CZ153499A3 - Process for preparing benzo[f]quinolinones - Google Patents

Abstract

Process for preparing benzoquinolin-3-one compounds pharmaceuticals which are effective as pharmaceuticals for the treatment of conditions resulting from the action of 5α-reductase

Description

Technical field

The present invention belongs to the field of organic chemistry, pharmaceutical chemistry and chemical production and provides a convenient and economical process for the preparation of benzo [18] quinolinones which are useful as 5α-reductase inhibitors and further provides intermediates for the preparation of these drugs.

BACKGROUND OF THE INVENTION

The current field of pharmaceutical research is the inhibition of 5α-reductase, an enzyme converting testosterone to dihydrotestosterone, which is a more potent androgen. It has been shown that 5α-reductase inhibitors can block the formation of dihydrotestosterone and improve the incidence of highly undesirable conditions including male baldness and benign prostatic hypertrophy. Audia et al. have disclosed a number of benzo [f] quinolinone compounds which are 5α-reductase inhibitors. See: U.S. Pat. Nos. 5,239,075 and 5,541,190 to Tet. Let., 44, 7001 (1993), J. Med. Chem., 36, 421 (1993) and European patent application 0703221.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of benzo [f] quinolinones, which are potent inhibitors of 5α-reductase. This method is more efficient than the previous methods, is feasible in large-scale synthesis and prevents the formation of undesirable by-products. The present invention also provides intermediates for the preparation of these medicaments.

· · · · · · · · · · · · · · · · · · • · · · · · · ·

- 2 -..........

The present invention provides a process for preparing benzo [f] quinolinones and further provides intermediates useful in the preparation of benzo [f] quinolinones. More particularly, the present invention is directed to a process for preparing a compound of Formula I

(I) in which

R ¹ represents 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitronaphthyl,

4-nitronaphthyl, 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolyl, 4-quinolyl, 7-quinolyl,

1-isoquinolyl, 3-isoquinolyl, 8-isoquinolyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-1H-indazolyl, 2-benzoxazolyl, 3-1,2-benzoisothiazolyl, 2-pyridyl , 4-pyridyl, 2-pyrazinyl,

2-naphtho [2,3-d] thiazolyl, 2-naphtho [1,2-d] thiazolyl, 9-anthryl, 2-thiazolyl, 2-benzimidazolyl · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

00 · 0 · · - 3 nu, 1-benzo [g] isoquinolyl, 8-benzo [g] isoquinolyl, 5-1H-tetrazolyl, 2-quinazolinyl, 2-thiazolo [4,5-b] pyridyl a group, 4-10H-pyridazino [3,2-b] -2-quinazolinyl, 2-1,4-benzodioxinyl, 2-triazine, 2-benzoxazine, 4-benzoxazine, 2-purine or 8 -purinyl group, wherein the above listed radicals R ¹ are unsubstituted or substituted by one to three functional groups selected from trifluoromethyl, trifluoroethoxy, C ^ -C ^ alkyl, trifluoromethoxy, hydroxy, C -C alkoxy, nitro, _C - C ₃ alkylthio,

C -C alkanoyl, phenyl, oxo, phenoxy, phenylthio, C _x ^- C ₃ alkylsulfinyl, _C -C alkylsulfonyl, cyano, amino, C ^ -C alkylamino, difenylmethylaminoskupina, trifenylmethylaminoskupina, benzyloxy, benzylthio, (mono -halo, nitro or -CF ₃₎ benzyl (oxy or thio), di (C ₃ -C ₃ alkyl, C ₃ -C _e cycloalkyl or C₁₋₄ -Οθ cycloalkylalkyl) amino, (mono-C ^ - C 1-6 alkyl, C 1 -C ₃ alkoxy or halo) - (phenyl, phenoxy, phenylthio, phenylsulfonyl or phenoxysulfonyl), C 1 -C 6 alkanoylamino, benzoylamino, diphenylmethylamino- (C 1 -C 4 alkyl), aminocarbonyl, C 1-6 alkyl C alkylaminocarbonyl, di (C -C alkyl) -aminokarbonylová group, halo (C _i -C _e alkanoyl group), aminosulfonyl, alkylaminosulfonyl, di (C -C alkyl) aminosulfonyl, phenyl (oxy or thio) - ((C ₃ -C 4 alkyl)), (halo, C 1 -C 6 alkyl or C ₁ -C ₃ a alkoxy) phenyl (oxy or thio) - (C ₁ -C ₃ alkyl), benzoyl or [amino, (ζ- (ζ alkylamino or di (C ₃ -C ₃ alkyl) amino)] - (C ₁ -C ₃₎

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 9 9 9 9 99 99).

One aspect of the present invention involves the conversion of a ketone of formula

in which

R is a halogen atom, preferably bromine or iodine, to the protected ketal, preferably using trimethylsilyl trifluoromethanesulfonate and 1,3-bis-trimethylsilyloxypropanediol in methylene chloride, reacting the protected ketal with a reactive alkyllithium compound such as n-butyl lithium and a sulfur transfer agent such as dimethyl disulfide to obtain the S-methylated ketal compound and deprotection of the S-methylated ketal compound to obtain the methyl-thiotetralone compound of formula II

sch ₂ (II)

Another aspect of the invention includes the preparation of a compound of formula II

(II) reacting a compound of formula

with lithium diisopropylamidexia, n-butyllithium and dimethyl disulfide or by conversion of a compound of formula XI

sch ₂ (XI)

to an acid halide, for example an acid chloride, reacting the acid halide with Lewis acid and ethylene to give a compound of formula II.

In another aspect, the invention includes converting a compound of Formula II to a compound of Formula I. One such preferred method involves reacting a compound of Formula II with (R) - (+) - phenethylamine to obtain a compound of Formula III

(III) reacting the compound of formula III with a strong lithium phase to obtain a lithioenamine compound of formula IV

(IV)

00 ·· ·· ·· ·· 00 ··

Methylation of the resulting lithioenamine of formula IV to the compound of formula V, for example by reacting the resulting lithioenamine with methyl iodide in an ether solvent to prepare the compound of formula V

SCH ₃ (V) reacting a compound of Formula V with an acyl halide or acrylic anhydride to prepare a compound of Formula VI

(VI) quenching the base reaction and combining the residue containing the compound; · ·

- 8 nu of formula VI with the appropriate strong and trifluoroacetic acid in the absence of a solvent for the preparation of a compound of formula VII

sch ₃ (VII) reacting a compound of formula VII with a methyl halide, for example methyl iodide, in a reaction mixture containing an organic solvent and a strong base to give an arylmethylsulfide compound of formula VIII

SCH ₃ (VIII) oxidation of a compound of formula VIII to a sulfoxide compound of formula IX * · · * · · 3 IX IX IX 3 IX IX IX _{3 3} IX IX IX · IX • · ··· · · ··· · ··· ··· * ··· * · ··

- 9 O

(ix) reacting the sulfoxide compound of Formula IX with an acylating agent to obtain a Pummerer rearrangement product, reacting the Pummerer rearrangement product with an electrophilic composition selected from the group consisting of AR ¹ wherein A is a leaving group and R ¹ is 2-nitrophenyl, 4-nitrophenyl , 2-cyanophenyl, 4-cyanophenyl,

2-nitronaphthyl, 4-nitronaphthyl,

2-cyanonaphthyl, 4-cyanonaphthyl,

2-quinolyl, 4-quinolyl,

7-quinolyl, 1-isoquinolyl,

3-isoquinolyl, 8-isoquinolyl,

2-quinoxalinyl, 2-benzothiazolyl,

3- 1H-indazolyl, 2-benzoxazolyl,

3- 1,2-benzisothiazolyl, 2-pyridyl,

4-pyridyl, 2-pyrazinyl, 2-naphtho [2,3-d] thiazolyl, 2-naphtho [1,2-d] thiazolyl, 9-anthryl, 2-thiazolyl, 2-benzimidazolyl , 1-benzo [g] isoquinolyl, 8-benzo [g] isoquinolyl, 5-1H-tetrazolyl, 2-quinazolyl, 2-thiazolo [4,5-b] pyridyl, 4-10H-pyridazino [ 3,2-b] -2-quinazo- 10 ··· «· ······················ 99 99 99 vinyl group, 2-1,4-benzodioxinyl group,

2-triazine, 2-benzoxazine,

4-benzoxazine, 2-purine or

An 8-purine group wherein the above-mentioned R ¹ groups are unsubstituted or substituted by one to three groups selected from trifluoromethyl, trifluoroethoxy, C 1 -C 3 alkyl, trifluoromethoxy, hydroxyl, C ₃ -C ₃ alkoxy, nitro,

C ₁ -C ₃ alkylthio, _C "C ₆ alkanoyl, phenyl, oxo, phenoxy, phenylthio, C -C alkylsulfinyl, C _x -C ₃ alkylsulfonyl, cyano, amino, C _x -C ₃ alkylamino, difenylmethylaminoskupina , trifenylmethylaminoskupina, benzyloxy, benzylthio, (mono-halo, nitro or _CF3) benzyl (oxy or thio), di (C _x -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, or C _"C cycloalkylalkyl) amino, (mono-C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy or halo) -phenyl, phenoxy, phenylthio, phenylsulfonyl or phenoxysulfonyl), C 1 -C 6 alkanoylamino, benzoylamino, diphenylmethylamino- (C ₁ -C 3) ₃ alkyl) aminocarbonyl, C _x -C ₃ alkylaminocarbonyl, di (C _x -C ₃ alkyl) -aminokarbonylová group, a halo- (C _x -C ₆ alkanoyl group), aminosulfonyl, C _x -C ₃ alkylaminosulfonyl a di (C ₁ -C ₃ alkyl) aminosulfone group yl, phenyl (oxy or thio) - (C _x -C ₃ alkyl group ·), (halo, _ϋ χ -ϋ ₃ alkyl or C _x -C ₃ alkoxy) phenyl (oxy or thio) - (C _x -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, hydride reduction a composition and a base for preparing a compound of formula I.

According to a further aspect of the present invention, a compound of formula VIII is prepared.

(VIII) by a method comprising reacting a compound of formula XII

(XII) with a reaction mixture comprising a base such as lithium diisopropylamide or lithium hexamethyldisilazide and an ether solvent to obtain an amido-enolate solution by reacting the amido-enolate solution with an alkyl lithium compound;

- 12 · · φ · · · · · · · · · · · φ e * * * * φ φ · · s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s

and reacting the dianionic compound with dimethyl disulfide to give an arylmethylsulfide compound of formula VIII.

Preferred intermediates of the invention are compounds of formulas II, VI and VIII

SCH ₃ (II) •

- 13 ft · · · ·

9 9 4

9 9 «· · 9 999

9 9

44 · 4

(VI)

(VIII) or salts thereof.

The starting materials for the compounds in the method of the claim are substances that are either commercially available, known in the art, or can be prepared by methods known in the art, see, for example, Audia et al. in U.S. Pat.

