KR100699457B1 - Process for preparing dibenzothiepin derivatives and intermediates thereof - Google Patents

Abstract

The present invention provides compounds 2- (10,11-dihydro-10-oxobenzo [ b, f ] thipin-2-yl) propionic acid (hereinafter referred to as' dibenzo of formula I) having pharmaceutical activity And a process for preparing a cyclized haloketone compound of formula IV:

Wherein X is a halogen atom.

According to the preparation method of the present invention, the dibenzothione derivative of Structural Formula I having pharmaceutical activity can be prepared in high purity and high yield by a simple method compared with the conventional method.

Dibenzothiene derivatives, anti-inflammatory analgesic, cyclization reaction, production yield

Description

Process for preparing dibenzothiepin derivatives and intermediates

The present invention relates to 2- (10,11-dihydro-10-oxobenzo [ b, f ] thipin-2-yl) propionic acid, which is a dibenzothiepine derivative of the formula It relates to a process for preparing the cyclized haloketone compound of formula IV.

Wherein X is a halogen atom.

Dibenzothiepine derivatives are commercially available as drugs with anti-inflammatory analgesic (common name: zaltoprofen), and several attempts have been made to prepare them.

(a) Japanese Patent Application Laid-Open No. 1980-53282 discloses a method for preparing dibenzothiene derivatives by subjecting 3- (α-cyanoethyl) -6-phenylthiophenylacetic acid to cyclization and hydrolyzing them. Intervened.

Wherein X is a halogen atom.

(b) Japanese Patent Application Laid-Open No. 1982-106678 discloses a dicarboxylic acid derivative by hydrolyzing a phenylacetate ester having a nitrile group, and dibenzoic acid through a cyclization reaction using a condensing agent such as sulfuric acid or polyphosphoric acid. A method for preparing a thiepine derivative is described.

Wherein, R is C _{1 - 5} of a lower alkyl.

(c) Japanese Patent Application Laid-Open No. 1983-113168 describes a method for preparing a dicarboxylic acid derivative from which a propiophenone derivative is once converted to hydroxyacetal and then preparing a dibenzo thiepine derivative therefrom. .

Wherein, X is Cl or Br, R is a C _{1 - 5} lower alkyl or hydrogen, R 'is C _{1 - 5} lower alkyl and R''is -CH _3, or para-methylphenyl.

(d) Japanese Patent Laid-Open Publication No. 1987-292780 and Korean Patent Publication No. 92-5417 have synthesized a halogenoacetal compound using 5-propionyl-2-thiophenyl-phenyl-acetic acid as a starting material. A method for preparing a dicarboxylic acid derivative by preparing a diester compound through rearrangement under an acid or a base, followed by hydrolysis to prepare a dicarboxylic acid derivative, and cyclizing it with polyphosphoric acid is described.

Wherein R and R 'are the same or different and represent a lower alkyl group.

These known methods can also be used to prepare the dibenzothione derivatives of formula I, but these methods have manufacturing problems. In other words, the methods (a) and (b) are difficult to apply industrially because they use highly toxic reagents such as NaCN or KCN, have to undergo several stages of reaction, and the process after the reaction is complicated, resulting in low production yield. In addition, there is a problem that the production time is long, the production yield is reduced. In the case of the method (c), there is a process problem in that the reaction should be carried out at low temperature and anhydrous state in the preparation of the dibenzothiepine derivative, and in the preparation step, the solvent is distilled under reduced pressure after the reaction to obtain a syrup form or a foam product. It is a cause of difficulty in manufacturing. In addition, the method (d) has a problem in that the operation is inconvenient due to a decrease in the solubility of the compound in the final cyclization step using a strong acid, and difficult to remove the formed impurities.

As listed above, the conventional methods for preparing dibenzothione derivatives of the general formula (I), which have been known to date, have their own technical limitations for producing economically on an industrial scale.

Therefore, the present inventors focused on developing a new manufacturing method that can be used more efficiently, economically, and industrially safely by supplementing the disadvantages of the methods for preparing the dibenzothione derivative of the conventional structure I as mentioned above. Studies have been carried out to complete the present invention.

As a result, the cyclized haloketone compound of formula IV, which is an intermediate prepared according to the preparation method of the present invention, has good color as a crystalline compound and maintains high purity of 99% or more. It is characterized in that the dibenzothiene derivative of formula I in high yield and high purity under safe and safe conditions.

