CZ20004702A3 - Process for preparing benzo[f]quinolinones - Google Patents

Abstract

The present invention relates to a process for the preparation of intermediates a benzoquinolin-3-one pharmaceutical agents, these pharmaceuticals are effective in the treatment of conditions associated with it 5α-reductase.

Description

A process for the preparation of benzo [f] quinolinones

Technical field

The present invention relates to a process for the preparation of benzo [f] quinolinones. It relates to the field of organic chemistry, pharmaceutical chemistry and chemical production and provides a convenient and economical process for the production of benzo [f] quinolinones which are useful as 5α-reductase inhibitors and also provides compounds which are intermediates for the production of such pharmaceutical agents.

BACKGROUND OF THE INVENTION

One area of pharmaceutical research that is currently active is the inhibition of 5α-reductase, an enzyme that converts testosterone to dihydrotestosterone, a more potent androgen. It has been shown that 5-reductase inhibitors can block the formation of dihydrotestosterone and ameliorate a number of highly undesirable conditions, including male-type baldness and benign prostate hypertrophy. Audia et al. have discovered a number of benzo [f] quinolinone compounds which are 5α-reductase inhibitors. See U.S. Pat. patents 5,239,075 and 5,541,190; Tet. Let., 44, 7001 (1993); J. Med. Chem., 36, 421 (1993); and published European patent application 0703221.

• · ··· »

SUMMARY OF THE INVENTION - 2 - • · · · • · · · ···· · · · · • · · • · · • 1 · 1 The present invention relates new way production benzo [f] quinolinones, which are potent inhibitors 5a- reductases. The method of the invention is more efficient than ways

according to the state of the art and suitable for industrial scale synthesis. The present invention also relates to intermediates for the manufacture of such pharmaceutical agents.

The present invention relates to a novel process for the production of benzo [f] quinolinones and also to intermediates useful for the production of benzo [f] quinolinones. More particularly, the present invention relates to 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-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1-isoquinolinyl,

3-isoquinolinyl, 8-isoquinolinyl, 2-quinoxalinyl,

2-benzothiazolyl, 3-1H-indazolyl, 2-benzoxazolyl,

3- 1,2-benzoisothiazolyl, 2-pyridinyl, 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] isoquinolinyl,

8-benz [g] isoquinolinyl, 5-1H-tetrazolyl, 2-quinazolinyl,

2-thiazolo [4,5-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 R ¹ groups are unsubstituted or substituted with 1-3 functional groups selected from the group consisting of trifluoromethyl, trifluoroethoxy, C 1 -C ₄ alkyl, trifluoromethoxy, hydroxy, C 1 -C ₃ alkoxy, nitro, C 1 -C ₃ alkylthio, C 1 -C ₄ alkyl Cg alkanoyl, phenyl, oxo, phenoxy, phenylthio, C ₃ alkylsulfinyl, _Ci-C3 alkylsulfonyl, cyano, amino, C ₃ -C ₃ alkylamino, diphenylmethylamine, 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 ₄ -C 8 cycloalkylalkyl) amino, (mono-C 1 -C ₃ alkyl, C ₃ -C 3 alkoxy or halogen) ( phenyl, phenoxy, phenylthio, phenylsulfonyl or phenoxysulfonyl), 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, halogen-C 1 -C ₆ alkyl Cg alkanoyl, aminosulphonyl, _Ci-C3 alkylaminosulfonyl, di (C1-C3 alkyl) aminosulfonyl, phenyl (oxy or thio) _(Ci-C3 alkyl), (halo, C1-C3 alkyl or _Ci-C3 alcohol xy) 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).

The present invention also relates to the conversion of a ketone of the general formula:

R

wherein R represents a halogen atom, preferably a bromine atom; to a protected ether, preferably using trimethyl orthoformate in methanol in the presence of an acid catalyst;

reacting the protected ether with a reactive alkyllithium compound such as n-butyllithium and a sulfur transfer reagent such as dimethyl disulfide to obtain an S-methylated ether compound; and deprotecting the S-methylated ether compound to obtain the methylthiotetralone compound of formula II

II

The present invention further relates to the conversion of 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 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

reacting the compound of formula III with a strong lithium base to obtain a lithioenamine compound of formula IV

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

sch ₃ reacting a compound of formula V with an acyl halide or an acrylic acid anhydride of formula VI to prepare the compound

sch ₃

VI terminating the base reaction and combining the residue containing the compound of formula VI with a suitable strong and trifluoroacetic acid in the absence of a solvent for the preparation of the 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 obtain an arylmethylsulfide compound of formula VIII

oxidizing a compound of formula VIII to a sulfoxide compound of formula IX

0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 * 0 «0

- 8. Ί

• · · 0 0 0 000 0000 00 ·· MM 00 000

reacting the sulfoxide acylating agent of a compound of Formula IX with a Pummerer rearrangement product;

reacting the product formed by the Pummerer rearrangement with an electrophile 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-quinolinyl, 4-quinolinyl, 1-quinolinyl, 1-isoquinolinyl,

3-isoquinolinyl, 8-isoquinolinyl, 2-quinoxalinyl,

2-benzothiazolyl, 3-1H-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-benzimidazolyl, 1-benz [g] isoquinolinyl,

8-benz [g] isoquinolinyl, 5-1H-tetrazolyl, 2-quinazolinyl, 2-thiazolo [4,5-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 R ¹ groups are unsubstituted or substituted by 1-3 groups selected from the group consisting of trifluoromethyl, trifluoroethoxy, C 1 -C ₄ alkyl, φ • etφφφφφ ,φ triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu triflu, trifluoromethoxy, hydroxy, C1-C3 alkoxy, nitro, C1-C3 alkylthio, C1- _C6 alkanoyl, phenyl, oxo, phenoxy, phenylthio, C1-C3 alkylsulfinyl, C1-C3 alkylsulfonyl, cyano, amino, C1-C3 alkylamino, diphenylmethylamino, triphenylmethylamino, benzyloxy , benzylthio, (mono-halogen, nitro or CF ₃ ) benzyl (oxy or thio), di (C 1 -C 3 alkyl, C ₃ -C ₆ cycloalkyl, or C ₄ -C 8 cycloalkylalkyl) amino, (mono-C 1 -C ₃₎ alkyl, C1-C3 alkoxy or halo) (phenyl, phenoxy, phenylthio, phenylsulfonyl or phenoxysulfonyl), C ₂ -C ₆ alkanoylamino, diphenylmethylamine (C1-C3 benzoylamino, aminocarbonyl,

C1-C3 alkylaminocarbonyl, alkyl), di (C1-C3 alkyl) aminocarbonyl, halogen-C1- _C6 alkanoyl, aminosulfonyl, alkyl) aminosulfonyl, (halogen, C1-C3 alkyl thio) (C1-C3 alkyl),

C 1 -C 3 alkylaminosulfonyl, di (C 1 -C ₃ phenyl (oxy or thio) (C 1 -C 3 alkyl), or C 1 -C 3 alkoxy) phenyl (oxy or benzoyl, or (amino, C 1 -C 3 alkylamino or di (C 1 -C 3)) ₃ alkyl) amino) (C1 -C3 alkyl) in the presence of a phase transfer catalyst, a hydride reducing reagent and a base to produce a compound of formula I.