No. 239,075, issued August 24, 1993, and European Patent Publication 073221.

Throughout this document, all temperatures are in ° C and all concentrations, percentages, and proportions are expressed as • 0

0 0

- 14 00 · * · · · · · · ·

0 0 0 0

0 0 in weight units, except for the solvent mixtures described in volume units, unless otherwise indicated.

References to compounds herein include pharmaceutically acceptable salts of these compounds, unless otherwise indicated.

The different positions on the benzo [f] quinoline ring are described below.

The spatial configuration of the group at position 10b and the hydrogen atom at position 4a are required. It will be appreciated that many 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, the individual enantiomers are prepared in pure form and are referred to as (+) or (-). In other cases, a mixture of diastereomers is prepared.

Group SR ¹ occupies position 8.

The term halogen or halo includes a chlorine, bromine, fluorine or iodine atom.

Φ φ · · • · · • • φ φ φ φ

- 15 -

Various alkyl groups such as a C ₁ -C ₄ alkyl group and the like include groups such as methyl, ethyl, propyl, isopropyl, tert-butyl, n-butyl and isobutyl. Alkenyl groups and alkynyl groups form linking groups which are bivalent and are attached to two other groups. For example, C ₂ -C ₄ alkenyl includes ethenyl, 2-propenyl, 3-butenyl and 2-butenyl and C ₂ -C ₄ alkynyl includes, for example ethynyl, 2-propynyl, 2-butynyl and iso -2-butynyl.

The C-alkanoyl group includes a formyyl group, acetyl group, propionyl group, isobutyryl group, 2-ethylpropionyl group and hexanoyl group. C ₃ -C _e cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and (C ^ -Οθ cycloalkyl) alkyl group includes, for example cyclopropylmethyl, cyclohexylethyl, cyklobutylbutylovou and cyclohexylmethyl.

Terms such as halo- (C ₁ -C ₆ alkanoyl), halophenyl or C 1 -C 6 alkylphenyl refer to a given basic group substituted with 1, 2 or 3 halogen atoms or C 1 -C 6 alkyl groups, as may be describe in individual cases.

The process described is for the preparation of compounds of formula I having all the benzo [f] quinoline nucleus wherein the fused benzene nucleus is substituted with a cyclic group R ¹ attached via a sulfur atom. The group R ¹ may be substituted with other organic groups.

- 16 and can carry up to three listed substitution groups. The multiple substituents may all be the same or different.

Certain aspects of this method are preferred and described specifically below. It will be appreciated that each of the following aspects is meaning in itself, and that preferred aspects may be combined to form other more limited or broader preferred aspects.

Synthesis of 6-methylthio-2-tetralone

The starting material for the synthesis of 6-methylthio-2-tetralone is 4-methylthiophenylacetic acid. 4-Methylthiophenylacetic acid can be obtained commercially (Aldrich Catalog Handbook of Fine Chemicals 1994-5, p. 1000) or can be prepared by procedures well known to one skilled in the art. For example, 4-methylthiophenylacetic acid can be prepared by Kindler's modification of the Willgerodt reaction. 4-Methylthioacetophenone is reacted with sulfur and a primary or secondary amine, preferably morpholine, followed by hydrolysis (Scheme I). Alternatively, 4-methylthiophenylacetic acid can be prepared by hydrolysis of the corresponding nitrile or in two steps from benzyl alcohol (Scheme II).

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Scheme I

6-Methylthio-2-tetralone is prepared by acid reaction

4-methylthiophenylacetic acid with thionyl chloride, phosphorus trichloride, oxalyl chloride or phosphorus pentachloride under conditions known to those skilled in the art to obtain 4-methylthiophenacetyl chloride (Scheme III). Preferably, thionyl chloride and Ν, Ν-dimethylformamide are used to obtain 4-methylthiophenacetyl chloride. Friedel-Crafts acylation reaction of 4-methylthiophenacetyl chloride with ethylene gas in the presence of a Lewis acid catalyst

- 18 • 9 · 9 · ·

999 9 9 9 · · · ·

And an inert or substantially inert solvent or solvent mixture is accomplished by ring closure to give 2-tetralone II.

Scheme III

SCH ₃

II

Suitable Lewis acids used as catalysts include aluminum bromide, aluminum chloride, aluminum iodide, gallium chloride, ferric chloride, antimony chloride, zirconium chloride, tin tetrachloride, boron trichloride, boron trifluoride, antimony trichloride and the like, preferably aluminum bromide. Solvents used for this reaction include carbon disulfide, methylene chloride, nitromethane, 1,2-dichloroethane, nitrobenzene and the like, preferably methylene chloride. Cyclization of thiomethyltetralone requires rigorous conditions and is characterized by difficult isolation. Improved yields of 6-methylthio-2-tetralone are achieved under stringent conditions using aluminum bromide as Lewis acid. The cyclization is carried out at temperatures of about -78 ° C to 25 ° C, preferably less than 0 ° C.

Ethylene addition is exothermic in nature and temperatures of -78 ° C to about 30 ° C are used in standard cooling processes. Significantly improved yields of 6-methylthio-29 9 9 9 · 9 9

9 9 9 9 9

9999 999 999

The 19-tetralone is achieved with the simultaneous addition of 4-methylthiophenacetyl halide and ethylene to methylene chloride and aluminum bromide at temperatures from about 5 ° C to about -15 ° C.

Alternatively, the preparation of 6-methylthio-2-tetralone can be carried out according to the following Scheme IV.

Scheme IV

wherein R is a halogen atom, preferably bromine.

The ketone group of tetralone is first protected in the form of ketal. Preferably, ketalization is achieved by slowly adding 1,3-bis-trimethylsilyloxypropanediol to a solution of trifluoromethanesulfonate in methylene chloride. Temperatures from about -70 ° C to about -60 ° C are used with standard refrigerators

00

0 0

0 ·

000 000

0

00

0 0 00

0 ·

ways. For example, 6-bromo-2-tetralone is slowly added to a solution of 1,3-bis-trimethylsilyloxypropanediol and trifluoromethanesulfonate in methylene chloride to give

Of 6-bromo-2-tetralonopropylene ketal.

The halogen-metal exchange is then carried out by reacting the protected ketal with a reactive organolithium compound, preferably n-butyllithium. Alkylation of the resulting lithium compound with an appropriate sulfur transfer agent, e.g., a sulfenyl halide or dimethylsulfide, provides a 6-methylthio-2-tetralone-propylene ketal compound. Deprotection

The S-methylated ketal compound is carried out by treatment with aqueous acid, preferably hydrochloric acid, to obtain the desired 6-methylthio-2-tetralonic compound.

Alkylation and formation of a heterocyclic ring with a nitrogen atom

Previous synthesis of intermediate VII

(VII) is disclosed in U.S. Patent No. 5,239,075 and U.S. Patent Application No. 08 / 443,994, both of which are incorporated herein by reference. Further synthesis of a compound of formula VII for which ten99 99

9 9 9

9 9 9

9 ··· ·

99 • 9

9 9 9

9 9 9 · 999 9

The present invention is an improvement, disclosed in European Patent Publication No. 0564193. The methylthio group of the compound of formula VII is placed at the 8-position.

6-Thiomethyl-2-tetralone reacts with (R) - (+) - phenethylamine to form the intermediate of formula III

99

9 9 · · ·

999 999 ·

The reaction is conveniently carried out at elevated temperature, in particular at reflux temperature, in toluene in the presence of a strong acid such as p-toluenesulfonic acid. It is necessary to remove the water as it is formed in this reaction and the absence of the water formed indicates the completion of the reaction. A slight excess of phenethylamine, such as about 1.05-1.10 equivalents, should be used. Alternatively, tetrahydrofuran may be used as the solvent, and in this case it is particularly preferred to use molecular sieves to dehydrate the reaction mixture using at least twice the weight of the molecular sieves compared to the weight of water that will be released during the reaction.

The phenethylamine compound described above is reacted with a lithium compound, for example n-butyllithium or lithium diisopropylamide, to give a compound of formula

9

9 · 9 9 9 9 9 9 99 99 999 999

99 99

IV

(IV)

When the reaction is carried out with lithium diisopropylamide, which is the preferred case, best results are obtained when lithium diisopropylamide is formed freshly from diisopropylamine and n-butyllithium immediately prior to using this process. For best results, a substantial excess of about 15 to 25% lithium diisopropylamide should be used.

The reaction with lithium diisopropylamide is preferably carried out in tetrahydrofuran at room temperature in the range of about -100 ° C to about 0 ° C, preferably about -78 ° C to about -10 ° C. The phenethylamine compound need not be purified or isolated, but the first reaction mixture should be evaporated in vacuo and the residue taken up in tetrahydrofuran. It is preferred to add the phenethylamine substance in solution to a solution of lithium diisopropylamide in cold tetrahydrofuran. The opposite method of addition is feasible, but provides lower yields. Generally, the reaction can be performed in less than 1 hour.

The lithium compound is difficult to isolate and purify for 23

· »·

1

112 · »«

911 911 this should be fed to the reaction for preparation according to the invention in the form of a solution in the reaction mixture for lithiation.

Alkylation

The lithium compound is methylated, for example, by reacting the resulting lithioenamine with methyl iodide to give a compound of formula V

(IN)

For the methylation of lithioenamine, dimethylsulfate, methyl bromide, methyl chloride, methyl iodide and the like can be used. It is convenient to use about 15-25% excess methyl iodide and carry out the reaction in a solvent, preferably an ether solvent such as diethyl ether, methyl tert-butyl ether or preferably tetrahydrofuran. The reaction is very rapid at low temperatures in the range of about -100 ° C to about -50 ° C, preferably about -80 ° C to about -60 ° C. Reaction times ranging from about 5 minutes to about 1 hour are adequate, and a reaction time of 20 minutes is preferred.

When the lithium compound is in the form of a reaction mixture of lithiation with lithium diisopropylamide, so the reaction mixture

• · · · · · · · · · · · · · · · · · · · ·

contains residual diisopropylamine, this amine must be neutralized before methylation. Preferably, the methyl iodide mixture is allowed to warm to a temperature in the region of 0 ° C and sufficient methanesulfonic acid is added to neutralize the diisopropylamine. Other strong acids may be used, but methanesulfonic acid is particularly suitable and preferred since the resulting diisopropylamine methanesulfonate salt is only slightly soluble and can therefore be easily removed by simple filtration or centrifugation.

Step of forming a heterocyclic ring with a nitrogen atom

The reaction mixture containing the compound of formula V is mixed with an acyl halide or acrylic anhydride or acryloyl chloride or the like to initiate a nitrogen-containing heterocyclic ring reaction to give a compound of formula VI

0 '

CH 3 CeH 5 H

SCH ₃ (VI)

It is best to form acrylic anhydride, which is the preferred reagent, immediately prior to use by reacting acryloyl chloride and acrylic acid using triethylamine and a stabilizer such as hydroquinone and butylated.

hydroxytoluene in tetrahydrofuran.

