (2.91 grams) of this unpurified sulfoxide in 10 L of toluene-ds sa treated with 2.20 mL of trifluoroacetic anhydride at 5-10 ° C. after 30 minutes, the XH NMR analysis of an aliquot of 0.50 mL did not show the starting sulfoxide (absent singlet of ArSOCH3 at d = 2.25 ppm) and the exclusive formation of the Pummerer Product (ArSCH2OCOCF3, singlet at d = 5.31 ppm). The reaction mixture was subjected to vacuum (5-10 torr) for 30 minutes after which the contents were added to a stirred mixture (under nitrogen) of water (20 mL), tet ra-n-but hydrogen sulfate ilamonium (0.1 gram), and 7.1 mL of water-soluble borohydride (12% by weight of sodium borohydride in 14 N sodium hydroxide) at 5-10 ° C for 20 minutes. After an additional 20 minutes, 2-chloro-4-ethylbenzothiazole (3.00 grams with an additional 9.5 mL of toluene-ds) and another portion of tetra-n-butylammonium hydrogen sulfate (0.50 gram) were added. The reaction was stirred at 37-39 ° C during which four 0.25 mL portions were removed by direct 1 H NMR test and high pressure liquid chromatography by analysis of product conversion and distribution. After 26 hours, the uppermost layer (toluene containing (+) - (4aR) - (10 bR) -4 -met i 1-8- (4 -eti 1-2 -benzot ia zol i lt io) -10b -methyl-1, 2, 3, 4, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one and an excess of 2-chloro-4-ylbenzothiazole) of the three-phase mixture, separated and diluted with 25 mL of methylene chloride. This organic layer was washed with IN aqueous sulfuric acid, 5% aqueous sodium bicarbonate, dried with 4 A molecular sieves, concentrated in vacuo to 5.24 grams. The resulting solid was taken up in warm methyl t-butyl ether (30 mL) after which it was concentrated under vacuum to 20 mL and then cooled to 0 ° C. The mixture was filtered and the white solid was dried to give 2.92 grams of (+) - (4 aR) -lObR) -4-met il-8 - (4-yl-2-benzothiazolylthio) -lOb-met i 1- 1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [f] quinolin-3-one (IR, NMR, MS). Calculated for C 24 H 26 N 2 OS 2: C, 67.93; H, 6.16; N, 6.83; S, 15.08. Found C, 68.21; H, 6.20; N, 6.63; S, 15.17.

Preparation 5 (+) - (4aR) - (10bR) -4 -met-il-8- (4-ethyl-2-benzothiazolium) -10b-methyl-1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [f] quinolin-3-one.

A solution of meta-chloroperoxybenzoic acid (35.2 mmoles in 100 mL of methylene chloride) was added to (+) - 4aR) - (lObR) -mt-il-8-met ilt io-lOb-methyl-l, 2,3,4,4a, 5, 6,10b-octahydrobenzo [f] quinolin-3-one (10.0 grams, 98% pure by heavy standard power assay, . 6 mmole) in a biphasic mixture of methylene chloride (200 mL) and aqueous sodium bicarbonate. (8.90 grams in 89 mL of water) at -2 to 0 ° C for a period of 1 hour. The layers were separated and the methylene chloride layers were washed once with sodium metabisulfide (1.00 grams in 25 mL) and three times with sodium bicarbonate (1.00 grams in 100 mL). The dried methylene chloride extract (4Á molecular sieves) was concentrated to approximately 20 mL and diluted with 100 mL of toluene. The mixture was then concentrated under vacuum at 30-35 ° C. This process was repeated twice with fresh toluene (100 mL each portion) after which the sulfoxide (usually crystalline) was diluted with toluene (100 mL). The mixture was then treated with trifluoroacetic anhydride (7.30 mL) for 10 minutes at 0 to 10 ° C. After 30 minutes at 0 ° C, this solution was subjected to vacuum (<10 torr) for 30 minutes and added for 30 minutes to a degassed (nitrogen) mixture of potassium carbonate (41 grams), sodium borohydride (2.88 grams), tetra-n-butylammonium hydrogen sulfate (2.00 grams) , and 2-chloro-4-ethylbenzothiazole (8.20 grams at 96.5% purity dissolved in 5 mL of toluene) and water (87 mL) at 0-5 ° C. The mixture was heated to 40 ° C for one hour and then stirred at 40 ° C for 26 hours. The toluene layer was separated (while it was lukewarm) and washed with 3xl00-mL portions of water. The toluene layer was diluted with 125 mL of ethyl acetate and then washed sequentially with portions of 3x200 mL of 0.25N hydrochloric acid, 100 mL of 1% sodium bicarbonate and 100 mL of saturated aqueous sodium chloride. The organic layer was dried (10 grams of molecular sieves 4A), concentrated to a total volume of 25 mL and treated with 100 mL of methyl t-butyl ether (at reflux temperature for 30 minutes then, at 0 ° C. for 1 hour) provided (+) - (4aR) - (lObR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) -lOb-met il-1, 2, 3, 4, a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one.