Preferred intermediates according to the general formula:

of the present invention

AND

(B)

Starting materials for preparing the compounds in the claimed methods are either commercially available, known in the art, or can be prepared by methods known in the art, for example, see Audia et al., U.S. Pat. No. 5,239,075, issued Aug. 24, 1993, and European Patent Application 0703221.

Throughout the text, all temperatures are in degrees Celsius, and all concentration, percentage, and proportions data are expressed in weight units except for solvent mixtures, which are expressed in volume units unless otherwise indicated.

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

The different positions on the benzo [f] quinolinone ring are shown below.

♦ · · * * * φ • φ • • • • «« «« φ φ φ φ φ φ φ φ φ φ φ φ φ φ

The spatial configurations of the groups at position 10b and the hydrogen atom at position 4a must be considered. It will be appreciated that many compounds may exist in two or more stereochemical forms and that all stereochemical forms are included within the scope of the present invention. For some of the compounds prepared or described below, the individual enantiomers are prepared in pure form and are designated by the (+) or (-) nomenclature. In other cases, mixtures of diastereomers are prepared.

Group SR ¹ is in position 8.

The terms halogen and halogen include chlorine, bromine, fluorine and iodine atoms.

Various alkyl groups such as C 1 -C ₄ alkyl and the like include groups such as methyl, ethyl, propyl, isopropyl, tert-butyl, n-butyl and isobutyl. Alkenyl and alkynyl groups are linking groups that are bivalent and are bonded 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

- 12 ♦ 4 4 9

9 4

4 4

4 9 • 449 99 · ftft ··

9 9 9 9 9

9

4 4 4 4 9 5

9 9 9 4

9949 99 9 ethynyl, 2-propynyl, 2-butynyl and iso-2-butynyl.

The C 1 -C ₆ alkanoyl group includes such groups as formyl, acetyl, propionyl, isobutyryl, 2-ethylpropionyl and hexanoyl. C3 -C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and the group C ₄ -Cg cycloalkylalkyl includes, for example cyclopropylmethyl, cyclohexylethyl, cyclobutylbutyl and cyclohexylmethyl.

Terms such as halo-C 1 -C ₆ alkanoyl, halophenyl or C 1 -C 3 alkylphenyl refer to basic groups on which 1, 2 or 3 halogen atoms or C 1 -C 3 alkyl groups are substituted, as may be mentioned in individual cases.

The methods of the present invention pertain to the preparation of compounds of formula I, all of which include a benzo [f] quinolinone nucleus on which the benzo ring is a substituted cyclic group R ¹ , attached to a benzoquinoline with a sulfur-containing linker. The R ¹ groups may be substituted with other organic groups and may carry up to three of said substituent groups. The multiple substituents may be the same or different.

Certain embodiments of the process according to the invention are preferred and will be explicitly set forth below. It will be understood that the following embodiments of the invention are each individually important and the preferred features may also be combined to form other embodiments that are more restrictive or more determined.

Synthesis of 6-methylthio-2-tetralone

Φ φ φ φ φ φ φ φ φ φ • • • • • φ φ φ φ φ φ φ φ φ

φφ φ φ φ ♦ φ φ

The starting material for the synthesis of 6-methylthio-2-tetralone is

4-halophenylacetic acid (for example, 4-bromophenylacetic acid will be used). 4-Bromophenylacetic acid is commercially available (Aldrich Catalog Handbook of Fine Chemicals 1994-5, pg. 233) or can be prepared by methods well known to those skilled in the art. 4-Bromophenylacetic acid is used to prepare 6-bromo-2-tetralone.

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

4-bromophenylacetic acid with thionyl chloride, phosphorus trichloride, oxalyl chloride, or phosphorus pentachloride, under conditions known in the art, to obtain 4-bromopheneacetyl chloride (Scheme 1). Preferably, thionyl chloride and methylene chloride are used to obtain 4-bromophenacetyl chloride. By Friedel-Crafts acylation reaction of 4-bromopheneacetyl chloride with ethylene gas in the presence of a Lewis acid catalyst and an inert or substantially inert solvent or solvent mixture, ring closure is performed to obtain 6-bromo-2-tetralone.

SCHEME 1

Suitable Lewis acid catalysts include AlBr ₃ , AlCl ₃ , AlCl ₃ , GaCl ₃ , FeCl ₃ , SbCl ₅ , ZrCl ₄ , and the like.

9 9

Φ φ

• Φ

9 9 9

9 9

9999 99 • Φ Φ Φ · ΦΦΦΦ

Φ ΦΦ Φ

SnCl ₄ , BCl ₃ , BF ₃ , SbCl ₃ and the like, preferably AlCl ₃ . 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-tetralone is protected by reaction with trimethyl orthoformate in a solvent such as methanol to provide the corresponding ethers by the following Scheme 2. Hydrochloric acid formed in situ by addition of thionyl chloride acts as a catalyst in this reaction. One skilled in the art will appreciate that other acid catalysts may be used, for example p-toluenesulfonic acid, phosphoric acid, and the like. Temperatures from about 20 ° C to about 65 ° C are used using standard cooling methods.

SCHEME 2

The exchange reaction of halogen and β-bromo-protected metal ethers is then induced by reaction (A

B) with reactive n-butyllithium.

with an organolithium compound, preferably Alkylation of the resulting lithiated substance with a suitable sulfur transfer reagent, for example a sulfenyl halide or dimethyl disulfide, affords the ether protected 6-methylthiophide

- 15 φφφ • φφφ φφ

2-tetralones. Deprotection is performed by methods known to those skilled in the art. A preferred method of deprotection is treatment with aqueous acid, preferably hydrochloric acid, to obtain the desired 6-methylthio-2-tetralone compound (Schemes 3 and 4).

SCHEME 3

CHjO '

n-BuLi (CH, S)

SCHEME 4

.SCH,

II

All transformations,

4-bromophenylacetic acid starting from the desired acid

6-methylthio-2-tetralone, may preferably be carried out in a single reaction vessel without isolation of the intermediates. This improved process yields increased yields and the single pot reaction process utilizes readily available reactants and is suitable for industrial scale production. Required 6-methylthio00 ··

0 0

0

0

0 0 0 • 000 000 • 0

• t • 0 0000

The 2-tetralone can be isolated by standard methods, preferably by crystallization from the reaction mixture.

Alkylation and aza-cyclization

The foregoing synthesis of intermediate VII

has been described in U.S. Pat. No. 5,239,075 and U.S. Pat. No. 08 / 443,994, which are incorporated herein by reference. Another synthesis of a compound of formula VII, which is improved by the process of the present invention, is disclosed in European patent application 0564193. The methylthio group of a compound of formula VII is located at position 8. This preferred method of preparing a compound of formula VII described below can be performed. without purification or isolation of intermediate products.

6-thiomethyl-2-tetralone is reacted with (R) - (+) - phenethylamine to prepare an intermediate of formula III

The reaction is preferably carried out at elevated temperature, in particular at reflux, in toluene in the presence of a strong acid such as p-toluenesulfonic acid. Water must be withdrawn as it is formed during this reaction, and the absence of water being formed indicates 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 convenient to use molecular sieves to dehydrate the reaction mixture using at least twice the weight of the molecular sieves as compared to the amount of water released during the process.