The formation of the nitrogen-containing heterocyclic ring is best accomplished by the addition of acrylic anhydride or acryloyl chloride at a very low temperature such as about -100 ° C to about -70 ° C and allowing very slow heating of the mixture to about -20 ° C with stirring. up to about 0 ° C or even up to about 10 ° C to 20 ° C. A period of 12 to 15 hours is a reasonable time to heat the mixture. When the reaction progressed to completion as desired, solid sodium bicarbonate was added. It is preferred to use about 1.5 to 4 equivalents of base, preferably about 2 equivalents. The base may also be added as a solution, for example in water or in an aqueous solvent such as water / dimethylaminopyridine, but the addition of the base in solid form is preferred. The reaction mixture is stirred with this base for a short time 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 treated by washing with aqueous base and aqueous acid and optionally further purification steps, is washed with saturated brine. When these processing steps are used, the solution is dehydrated and evaporated in vacuo to give the non-volatile portions of the reaction mixture containing the final intermediate of formula VI. On the other hand, if desired, the residue from the complete reaction can be used without workup.

Reduction-cleavage step

The residue from the nitrogen-forming heterocyclic ring step is cooled and a cooled mixture of the appropriate silane and trifluoroacetic acid is added. A suitable strong is a soluble silane, for example a dialkylsilane or a trialkylsilane or the like. Addition should take place at low temperature. · Addition should take place at low temperature. In the range of about -40 ° C to about 0 ° C without the use of an additional solvent. A large amount of trifluoroacetic acid is used, in the range of about 10 to 50 equivalents, preferably about 20 to 30 equivalents. Preferred trialkylsilane is triethylsilane, although trimethylsilane, tripropylsilane and the like can also be used. A substantial excess of trialkylsilane is used, in the range of about 5 to 20 equivalents, most preferably about 7 to 15 equivalents. The mixture is stirred for about 10 to 20 h while allowing to slowly warm to about 30 ° C and then slowly warming to elevated temperature, preferably to reflux, and stirring at this temperature for several hours, about 2 to 6 h, to terminate formation of the compound of formula VII.

(VII)

Cleaning

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 evaporated in vacuo. The residue can be thoroughly washed with, for example, an ether solvent, preferably diethyl ether, to give the purified compound of formula VII.

N-alkylation

In the synthesis, nitrogen must be methylated at the 4-position of the benzo [f] quinoline ring. U.S. Patent No. 5,239,075 shows this alkylation by reaction with an alkyl iodide in the presence of a strong base such as sodium hydride. Additional alkylation is described in EPO 0703221.

N-methylation involves reacting a compound of formula VII with methyl halide, for example methyl iodide, in a reaction mixture containing an organic solvent, for example a solvent selected from the group consisting of tetrahydrofuran, dimethoxyethane, diethoxyethane and methyl tert-butyl ether, and a base such as aqueous sodium or potassium hydroxide , to obtain a compound of formula VIII.

(VIII)

This method allows efficient alkylation under mild and easily controlled conditions and easy product isolation.

Alkylation is carried out in conventional chemical operations 9 9 9 9

9 9

9 9

9 9 9 9 ·

9 • 9 '9 9

· • ·

- 28 ♦ 9 9 9 9 9 9

999 · · 9 9999

9

9 9 9 9 9 devices, preferably at ambient pressure and normal temperatures. Preferably, it is initiated by suspending the starting material of formula VII in an organic solvent at a temperature close to ambient temperature, such as from about 0 ° C to about 50 ° C, more preferably from about 15 ° C to about 25 ° C. The most preferred organic solvent is tetrahydrofuran and it is preferred to use 5-15 liters of solvent per kg of starting material, more preferably about 10 liters per kg of solvent. The alkyl iodide is then added as a pure liquid. Preferably, a substantial excess of alkyl iodide is used, such as about 1.2 to 1.8 equivalents relative to the starting material, most preferably about 1.5 equivalents.

An aqueous solution of sodium or potassium hydroxide is then added, still at a temperature close to ambient temperature, in an amount of about 1 to 4 liters per kg of 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 using the most preferred base, a 50% sodium hydroxide solution, the most preferred amount is about 2 liters per kg of starting material. Thereafter, the solid-containing reaction mixture is suspended in two liquid phases, heated to about 25 to 65 ° C with vigorous stirring, and the reaction is allowed to proceed at a roughly constant temperature and under constant stirring conditions. The preferred reaction temperature is about 35-40 ° C. As the reaction progresses to completion, the starting material and the alkyl iodide dissolve and react so that the disappearance of the solids provides a rough indication of the completion of the reaction. The reaction may be followed by high pressure liquid chromatography on a c-18 silica gel column, eluting with 1: 1 acetonitrile: aqueous buffer (5% ammonium acetate) and monitoring at 220 nm.

When the reaction has come to completion as desired, the reaction mixture is cooled to about ambient temperature and the aqueous layer

0 «· * · · 00 · * 00

00 0 0 00 0 0 · 0 0 0000 <000 0000 0 0 00040 0 000 000 000 000

0000 0 0 0

- · · · · ** ** ** ** ** ** ** ** ** ** ** ** se ** ** ** · **

Preferred purification and isolation methods are carried out by diluting the organic layer with water and neutralizing with aqueous inorganic acid. Thereafter, the solution is distilled until the vapor temperature rises to about 69-80 ° C, removing most of the tetrahydrofuran. Slow cooling to about 5 ° C over about 1 to 14 hours results in crystallization of the product, which only requires washing with water and drying for use as an intermediate or pharmaceutical.

Alkylation provides the product in the same stereochemical form as the starting material, in satisfactory purity for the pharmaceutical industry, and with yields of about 90% or more when carried out according to preferred methods.

Thioalkylation

The compound of formula VIII can also be prepared by thiomethylation of (+) - (4aR) - (10bR) -4-methyl-8-halo-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [ f] quinolin-3-one. Preferably, the amide enolate is obtained by mixing (+) - (4aR) - (10bR) -4-methyl-8-bromo-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one with a lithium salt, for example lithium chloride in an organic solvent, preferably tetrahydrofuran. A weak base such as lithium hexamethyldisilazide [LiN (TMS) ₂ ] is slowly added and the mixture is stirred at room temperature. Methyllithium may be added to facilitate deprotonation of hexamethyldisilazide. The reaction mixture is then cooled to -70 ° C and an alkyl lithium compound such as n-butyllithium is added to aid in the formation of the dianion.

The amido-enolate solution can also be obtained by a stepwise step

9 · 9 • · · 9 ft 9,999

9 9

9 9 9 ftft ft ft ft ft ft ft ft ft ft ft ft ft

• ft treatment of (+) - (4aR) - (10bR) -4-methyl-8-halo-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3 a strong base such as lithium diisopropylamide in an ether solvent, preferably tetrahydrofuran followed by a lithium halogen exchange with matured n-butyllithium, sec-butyllithium or the like (Scheme V).

The dianionic compound is then reacted with dimethyl disulfide to give the arylmethylsulfide compound of formula VIII. A very high degree of chemical selectivity of dianion with dimethyl disulfide can be observed.

Scheme V

CH ₃

VIII • 9

9 9 9

9 ** 99 * 99 9,999 91

Wherein R is a halogen atom, preferably a bromine atom.

Electrophilic attachment

The electrophilic coupling of the substituent R ¹ to the sulfur-containing group on the benzo [f] quinoline ring can be carried out according to the following scheme VI.

Scheme VI

wherein R ^{1 is as} defined above for Formula I.

• 9 · 9 · 9 · 9 · 9 · 9 · 9 · 999 · 9 9 999 9 999 9 ··

9 9 9 9 9 9

- 33 - * ...........

(+) - (4aR) - (10bR) -4-Methyl-8-methylthio-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one se oxidizes to the sulfoxide compound. A preferred oxidizing agent is m-chloroperoxibenzoic acid. The compound, after or without isolation, is subjected to the Pummerer reaction as described by Young et al., Tetrahedron Lett., 25, 1753 (1984) so that the sulfoxide is reacted with an acylating agent such as trifluoroacetic anhydride to give the trifluoroacetyloxymethylene sulfide compound. The trifluoroacetyloxymethylene sulfide compound is reacted with an electrophilic agent, a hydride reducing agent such as sodium borohydride, potassium borohydride, lithium borohydride or the like, and a base, preferably a hydroxide or carbonate, preferably potassium carbonate, to prepare a compound of formula X. the reactions include suitable acylating agents acyl halides such as acetyl chloride, sulfonic acid halides, reactive anhydrides such as trichloroacetic anhydride, phosphoric anhydride, sulfonic anhydride and the like capable of providing a Pummerer rearrangement product.

By methods well known in the art, the electrophilic agent is substituted with a leaving group such as a halogen atom, a sulfate group, a sulfonate group or the like. An electrophilic reagent is then added to the sulfur on the benzo [quinoline ring]. A preferred electrophilic reagent is 2-chloro-4-ethylbenzothiazole and this reagent is attached to the compound of formula X to give (+) - (4aR) - (10bR) -4-methyl-8-methylthio-10b-methyl-1,2, 3,4,4a, 5,6,10b-octahydrobenzo [fquinolin-3-one.

Preferably, a catalyst such as tetrabutylammonium hydrogen sulphate is used to direct the coupling of tri33 to 933. ··· 9 9,999 β 99,999

9 9 9 9 9 Fluoroacetyloxymethylene sulfide with an electrophilic reagent. Sodium borohydride has been found to induce a reduction in the trifluoroacetyloxymethylene sulfide compound. Formaldehyde is also formed in situ, which is unacceptable for environmental and pharmaceutical use. The process described herein reduces the amount of formaldehyde as it is converted to methanol. According to this method, the amount of disulfides produced by in situ air oxidation is also reduced. This step of the process allows fuller use of the starting materials and there is no need to rigorously exclude the presence of oxygen or oxidation-promoting impurities. Adding a base to the mixture is not essential to assist attachment. However, the decomposition of the borohydride is slowed and the relative coupling rate is increased by the added base.

DETAILED DESCRIPTION OF THE INVENTION

The following preparations further illustrate the process of the invention. These preparations are not intended to limit the scope of the invention in any way and should not be considered in this way.

Unless otherwise stated, starting materials are obtained from commercial suppliers and used without further purification. Toluene, dimethylformamide and methylene chloride are deposited over molecular sieves of 0.4 nm. Tetrahydrofuran is removed from sodium benzophenone ketyl by distillation. Reactions using organometallic reagents are carried out under a nitrogen atmosphere. The reactions were monitored by high pressure liquid chromatography under the conditions described below. Thin layer chromatography was performed using Merck plates on Silica gel 60 with fluorescence indicator (F ₌ ) - ¹ H and ¹³ C NMR spectra were recorded on a General Electric QE spectrophotometer or «· · • • • •

- 34 -......