Preparation 6 (+) - (4aR) - (10bR) -4-methi 1-8- (4-ethyl-2-benzothiazolium) -10b-methyl-1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [f] quinolin-3-one.

Dry sulfoxide IX (96% purity by gas chromatography, 8.90 grams, corrected 29.4 mmol) as a suspension in toluene (89 mL) was treated dropwise with trifluoroacetic anhydride (5.2 mL) at 0-5 ° C at 20 ° C. minutes (dissolution occurred). After 30 minutes, the solution was added to the mixture of potassium carbonate (32 grams), water (45 mL), tetrabutylammonium hydrogen sulfate (2.25 grams), sodium borohydride (1.0 grams), 2-chloro- 4-ylbenzothiazolo (7.07 grams, approximately 96.5% purity by gas chromatography), and toluene (10 mL) at about 5-15 ° C for 30 minutes. The biphasic mixture was then stirred for 20 hours at 43 ° C after which a small amount of solid was filtered out of the reaction mixture. The warm toluene layer was washed once with 400 mL of water (45 ° C) and then evaporated under vacuum with 13.86 grams of a "Ja, -sÜS, 0» a¿ai3p- -, a. * -? and. white solid consisting mainly of (+) - (4aR) - (lObR) -4-met i 1-8- (4-ethyl-2-benzothiaolthio) -10b-methyl-1, 2, 3, 4, 4a, 5 , 6, 10b-octahydrobenzo [f] quinolin-3-one and 2-chloro-4-ethylbenzothiazole. 13.0 grams of this mixture were treated with methyl t-butyl ether (50 mL at reflux temperature and then at 0 ° C for 2 hours) yielding 11.05 grams of (+) - (4aR) - (lObR) -4-methyl -8- (4-ethyl-2-benzothiaolthio) -10b-methyl-1, 2,3,4,4, 5,6,10b-octahydrobenzo [f] quinolm-3-one (IR, NMR, MS) . Calculated for C, 68.21; H, 6.20; N, 6.63. Found C, 68.29; H, 6; N, 6.67.

Preparation 7 (+) - (4aR) - (10bR) -4 -met i 1-8- (4-ethyl-2-benzothiazol) -10b-methyl-1, 2,3,4,4a, 5,6, 10b-octahydrobenzo [fj quinolin-3-one.

Meta-chloroperoxybenzoic acid (approximately 92 grams, approximately 50% power, in 1.0 L of methylene chloride) was added at 0 ° C to a solution of (+) - (4aR) - (10bR) -4-met? l-8-met ? l ti or -10b-methyl-1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo [f] quinolin-3-one (79.5 grams, 92.9% strength, 0.269 moles) in methylene chloride (2.2 L). The progress of the reaction was monitored by high pressure liquid chromatography (240 nm) by the oxidation of (+) - (4aR) - (lObR) -4-methyl-8-methylthio-10b-methyl- 1, 2, 3 ,, 4a, 5, 6, lOb-octahydrobenzo [f] quinolin-3-one to a level of less than 0.3% per area. The organic solution was stirred with a solution of sodium bisulfate (75 grams in 1 L of deionized water). The organic layer was separated, and washed with a 6% sodium bicarbonate solution (3 x 1 L). The organic layer was dried over sodium sulfate and concentrated. Toluene (1 L) was added to the intermediate sulfoxide and this solution was concentrated under vacuum. This was repeated twice with fresh toluene (1.1 L each) after which the sulfoxide was dissolved in 1.1 L of toluene and cooled in an ice bath. Trifluoroacetic anhydride (51 mL) was added dropwise to the sulfoxide at 0 ° C for 15 minutes. After 30 minutes of stirring at 0 ° C, the Pummerer product (ArSCH2OCOCF3) was added through a cannula to a well-stirred mixture of deionized water (414 mL), potassium carbonate (319 grams), sodium borohydride (15.2 grams), 2-chloro-4-ethylbenzothiazole (65.7 grams) approximately 96.5% purity), tetrabutylammonium hydrogen sulfate (21.6 grams), and toluene (170 mL) at 10 ° C. The reaction was slowly heated to 42 ° C while the progress was monitored by high pressure liquid chromatography. After 18 hours, an additional volume of toluene (1.0 L) was added and the toluene layers were washed with deionized water (3 x 1 L, 45 ° C). Ethyl acetate (1 L) was added to the organic layer, then the organic layer was washed with 0.25 M hydrochloric acid solution (3x1 L), IN sulfuric acid solution (3x1 L), 6% sodium bicarbonate solution. % (1.5 L), and saturated sodium chloride solution (2 L). The organic extracts were dried over 4Á molecular sieves (500 grams) and then concentrated. Methyl t-butyl ether (400 mL) was added and the mixture was heated to reflux temperature. After 30 minutes of stirring at reflux temperature, the mixture was cooled to 5 ° C. The suspension was filtered and washed with methyl t-butyl ether (100 mL). The solution was filtered and the product was dried at 50 ° C to about 5 mm for 18 hours «M ^ ^ S ^ Ii» a) μ- »proprocionado 90.1 grams (80%) of (+) - (4aR) -lObR) -4-methyl-8- (4-ethyl-2-benzothiazoliltio) -10b- methyl-l, 2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (5)

