KR100515922B1 - Process for preparing of dibenzothiepin - Google Patents

Abstract

The present invention relates to a process for preparing a dibenzothiepyne compound of formula (I), specifically a) a reaction mixture comprising a propiophenone derivative of formula (II) and an alcohol selected from alkylenediol or monoalcohol Adding iodine (I ₂ ) catalyst with iodine chloride (ICl) or iodine bromide (IBr), and then adding a peroxide to the reaction mixture to prepare a dicarboxylic acid ester compound of formula III; b) converting the dicarboxylic acid ester compound of formula III to a dibenzothiefine compound of formula I in the presence of an acid condensing agent; Characterized in that consists of.

Description

Process for preparing of dibenzothiepin

The present invention relates to a process for preparing a dibenzothiepyne compound of formula (I), specifically a) a reaction mixture comprising a propiophenone derivative of formula (II) and an alcohol selected from alkylenediol or monoalcohol Adding an iodine (I ₂ ) catalyst and iodine chloride (ICl) or iodine bromide (IBr), and then adding a peroxide to the reaction mixture to prepare a dicarboxylic acid ester compound of formula III; b) converting the dicarboxylic acid ester compound of formula III to a dibenzothiefine compound of formula I in the presence of an acid condensing agent; Characterized in that consists of.

[Wherein R ₁ is a C ₁ -C ₆ linear or branched alkyl, phenyl or benzyl group, and the phenyl group contained in the phenyl group and the benzyl group is C ₁ -C ₆ linear or branched alkyl, nitro, halogen, May be substituted with methoxy, and R ₂ is a C ₁ -C ₆ straight or branched alkyl group.]

Dibenzothiefine compounds of formula (I), i.e. 2- (10,11-dihydro-10-oxodibenzo [b, f] thipin-2-yl) propionic acid, are useful compounds with high anti-inflammatory and high analgesic activity In particular, it is known as a practically useful anti-inflammatory agent with little side effects.

As a method for preparing a dibenzothione compound of Formula (I), Japanese Patent Application Laid-Open No. 58-113168 discloses a dicarboxyl by preparing a tosylated acetal compound from a bromoketone derivative as shown in Scheme 1. It is known to prepare dibenzothiepyne compounds of formula (I) by the preparation of acid compounds followed by cyclization reactions.

Scheme 1

In addition, Korean Patent Publication No. 1992-6613 discloses a method for preparing a dibenzothione compound of Formula (I) through the steps shown in Scheme 2 below.

Scheme 2

The above known methods are a method of producing a dicarboxylic acid by inverting a halo acetal or tosylated acetal under ZnCl ₂ or basic conditions, and when a metal salt Lewis acid such as ZnCl ₂ is used, Lewis acid is only expensive. In addition, there is a problem of removing metal salts harmful to the human body, such as ZnCl ₂ , and the potential reaction under basic conditions requires heating for a long time at a high temperature of 100 ° C. or higher, thereby lowering productivity and lowering yields due to side reactions.

Accordingly, an object of the present invention is to provide a method for preparing a dibenzothiepine compound under economic and mild reaction conditions, and another object is a 5-yield with high yield in a single reactor from 5-propionyl-2-phenylthiophenylacetate. It is to provide a method for producing a (1-carboxyethyl) -2-phenyl-thioacetate derivative.

The present invention relates to a process for preparing a dibenzothiepyne compound of formula (I), specifically a) a reaction mixture comprising a propiophenone derivative of formula (II) and an alcohol selected from alkylenediol or monoalcohol Adding an iodine (I ₂ ) catalyst and iodine chloride (ICl) or iodine bromide (IBr), and then adding a peroxide to the reaction mixture to prepare a dicarboxylic acid ester compound of formula III; b) converting the dicarboxylic acid ester compound of formula III to a dibenzothiefine compound of formula I in the presence of an acid condensing agent; Characterized in that consists of.

[Wherein R ₁ is a C ₁ -C ₆ linear or branched alkyl, phenyl or benzyl group, and the phenyl group contained in the phenyl group and the benzyl group is C ₁ -C ₆ linear or branched alkyl, nitro, halogen, May be substituted with methoxy, and R ₂ is a C ₁ -C ₆ straight or branched alkyl group.]