• · · «# # # # # # # # # # # # #

Bruker 300 MHz at ambient temperature using CDC1 ₃ as solvent, unless otherwise stated. NMR chemical shifts are recorded in ppm with the solvent as internal standard on a d scale and J values are in Hz. Infrared, ultraviolet and mass spectra analyzes are performed in the Eli Lilly physicochemical laboratory. High pressure liquid chromatography conditions: Hitachi model L-6200A Intelligent Pump with D-2500 chromatographic integrator, Zorbax RX C-18 25 cm column, acetonitrile / water 60:40, 1.0 mL / min, 275 nm, 10 μΐ injection . Gas Chromatography Conditions (GC): HP 5890A GC with DB1 column 0.25 μια x 25 m, injection temperature 300 ° C, detection at 300 ° C (FID), column at 5 ° C (5 min), 18 ml / min to 250 ° C then at 250 ° C for 20 min. The terms NMR, mass spectrum, IR and / or pl. chrome. means that the spectrum of the product was analyzed and was consistent with the desired structure.

Preparation 1 (6-Bromo-2-tetralone) propylene ketal

1,3-Bis-trimethylsilyloxypropanediol (38.5 g, 175 mmol) prepared from 1,3-propanediol, triethylamine and chlorotrimethylsilane in tetrahydrofuran is slowly added to a stirred solution of trimethylsilyltrifluoromethanesulfonate (0.5 mL, 2.6 mmol) in methylene chloride ( 100 mL, -70 ° C) while maintaining the reaction temperature between -70 ° C and -60 ° C. The solution was stirred for 10 min at -70 ° C. Solution

6-bromo-2-tetralone (35.5 g, 158 mmol) in methylene chloride (100 mL) was added slowly over 10 min. The resulting reaction mixture was allowed to slowly warm to 15 ° C over 15 h, after which time thin layer chromatography (diethyl 35) was added.

Φ φ φ φ φ φ · · · · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ vykaz vykaz vykaz vykaz tetralone. The reaction was quenched by addition of saturated sodium bicarbonate (200 mL) and the layers were separated. The aqueous layer was extracted with methylene chloride (50 mL). The combined methylene chloride solutions were washed with brine (200 mL), dried over sodium sulfate and evaporated under reduced pressure to give a gold-colored residue. This was filtered through a pad of silica gel (300 g) and eluted with hexane / ethyl acetate 3: 1. The filtrate was evaporated under reduced pressure and the product was recrystallized from hexane to give 33.5 g (75% yield) of (6-bromo-2-tetralone) propylene ketal as white crystals (NMR, mass spectral).

Calcd for C _i3 H _with Br ₂ 0 (%): C 55.14, H 5.34. Found (%): C 55.05, H 5.52.

Preparation 2 (6-Methylthio-2-tetralone) propylene ketal

To a stirred solution of (6-bromo-2-tetralone) propylene ketal (0.511 g, 1.81 mmol) in tetrahydrofuran (5 mL, -75 ° C) was added dropwise a 2.5 M solution of n-butyllithium (0.76 mL). ,

1.90 mmol) while maintaining the temperature between -73 ° C and -70 ° C. The resulting solution was stirred at -70 ° C for 15 min or until thin layer chromatography showed no starting material (hexane / ethyl acetate 70:30) upon completion of the reaction in an aliquot with benzaldehyde. After 15 min, dimethylsulfide (0.18 mL, 2.00 mmol) was added dropwise at -75 ° C. After stirring at 75 ° C for 20 min, the reaction mixture was diluted with ethyl acetate (25 mL) and quenched with saturated ammonium chloride solution (10 mL). The organic layer was separated, washed with brine (10 mL),

44 44 44

4 4 4 4 4

4444 4444 3

4 44444 4,444 «» · 4 4 4 4 _ 4 4 4 «44 44 • 4

4

The residue was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a yellow oil. The crude product was purified by silica gel flash chromatography (50 g), eluting with hexane / ethyl acetate 3: 1 to give 0.39 g (87%) of (6-methylthio-2-tetralone) propylene ketal as a clear viscous oil (IR, NMR, mass spectrum).

Calcd for C ₁₄ H _i O _{2 S} (%): C 67.17, H 7.25. Found (%): C 67.04, H 7.20.

Preparation 3 l

6-Methylthio-2-tetralone

A solution of (6-methylthio-2-tetralone) propylene ketal (29.7 g, 118 mmol) in tetrahydrofuran (50 mL) was treated with 6N hydrochloric acid solution (9 mL, 54 mmol) and stirred at room temperature for 3 h, or until thin layer chromatography (methylene chloride / hexane 80:20) showed complete consumption of the starting material. The reaction mixture was diluted with ethyl acetate (60 mL) and saturated aqueous sodium bicarbonate (110 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (30 mL). The combined organic solutions were shaken with brine (100 mL), dried over sodium sulfate and evaporated under reduced pressure to give an off-white solid. The crude product was purified by silica gel flash chromatography (400 g) and eluted with 5: 1 hexane / ethyl acetate to give 19.5 g (85%) of 6-methylthio-2-tetralone as a white solid (IR, NMR, wt. spectra).

Calcd for C19H18N3O (%): C 68.71, H 6.29. Found (%): C, 68.60, H, 6.31.

· 99 99 99 «9 • 99 99 99 99 99 99 99 99 99 99 99 99 999 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99

Preparation 4

6-Methylthio-2-tetralone

A solution of 4-methylthiophenylacetic acid (10 g, 54.8 mmol) and dimethylformamide (0.1 g, 1.37 mmol) in methylene chloride (50 mL) at 35 ° C was treated with thionyl chloride (4.4 mL, 60.25 mmol). ). The solution was kept at 35 ° C for 30 min and then the solvent was removed by distillation under reduced pressure and replaced with fresh methylene chloride (50 mL). A solution of the acid chloride and ethylene (4.6 g, 164 mmol) was added simultaneously to a stirred mixture of aluminum bromide (36.5 g, 137 mmol) in methylene chloride (450 mL) at -15 to -10 ° C over 25 min. The resulting reaction mixture was stirred for 2.5 h at -10 to 0 ° C. Water (200 mL) was slowly added (<25 ° C) and the layers were separated. The organic layer was washed sequentially with 5% sodium bicarbonate solution (200 mL) and brine (200 mL), dried over sodium sulfate, and evaporated under reduced pressure to give a dark colored oil. The oily liquid was dissolved in alcohol 3A (12 mL) and treated with a solution of sodium bisulfite (22.8 g) in water (40 mL) and alcohol 3A (12 mL). After 30 min at 20 ° C and 1 h at 0 ° C, the precipitated bisulfide addition complex is filtered, washed with cold alcohol 3A (15 mL) and ether (50 mL). The filtered solid was added to a mixture of ether (100 mL) and potassium carbonate (22.7 g,

164 mmol), dissolved in water (75 mL) and stirred vigorously at 22 ° C until the solid dissolved. The organic layer was separated, washed with 1N hydrochloric acid solution (100 ml), then water (200 ml), dried over sodium sulfate and evaporated under reduced pressure to give 5.8 g (48%) of 6-methylthio-2-tetralone as beige solids (purity found in 44)

4 4 9

4 4 4

4 444

4 4

4 4 9

4 4 *

4 4 4

444 444 • 4 · · 4 4

4 444 • · 4 HPLC (88%).

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

A solution of 6-methylthio-2-tetralone (1 g, 5.2 mmol, 1 equivalent) in dry toluene (18 mL) was treated with (R) - (+) - phenethylamine (0.72 mL, 5.7 mmol, 1 mL). , 1 equivalent) and p-TsOH (6 mg). The solution is degassed 3 times under gentle vacuum / nitrogen and positive nitrogen pressure is maintained. The solution was refluxed under Dean-Stark conditions to remove water. The progress of imine formation is monitored by nuclear magnetic resonance. After 2.5 h at reflux, no starting ketone should be detected by ¹ H NMR. Toluene is distilled off under a slight vacuum and under nitrogen and care should be taken not to expose the mixture to air. Dry tetrahydrofuran (14 mL) was added to give a light purple solution, which was maintained at -70 ° C under a nitrogen atmosphere. Lithium diisopropylamide is generated by dropwise addition of a solution of 2.5 M n-butyllithium in hexane (2.4 mL, 6.0 mmol, 1.15 equivalents) to a diisopropylamine solution (0.78 mL, 6.0 mmol, 1, 15 equivalents) in tetrahydrofuran (19 mL) at 45 ° C under a nitrogen atmosphere. The temperature is maintained between -45 ° C and -30 ° C during the addition. After the addition was complete, the solution was stirred for 10 min at -45 ° C. While cooling the lithium diisopropylamide solution to -75 ° C, the imine solution is added dropwise over 15 minutes via cannula over 15 minutes, maintaining the temperature between -70 ° C and -75 ° C. The resulting yellow-orange solution was allowed to warm to -20 ° C over 20 min and then recooled to -75 ° C. Iodomethane (0.36 ml, 5.8 · 00)

0 0 · 0 0 0 0

0 000 • 0 0 ♦ 0

0

0 0

0 0

000 000

0

00 mmol, 1.15 equivalents) is added at temperatures between -75 ° C and -72 ° C. The solution is warmed (with acetone bath) to 0 ° C over 15 min. On cooling to -5 ° C, methanesulfonic acid (0.43 mL, 6.6 mmol, 1.3 equivalents) was added at temperatures between -5 ° C and 1 ° C. After 5 min at 0 ° C a gray heterogeneous mixture is formed. This mixture was recooled to -75 ° C. A 1.125 M tetrahydrofuran acrylic anhydride solution (11 mL, 12.5 mmol,

2.4 equivalents). The mixture was kept in the cooling bath for 15 h and during this time warmed to 13 ° C. The reaction mixture was allowed to warm to 15 C. Water (2 mL) was added and the mixture was stirred while warming to room temperature. The solution was diluted with diethyl ether (50 mL) and washed sequentially with 1N sodium hydroxide solution (20 mL), 1N hydrochloric acid solution (20 mL), water (20 mL), saturated sodium bicarbonate solution (40 mL), and brine (20 mL). ). The solution was dried over sodium sulfate, evaporated and flash chromatographed on silica gel (120 g), eluting with hexane / ethyl acetate (70:30) to give 1.3 g (yield 69%) of (+) - (10bR) -4- ( 2- (R) -phenethyl) -8-methylthio-10b-methyl-1,2,3,4,6,10b-hexahydrobenzo [f] quinolin-3-one (NMR). A mixture of triethylsilane (12 mL, 75 mmol) and trifluoroacetic acid (14.5 mL, 188 mmol), pre-cooled to -15 ° C, is added to (+) - (10bR) -4- (2- (R) - phenethyl) -8-methylthio-10b-methyl-1,2,3,4,6,10b-hexahydrobenzo [f] quinolin-3-one (2.6 g, 7.6 mmol) pre-cooled in a -15 bath Deň: 32 ° C. The mixture was stirred for 15 h, during which time it was warmed to 13 ° C. Thin layer chromatography (hexane / ethyl acetate 70:30) and high pressure liquid chromatography showed complete disappearance of (+) - (10bR) -4- (2- (R) -phenethyl) -8-methylthio-10b-methyl-1, 2,3,4,6,10b-hexahydrobenzo [f] -quinolin-3-one and the appearance of a new product indicating complete reduction of the double bond. The mixture is then refluxed

9 9 9 9 9

999 9,999,999

9 9 9 ·· 99

9

9

9,999 9 9

9 9 9 for 2 h to remove the chiral composition. After cooling to room temperature, the mixture was evaporated under reduced pressure. The residue was taken up in methylene chloride (50 mL) and washed twice with a saturated aqueous solution of sodium bicarbonate (35 mL) and brine (50 mL). The dried sodium sulfate and the evaporated crude product were purified by silica gel flash chromatography (100 g) eluting first with hexane / ethyl acetate 3: 1 to remove triethylsilane and then 14% methanol in methylene chloride with 1% acetic acid to give a foamy solid. Recrystallization from hot ethyl acetate gave 1.6 g (82%) of (+) - (4aR) - (10bR) -8-methylthio-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one (92% ee, IR, NMR, mass spectral).