Claims A process for preparing a compound of the formula I characterized in that R1 represents: 2-Nitrophenyl, -nitrophenol, 2-cyanophenyl, 4-cyanophenyl, 2-nitrophenolyl, 4-nitrophenyl-2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, isoquinolinyl, 3-isoquinol in i lo, 8 -i soquinolinilo, 2-quinoxal ini lo, 2-benzotiazolilo, 3- lH-inda zoli lo, 2-benzoxazolilo, 3- 1, 2-benzoisot aiazolilo, 2-piridinil, 4 -pyridinyl, 2-pyrazinyl, 2-naphtho [2,3-d] thiazolyl, 2-naphtho [1,2-d] thiazolyl, 9-anthryl, 2-thiazolyl, 2-benzimidazolyl, 1-benz [g] isoquinolini lo, 8-benz [g] isoquinol inyl, 5-lH-tetrazolyl, 2-quinazolinyl, 2-t-azolo [4, 5-b] pyridinyl, 4-10H-pyridazino [3,2-b] -2-quinazolinyl , 2-1, 4-benzodioxinyl, 2-triazine, 2-benzoxazino, 4-benzoxazino, 2-purine or 8-purine; wherein the above groups R1 are substituted or unsubstituted with 1-3 functionalities selected from the group consisting of trifluoromethyl, trifluoroethoxy, C? -C4 alkyl, trifluoromethoxy, hydroxy, C1-C3 alkoxy, nitro, C1-C3 alkylthio, C-alkanoyl -Ce, phenyl, oxo, phenoxy, phenylthio, alkylsulfin C1-C3, C1-C3 alkylsulfonyl, cyano, amino, C1-C3 alkylamino, diphenylmethylamino, triphenylmethallyn, benzyloxy, benzylthio, (mono-halo, nitro or CF3 ) benzyl (oxy or thio), di (C1-C3 alkyl, C3-C6 cycloalkyl, or C4-Cj cycloalkylalkyl) amino, (mono-C1-C3 alkyl, C1-C3 alkoxy or halo) (phenyl, phenoxy, phenylthio, phenylsulfonyl or phenoxysulfonyl), C2-C2 alkanoylamino, benzoylamino, diphenylmetylamino (C1-C3 alkyl), aminocarbonyl, C1-C3 alkylaminocarbonyl, di (C1-C3 alkyl) aminocarbonyl, halo-Ci-C6 alkanoyl, aminosulfonyl, alkylaminosul fonilo C1-C3, di (C? -C3 alkyl) aminosulfonilo, phenyl (oxy or thio) (C1-C3 alkyl), (halo, C1-C3 alkyl, or C1-C3 alkoxy) feni l (oxy thio) (C 1 -C 3 alkyl), benzoyl, or (amino, C 1 -C 3 alkylamino, or di (Cinylamino alkyl) (C 1 -C 3 alkyl); which comprises converting a ketone of the formula where R is halogen, preferably bromene to a protected ether, reacting the protected ether with a reactive alkylthio compound and a sulfur transfer reagent to provide a S-methylated ether compound; deprotecting the S-methylated ether compound to provide a methototreotone compound of the formula II reacting the compound of formula II with (R) - (+) - phenethylamine to provide a compound of formula III reacting the compound of formula III with a strong lithium base to provide a lithium-enamine compound of formula IV methylating the resulting lithioanamine of formula IV for a compound of formula V reacting the compound of the formula V with an acyl halide or an acrylic acid anhydride to prepare a compound of the formula VI quenching the reaction with a base, and combining the residue comprising the compound of formula VI with an appropriate silane and trifluoroacetic acid in the absence of a solvent to prepare a compound of formula VII reacting the compound of the formula VII with a methyl halide in a reaction mixture comprising an organic solvent and a strong base to provide an arylmethyl sulfide compound of the formula VIII oxidizing the compound of formula VIII for a sulfoxide compound of formula IX reacting the sulfoxide compound of formula IX with an acylating agent to provide a Pummerer reconfiguration product; reacting the reconfiguration product Pummerer with an electrophile selected from the group • consisting of A-R1 wherein A is a starting group, in the presence of a phase transfer catalyst, a hydride reagent reagent and a base, to prepare a compound of the formula I. 2. A process for preparing the compound of formula II characterized in that it comprises: converting a ketone of the formula wherein R is halogen; to a protected ether; reacting the protected ether with an alkyl lithium reactive compound and a sulfur transfer reagent to provide an S-methylated ether compound; deprotecting the S-methylated ether compound to provide a methototothiatalone compound of the formula II. 3. The process according to claim 2, characterized in that R1 is bromine, the sulfur transfer reagent is dimethyl disulfide and the trimethyl orthoformate was used to produce the protected ethers A and B: A CH, 0 B. 4. The process according to claim 3, characterized in that the S-methylated ether compounds are C and D: 5. The process according to claim 2, characterized in that the halogen is bromine; the protected ether was prepared using trimethyl orthoformate in methanol in the presence of a catalyst acid; the reactive alkyllithium compound is n-butyllithium; the sulfur transfer reagent is dimethyl disulfide and the S-methylated ether compound is deprotected using hydrochloric acid. 6. The process according to claim 5, characterized in that the 6-bromo-2-tetralone is prepared by reacting the 4-bromophenylacetic acid with methylene chloride and a reagent selected from thionyl chloride, phosphorus trichloride, oxalyl chloride, and phosphorus pentachloride followed by reaction with ethylene gas in the presence of a Lewis acid catalyst. 7. The process according to any of claims 2, 3, 4, 5 or 6, characterized in that it additionally comprises converting the compound of the formula II to a compound of the formula I S-Ri where R1 represents: 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitronaftyl, 4-nitroponate, 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1-isoquinolinyl , 3-isoquinolinyl, 8-isoquinolinyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-lH-indazolyl, 2-benzoxazolyl, 3-1, 2-benzisothiazolyl, 2-pyridinyl, 4-pyridinyl, 2-pyrazinyl, 2-naphtho [2, 3-d] thiazolyl, 2-naphtho [1,2-d] thiazolyl, 9-anthryl, 2-thiazolyl, 2-benzimide zolyl, 1-benz [g] isoquinolinyl, 8-benz [g] isoquinolinyl , 5-lH-tet, razolyl, 2-quinazolinyl, 2-t-azolo [4, 5-b] pyridinyl, 4-OH-pyridine zino [3,2-b] -2-qumazolinyl, 2-1, 4 - benzodioxinyl, 2-triazine, 2-benzoxazine, 4-benzoxazine, 2-purine or 8-purine; wherein the above groups of R1 are substituted or unsubstituted with 1-3 groups selected from the group consisting of trifluoromethyl, tri-fluoroethoxy, Cj-C4 alkyl, trifluoromethoxy, hydroxy, C1-C3 alkoxy, nitro, alkylthio C? -C3, C?-C6 alkanoyl, phenyl, oxo, phenoxy, phenylthio, C?-C3 alkylsul finyl, C?-C3 alkylsulfonyl, cyano, amino, C?-C3 alkylamino, diphenylmethylamino, tri-phenylethylamino, benzyloxy, benzylthio, (mono-halo, nitro or CF3) benzyl (oxy or thio), di (C? -C3 alkyl, C3-C6 cycloalkyl, or C4-C8 cycloalkylalkyl) amino, (mono-C1-C3 alkyl, C1-C3 alkoxy, or halo) (phenyl, phenoxy, phenylthio, phenylsul fonyl or phenoxysulfonyl), C2-C6 alkanoylamino, benzoylamino, diphenylmetilamino (C1-C3 alkyl), aminocarbonyl, C1-C3 alkylaminocarbonyl, di (C1-C3 alkyl) aminocarbonyl, halo- Ci-Cβ alkanoyl, aminosul fonyl, C1-C3 alkylaminosul fonyl, di (C1-C3 alkyl) aminosulfonyl, phenyl (oxy or thio) (C1-C3 alkyl), (halo, C1-C3 alkyl or Ci-C3 alkoxy) phenyl oxy or thio) (C1-C3 alkyl), benzoyl, or (amino, C1-C3 alkylamino or di (C1-C3 alkyl) amino) (C1-C3 alkyl) • 8. The process according to any of claims 2, 3, 4, 5 or 6, characterized in that it additionally comprises converting the compound of the formula II in (+) - (4aR) - (10bR) -4 -met-il-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl

1-1, 2, 3, 4, 4a, 5, 6, 10b -octahydrobenzo [f] quinolin-3-one. 9. The process according to any of claims 2, 3, 4, 5 or 6, characterized in that it additionally comprises: reacting the compound of the formula II II with (R) - (+) - phenethylamine to provide a compound of the formula III reacting the compound of the formula III with a strong lithium base to provide a lithium-enamine compound of the formula IV methylating the resulting lithioenamine of formula IV to a compound of formula V reacting the compound of the formula V with an acyl halide or an acrylic acid anhydride to prepare the compound of the formula VI quenching the reaction with a base, and combining the residue comprising the compound of formula VI with an appropriate silane and trifluoroacetic acid in the absence of a solvent to prepare a compound of formula VII 10. The process according to claim 9, characterized in that it additionally comprises: reacting the compound of the formula VII with a methyl halide in a reaction mixture comprising an organic solvent and a strong base to provide an arylmethyl sulfide compound of the formula VIII CH3 by oxidizing the compound of the formula VIII to a sulfoxide compound of the formula IX reacting the sulphoxide compound of formula IX with an acylating agent to produce a Pummerer rearrangement product: reacting the Pummerer rearrangement product with an electrophile selected from the group consisting of A-R1 wherein A is a starting group and R1 represents:

2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nor tronaftyl, 4-nor tronaftyl, 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinol inyl, 1 - isoquinolinyl,

3-isoquinolinyl, 8-isoquinol inyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-lH-indazolyl, 2-benzoxazolyl, 3- 1, 2-benzisothiazolyl, 2-pyridinyl,

4-pyridinyl, 2-pyrazinyl, 2 -naphtho [2,3-dithiazolyl, 2-naphtho [1,2-d] thiazole ilo, 9-anthryl, 2-thiazolyl, 2-benzimidazole, 1-benz [g] isoquinolinyl, 8 -benz [g] isoquinolinyl ,

5-lH-tetrazolyl, 2-quinazolinyl, 2-thia zolo [, 5-b] pyridinyl, 4-10H-pyridazino [3,2-b] -2-quinazolinyl, 2-1, 4-benzodioxinyl, 2- triazine, 2-benzoxazine, 4-benzoxazine, 2-purine or 8-purine; wherein the above groups of R1 are substituted or unsubstituted with 1-3 groups selected from the group consisting of trifluoromethyl, trifluoroethoxy, C? -C4 alkyl, trifluoromethoxy, hydroxy, C? -C3 alkoxy, nitro, alkylthio C? -C3, C? -C6 alkanoyl, f or lo, oxo, phenoxy, phenylthio, C1-C3 alkylsulfinyl, C? -C3 alkylsulfonyl, cyano, amino, C? -C3 alkylamino, diphenylmethylamino, triphenylmethylamino, benzyloxy, benzylthio, -halo, nitro or CF3) benzyl (oxy or thio), di (C1-C3 alkyl, C3-C6 cycloalkyl, or C4-Ce cycloalkylamino) amino, (mono-C? -C3 alkyl, C? -C3 alkoxy, or halo) (phenyl, phenoxy, phenylthio, phenylsul fonyl or phenoxysul foni lo), C2-Cd alkanoylamino, benzoylamino, diphenylmetylamino (C1-C3 alkyl), aminocarbonyl, C1-C3 alkylaminocarbonyl, di (C1-C3 alkyl) aminocarbonyl, halo -alkanyl Ci-C e, aminosulfonyl, alkylaminosul fonyl C1-C3, di (C1-C3 alkyl) aminosulfonyl, phenyl (oxy or thio) (C1-C3 alkyl), (halo, C-C3 alkyl or Ci-C3 alkoxy) ) faith nil (oxy or thio) (C 1 -C 3 alkyl), benzoyl, or (amino, C 1 -C 3 alkylamino or di (C 1 -C 3 alkyl) amino) (C 1 -C 3 alkyl); in the presence of a phase transfer catalyst, a hydride reducing reagent and a base, to prepare a compound of formula I. 11. A compound of formula A: 12. A compound to the formula B CH30 B. 13. A compound of the formula C 14 A compound of the formula D. «.-, *. or