The aforementioned phenethylamine compound is lithiated with, for example, n-butyllithium or lithium diisopropylamide to obtain a compound of formula IV.

When the reaction is carried out, preferably, using lithium diisopropylamide, best results are obtained when lithium diisopropylamide is freshly formed from diisopropylamine and n-butyllithium just prior to use. A significant excess of approximately 15-25% lithium diisopropylamide should be used for best results.

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

The lithium compound is difficult to isolate and purify and should therefore be introduced as a solution in the lithiation reaction when carrying out the process of the present invention.

- 19 - «· Flfl • fl · • «· fl ♦ e ·· « ··· «···· ·· flfl flfl · • flfl · • flfl • flflfl flfl fl • fl flflflfl · mixtures. Alkylation Lithium the compound is methylated, for example reactions resulting lithium enamine with methyl iodide for acquisition compounds of formula V

Dimethyl sulfate, methyl bromide, methyl chloride, methyl iodide and the like can be used to methylate the lithioenamine. It is convenient to use an approximately 15-25% excess of 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 ranging from about -100 ° C to about -50 ° C, most preferably from about -80 ° C to about -60 ° C. Correspondingly, reaction times ranging from about several minutes to about one hour and a reaction time of 20 minutes are preferred.

If the lithium compound in the form of a lithium reaction mixture is lithium diisopropylamide, and the reaction mixture may therefore contain residual diisopropylamine, the amine must be a diisopropylamine. 9 9 9

9999 99 99 9090 «« 9 sufficient neutralization before methylation neutralized. Preferably, the methyl iodide mixture is allowed to warm to a temperature in the region of 0 ° C and the amount of methanesulfonic acid for diisopropylamine is added. Other strong acids may be used, but methanesulfonic acid is particularly suitable and preferred because the resulting diisopropylamine methanesulfonate salt is only slightly soluble and therefore can be easily removed by simple filtration or centrifugation.

Aza-cyclization step

A reaction mixture comprising a compound of formula V is combined with an acyl halide or acrylic anhydride or acryloyl chloride or the like to initiate an aza-cyclization reaction to form a compound of formula VI

It is most convenient to generate acrylic anhydride, a preferred reagent, immediately prior to use by the reactions of acryloyl chloride and acrylic acid, using triethylamine and stabilizers such as hydroquinone and butylated hydroxytoluene, in tetrahydrofuran.

• Φ · · r r r r r r r φ φ

φ • φ, ···

Aza-cyclization is best accomplished by adding acrylic anhydride or acryloyl chloride at a very low temperature, such as from about -100 ° C to about -70 ° C, and allowing the mixture to warm very slowly and with stirring to a temperature in the range of about -20 ° C to about 0 ° C, or even to about 10 ° C-20 ° C. A time of 12-15 hours is a reasonable time to allow the mixture to warm up. If the reaction has gone to completion as required, it is quenched by the addition of solid sodium bicarbonate. It is preferred to use from about 1.5 to about 4 equivalents of base, most preferably about 2 equivalents. The base may be added in solution, for example in water or in an aqueous solvent such as a water / dimethylaminopyridine mixture, but it is preferable to add the base in solid form. The reaction mixture is stirred with a stopping 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 be treated with aqueous base and aqueous acid washing, optionally followed by an additional purification step such as is washed with saturated sodium chloride solution. If such a processing step is used, the solution is dehydrated and evaporated in vacuo to give a nonvolatile portion of the reaction mixture containing the final intermediate of formula VI. On the other hand, the residue from the reaction mixture can be used without finishing if desired.

Step of reduction and cleavage

The residue from the aza-cyclization step is cooled and a cold mixture of the appropriate silane and trifluoroacetic acid is added.

· · Fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe fe · ·· ···· · 4 ·

A suitable silane is a soluble silane, for example a dialkylsilane or a trialkylsilane or the like. The addition should occur at a low temperature in the range of about -40 ° C to about 0 ° C and no additional solvent is used. A large amount of trifluoroacetic acid is used, ranging from about 10-50 equivalents, most preferably about 20-30 equivalents. Preferred trialkylsilane is triethylsilane, although trimethylsilane, trisopropylsilane and the like can also be used. A large excess of trialkylsilane is used, ranging from about 5-20 equivalents, most preferably about 7-15 equivalents. The mixture is stirred for about 10-20 hours while being allowed to warm slowly to about 30 ° C and then the mixture is slowly heated to elevated temperature, preferably reflux, and stirred at this temperature for several hours, such as about 2-6 hours to complete formation of the compound of formula VII

Cleaning

The residue containing the product of formula (VII) may be dissolved, preferably in a haloalkane such as dichloromethane, washed with a base such as aqueous sodium bicarbonate, and concentrated in vacuo. Purification is achieved by recrystallization from, for example, ethyl acetate and methyl tert-butyl ether or acetone or the like.

N-Alkylation process

In the synthesis it is necessary to methylate the nitrogen atom at the 4-position on the benzo [f] quinolinone ring. U.S. Pat. No. 5,239,075 discloses such alkylation by reaction with an alkyl iodide in the presence of a strong base such as sodium hydride. Further alkylation is described in published application EPO 0703221.

N-methylation involves reacting a compound of formula VII in a reaction such as diethoxyethane and methyls with a methyl halide such as methyl iodide of a mixture comprising an organic solvent, a solvent selected from tetrahydrofuran, dimethoxyethane, tert-butyl ether and a base such as potassium t-butoxide and tetrahydrofuran; aqueous sodium or potassium hydroxide to give a compound of formula VIII

0 ·

This alkylation process allows efficient alkylation under mild and easily controllable conditions and allows easy product isolation.

The alkylation is carried out in conventional chemical equipment, preferably at atmospheric pressure and at moderate temperatures. Preferably, it begins by forming a suspension of the starting material of formula VII in an organic solvent at a temperature near 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 about 5-15 liters of solvent per kilogram of starting material; a more preferred volume of solvent is about 10 liters per kilogram. The alkyl iodide is then added as a plain liquid. Preferably, a substantial excess of alkyl iodide is used, such as about 1.2-1.8 equivalents relative to the starting material, most preferably about 1.5 equivalents.

Aqueous sodium or potassium hydroxide is then added, still at a temperature equal to about ambient temperature, in an amount of about 1-4 liters per kilogram 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 a most preferred base, 50% sodium hydroxide is used, its most preferred amount is about 2 liters per kilogram of starting material. Thereafter, the reaction mixture consisting of the solid material suspended in the two liquid phases is heated to about 25-65 ° C with vigorous stirring, and the reaction is allowed to proceed at an approximately constant temperature with continuous stirring. The preferred reaction temperature is about 35-40 ° C. As the reaction proceeds to completion, the solid starting material and the alkyl iodide dissolve and react so that the disappearance of the solid is a crude 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 a 1: 1 mixture of acetonitrile: aqueous buffer (5% ammonium acetate) and monitoring at a wavelength of 220 nanometers.

When the reaction reaches the desired degree of completion, the mixture is cooled to about ambient temperature and the aqueous layer is separated and discarded.