Calcd for C H _{IB IQ} NOS (%): C 68.93, H 7.33. Found (%): C 69.05, H 7.44.

Preparation 6 (+) - (4aR) - (10bR) -4-Methyl-8-methylthio-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3- on (+) - (4aR) - (10bR) -8-Methylthio-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one (0.423g, 1.62 mmol, 1.0 equivalent) was treated with potassium tert-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 for 5 min, methyl iodide (0.116 mL, 1.15 equivalents) was added and the mixture was further stirred for 2 h at 0 ° C. The mixture was then treated with about 100 mg of acetic acid and the solvents removed in a stream of nitrogen. The solid was dissolved in about 50 mL of methylene chloride and washed

··

0 · 0 ·

0 0

0 0

000 000

0

0

000

0

000 0

0

0 0

0 twice with water. The extracts were dried (0.4 nm molecular sieves) and filtered through silica gel (2 g, washed with ethyl acetate containing 2% methanol). The solid after evaporation of the methylene chloride extracts was chromatographed on silica gel with methylene chloride, ethyl acetate and methanol (50: 50: 1) as eluent (pl. Chrom.).

Preparation 7 (+) - (4aR) - (10bR) -4-Methyl-8-methylthio-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3- on (+) - (4aR) - (10bR) -4-Methyl-8-bromo-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one (20.0 g, 64.9 mmol, in 150 mL tetrahydrofuran) was added to a freshly prepared solution of lithium diisopropylamide in 500 mL tetrahydrofuran at -20 ° C. After standing in an ice bath for 90 min, the resulting amide-enolate solution was cooled to -70 ° C and added via cannula over 10 min to a freshly prepared stirred solution of n-butyllithium (60.0 mL = 2.54 M solution in hexane, 152). mmol, 2.34 equivalents) at -72 to -75 ° C in 300 mL of tetrahydrofuran. The homogeneous solution was stirred at about -75 ° C for 45 min and quenched with dimethyl disulfide (11.0 mL, 123 mmol, 1.9 equivalents) at about -75 ° C. After 30 min at -75 ° C, the mixture was treated with acetic acid (18 mL) and all volatiles removed in vacuo. The resulting solid was treated with 300 mL of heptane-water (1: 1, v / v) and the pH was adjusted to 3 N with hydrogen sulfate solution. The biphasic mixture was filtered and the cake washed with 1% aqueous sodium bicarbonate solution (2 x 50 mL) and water (200 mL). The resulting material was dried at 50 ° C under vacuum to give (+) - (4aR) - (10bR) -4-methyl-8-methylthio-10b-methyl-1,2,3,4,4a, 5,6, 10b-octa-hydrobenzo • BB BB BB BB

ΒΒΒΒ Β B B B · B B B B BB • • • BB BB • • • • • • • • • • BB BB BB

- 42 [f] quinolin-3-one (IR, NMR, mass spectral)

Calcd for ^C 16 ^H 2; l ^nose (%) · C 69.77, H 7.69, N 5.09. Found (%): C 69.70, H 7.62, N 5.06.

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

Lithium chloride (1.80 g, 2.46 mmol, 10 equivalents) was quickly weighed and placed in a 500 mL flask equipped with mechanical stirring, pressure equalizing funnel, thermocouple, injection bar, and nitrogen inlet. (+) - (4aR) - (10bR) -4-methyl-8-bromo-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3- on (13.09 g, 2.46 mmol, 1.0 equivalent) and 100 mL of dry tetrahydrofuran and the mixture was stirred to dissolve (10-15 min). 46.71 mL of lithium hexamethyldisilazide [LiN (TMS) ₂ , 46.71 mmol, 1.1 equivalents] in tetrahydrofuran was then added via syringe over 10 min. The resulting clear yellow solution was stirred at room temperature for 1 h. Methyl lithium (1.4 M solution in diethyl ether, 33.36 mL,

46.71 mmol, 1.1 equivalents) via syringe over 50 min. Gas evolution is observed and the reaction is exothermic from 23 to 26 degrees. The exothermic reaction is checked by standard methods. The reaction mixture was stirred at room temperature for 45 min and then cooled to -70 ° C. Add n-butyllithium (1.6 M solution in hexane, 29.2 mL,

46.71 mmol, 1.1 equivalents) over 25 min while maintaining the temperature of the reaction mixture at -71 / -70 ° C. The yellow solution is kept at -70 ° and stirred for 35 min. High pressure liquid chromatography shows almost complete formation of the di 9 9 9 9 9 9 9 9 4 4 9

4,444 49 · ··· * 944,994

4 4 9 4

99 94 94 99

- 43 anions after 15 min. Dimethylsulfide (4.00 g, 42.46 mmol, 1.0 equivalents) was dissolved in 25 mL tetrahydrofuran and added over 50 min. The mixture was stirred for 30 min (-70 ° C). HPLC indicated completion of the reaction after 10 min. A 1N hydrochloric acid solution (100 mL, -70 ° C) was added to the mixture. The reaction mixture was warmed to room temperature and the aqueous layer was extracted with 200 mL of methyl tert-butyl ether. The organic layers were combined and washed with 50 mL of brine. The organic layers were dried over magnesium sulfate, filtered and evaporated on a rotavap ™ 35 ° C and house-vac. As the volume decreases, a white solid forms. The organic layers were evaporated from 550 ml to about 30 to 40 ml of a white suspension. This suspension was stirred at room temperature for several hours followed by filtration with small portions of methyl tert-butyl ether until colorless filtrates from the washings were obtained. The white solid was dried to give 7.73 g (66%) of (+) - (4aR) - (10bR) -4-methyl-8-methylthio-10b-methyl-1,2,3,4,4a, 5 6,10b-octahydrobenzo [f] quinolin-3-one.

Preparation 9 (+) - (4aR) - (10bR) -4-Methyl-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1,2,3,4,4a, 5,6,10b- octahydrobenzo [f] quinolin-3-one

M-chloroperoxybenzoic acid solution (about 56%,

6.32 g as a solution in methylene chloride) is added to (+) - (4aR) - (10bR) -4-methyl-8-methylthio-10b-methyl-1,2,3,4,4a, 5, 6, 10b-octahydrobenzo [f] quinolin-3-one (5.50 g in 110 ml methylene chloride) and aqueous sodium bicarbonate (9.4 g in 110 ml water) at 0 to 1 ° C in about 1 hour. The layers were separated for 8 h and the organic extracts were washed twice with an aqueous 1% sodium bicarbonate solution.

9

9

• · 4

99 • 9 9

9 9 9

999 9

9 9

9 99 dried (0.4 nm molecular sieves) and evaporated to a total weight of 5.90 grams. The proportion (2.91 grams) of this non-purified sulfoxide in 10 mL of toluene-d _e is treated with 2.20 ml of trifluoroacetic anhydride at 5 Low: 14 ° C. After 30 min., An aliquot NMR analysis of 0.50 mL showed no starting sulfoxide (ArSOCH ₃ singlet absent at d = 2.25 ppm) and showed exclusive formation of Pummerer product (ArSCH ₂ OCOCF ₃ singlet at d = 5.31 ppm). The reaction mixture is subjected to vacuum (0.66 to 1.33 kPa) for 30 min, and then the contents are added to a stirred mixture (under nitrogen atmosphere) of water (20 mL), tetra-n-butylammonium hydrogen sulfate (0.1 mL). g) and 7.1 ml of water-soluble borohydride (12 weight percent sodium borohydride in 14 N sodium hydroxide solution) at 5 to 10 ° C over 20 min. After a further 20 min, 2-chloro-4-ethylbenzothiazole (3.00 g with additional 9.5 mL of toluene) was added and another portion of tetra-n-butylammonium hydrogen sulfate (0.50 g) was added. The reaction mixture was stirred at 37-39 ° C and 4 portions of 0.25 ml each were taken for direct analysis by 1 H-NMR and high pressure liquid chromatography to analyze product conversion and distribution. After 26 h, the top layer [toluene containing (+) - (4aR) - (10bR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1,2,3,4,4a 5,6,1,10b-octahydrobenzo [f] quinolin-3-one and excess 2-chloro-4-ethylbenzothiazole] are separated from this three-phase mixture and diluted with 25 ml of methylene chloride. This organic layer was washed with aqueous 1 N sulfuric acid, aqueous 5% sodium bicarbonate, dried over 0.4 nm molecular sieves and evaporated in vacuo to 5.24 g. The resulting solid was treated with hot methyl tert-butyl ether (30 mL). ) and then evaporated in vacuo to 20 ml and cooled to 0 ° C. The mixture was filtered and the white solid was evaporated to give 2.92 g of (+) - (4aR) - (10bR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1,2b. , 3,4,4a, 5,6, 10b-octahydrobenzo [f] • 00 • 0 0 «00 00 00 ··· * 0 00 0 0 0 0 • 00 0 0 0 0 0 0 00 • 0 000 0 0 0 000 0 000 000000 00

00 00 00 00 00

45 quinolin-3-one (IR, NMR, mass spectral).

Calculation for C Η N OS (%): C 67.93, H 6.16, N 6.83,

4 25 2 2

S, 15.08. Found (%): C 68.21, H 6.20, N 6.63, S 15.17.