Hereinafter, the present invention will be described in detail.

The process for preparing the dibenzothiefine compound of formula (I) according to the present invention is carried out from 5-propionyl-2-phenylthiophenylacetate of formula (II) as starting material, as shown in Scheme 3 below. Preparing a 1-carboxyethyl) -2-phenyl-thioacetate derivative and a 5- (1-carboxyethyl) -2-phenyl-thioacetate derivative of formula III prepared from the first reaction step by condensation reaction. Cyclization to prepare a dibenzothiepyne compound of formula (I) as a target compound.

Scheme 3

The first step is an iodine (I ₂ ) catalyst and iodine chloride (ICl) or iodine bromide in a reaction mixture consisting of a 5-propionyl-2-phenylthiophenylacetate derivative of formula II and an alcohol selected from alkylenediol or monoalcohol. After adding (IBr), a peroxide is added to the reaction mixture to prepare a dicarboxylic acid ester compound of formula III.

Iodine is preferably used as the catalytic amount, and iodine chloride or iodine bromide is preferably used at 0.5 to 1 mole per mole of 5-propionyl-2-phenylthiophenylacetate derivative of formula II.

The peroxide added in this step is preferably a peroxide of C ₁ -C ₅ alkyl carboxylic acid, perbenzoic acid, m-chloroperbenzoic acid or hydrogen peroxide, more particularly peracetic acid or m-chloroperbenzoic acid, The content used is 30 to 40%.

The alkylene diol is preferably 1,2-ethanediol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 2,3-butanediol, and monoalcohol is methanol , Ethanol, n-propanol, i-propanol are preferred, and in the case of alkylenediol, cyclyl of 5- (1-carboxyethyl) -2-phenyl-thioacetate derivative of formula III during the reaction by forming cyclized acetal Not only is it excellent in the stereoselectivity of the benzyl position substituted with acid esters, but also there are few side reactions, and especially a 1, 2- ethanediol, a 1, 2- propanediol, or 1, 3- propanediol is the most preferable.

On the other hand, in order to overcome the decomposition of the iodine complex under the influence of the water present in the solvent in the above reaction step, it is preferable to add a metal salt of C ₁ -C ₅ alkyl carboxylic acid with a peroxide as a buffer, the carboxyl The addition of the metal salt of acid not only makes the reaction conditions more gentle, but also has the advantage that the reaction proceeds without side reactions. Particularly, preferable materials for use as a metal buffer solution are sodium acetate and potassium acetate.

The solvent used in the potential reaction can be carried out in a solvent that does not participate in the reaction, such as methylene chloride, carbon tetrachloride, diethyl ether, tetrahydrofuran, benzene, toluene, and also can be carried out using an alcohol used as a reactant as a solvent. The reaction is carried out at a temperature of -10 to 70 ℃, particularly preferably a reaction temperature of 0 to 30 ℃, the reaction time is carried out for 0.5 to 4 hours, most of the reaction is completed within 1 hour do.

The dislocation reaction step of the method for preparing the dibenzothiepyne compound of formula I according to the present invention is carried out by dislocation reaction to form a peroxide alpha-iodine acetal complex intermediate (IV) as shown in Scheme 4 below. -(1-carboxyethyl) -2-phenyl-thioacetate derivative is prepared.

Scheme 4

[Wherein R ₁ and R ₂ are the same as described above, and R ₃ is a C1-C5 alkyl group or R ₃ bonded to each other with-(CH ₂ ) _n- .]

The alpha-iodoacetal complex intermediate (IV) is subjected to an iodine bromide (or iodine chloride) again during the preparation of the 5- (1-carboxyethyl) -2-phenyl-thioacetate derivative of Formula III after the rearrangement, and then to the alpha-iodine It is a cyclic reaction that is involved in the formation of the acetal complex intermediate (IV).

According to the present invention, the iodine catalyst and iodine chloride (ICl) or iodine bromide (IBr) may be reacted by adding a carboxylic acid metal salt together with a peroxide and a buffer solution, and the carboxylic acid metal salt may be reacted with a peroxide and a buffer solution. After addition, it is also possible to react by adding iodine chloride (ICl) or iodine bromide (IBr).