The preferred purification and isolation procedure proceeds by diluting the organic layer with water and neutralizing with aqueous inorganic acid. The solution is then distilled at a temperature rise to about 69-80 ° C to remove most of the tetrahydrofuran. Slow cooling to about 5 ° C over about 1-14 hours results in crystallization of the product, which only requires washing with water and drying to be useful as an intermediate or as a pharmaceutical. The most preferred isolation and purification is recrystallization of the residue after removal of tetrahydrofuran in ethyl acetate.

The alkylation process yields the product in the same stereochemical form as the starting material, in a purity sufficient for the pharmaceutical industry and with yields equal to or greater than 90%, if preferred.

Electrophilic Coupling> 4

4444 44

The electrophilic coupling of the substituent R ¹ to the sulfur group on the benzo [f] quinolinone ring can be achieved by the following scheme V.

SCHEME V

OCOCF,

wherein R ¹ is as defined above in formula I.

(+) - (4aR) - (10bR) -4-methyl-8-methylthio-10b-methyl1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolinon-3-one is oxidized to the sulfoxide compound, m-chloroperoxybenzoic acid is a preferred oxidizing agent. Whether with or without isolation, the sulfoxide compound is subjected to the Pummerer reaction as described by Young et al., Tetrahedron Lett. 25, 1753 (1984) by reacting the sulfoxide with an acylating agent such as the acid anhydride obtained for trifluoroacetic acid.

φ φ

Trifluoroacetyloxymethylene sulfide may be 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, most preferably potassium carbonate, to prepare a reagent suitable for Formula ac. include halides such as acetyl chloride, sulfonic acid halides, reactive anhydrides such as trichloroacetanhydride, phosphoric anhydride, sulfonic acid anhydride and the like which are capable of yielding a Pummerer rearrangement product.

By methods known in the art, the electrophilic reagent is substituted with a leaving group such as halogen, sulfate, sulfonate or the like. The electrophilic reagent is then coupled to sulfur on the benzo [f] quinolinone ring. A preferred electrophilic reagent is 2-chloro-4-ethylbenzothiazole and this reagent is coupled with a compound of formula X to give (+) - (4αR) - (10bR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) - 10b-methyl-1,2,3,4,4a, 5,6,10boctahydrobenzo [f] quinolinon-3-one.

Preferably, a catalyst, such as tetrabutylammonium hydrogen sulfate, is used for the direct coupling of trifluoroacetyloxymethylene sulfide with an electrophilic reagent. Sodium borohydride has been found to induce a reduction of the trifluoroacetyloxymethylene sulfide compound. In addition, formaldehyde is formed in situ, which is also unacceptable from an environmental point of view. The process of the present invention reduces formaldehyde once compound (X).

the compound is left

In the method according to the airborne formed, it is formed into methanol. In addition, the present invention disulfides, by oxidation, reduce in situ. This step of the manufacturing process allows the starting materials to be utilized more fully, and there is no need to consistently eliminate oxygen or oxidation-promoting impurities. The addition of a base to the mixture is not essential to promote coupling. However, the decomposition of the borohydride slows and the relative coupling rate is increased by the addition of a base.

DETAILED DESCRIPTION OF THE INVENTION

The following Preparations further illustrate the process of the present invention. The preparations are not intended to limit the scope of the present invention in any way and should not be construed as such.

Unless otherwise stated, starting materials were obtained from commercial suppliers and used without further purification. Toluene, dimethylformamide and methylene chloride were stored on 4A molecular sieves. Reactions using organometallic reagents were carried out under a nitrogen atmosphere. The reactions were monitored by high pressure liquid chromatography under the conditions below. Thin layer chromatography was performed on Merck Silica gel 60 plates with fluorescent indicator (F254) · ¹ H and ¹³ C NMR spectra were recorded on a General Electric QE or Bruker 300 MHz spectrophotometer at ambient temperature using CDCl ₃ as solvent unless otherwise noted. NMR chemical shifts are reported in ppm with solvent as internal standard on the d scale and J values are in Hertz. IR, UV and MS analyzes 9 9 9 Mass spectrography (MS) was performed in the Eli Lilly Physicochemical Laboratory . Conditions under which high pressure liquid chromatography was performed: Hitachi model L-6200A Intelligent Pump with D-2500 Chromatography Integrator. Column 25 cm Zorbax RX C-18, 60:40

CH3CN / H2O, 1.0 ml / min, 275 nm, injection - 10 μΐ.

Conditions under which gas chromatography (GC) was performed: HP 5890A GC with a DB1 0.25 μ x 25 m column; 300 ° C injection temperature; 300 ° C detection (FID); column at 5 ° C (5 minutes), 18 ml / minute at 250 ° C then 250 ° C for 20 minutes. The terms NMR, MS, IR and / or GC indicate that the spectrum of the product was analyzed and was consistent with the desired structure.

Preparation 1

6-bromo-2-methyl ethers (A and B) 6-methylthio-2-methyl ethers (C and D) and 6-methylthio-2-tetralone (11).

Trimethyl orthoformate (26.7 mL, 0.24 mole) and thionyl chloride (260 mg, 2 ₂ mmol) were added to a suspension of 6-bromo-2-tetralone (50 g, 0.22 mol) in methanol (500 mL) under nitrogen. After stirring for 3-5 hours at ambient temperature the solvent was removed under reduced pressure. Heptane (500 mL) was added to the residue, and the solvent was removed again under reduced pressure to give a residual oil.

The residual oil was dissolved in tetrahydrofuran (400 mL) and cooled to -78 ° C under a nitrogen atmosphere, n-butyllithium (1.3 M in hexanes, 190 mL, 0.24 mol) was added to solution, followed 15 minutes later by slow addition of methyldisulfide (23.8 mL, 0.26 mol). The mixture was stirred at -78 ° C for 10 minutes and then allowed to warm to 10 ° C over 45 minutes. After addition of 1N hydrochloric acid (200 ml), the mixture was concentrated under reduced pressure on a rotary evaporator (bath temperature 45 ° C) for 1 hour. Additional tetrahydrofuran (50 mL) was added to the mixture and the concentration was continued until the hydrolysis of the enol ether intermediate was complete as determined by GLC. The mixture was then extracted with ethyl acetate (2 x 100 mL). The ethyl acetate layers were dried and concentrated under reduced pressure to a volume of 50 mL. Heptane (400 mL) was slowly added to the ethyl acetate concentrate and the resulting crystals were stirred for 1 hour at 0 ° C, filtered and dried to give 30.6 g of 6-methylthio-2-tetralone (72% yield).

Melting point: 57-58 ° C GLC 99,5%

Preparation 2a (+) - (4aR) - (10Bi) -8-methylthio-10b-methyl1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolinon-3-one.