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

A solution of m-chloroperoxybenzoic acid (35.2 mmol in 100 mL methylene chloride) was added to (+) - (4aR) - (10bR) -methyl-8-methylthio-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one (10.0 g, 98% purity by weighted standard analysis, 35.6 mmol) in a biphasic mixture of methylene chloride (200 mL) and aqueous sodium bicarbonate (8 90 g in 89 mL of water) at -2 to 0 ° C over 1 h. The layers were separated and the methylene chloride layers were washed once with sodium metabisulfite (1.00 g in 25 mL) and three times with sodium bicarbonate (1.00 g in 100 mL). ml). The dried methylene chloride extract (0.4 nm molecular sieves) was evaporated to about 20 ml and diluted with 100 ml of toluene. The mixture was then evaporated in vacuo at 30-35 ° C. This step was repeated twice with fresh toluene (100 mL each) and then the sulfoxide (usually crystalline) was diluted with toluene (100 mL). The mixture was then treated with trifluoroacetic anhydride (7.30 mL) for 10 min at 0-10 ° C. After 30 min at 0 ° C, this solution is subjected to vacuum (< 1.33 kPa for 30 min) and added over 30 min to a mixture of degassed (nitrogen) potassium carbonate (41 g) sodium borohydride (2). 88 g), tetra-n-butylammonium hydrogen sulfate (2.00 g) and 2-chloro-4-ethylbenzothiazole (8.20 g at 96.5% purity dissolved in 5 ml toluene) and water (87 ml) at 0-5 ° C.

• 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 • · · · ···

The toluene layer was separated (hot) and washed with 3 portions of water each of 100 ml. The toluene layer was diluted with 125 ml of ethyl acetate and then washed successively with 3 portions of 0.25 N hydrochloric acid solution each of 200 ml, 100 ml of 1% sodium bicarbonate solution and 100 ml of saturated aqueous sodium chloride solution. The organic layer was dried (10 g of 0.4 nm molecular sieves), evaporated to a total volume of 25 ml and treated with 100 ml of methyl tert-butyl ether (reflux for 30 min, then left at 0 ° C for 1 h). ) to give (+) - (4aR) - (10bR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1,2,3,4,4a, 5,6,10b -octahydrobenzo [f] quinolin-3-one.

Preparation 11

CH ₃

IX

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

Dry sulfoxide IX (96% purity by gas chrome)

chromatography (8.90 g, 29.4 mmol with correction) as a slurry in toluene (89 mL) was treated dropwise with trifluoroacetic anhydride (5.2 mL) at 0-5 ° C over 20 min. dissolution). After 30 min, the solution was added to a mixture of potassium carbonate (32 g), water (45 mL), tetrabutylammonium hydrogen sulfate (2.25 g), sodium borohydride (1.0 g), 2-chloro-4-ethylbenzothiazole (7 g). 96 g (purity about 96.5% by gas chromatography) and toluene (10 mL) at about 5-15 ° C over 30 min. The biphasic mixture was then stirred for 20 h at 43 ° C and then a small amount of solid was filtered from the reaction mixture. The warm toluene layer was washed once with 400 mL of water (45 ° C) and then evaporated in vacuo to give 13.86 g of a white solid containing mainly (+) - (4aR) - (10bR) -4-methyl-8- ( 4-ethyl-2-benzothiazolylthio) -10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one and 2-chloro-4-ethylbenzothiazole. 13.0 g of this mixture was treated with methyl tert-butyl ether (50 mL at reflux and then left at 0 ° C for 2 h) to give 11.05 g of (+) - (4aR) - (10bR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one (IR, NMR) , mass spectra).

Calc'd (%): C 68.21, H 6.20, N = 6.63. Found (%): C 68.29, H 6.15, N 6.67.

Preparation, 12 (+) - (4aR) - (10bR) -4-Methyl-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1,2,3,4,4a, 5,6,10b -octahydrobenzo [f] quinolin-3-one

M-Chloroperoxybenzoic acid (about 92 g, about 50% in 1.0 liter methylene chloride) was added at 0 ° C at 0 ° C. To (+) - (4aR) - (10bR) -4-methyl-8-methylthio solution (+) - (4aR) - (4bR) -10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one (79.5 g, 92.9%, 0.269 mol) in methylene chloride (2.2 liters). The progress of the reaction was monitored by high pressure liquid chromatography (240 nm) for the oxidation of (+) - (4aR) - (10bR) -4-methyl-8-methylthio-10b-methyl-1,2,3,4,4a, 5,6 , 10b-octahydrobenzo [f] quinolin-3-one to a level of less than 0.3% by area. The organic solution was stirred with a solution of sodium bisulfite (75 g in 1 liter of deionized water). The organic layer was separated and washed with 6% sodium bicarbonate solution (3 x 1 L). The organic layer was dried over sodium sulfate and evaporated.

Toluene (1 L) was added to the sulfoxide intermediate and this solution was evaporated in vacuo. This was repeated twice with fresh toluene (1.1 L each) and then the sulfoxide was dissolved in 1.1 L toluene and cooled in an ice bath. Trifluoroacetic anhydride (51 mL) was added dropwise to the sulfoxide at 0 ° C over 15 min. After stirring at 0 ° C for 30 min, Pummerer's product (ArSCH ₂ OCOCF ₃ ) was added via cannula to a well stirred mixture of deionized water (414 mL), potassium carbonate (319 g), sodium borohydride (15.2 g), 2-chlorine. -4-ethylbenzothiazole (65.7 g, purity about 96.5%), tetrabutylammonium hydrogen sulfate (21.6 g) and toluene (170 mL) at 10 ° C. The reaction mixture was slowly heated to 42 ° C while monitoring the progress by high pressure liquid chromatography. After 18 h, an additional volume of toluene (1.0 L) was added and the toluene layers were washed with deionized water (3 portions of 1 L, 45 ° C). Ethyl acetate (1 liter) was added to the organic layer, then the organic layer was washed with a 0.25 M hydrochloric acid solution (3 portions of 1 liter), 1 N sulfuric acid solution (3 portions of 1 liter), 6% sodium hydrogen carbonate solution ( 1.5 liters) and saturated sodium chloride solution (2 liters). The organic layers were dried with 0.4 nm molecular sieves (500 g) and then evaporated. Methyl · ····· · ·

- * · · * ·· ·· ** · *

tert-butyl ether (400 mL) and the mixture was heated to reflux. After stirring at reflux for 30 min, the mixture was cooled to 5 ° C. The suspension was filtered and washed with methyl tert-butyl ether (100 mL). The solution is filtered and the product is dried at 50 ° C for about 18 h to give 90.1 g (80%) of (+) - (4aR) - (10bR) -4-methyl-8- (4-ethyl-2- benzothiazolylthio-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one.

Claims (22)