This means that alpha-iodoacetal complex intermediates are produced simultaneously with acetalization and alpha iodide.

Preparing a dibenzothiene compound of formula (I) as a target compound by cyclization of 5- (1-carboxyethyl) -2-phenyl-thioacetate derivative of formula (III) prepared from the first reaction step by condensation; Is carried out under similar conditions to the step of proceeding the conventional cyclization reaction.

Specifically, the dicarboxylic acid is prepared by hydrolysis of the dicarboxylic acid ester of formula III, and then the dibenzoic acid compound of formula I is prepared in the presence of a condensing agent. The order of the steps of the reaction can be reversed. Hydrolysis is carried out by heating the dicarboxylic acid ester in a conventional method, for example, in an aqueous basic solution or an acidic aqueous solution, and the condensing agent is preferably used 1 to 10 times by weight based on 1 weight of dicarboxylic acid. As an example of the condensing agent, sulfuric acid, polyphosphoric acid or polyphosphoric acid ester is preferred, and the condensation reaction is carried out for 10 minutes to 10 hours in the temperature range of room temperature to 120 ° C. After completion of the reaction, an organic solvent is added to the acidic aqueous mixture of the reaction mixture to extract the reaction product, the organic solvent is distilled off, and the reaction product is obtained. The reaction product can be purified by a method such as recrystallization.

The step of preparing the dibenzothiefine compound of formula (I) by cyclization reaction is known in the conventional dibenzothiefine compound cyclization reaction, and thus detailed description thereof is omitted.

Preparation of the compound of formula III from the compound of formula II The yield is not only obtained in a high yield of 91% or more, but also the dibenzothiepine compound of formula 1 is prepared directly without separating the compound of formula III obtained due to mild reaction conditions and low side reactions. Even if the yield of the cyclization reaction is not only high, there is an advantage that the separation of the final product is easy.

The following examples illustrate the invention in more detail. In addition, the following examples do not limit the spirit of the present invention.

Example 1

Preparation of Methyl 5- (1-propoxycarbonylethyl) -2-phenyl-thioacetate

50.0 g of methyl 5-propionyl-2-phenylthiophenyl acetate was added to the reactor under a nitrogen atmosphere, and 400 mL of 1,3-propanediol was added.The reaction mixture was cooled to 0 ° C., and then the amount of iodine (I ₂ ) catalyst (5 mg) was added. And 25.9 g of iodine chloride (ICl) are added slowly.

After stirring the reaction solution for 30 minutes, 0.75 g of sodium acetate and a mixture of 38 to 40% peracetic acid 45 mL were slowly added at room temperature, followed by stirring at room temperature for 2 hours.

After concentrating the reaction solvent under reduced pressure, 500 mL of diethyl ether was added to the reaction product, followed by 300 mL of water, followed by three successive washings. The organic layer was washed with 400 mL of saturated sodium hydrogen carbonate solution and concentrated under reduced pressure to give 49.8 g (91.0%) of the title compound.

Example 2

Preparation of Methyl 5- (1-ethoxycarbonylethyl) -2-phenyl-thioacetate

50.0 g of methyl 5-propionyl-2-phenylthiophenyl acetate was added to the reactor under a nitrogen atmosphere, and 400 mL of 1,2-ethanediol was added thereto.The reaction mixture was cooled to 0 ° C., and the amount of iodine (I ₂ ) catalyst (5 mg) was added. And 25.9 g of iodine chloride (ICl) are added slowly.

After stirring the reaction solution for 30 minutes, 0.75 g of sodium acetate and a mixture of 38 to 40% peracetic acid 45 mL were slowly added at room temperature, followed by stirring at room temperature for 2 hours.

The reaction solvent was concentrated under reduced pressure, 500 mL of diethyl ether was added to the reaction product, followed by 300 mL of water, followed by three successive washings. The organic layer was washed with 400 mL of saturated sodium hydrogen carbonate solution, and then concentrated under reduced pressure to obtain 49.0 g (89.6%) of the title compound.