A solution of 6-methylthio-2-tetralone (1 grams, 5.2 mmol, 1 equivalents) in anhydrous toluene (18 mL) was treated with (R) - (+) - phenethylamine (0.72 mL, 5.7 mmol, 1 mL). , 1 equivalents) and p-TsOH (6 mg). The solution was degassed three times with a low vacuum / nitrogen cycle and nitrogen pressure was maintained. The solution was heated to reflux under Dean-Stark conditions to remove water. The progress of imine formation was monitored by NMR. After 2.5 ·· 94 »4 · 4 • · <

4 9 9

9 4 9 4 4 5

4494 44 hours at reflux, no starting ketone was detected by ¹ H NMR. Toluene was distilled off under a slight vacuum and under a nitrogen atmosphere, taking care not to expose the mixture to air. Anhydrous tetrahydrofuran (14 mL) was added to give a light purple solution, which was stored at 70 ° C under a nitrogen atmosphere. Lithium diisopropylamide was formed by dropwise addition of a 2.5 M hexane solution of n-butyllithium (2.4 mL, 6.0 mmol, 1.15 equivalents) to a solution of diisopropylamine (0.78 mL, 6.0 mmol, 1.15 equivalents) in tetrahydrofuran (19 mL) at -45 ° C under a nitrogen atmosphere. 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. After cooling the lithium diisopropylamide solution to -75 ° C, the imine solution was added dropwise over 15 minutes via cannula, maintaining the temperature between -70 ° C and -75 ° C. The resulting yellowish-orange solution was allowed to warm to 20 ° C over 20 minutes and then re-cooled to -75 ° C. Iodomethane (0.36 mL, 5.8 mmol, 1.15 equivalents) was added at a temperature between -75 ° C and -72 ° C. The solution was warmed (with acetone bath) to 0 ° C over 15 minutes. After cooling again to -5 ° C, methanesulfonic acid (0.43 mL, 6.6 mmol, 1.3 equivalents) was added over 2 minutes at a temperature between -5 ° C and 1 ° C. After 5 minutes at 0 ° C a gray heterogeneous mixture formed. The mixture was recooled to -75 ° C. A solution in 1.125 M tetrahydrofuran acrylic anhydride (11 mL, 12.5 mmol, 2.4 equivalents) was added rapidly. The mixture was kept in a cooling bath for 15 hours, during which time it was heated to 13 ° C. Reaction mixture • »

- 32 · · φφφφ was allowed to warm to 15 ° C. Water (2 mL) was added and the mixture was stirred while warming the mixture to ambient temperature. The solution was diluted with diethyl ether (50 mL) and washed sequentially with 1N sodium hydroxide (20 mL), 1N 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 hexanes / ethyl acetate) to yield 1.3 grams (69% yield) of (+) - (10bR) -4- ( 2- (R) -phenethyl) 8-methylthio-10b-methyl-1,2,3,4,6,10b-hexahydrobenzo [f] quinolinon-3-one (NMR). A mixture of triethylsilane (12 mL, 75 mmol) and trifluoroacetic acid (14.5 mL, 188 mmol), pre-cooled to -15 ° C under a nitrogen atmosphere, was added to (+) - (10bR) -4- (2- (R)). (phenethyl) -8-methylthio-10b-methyl-1,2,3,4,6,10b (2.76 grams, 7.6 mmol) The mixture was stirred for hexahydrobenzo [f] quinolinon-3-one pre-cooled in a -15 ° C bath, hours, during which time it was allowed to warm to 13 ° C. Thin layer chromatography (70:30 hexanes / ethyl acetate) and high pressure liquid chromatography showed complete disappearance of (+) - (10bR) -4- (2- (R) -phenethyl) 8-methylthio-10b-methyl-1,2, 3,4,6,10bhexahydrobenzo [f] quinolinon-3-one and formation of a new product, indicating complete reduction of the double bond. The mixture was then heated to reflux for 2 hours to remove chiral materials. After cooling to ambient 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 mL) and brine (50 mL). Dry sodium sulphate and concentrated crude

99 99

9 9 9 9 • 9 9 9

Φ · Φ · · · φ

9 9

The product was purified by flash chromatography on silica gel (100 grams), eluting first with 3: 1 hexanes / ethyl acetate to remove triethylsilane and then 14% methanol in methylene chloride with 1% acetic acid. to obtain a foamy solid. Recrystallization from hot ethyl acetate gave 1.6 grams (82%) of (+) - (4aR) - (10bR) 8-methylthio-10b-methyl-1,2,3,4,4a, 5,6,10boctahydrobenzo [f] quinolinon-3-one (92% enantiometric excess, IR, NMR, MS).

Calcd. For C ₁₅ H ₉ NOS: C, 68.93; H, 7.33. Found: C, 69.05; H, 7.44.

Preparation of 2b (+) - (4aR) - (10bR) -8-methylthio-10b-methyl1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolinon-3-one.

A solution of 6-methylthio-2-tetralone (9.6 g, 50 mmol), p-toluenesulfonic acid monohydrate (40 mg, 0.2 mmol) and R - (+) - α-methylbenzylamine (6.64 g, 55 mmol) mmol) in toluene (150 mL) was heated to reflux. The water formed during the reaction was removed with a Dean-Stark trap. The progress of the reaction was monitored by NMR (300 MHz, CDCl 3), which indicated 100% conversion after 2 hours of heating to reflux. The amine solution was concentrated to a volume of 30 ml by atmospheric distillation. The amine solution was then cooled to -78 ° C, diluted with tetrahydrofuran (100 mL) and added via cannula to a solution of lithium diisopropyl amide (2.0 M in heptane / THF) (28.7 mL, 57.5 mmol) and tetrahydrofuran ( 130 ml). After stirring for 30 minutes at -78 ° C, 1 was added

9 «···· ··

4944 iodomethane (3.6 mL, 57.5 mmol) and stirring was continued for an additional 30 minutes at -78 ° C. Methanesulfonic acid (4.05 mL, 62.5 mmol) was added, followed by warming the reaction mixture to 0 ° C. In a separate vessel, acrylic acid (6.6 g, 91.5 mmol) was slowly added 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) at -10 ° C to -15 ° C.

Trimethylacetyl chloride (11.0 g, 91.5 mmol) was added slowly while maintaining the temperature below -5 ° C. The reaction mixture was stirred at -10 ° C for 2 hours and then filtered, and the filtered solids were washed with 20 mL of filtrate and sodium bicarbonate (110 mmol) were added to the enamine solution and the resulting mixture was stirred at 0 ° C for 4 hours. Deionized water (90 mL) was added and stirring was continued for 0.5 h at 0 ° C. The solvent was then removed by vacuum distillation (temperature <30 ° C). Methylene chloride (90 mL) was added and the layers were separated. The methylene chloride layer was washed successively with 1N NaOH solution (4 X 25 mL), 1 N tetrahydrofuran. (NaHCO 3) (9.2 g, hydrochloric acid solution (20 mL), sodium bicarbonate solution (20 mL) was then removed from the reaction mixture by vacuum distillation (<30 ° C). Triethylsilane (80 mL, 500 mmol) was added and trifluoroacetic acid (100 mL, 1.3 mol) and the resulting mixture was stirred at 27-32 ° C for 12 hours and then at reflux for 6 hours was monitored by HPLC (such as

Supelcosil LC-ABZ, isocratic 40% deionized water / 60% acetonitrile, 220 nm, 2 mL / min), showed> 95% and saturated Solvent

Procedure 25 cm

99 99 99 99 «999 9900 9

9 »· 99 9 99 • 9 999 9 9 99 9 The reaction mixture was then concentrated by vacuum distillation to a volume of approximately 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). Saturated sodium bicarbonate solution (150 mL) was added slowly and the layers were separated. The methylene chloride layer was washed with saturated sodium bicarbonate solution (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 (-30 ° C) ethyl acetate (10 mL) followed by drying at 50 ° C to give 6.22 g (49%) of (+) - (4aR) - (10bR) - 8-methylthio10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolinon-3-one (GLC purity 99.5%).