A process for the preparation of a compound of formula (I) wherein: R ¹ represents 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitronaphthyl, 4-nitronaphthyl, 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolyl, 4-quinolyl, 7-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 8-isoquinolyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-1H-indazolyl, 2-benzoxazolyl, 3-1,2-benzoisothiazolyl, 2-pyridyl , 4-pyridyl, 2-pyrazinyl, 2-naphtho [2,3-d] thiazolyl, 2-naphtho [1,2-d] thiazolyl, 9-anthryl, 2-thiazolyl, 2-benzimidazolyl, 1-benzo [g] isoquinolyl , 8-benzo [g] isoquinolyl, 5-1H-tetrazolyl, 2-quinazolinyl, 2-thiazolo [4,5-b] pyridyl, 4-10H-pyridazino [3,2-b] -2- quinazolinyl, 2-1,4-benzodioxinyl, 4 4 2-triazine, 2-benzoxazine, 4-benzoxazine, 2-purine or 8-purine, wherein the above-mentioned R ¹ groups are unsubstituted or substituted by 1 to 3 groups selected from trifluoromethyl, trifluoroethoxy, C ₁ -C 4 alkyl, trifluoromethoxy, hydroxyl, C ₁ -C ₃ alkoxy, nitro, C "C ₃ alkylthio, C _x -C _e alkanoyl, phenyl, oxo, phenoxy, phenylthio, C _x -C ₃ alkylsulfinyl group, a C _x -C ₃ alkylsulfonyl, cyano, amino, C -C alkylamino, difenylmethylaminoskupina, trifenylmethylaminoskupina, benzyloxy, benzylthio, (mono-halo, nitro or _CF3) benzyl (oxy or thio), di (C _x -C ₃ alkyl, C ₃ -C _e cycloalkyl or C -C ^ _g cycloalkylalkyl) amino, (mono-C _x -C ₃ alkyl, C, _X ~ C ₃ alkoxy or halo) - (phenyl, phenoxy, phenylthio, phenylsulfonyl or fenoxysulfonylová group), a C ₂ -C ₆ alkanoylamino, benzoylamino, diphenylmethylamino- (C ₁ -C ₃ alkyl), aminocarbonyl, C ₁ -C ₃ alkylaminocarbonyl, di- (C ₁ -C ₃ alkyl) aminocarbonyl, halo- (C ₁ -C ₆ alkanoyl), aminosulfonyl group , C ₁ -C ₃ alkylaminosulfonyl, di- (C ₁ -C ₃ alkyl) -aminosulfonyl, phenyl (oxy or thio) - (C ₁ -C ₃ alkyl), (halo, C -C alkyl or C - C 1 alkoxy) phenyl (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 group ), characterized in that the ketone of formula • 4 4 4 · 4 4 4 4 4 4 4 4 4 4 4 4 4 · · 4 4 4 4 4 4 4 444 44 444 44 444 44443 4 4 4 44 44 44 44 44 44 where R is a halogen atom, converted to a protected ketal, the protected ketal reacts with a reactive alkyllithium compound and a sulfur transfer agent to obtain an S-methylated ketal compound, the S-methylated ketal deprotects to give methyl- thiotetralone compounds of formula II sch ₃ (II) This compound of formula II is reacted with (R) - (+) - phenethylamine to obtain a compound of formula III (III). 111 1 99 9 9 9 9 • 9 1 9 9 99 99 compound of formula III reacts with a strong lithium base to give a lithioenamine compound of formula IV (IV), the resulting lithioenamine of formula IV reacts to give a compound of formula V (V) compound of formula V reacts with an acyl halide or acrylic anhydride 9 · 9 9 · 9 9 9 99 9 9,999,999,999,999,999,999 99999 9 9 9 99 9 9 99 99 99 99 Reaction was quenched with a base and the residue containing compound of formula VI is treated with an appropriate silane and trifluoroacetic acid in the absence of a solvent to prepare a compound of formula VII, SCH ₃ (VII) a compound of formula VII with a methyl halide in a reaction mixture comprising organic a solvent and a strong base to obtain an arylmethylsulfide compound of formula VIII, the compound of formula (VIII). of formula VIII is oxidized to the sulfoxide compound of formula IX O And (ix) a sulfoxide compound of formula IX is reacted with an acylating agent providing a product Pummerer rearrangement product Pummerer rearrangement is reacted with an electrophilic agent zvoleným.ze group consisting of ^Arl, wherein A is a leaving group, in the presence of a phase transfer catalyst, a hydride reducing reagent and a base to form a compound of formula I. 2. A process for the preparation of a compound of formula (II) wherein the ketone of the formula wherein R is halogen is converted to a protected ketal, the protected ketal reacts with a reactive alkyllithium compound and a transfer agent. S-methylated ketal compound and S-methylated ketal compound are deprotected to give the methylthiotetralone compound of formula II. 3. The process of claim 2 wherein the sulfur transfer agent is dimethyl disulfide and the protected ketal is 4. A process for the preparation of a compound of formula II according to claim _3, wherein the compound of formula II is reacted with lithium diisopropylamide, n-butyllithium, and dimethyl disulfide. 5. A process for the preparation of a compound of formula (II), characterized in that: SCH ₃ ·· ·· · 4 · «4 4 444 444 4 · The compound (II) (XI) is converted to an acid halide and the acid halide is reacted with a Lewis acid and ethylene to give a compound of formula II. 6. The process of claim 5, wherein methylene chloride, thionyl chloride and a catalytic amount of dimethylformamide are used to obtain the acid halide and the Lewis acid used is aluminum bromide. A process according to any one of claims 2, 3, 4, 5 or 6, characterized in that the compound of formula II in which R ¹ represents 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitronaphthyl, 4-nitronaphthyl, 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolyl, 4'-nitrophenyl -quinolyl, 7-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 8-isoquinolyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-1H-indazolyl, 2-benzoxazolyl, 3-1,2-benzoisothiazolyl, 2-pyridyl , 4-pyridyl, 2-pyrazinyl, 2-naphtho [2,3-d] thiazolyl, 2-naphtho [1,2-d] 4 · 4 4 4 4 · 4 4 4 4 4 4 4 4 4 4 4 · 44 · 44 4,444 4,444,444 444444 44 44 44 44 44 44 44 thiazolyl, 9-anthryl, 2-thiazolyl, 2-benzoimidazolyl, 1-benzo [g] isoquinolyl, 8-benzo [g] isoquinolyl, 5-1H-tetrazolyl 2 quinazolinyl, 2-thiazolo [4,5-b] pyridyl, 4-10H-pyridazino [3,2-b] -2-quinazolinyl, 2-1,4-benzodioxinyl, 2-triazine, 2 a benzoxazine group, a 4-benzoxazine group, a 2-purine group or an 8-purine group, wherein the above-mentioned R ¹ groups are unsubstituted or substituted by 1 to 3 groups selected from trifluoromethyl, trifluoroethoxy C ₁ -C ₄ alkyl, trifluoromethoxy, hydroxy, C -C alkoxy, nitro, C, -C ₃ alkylthio, C _i -C _e alkanoyl, phenyl, oxo, phenoxy, phenylthio, C -C alkylsulfinyl, C ₃ -C ₃ alkylsulfonyl, cyano, amino, C 1 -C 6 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 < \ -C _q cycloalkylalkyl) amino, (mono-C _i -C ₃ alkyl, C _i -C ₃ alkoxy or halo) - (phenyl, phenoxy, phenylthio, phenylsulfonyl or xysulfonylová phenol group), a C ₂ -C ₆ alkanoylamino, benzoyl amino, diphenylmethylamine-fC ^ C. * alkyl) aminocarbonyl, C -C Skupi to alkylaminocarbonyl, di-IC ^ -C alkyl) aminocarbonyl, halo (C _i -C _<. alkanoyl group), aminosulfonyl , C 1 -C ₃ alkyl aminosulfonyl, di- (C 1 -C ₃ alkyl) aminosulfonyl, phenyl (oxy or thio) - (C ₁ -C ₃ alkyl), (halo, C ₁ -C ₃ alkyl or C 1 -C ₃ alkyl) (C1-alkoxy) phenyl (oxy or 61 thio) - (C ₁ -C ₃ alkyl), benzoyl or [amino, C ₁ -C ₃ alkylamino or di [(C ₁ -C ₃ alkyl) amino] "(CC alkyl). · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· A process according to any one of claims 2, 3, 4, 5 or formula II (II) to convert to (+) - (4aR) - (10bR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) - 10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one. A method according to any one of claims 2, 3, 4, 5 or 6, characterized in that the compound of formula II * SCH ₃ 0 '(II) 99 99 99 9 9 9 9 9 9 9 9 9 9 999 9 999 999 9 9 999 999 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 99 is reacted with (R) - (+) - phenethylamine to provide a compound of formula III SCH ₃ (III) compound of formula III reacts with a strong lithium base to give a lithioenamine compound of formula IV (IV) The resulting lithioenamine of formula IV is methylated to a compound of formula V compound of formula V reacts with an acyl halide or acrylic anhydride to form of the compound of formula VI and the reaction is terminated with a base and the residue containing the compound of formula VI is combined with the appropriate silane and trifluoroacetic acid in the absence of a solvent for the preparation of the compound of formula VII H · * · · · · · · · · · · · · · · · · · · · · · · · · · · · · A process according to claim 9, wherein the compound of formula VII is reacted with methyl halide in a reaction mixture comprising an organic solvent and a strong base to obtain an arylmethylsulfide compound of formula VIII · 9 · 99 <99 9 · 9 9 · 9 · · 99 9 9 ♦ ♦ the compound of formula VIII is oxidized to the sulfoxide compound of formula IX the sulfoxide compound of formula IX is reacted with an acylating agent to obtain a Pummerer rearrangement product; - a 65 ”Pummerer rearrangement reacts with an electrophilic composition selected from the group consisting of AR ¹ , wherein A is a leaving group and R ¹ is a 2-nitrophenyl group, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitronaphthyl, 4-nitronaphthyl, 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolyl, 4-quinolyl, 7-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 8-isoquinolyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-1H-indazolyl, 2-benzoxazolyl, 3-1,2-benzoisothiazolyl, 2-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-naphtho [2,3-d] thiazolyl, 2-naphtho [1,2-d] thiazolyl, 9-anthryl, 2-thiazolyl, 2-benzoimidazolyl, 1-benzo [g] isoquinolyl, 8-benzo [g] isoquinolyl, 5-1H-tetrazolyl, 2-quinazolinyl, 2-thiazolo [4,5-b] pyridyl, 4-10H-pyridazino [3,2-b] -2-quinazolinyl, 2-1,4-benzodioxinyl a group, a 2-triazine group, a 2-benzoxazine group, a 4-benzoxazine group, a 2-purine group or an 8-purine group, wherein the above-mentioned R ¹ groups are unsubstituted or substituted by 1 to 3 groups selected from trifluoromethyl, trifluoroethoxy, C -C alkyl, trifluoromethoxy, hydroxyl, C -C alkoxy, nitro, C -C ₃ al kylthio, C 1 -C 3 alkanoyl, phenyl, oxo, phenoxy, phenylthio, C ₃ -C ₃ alkylsulfinyl, C ₁ -C ₃ alkylsulfonyl, cyano, amino, C ₁ -C ₃ alkylamino, diphenylmethylamino, trife - 66 * · nylmethylaminoskupina, benzyloxy, benzylthio, (mono-halo, nitro or _CF3) benzyl (oxy or thio), di _{(C L} -C ₃ alkyl, C ₃ -C _g cycloalkyl or C ₄ - _C cycloalkylalkyl) amino, (mono-C ^ -C ^ alkyl, C ^ -C ^ alkoxy or halo) - (phenyl, phenoxy, phenylthio, phenylsulfonyl or xysulfonylová phenol group), a C ₂ -C ₆ alkanoylamino group, benzoyl amino, diphenylmethylamine-fC ^ C ^ alkyl) aminocarbonyl, C ₃ -C alkylaminocarbonyl Skupy to, di- (C -C alkyl) aminocarbonyl, halo (C _i -C ₆ alkanoyl group), aminosulfonyl, _C -C ₃ alkyl aminosulfonyl, di- (C ₁ -C ₃ alkyl) -aminosulfonyl, phenyl (oxy or thio) - (C ₁ -C ₃ alkyl), (halo, C -C alkyl or C -C ₃ alkoxy) phenyl (oxy or thio) - (C ₁ -C ₃ alkyl), benzoyl or [amino, C 1 -C 3 alkylamino or ά ₃ - ((C ₁ -C ₃ alkyl) amino) - (C ₁ -C ₃₎ alkyl group), in the presence of a phase transfer catalyst of a hydride reducing agent and a base to form a compound of formula I A process for preparing a compound of the formula wherein: R ¹ represents 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitronaphthyl, 4-nitronaphthyl, 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolyl, 4-quinolyl, 7-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 8-isoquinolyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-1H-indazolyl, 2-benzoxazolyl, 3-1,2-benzoisothiazolyl, 2-pyridyl , 4-pyridyl, 2-pyrazinyl, 2-naphtho [2,3-d] thiazolyl, 2-naphtho [1,2-d] thiazolyl, 9-anthryl, 2-thiazolyl, 2-benzoimidazolyl, 1-benzo [g] isoquinolyl, 8-benzo [g] isoquinolyl, 5-1H-tetrazolyl, 2-quinazolinyl, 2-thiazolo [4,5-b] pyridyl, 4-10H-pyridazino [3,2-b] -2-quinazolinyl a group, 2-1,4-benzodioxinyl, 2-triazine, 2-benzoxazine, 4-benzoxazine, 2-purine or 8-purine, wherein the above-mentioned R ¹ groups are unsubstituted or sub-substituted. 