Example 3

Preparation of Methyl 5- (1-propoxycarbonylethyl) -2-phenyl-thioacetate

50.0 g of methyl 5-propionyl-2-phenylthiophenyl acetate was added to the reactor under a nitrogen atmosphere, and 400 mL of 1,3-propanediol was added.The reaction mixture was cooled to 0 ° C., and then the amount of iodine (I ₂ ) catalyst (5 mg) was added. 25.9 g of iodine monochloride (ICl) and 0.75 g of sodium acetate and 45 to 40% peracetic acid mixture were added thereto, followed by stirring at room temperature for 2 hours. The reaction solvent was concentrated under reduced pressure, 500 mL of diethyl ether was added to the reaction product, followed by 300 mL of water, followed by three successive washings. The organic layer was washed with 400 mL of saturated sodium hydrogen carbonate solution and concentrated under reduced pressure to give 48.0 g (87.8%) of the title compound.

Example 4

Preparation of 5- (1-carboxyethyl) -2-phenylthiophenyl-acetic acid

30 g of methyl 5- (1-propoxycarbonylethyl) -2-phenyl-thioacetate obtained in Example 1 was dissolved in 150 mL of methanol, cooled to 0 ° C., and a solution of 9 g of NaOH in 30 mL of purified water was slowly added thereto. After stirring for 30 minutes. The reaction was warmed to room temperature and stirred for 4 hours. The solvent of the reaction mixture was concentrated under reduced pressure to remove methanol, and 200 mL of water was added thereto. The resulting mixture of the aqueous layer was washed with 150 mL of diethyl ether, the aqueous layer was cooled to 5 ° C., the pH was adjusted to 1.0 with 3N-HCl, extracted three times with 200 mL of methylene chloride, and the organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure to give 24.4 g (88.4%) of the title compound.

NMR (CDCl ₃ ) δ: 3.82 (1H), 3.48 (2H), 1.46 (3H), 7.22-7.6 (8H)

Example 5

Preparation of 5- (1-carboxyethyl) -2-phenylthiophenyl-acetic acid

30 g of methyl 5- (1-ethoxycarbonylethyl) -2-phenyl-thioacetate obtained in Example 2 was dissolved in 150 mL of methanol, cooled to 0 ° C., and a solution of 9 g of NaOH in 30 mL of purified water was slowly added thereto. After stirring for 30 minutes. The reaction was warmed to room temperature, stirred for 4 hours, the solvent of the reaction mixture was concentrated under reduced pressure to remove methanol, and 200 mL of water was added thereto. The resulting mixture of the aqueous layer was washed with 150 mL of diethyl ether, the aqueous layer was cooled to 5 ° C., the pH was adjusted to 1.0 with 3N-HCl, extracted three times with 200 mL of methylene chloride, and the organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure to give 24.9 g (90.1%) of the title compound.

NMR (CDCl ₃ ) δ: 3.82 (1H), 3.48 (2H), 1.46 (3H), 7.22-7.6 (8H)

Example 5

Preparation of 2- (10,11-dihydro-10-oxodibenzo [b, f] thiin-2-yl) propionic acid

After mixing 20 g of 5- (1-carboxyethyl) -2-phenylthiophenyl-acetic acid obtained in Example 4 and 100 g of PPA (polyphosphoric acid), the mixture was gradually heated to 80 ° C. to maintain the temperature of the reactant. After stirring for 4 hours, the reaction mixture was added to 300 mL of ice water, and extracted four times with 300 mL of ethyl acetate. The organic layer was washed with 400 mL of water, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure to obtain 15.3 g (81.3%) of the title compound.

NMR (CDCl ₃ ) δ: 1.46 (3H), 3.80-3.84 (3H), 6.6-7.81 (7H)

Comparative Example 1

Preparation of Methyl 5- (2-bromopropionyl) -2-phenyl-thiophenylacetate

50.0 g (0.159 mol) of 5-propionyl-2-phenylthiophenyl acetate was added to the reactor under a nitrogen atmosphere, and 340.0 mL of methylene chloride was added thereto to dissolve. The reaction solution was cooled to 0 to 5 ° C, and bromine 8.15 mL was dissolved in methylene chloride. Dilute to 50.0 mL, and slowly add dropwise to the reaction solution, and stir for 1.5 hours while maintaining the temperature of the reaction solution.