Preparation 3 (+) - (4αR) - (10bR) -4-methyl-8-methylthio-10b-methyl1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolinon-3-one .

(+) - (4aR) - (10bR) -8-methylthio-10b-methyl1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolinon-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 for 5 minutes, methyl iodide (0.116 mL, 1.15 equivalents) was added and the mixture was allowed to stir at 0 ° C for 2 hours. Mixture

0 «

0 0

0

0 * ♦ 00 00 0 00 0 0 0 0

0 0 0 0 0

0 0 0 0 0 0

0 ·· 000 0000 00 00 0000

About 100 mg of acetic acid was then treated and the solvents were removed under a stream of nitrogen. The solid was dissolved in approximately 50 mL of methylene chloride and washed twice with water. The extracts were dried (4 molecular sieves) and filtered on silica gel (2 grams, washing with ethyl acetate containing 2% methanol). The solid remaining after 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 (+) - (4α) - (10b) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) 10b-methyl-1,2,3,4,4a, 5,6,10b -octahydrobenzo [f] quinolinon-3-one.

A solution of meta-chloroperoxybenzoic acid (approximately 56% concentration, 6.32 grams as a solution in methylene chloride) was added to (+) - (4aR) - (10bR) -4-methyl-8-methylthio-10bmethyl-1,2, 3,4,4a, 5,6, 10b-octahydrobenzo [f] quinolinon-3-one (5.50 grams in 110 ml methylene chloride) and aqueous sodium bicarbonate (9.4 grams in 110 ml water) at 0 to - 1 ° C over approximately one hour. After 8 hours, the layers were separated and the organic extracts were washed twice with aqueous 1% sodium bicarbonate, dried (4A molecular sieves) and evaporated to a total weight of 5.90 grams. A portion (2.91 grams) of this unpurified sulfoxide in 10 mL toluene-ds was treated with 2.20 mL trifluoroacetic anhydride at 5-10 ° C. After 30 minutes ¹ H NMR analysis • φ · »· φ φ φ φ φ φ φ φ • φ φ φ φ φ · · · · ·

A 0.50 ml aliquot showed that no starting sulfoxide was present (ArSOCH ₃ singlet absent d = 2.25 ppm) and the exclusive formation of Pummerer product (ArSCH ₂ OCOCF ₃ , singlet at d = 5.31 ppm). The reaction mixture was subjected to vacuum (5-10 torr) for 30 minutes, and then the contents were added to a stirred mixture (under a nitrogen atmosphere) of water (20 mL), tetra-n-butylammonium hydrogen sulfate (0.1 g) and 7.1. ml of water-borohydride (12 wt% sodium borohydride in 14 N sodium hydroxide) at 5-10 ° C over 20 minutes. After a further 20 minutes, they were added

2-chloro-4-ethylbenzothiazole (3.00 grams with an additional 9.5 mL toluene-dg) and another portion of tetra-n-butylammonium hydrogen sulfate (0.50 grams). The reaction mixture was stirred at 37-39 ° C during this time were collected four 0.25 ml samples of the direct ^X H NMR assay and high pressure liquid chromatography for studying the conversion product distribution. After 26 hours, the top layer (toluene containing (+) - (4aR) - (10bR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) 10b-methyl-1,2,3,4,4a) 5,6, 10b-octahydrobenzo [f] quinolinon-3-one and excess 2-chloro-4-ethylbenzothiazole) of the three-phase mixture separated and diluted with 25 ml methylene chloride. This organic layer was washed with aqueous 1 N sulfuric acid, aqueous 5% sodium bicarbonate, dried with 4A molecular sieves and concentrated in vacuo to 5.24 grams. The resulting solid was digested with hot methyl tert-butyl ether (30 mL) and then concentrated in vacuo 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 (+) - (4aR) - (10bR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-12 3,4,4a, 5,6,10boctahydrobenzo (f) quinolinon-3-one (IR, NMR, MS).

· · · · · · · · · · · · · · · · ·

Calcd. For C 24 H 26 N 2 OS 2: C, 67.93; H, 6.16; 15.08. Found: C, 68.21; H, 6.20; N, 6.63; WITH,

N, 6.83; S, 15.17.

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

A solution of meta-chloroperoxybenzoic acid (35.2 mmol in 100 mL of methylene chloride) was added to (+) - (4α) - (10bR) -methyl8-methylthio-10b-methyl-1,2,3,4,4a, 5 6,10boctahydrobenzo [f] quinolinon-3-one (10.0 grams, 98% purity, 35.6 mmol) in a biphasic mixture of methylene chloride (200 mL) and aqueous sodium bicarbonate (8.90 grams in 89 mL of water) at to -2 to 0 ° C over 1 hour. The layers were separated and the methylene chloride layers were washed once with sodium metabisulfite (1.00 grams in 25 mL) and three times with sodium bicarbonate (1.00 grams in 100 mL). The dried (4A molecular sieves) methylene chloride extract 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) 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 minutes at 0-10 ° C. After 30 minutes at 0 ° C, this solution was subjected to vacuum (<10 torr) for 30 minutes and added to the degassed (nitrogen) mixture of potassium carbonate (41 grams), sodium borohydride (2.88 grams) over 30 minutes. ), tetra-n 9 9 4 9 9 4 4 9 4 4

444 · ♦ · 44 4494 94 butylammonium hydrogen sulphate (2.00 grams) and 2-chloro-4-ethylbenzothiazole (8.20 grams, 96.5% purity, dissolved in 5 ml toluene) and water (87 ml) at 0-5 Deň: 32 ° C. The mixture was heated to 40 ° C over one hour and then stirred at 40 ° C for 26 hours. The toluene layer was separated (while warm) and washed with 3x100 ml of water. The toluene layer was diluted with 125 mL of ethyl acetate and then washed successively with 3x200 mL of 0.25 N hydrochloric acid, 100 mL of 1% sodium bicarbonate, and 100 mL of saturated aqueous sodium chloride. The organic layer was dried (10 grams on 4A molecular sieves), concentrated to a total volume of 25 mL and treated with 100 mL of methyl tert-butyl ether (heated to reflux for 30 minutes, then to 0 ° C for 1 hour). dalo (+) - (4af) (10bf) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) -10bmethyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [ f] quinolinon-3-one.