9 9 9 9 6d * - · * ··· · 999 999 9 9 9 9 9 9 substituted with 1 to 3 groups selected from trifluoromethyl, trifluoroethoxy, C 1 -C 6 alkyl, trifluoromethoxy, hydroxyl, C ₁ -C ₆ alkoxy, nitro, C ₃ -C ₃ alkylthio, C ₁ -C ₆ alkanoyl, phenyl, oxo, phenoxy, phenylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, cyano, amino, C 1 -C 6 alkylamino, diphenylmethylamino, triphenylmethylamino, benzyloxy, benzylthio, (mono-halo, nitro or CF ₃ ) -benzyl (oxy- or thio), di- (C-alkyl, C-cycloalkyl or C-cycloalkylalkyl) amino, (mono-C _i -C ₃ -alkyl, C _x -C ₃ alkoxy or halo) - (phenyl, phenoxy, phenylthio, phenylsulfonyl or fenoxysulfonylová group), a C _, - C ₆ alkanoylamino, benzoylamino, difenylmethylamino- (C_ _L - (C ₃ alkyl), aminocarbonyl, C -C alkylaminocarbonyl, di- (C 1 -C 4 alkyl) aminocarbonyl, halo (C 1 -C 4, alkanoyl), aminosulfonyl, C -C alkylaminosulfonyl, di- ( (C 1 -C 3 alkyl) -aminosulfonyl, phenyl (oxy or thio) - (C ₁ -C ₃ alkyl), (halo, C ₁ -C ₃ alkyl or C 1 -C ₃ alkoxy) phenyl (oxy or thio) - (C ₍ 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 group, characterized by in that the arylmethylsulfide compound of formula (VIII) φ φ ΦΦΦ φ φ φ φ - 68 ** - ** The sulfoxide compound of formula (IX) reacts with an acylating agent to give a Pummerer rearrangement product and a Pummerer rearrangement product from the rearrangement agent. a group comprising AR ¹ , wherein A ^{1 is a} leaving group, in the presence of a phase transfer catalyst, a hydride reducing agent, and a base to give a compound of formula I. 12. The process of claim 11 wherein the acylating agent is trifluoroacetic anhydride and the Pummerer rearrangement product is trifluoroacetic acid. - 70 00 • 0 00 00 0 0 · 0 · · 0 0 • 0 · · 0 0 R The acetyloxymethylenesulphide compound of formula X A process for preparing (+) - (4aR) - (10bR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1,2,3,4,4a, 5,6, 10b-octahydrobenzo [f] quinolin-3-one, wherein the trifluoroacetyloxymethylenesulfide compound of formula X is reacted with 2-halo-4-ethylbenzothiazole in the presence of a phase transfer catalyst, a hydride reducing agent and a base. Process according to claims 11 to 12, characterized in that the oxidizing agent is monoperoxyphthalic acid or 3-chloroperoxybenzoic acid, the electrophilic agent is 2-halo-4-ethyl-benzothiazole, the base is a carbon. 000 0 0 0 0 0 0 0000 0000 0 0000 0 0 0 00 00 ·· 00 - 71 • potassium borate, the reducing agent is sodium borohydride and the compound prepared is (+) - (4aR) - (10bR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) - 10b-methyl-1,2,3,4,4a, 5,6, 10b-octahydrobenzo [f] quinolin-3-one. A process for the preparation of a compound of formula VIII, characterized in that the compound of formula (XII) is reacted with a reaction mixture comprising a base and an ether solvent to obtain an amide-enolate solution, 9 · 9 «9 9 999 999 9 9 9 9 9 9 99999 • 9 9 9 The amide-enolate solution is reacted with an alkyl lithium compound to give a dianionic compound of formula and the dianionic compound reacts with dimethyl disulfide to provide an arylmethylsulfide compound of formula VIII. 16. The method of claim 15 wherein the base is lithium diisopropylamide. 17. The method of claim 15 wherein the base is lithium hexamethyldisilazide. A process according to any one of claims 16 or 17, characterized in that lithium salt and methyllithium are added. 1 $. A method according to any one of claims 15, 16, 17 or 18, characterized in that the compound of formula VIII is converted to a compound of formula I · · · φ · • · • · φφφφφφφφφ φφφφφ φ φ • • • • • • • • - ............... in which R ¹ represents 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitronaphthyl, 4-nitronaphthyl, 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolyl, 4-quinolyl, 7-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 8-isoquinolyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-1H-indazolyl, 2-benzoxazolyl, 3-1,2-benzoisothiazolyl, 2-pyridyl , 4-pyridyl, 2-pyrazinyl, 2-naphtho [2,3-d] thiazolyl, 2-naphtho [1,2-d] thiazolyl, 9-anthryl, 2'-thiazolyl, 2-benzoimidazolyl, 1-benzo [g] isoquinolyl , 8-benzo [g] isoquinolyl, 5-1H-tetrazolyl, 2-quinazolinyl, 2-thiazolo [4,5-b] pyridyl, 4-10H-pyridazino [3,2-b] -2- quinazolinyl, 2-1,4-benzodioxinyl, 2-triazine, 2-benzoxazine, 4-benzoxazine, 2-purine or • Β • Β · Β Β 4 4 Β ΒΒΒ ΒΒΒ Β Β - 74 * 9 Β Β • 9 949 44 · • · Β · 9 Β Β · • 9,444 4 9 An 8-purine group wherein the above-mentioned R ¹ groups are unsubstituted or substituted by 1 to 3 groups selected from trifluoromethyl, trifluoroethoxy, CC alkyl, trifluoromethoxy, hydroxyl, CC alkoxy, nitro, CC alkylthio, CC alkanoyl, phenyl , oxo, phenoxy, phenylthio, C ₁ -C ₃ alkylsulfinyl, CC alkylsulfonyl, cyano, amino, CC alkylamino, difenylmethylaminoskupina, trifenylmethylaminoskupina, benzyloxy, benzylthio, (mono-halo, nitro or _CF3) benzyl (oxy or thio), di (C -C alkyl, C ₃ -C ₆ cycloalkyl or C? -C _q cycloalkylalkyl) amino, (mono-C _i -C ₃ alkyl, C ^ alkoxy or halo) - (phenyl, phenoxy, phenylthio, phenylsulfonyl or fenoxysulfonylová group), a C -C alkanoylamino, benzoylamino, difenylmethylamino- _{(C L} -C _3- alkyl), aminocarbonyl, C- ₃ alkylaminocarbonyl, di- (C-alkyl) aminocarbonyl, halo- (C ₁ -C ₆ alkanoyl), aminosulfonyl, CC alkylaminosulfonyl, di- (C- C alkyl) aminosulfonyl, phenyl (oxy or thio) - (C ₃ -C ₃ alkyl), (halo, _ε χ -ΰ ₃ -C ^ alkyl or alkoxy) phenyl (oxy or thio-IC C. ^ alkyl), benzoyl, or [amino, alkylamino or di CC ^ C ^ -C alkyl) amino] - (C _i -C ₃ alkyl). A method according to any one of claims 15, 16, 17 or 18, wherein the compound of formula VIII - 75 • 0 0 0 • 0 0 0 0 · 00 « 0 0 0 0 0 0 · 0 0 0 0 0 · 0 0 0 0 0 000 000 0 0 0 0 0 0 · 00 00 00 00 oxidizes to the sulfoxide compound of formula IX O The ACH ₃ sulfoxide compound of formula IX reacts with an acylating agent to obtain a Pummerer rearrangement product, the Pummerer rearrangement product reacts with an electrophilic composition selected from the group consisting of AR ¹ , wherein A is a leaving group and R ¹ is 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitronaphthyl, 4-nitronaphthyl, 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolyl, 4-quinolyl, 7-quinolyl, 1-isoquinolyl, 3-isoquinolyl, - 76 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 8-isoquinolyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-1H-indazolyl, 2-benzoxazolyl, 3-1,2-benzoisothiazolyl, 2-pyridyl, 4-pyridyl, 2-pyrazinyl , 2-naphtho [2,3-d] thiazolyl, 2-naphtho [1,2-d] thiazolyl, 9-anthryl, 2-thiazolyl, 2-benzoimidazolyl, 1-benzo [g] isoquinolyl , 8-benzo [g] isoquinolyl, 5-1H-tetrazolyl, 2-quinazolinyl, 2-thiazolo [4,5-b] pyridyl, 4-10H-pyridazino [3,2-b] -2- a quinazolinyl group, a 2-1,4-benzodioxinyl group, a 2-triazine group, a 2-benzoxazine group, a 4-benzoxazine group, a 2-purine group or an 8-purine group, wherein the above-mentioned R ¹ groups are unsubstituted or substituted 1 to 3 trifluoromethyl, trifluoroethoxy, C ₁ -C ₄ alkyl, trifluoromethoxy, hydroxy Nominal group, C -C alkoxy, nitro, C -C alkylthio, C _i -C ₆ alkanoyl, phenyl, oxo, phenoxy, phenylthio, C, -C ₃ alkylsulfinyl group, C 1 -C 6 alkylsulfonyl, cyano, amino, C 1 -C 6 alkylamino, diphenylmethylamino, triphenylmethylamino, benzyloxy, benzylthio, (mono-halo, nitro or CF ₃ ) -benzyl (oxy- or thio), di- (C 1 -C 6 alkyl, C -C cycloalkyl or C -C cycloalkylalkyl) amino, (mono-C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy or halo) - (phenyl, phenoxy, phenylthio, phenylsulfonyl or phenoxysulfonyl), C ₂ -C ₆ alkanoylamino, benzoylamino, diphenylmethylamino- (CC alkyl) ), aminocarbonyl, C ₃ -C ₃ alkylaminocarbonyl, di- (C ₁ -C ₃ alkyl) aminocarbonyl, halo- (C ₆ -C 99) 99 99 99 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9,999,999,999,999,999,999 9 9 9 9 9 - 77 ** - (alkanoyl), aminosulfonyl, C ₁ -C ₃ alkylaminosulfonyl, di- (C 1 -C 4 alkyl) aminosulfonyl, phenyl (oxy or thio) - ( C ₁ -C ₃ alkyl), (halo, C ₁ -C ₃ alkyl or C 1 -C ₃ alkoxy) phenyl (oxy or thio) - (C ₁ -C ₃ alkyl), benzoyl or [amino, C 1 -C ₃ alkyl) ₃ alkylamino or di [(C ₁ -C ₃ alkyl) amino] - (C ₁ -C ₃ alkyl group) in the presence of a phase transfer catalyst, a hydride reducing agent and a base to give a compound of formula I 21. A process for preparing (+) - (4aR) - (10bR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1,2,3,4,4a, 5,6, 10b-octahydrobenzo [f] quinolin-3-one, characterized in that the compound of formula II O' SCH ₃ (II) φ φ φ φ • • · · · · · · · • • • • • • • 78 ** - reacts with (R) - (+) - phenethylamine to give a compound of formula III. SCH ₃ (III) The compound of formula III is reacted with a strong lithium base to give a lithioenamine compound of formula IV (IV) The resulting lithioenamine of formula IV is methylated to the compound of formula V 99 99 9 9 9 9 9 9 9 9 * 99 9 9 9 9 9 9 9 9 9 9 9 9 • 999 999 9 999 99999 9 9 9 9 9 - 79 ·· -.......... the compound of formula V is reacted with an acyl halide or acrylic anhydride to form a compound of formula VI, the reaction is terminated with a base and the residue containing compound VI is mixed with the appropriate strong and trifluoroacetic acid in the absence of solvent to give a compound of formula VII · · · · · · · Φ · φφφφφφφφφφφφφφφφφφφφφφφΦΦΦφφφφφφφ - 30 · _ ·· ·· ·· ·· ·· SCH ₃ (VII) compound of formula VII reacts with a methyl halide containing an organic solvent and a strong arylmethylsulfide compound of formula VIII in reaction mixture to obtain ₃ (VIII) a compound of formula VIII is oxidized to a sulfoxide compound of formula IX sulfoxide compound of formula IX reacts with anhydride trifluoroacetic acid to give the trifluoroacetyloxymethylenesulfide compound of formula X and this trifluoroacetyloxymethylenesulfide compound is reacted with 2-halo-4-ethylbenzothiazole in the presence of a phase transfer catalyst, sodium borohydride and a base to give (+) - (4aR) - (10bR) -4-methyl -8- (4-ethyl-2-benzothiazolylthio) -1Ob-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolin-3-one. A method for preparing (+) - (4aR) - (10bR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1,2,3,4,4a, 5,6, 10b-octahydrobenzo [f] quinolin-3-one, characterized in that it corresponds to any of the descriptions in the examples. 99 99 ·· ·· 99 ·· 9 9 9 9 · · · · 9 9 9 9 9 9 9 9 9 9 · 9,999,999,999,999,999,999 999999 99 - 82 * 23. A compound of formula II, which corresponds to any of the descriptions in the examples. A compound of formula VI of Sch ₃ (VI) or a salt thereof or a salt thereof.