200 mL of water was added to the reaction solution, the mixture was stirred for 30 minutes, and the organic layer was separated. The organic layer was separated and washed twice with 200 mL of water, and then concentrated under reduced pressure to remove the organic solvent. do.

The product solution is stirred at 0-5 ° C. for 5 hours to form crystals, and the resulting crystals are filtered off. The filtrate was washed with 20 mL of cooled methanol to give 52.9 g (84.6%) of the title compound.

NMR (CDCl ₃ ) δ: 5.21 (1H), 3.53 (2H), 3.68 (3H), 2.01 (3H), 7.0 ~ 7.5 (8H)

Comparative Example 2

Preparation of Methyl 5- (2-bromo-1,1-dimethoxypropyl) -2-phenyl-thioacetate

20.0 g of methyl 5- (2-bromopropionyl) -2-phenyl-thiophenylacetate compound obtained in Comparative Example 1 was added, 110 mL of methanol, 33 mL of trimethylorthoformate, and 0.05 mL of methanesulphonic acid were added for 18 hours. Reflux for a while.

200 mL of diethyl ether was added to the reaction solution, followed by washing twice with 150 mL of saturated sodium carbonate. Then, 150 mL of water was added to the organic layer, and then washed with 100 mL of saturated brine. The mixture was dried over anhydrous magnesium sulfate, filtered and the solvent was dried under reduced pressure. It removed, and 17.0 g (76.4%) of the target compounds were obtained.

NMR (CDCl ₃ ) δ: 4.62 (1H), 3.23 (6H)

Comparative Example 3

Preparation of Methyl 5- (1-ethoxycarbonylethyl) -2-phenyl-thioacetate

To 20 g of the halo acetal compound obtained in Comparative Example 2 was added 40 mL of toluene and 30 mol% of ZnBr ₂ (based on halo acetal) and refluxed under a nitrogen atmosphere for 20 hours.

The reaction was cooled to room temperature, 40 mL of water was added to the reaction, followed by extraction three times with 150 mL of diethyl ether. The extracted organic layer was washed with 150 mL of purified water, dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure to give 11.1 g (67.2%) of the title compound.

As can be seen from the examples and comparative examples, according to the present invention, the reaction time is shorter and the reaction conditions are milder than those of the conventional production method of alpha-bromination reaction, acetalization reaction, and potential reaction by Lewis acid. And, it can be seen that there is a very advantageous advantage in productivity because the yield is high.

Even if the reaction conditions are mild and the dibenzothiene compound of Formula 1 is prepared directly without separating the obtained compound (III) because of less side reactions, the yield of the cyclization reaction is high and the separation of the final product is easy.

Claims (5)

a) propiophenone derivative of formula (II) with 1,2-ethanediol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 2,3- After adding iodine (I ₂ ) catalyst and iodine chloride (ICl) or iodine bromide (IBr) to a reaction mixture consisting of alkylenediol or monoalcohol selected from butanediol, methanol, ethanol, n-propanol and i-propanol, step of the above reaction mixture was added a C ₁ -C ₅ alkyl peroxide is selected from a carboxylic acid peroxide, perbenzoic acid, m- chloroperbenzoic acid or hydrogen peroxide to dicarboxylic acid ester compound of formula III; b) converting the dicarboxylic acid ester compound of formula III to a dibenzothiefine compound of formula I in the presence of an acid condensing agent; Method for producing a dibenzothione compound of formula (I) comprising a. [Wherein R ₁ is a C ₁ -C ₆ linear or branched alkyl, phenyl or benzyl group, and the phenyl group contained in the phenyl group and the benzyl group is C ₁ -C ₆ linear or branched alkyl, nitro, halogen, May be substituted with methoxy, and R ₂ is a C ₁ -C ₆ straight or branched alkyl group.] delete delete The method of claim 1, The method of preparing a dibenzothione compound of formula (I), characterized in that the addition of a metal salt of C ₁ -C ₅ alkyl carboxylic acid with a peroxide as a buffer in step a). The method according to claim 1 or 4, A method for preparing a dibenzothione compound of formula (I), comprising reacting an iodine catalyst with iodine chloride (ICl) or iodine bromide (IBr) with a peroxide and a buffer with a metal salt of carboxylic acid.