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

Anhydrous sulfoxide IX (96% pure by gas chromatography, 8.90 grams, 29.4 mmol corrected) as a suspension in toluene (89 mL) was treated dropwise with trifluoroacetic anhydride (5.2 mL) at 0-5 ° C for 20 minutes (dissolution occurred). After 30 minutes, the solution was added to a mixture of potassium carbonate (32 grams), water (45 mL), tetrabutylammonium hydrogen sulfate (2.25 grams), sodium borohydride (1.0 grams), 2-chloro. 0 «0 * *» τ <«·· 0 · 0 0 0 0 0 0 0 0 0000 00 0

4-ethylbenzothiazole (7.07 grams, approximately 96.5% pure by gas chromatography) and toluene (10 mL) at approximately 5-15 ° C over 30 minutes. The biphasic mixture was then stirred for 20 hours 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 grams of a white solid consisting mainly of (+) - (4aR) - (10bR) 4-methyl-8- ( 4-ethyl-2-benzothiazolylthio) -1b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolinon-3-one and

2-chloro-4-ethylbenzothiazole. 13.0 grams of this mixture was treated with methyl tert-butyl ether (50 mL at reflux and then 0 ° C for 2 hours) to give

II, 05 grams of (+) - (4aR) - (10bR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1,2,3,4,4a, 5,6,10boctahydrobenzo [ f] quinolinon-3-one (IR, NMR, MS).

Calcd. For C, 68.21; H, 6.20; N, 6.63. Found: C, 68.29; H, 6.15; N, 6.67.

Preparation 7 (+) - (4α) - (10b) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) 10b-methyl-1,2,3,4,4a, 5,6,10b -octahydrobenzo [f] quinolinon-3-one.

Meta-chloroperoxybenzoic acid (about 92 grams, about 50%, in 1.0 L methylene chloride) was added at 0 ° C to a solution of (+) - (4aR) - (10bR) -4-methyl8-methylthio-10b-methyl -1,2,3,4,4a, 5,6,10boctahydrobenzo [f] quinolinon-3-one (79.5 grams, 92.9%,

0.269 mol) in methylene chloride (2.2 L). The progress of the reaction was · · · «« «« «« «« «« «« «« «« <<< Over 15 minutes at 0 ° C, was monitored by high pressure liquid chromatography (240 nm) for oxidation of (+) - (4aR) - (10bR) -4-methyl-8-methylthio-10bmethyl-1,2 3,4,4a, 5,6,10b-octahydrobenzo [f] quinolinon-3-one to less than 0.3 area%. The organic solution was stirred with sodium bisulfite solution (75 grams in 1 L 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 concentrated. Toluene (1 L) was added to the intermediate sulfoxide and this solution was concentrated under vacuum. This procedure 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. After 30 minutes of stirring, Pummerer product (ArSCH 2OCOCF ₃ ) was added via 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% pure), tetrabutylammonium hydrogen sulfate (21.6 grams), and toluene (170 mL) at 10 ° C. The reaction mixture was heated slowly to 42 ° C, while the progress of the reaction was monitored by high pressure liquid chromatography. After 18 hours, additional toluene (1.0 L) was added and the toluene layers were washed with deionized water (3x1L, 45 ° C). Ethyl acetate (1 L) was added to the organic layer, and then the organic layer was washed with a 0.25 M hydrochloric acid solution (3 x 1 L), 1 N sulfuric acid solution (3 x 1 L), 6% sodium bicarbonate solution (1.5 L), and saturated sodium chloride solution (2 L). The organic extracts were dried over 4

4444 4444 3

443 44 4 44

444 444 44 • 444 44 44 4444 44

4A molecular sieves (500 grams) and then concentrated. Methyl target was added. -butyl ether (400 mL) and the mixture was heated to reflux. After stirring at reflux for 30 minutes, the mixture was cooled to 5 ° C. The suspension was filtered and washed with methyl tert-butyl ether (100 mL). The solution was filtered and the product was dried at 50 ° C at about 5 mm for 18 hours to give 90.1 grams (80%) of (+) - (4aR) - (10bR) 4-methyl-8- (4 -ethyl-2-benzothiazolylthio) -1Ob-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f] quinolinon-3-one.

Represented by:

dr. O. Švorčík

Claims (13)

PATENT CLAIMS JUDr. Otakar Švorčík attorney Hálkova 2, 120 00 Prague 2 ··· ····························· ··· ··························································· 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-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-1H-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-benzimidazolyl, 1-benz [g] isoquinolinyl, 8-benz [g] isoquinolinyl, 5-1H-tetrazolyl, 2-quinazolinyl, 2-thiazolo [4,5-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 R ¹ groups are unsubstituted or substituted with 1-3 groups selected from the group consisting of trifluoromethyl, trifluoroethoxy, Οχ-alkyl ₄ alkyl, trifluoromethoxy, hydroxy, C 1 -C 3 alkoxy, nitro, C 1 -C 3 alkylthio, Οχ-β beta alkanoyl , phenyl, oxo, phenoxy, phenylthio, · · th · · · · · · · · · C 1 -C 3 alkylsulfinyl, C 1 -C ₃ alkylsulfonyl, cyano, amino, C 1 -C 3 alkylamino, diphenylmethylamino, triphenylmethylamino, benzyloxy, benzylthio, (mono-halogen, nitro or CF ₃ ) benzyl (oxy or thio), di (C _x - C ₃ alkyl, C ₃ -C ₆ cycloalkyl or C 4 -C 8 cycloalkylalkyl) amino, (mono-C 1 -C ₃ alkyl, C 1 -C 3 alkoxy or halogen) (phenyl, phenoxy, phenylthio, phenylsulfonyl or phenoxysulfonyl), 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, halogen-C 1 -C ₆ alkanoyl, aminosulfonyl, C 1 -C 3 alkylaminosulfonyl, di (C 1 -C 3) _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, C 1 -C 3 alkylamino or di (C 1 -C ₃ alkyl) amino (C 1 -C 3 alkyl); characterized in that it comprises the following steps: converting a ketone of the formula wherein R is halogen; to protected ether; reacting the protected ether with a reactive alkyllithium compound and a sulfur transfer reagent to obtain an S45 of the methyl ether compound; deprotection of the S-methylated ether compound to give the methylthiotetralone compound of formula II by reacting the compound of formula II with (R) - (+) phenethylamine to afford the compound of formula III III reacting a compound of formula III with a strong lithium base to give a lithioenamine compound of formula IV SCH-, Methylation of the resulting lithioenamine of formula IV to the compound of formula V In Sch _3, reacting a compound of formula V with an acyl halide or acrylic anhydride to prepare a compound of formula VI sch ₃ VI terminating the base reaction and combining the residue containing the compound of formula VI with a suitable silane and trifluoroacetic acid in the absence of a solvent to prepare a compound of formula VII sch ₃ Reacting a compound of formula VII with a methyl halide in a reaction mixture containing an organic solvent and a strong base to obtain an arylmethylsulfide compound of formula VIII by oxidizing a compound of formula VIII to a sulfoxide compound of formula IX > _CH3 Reacting sulfoxide acylating agent to obtain a compound of formula IX with a product formed Pummerer rearrangement; reacting a Pummerer rearrangement product with an electrophile selected from the group consisting of AR ¹ , wherein A is a leaving group, in the presence of a phase transfer catalyst, a hydride reducing reagent and a base, to prepare a compound of formula I. 2. A process for the preparation of a compound of formula (II) comprising the steps of: converting a ketone of the formula wherein R represents a halogen atom; to protected ether; reacting the protected ether with a reactive alkyllithium compound and a sulfur transfer reagent to obtain a methylated ether compound; deprotecting the S-methylated ether compound to give the methylthiotetralone compound of formula II. A process according to claim 2 wherein R is bromine, the sulfur transfer reagent is dimethyl disulfide and trimethyl orthoformate is used to form protected ethers A and B: The process according to claim 3, wherein the methylated ether compounds are C and D: that S · · · · · * * »S S S S S S S S S S S S S S S S · · · · CH, O Ca The process of claim 2 wherein the halogen is bromine; the protected ether is prepared using trimethyl orthoformate in methanol in the presence of an acid catalyst; the reactive alkyl lithium compound is n-butyllithium; the sulfur transfer reagent is dimethyl disulfide and the methylated ether compound is deprotected using hydrochloric acid. 6. The process of claim 5 wherein the 6-bromo-2-tetralone is prepared by reacting 4-bromophenylacetic acid with methylene chloride and a reagent selected from the group consisting of thionyl chloride, phosphorus trichloride, oxalyl chloride, and phosphorus trichloride followed by reaction with ethylene gas in the presence. a Lewis acid catalyst. The method of any one of claims 2, 3, 4, 5 or 6, further comprising converting a compound of formula (II) to 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-quinolinyl, 4-quinolinyl, 7-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-1H-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-benzimidazolyl, 1-benz [g] isoquinolinyl, 8-benz [g] isoquinolinyl, 5-1H-tetrazolyl, 2-quinazolinyl, 2-thiazolo [4,5-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 R ¹ groups are unsubstituted or 9 4 94 9 999 4 9 4 4 9 9 4 9 4 9 4 9 4 9 4 9449 94 49 4494 44 499 substituted with 1-3 groups selected from trifluoromethyl, trifluoroethoxy, C 1 -C ₄ alkyl, trifluoromethoxy, hydroxy, C 1 -C 3 alkoxy, nitro, C 1 -C 3 alkylthio, C 1 -C ₆ alkanoyl, phenyl , oxo, phenoxy, phenylthio, C1-C3 alkylsulfinyl, C1-C3 alkylsulfonyl, cyano, amino, C1-C3 alkylamino, diphenylmethylamino, triphenylmethylamino, benzyloxy, benzylthio, (mono-halogen, nitro or CF ₃ ) benzyl (oxy or thio) , di (C 1 -C ₃ alkyl, C ₃ -C ₆ cycloalkyl or C ₄ -C ₈ cycloalkylalkyl) amino, (mono-C 1 -C ₃ alkyl, C 1 -C 3 alkoxy or halogen) (phenyl, phenoxy, phenylthio, phenylsulfonyl or phenoxysulfonyl), 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, halogen-C 1 -C ₆ alkanoyl, aminosulfonyl, C 1 -C 3 alkylaminosulfonyl , di (C1-C3 alkyl) aminosulfonyl, phenyl (oxy or thio) (C1-C3 alkyl), (halogen, C1-C3 alkyl or C1-C3 alkoxy) phenyl (oxy or thio) (C1-C3 alkyl), benzoyl or (amino, C1 -C3 alkylamino or di (C1-C3 alkyl) amino) (C1-C3 alkyl). A process according to any one of claims 2, 3, 4, 5 or 6, further comprising converting a compound of formula II SCH 3 II ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft ftft · (+) - (4aR) - (10bR) -4-methyl-8- (4-ethyl-2-benzothiazolylthio) -10b-methyl-1,2,3,4,4a, 5,6,10boctahydrobenzo [f] quinolinone-3-one. The method of any one of claims 2, 3, 4, 5, or 6, further comprising the following steps: reacting a compound of formula II with (R) - (+) - phenethylamine to obtain a compound of formula III reacting a compound of formula III with a strong lithium base to give a lithioenamine compound of formula IV Flfl flfl Schiva • • flfl flflfl flfl flflfl flfl flfl ···· ·· methylation resulting lithioenaminu of formula IV to compound of formula V _SCH3 reacting a compound of formula V with an acyl halide or an anhydride of acrylic acid to prepare a compound of formula VI 00 0 « 0 0 0 0 0 0 0 0 0 0 0000 00 0 0 0 - 55 00 0 · 0 0 0 0 0 0 0 0 00 0000 VI sch ₃ terminating the reaction of the bases and combining the residue containing the compound of the formula VI with a suitable silane and trifluoroacetic acid in the absence of a solvent for the preparation of the compound of the formula VII The method of claim 9, comprising the following steps: characterized in that further reacting a compound of formula VII with a methyl halide in a reaction mixture comprising an organic solvent and a strong base to obtain an arylmethylsulfide compound of formula VIII 44 44 • 4 4 • 4 4 4 4 444 444 44 4444 44 44 4444 44 4 oxidation of a compound of formula VIII to a sulfoxide compound of formula IX A ch ₃ reaction with a sulfoxide acylating agent of a compound of formula IX to obtain the product formed Pummerer rearrangement; * reacting the product formed by the Pummerer rearrangement with an electrophile selected from the group consisting of AR ¹ , wherein A is a leaving group and R ¹ represents 2-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-cyanophenyl, 2-nitronaphthyl, 4-nitronaphthyl, 2-cyanonaphthyl, 4-cyanonaphthyl, 2-quinolinyl, 4-quinolinyl, 7-quinolinyl, · • φ φ • φ φ • φ φ • • • 1-isoquinolinyl, 3-isoquinolinyl, 8-isoquinolinyl, 2-quinoxalinyl, 2-benzothiazolyl, 3-1H-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-benzimidazolyl, 1-benz [g] isoquinolinyl, 8-benz [g] isoquinolinyl, 5-1H-tetrazolyl, 2-quinazolinyl, 2-thiazolo [4,5-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 R ¹ groups are unsubstituted or substituted by 1-3 groups selected from the group consisting of trifluoromethyl, trifluoroethoxy, C 1 -C ₄ alkyl, trifluoromethoxy, hydroxy, C 1 -C 3 alkoxy, nitro, C 1 -C 3 alkylthio, C 1 -C 6 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-halogen, nitro or CF ₃ ) benzyl (oxy or thio), di (C 1 -C ₃ alkyl, C ₃ -C 6 cycloalkyl or C ₄ -C ₈ cycloalkylalkyl) amino, (mono-C 1 -C ₃ alkyl, C 1 -C 3 alkoxy or halogen) (phenyl, phenoxy, phenylthio, phenylsulfonyl or phenoxysulfonyl), C ₂ -C ₆ alkanoylamino, benzoylamino, diphenylmethylamine (C1-C3 alkyl) aminocarbonyl, C1 -C3 alkylaminocarbonyl, di (C1 -C3 alkyl) aminocarbonyl, halo-Cl-C6 alkanoyl, aminosulfonyl, C1 -C3 alkylaminosulfonyl, di (C1-C3 alkyl) aminosulfonyl, phenyl (oxy or thio) (C1-C3 alkyl), (halogen, C1-C3 alkyl or C1-C3 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); in the presence of a phase transfer catalyst, hydride ΦΦ φ φ φ · · · φ φ φ φ φ · · · φ The reducing reagent and the base of formula (I) for the preparation of the compound 11. Compound of formula (A): 12. Compound of formula B: 13. Compound of formula (C):