The method for preparing a dibenzothione derivative according to the present invention for preparing a dibenzothiene derivative of formula I through a continuous process with a cyclized haloketone compound of the intermediate structure IV is known in the art (a) ~ ( Problems such as the use of toxic substances NaCN or KCN, reduction of production yield, waste water by-products from cyclization reaction using strong acid, and environmental pollution in d) can be solved simply. In addition, it is not only able to synthesize and produce dibenzothione derivatives in high purity and high yield, it is also an excellent method that can be economically mass-produced on an industrial scale, and is industrially safe and easily available.

The present invention relates to a novel method for preparing dibenzothione derivatives of formula (I) and intermediates thereof having pharmaceutical activity, and more particularly to preparing compounds of formula (IV) as intermediates, using a continuous process A method for the simple preparation of dibenzothione derivatives of formula (I) in high yield and high purity.

Wherein X is a halogen atom.

Method for preparing a dibenzothione derivative of formula I according to the present invention

(Iii) converting propiophenone of formula II to a haloketone compound of formula III by reacting with a halogenating agent;

(Ii) reacting the haloketone compound of formula III with a condensing agent in the presence of an acid to form a cyclized haloketone compound of formula IV below;

(Iii) reacting the cyclized haloketone compound of formula IV with alkylorthoformate to form cyclized haloacetal of formula V:

(Iii) reacting the cyclized haloacetal of formula V with a zinc halide to form an ester compound of formula VI: And

(Iii) hydrolyzing the ester compound of formula VI to prepare a dibenzothione derivative of formula I below.

Wherein, X is a halogen atom, R ₁ is C _{1 - 6} is alkyl, phenyl having a substituent selected from a _hydroxy-6 alkyl, phenyl, or hydrogen, halogen, C _1.

In addition, the method for preparing a cyclized haloketone compound of formula IV according to the present invention is converted to the haloketone compound of formula III by reacting propiophenone of formula II with a halogenating agent, and then The haloketone compound is reacted with a condensing agent in the presence of an acid to prepare a cyclized haloketone compound of formula IV.

Wherein X is a halogen atom.

In addition, the method for preparing a dibenzothione derivative of formula I according to the present invention

Reacting the cyclized haloketone compound of formula IV with alkylorthoformate to form a cyclized haloacetal of formula V:

Reacting the cyclized haloacetal of formula V with a zinc halide to form an ester compound of formula VI: And

Hydrolyzing the ester compound of formula VI is characterized in that it comprises the step of preparing a dibenzo thiepine derivative of formula (I).

Wherein, X is a halogen atom, R ₁ is C _{1 - 6} is alkyl, phenyl having a substituent selected from a _hydroxy-6 alkyl, phenyl, or hydrogen, halogen, C _1.

The present invention is also characterized by providing a cyclized haloketone compound of formula IV.

Wherein X is a halogen atom.

In the following, the present invention is described in more detail.

Preparation of Cyclic Haloketone Compound of Structural Formula IV as Intermediate

The propiophenone of formula II is converted to a haloketone compound of formula III by reacting with a halogenating agent. In this case, it is preferable to use a brominating agent or a chlorinating agent as the halogenating agent. More preferably a brominating agent is used. The haloketone compound of formula III thus prepared is subjected to cyclization reaction using a condensing agent in the presence of an acid to form a cyclized haloketone compound of formula IV below. The acid is preferably sulfuric acid (H ₂ SO ₄ ), methanesulfonic acid (CH ₃ SO ₃ H), benzenesulfonic acid or para-toluenesulfonic acid, more preferably methanesulfonic acid is used. As the condensing agent, polyphosphoric acid (preferably 105%, 110% or a mixture thereof) or polyphosphate ester may be used, but preferably polyphosphoric acid (preferably 105%, 110% or a mixture thereof) is used. . The cyclized haloketone compound of formula IV, which is an intermediate compound of the present invention, is a crystalline compound and has good color and maintains high purity of 99% or more, so that the dibenzothione derivative of formula I of high yield and high purity under safe conditions. To be prepared.

Wherein X is a halogen atom.

<Preparation of 2- (10,11-dihydro-10-oxobenzo [ b, f ] thipin-2-yl) propionic acid which is a dibenzothiefine derivative of formula I>

The cyclized haloketone compound of formula IV, the intermediate prepared above, is reacted with alkylorthoformate to form cyclized haloacetal of formula V below. The reaction is preferably carried out in an alcohol solvent, and the alkyl of the alcohol and the alkyl orthoformate is preferably alkyl having 1 to 6 carbon atoms. More preferably methyl or ethyl. In addition, the reaction is preferably carried out under an acid catalyst in anhydrous form, wherein the anhydrous acid is preferably sulfuric acid, methanesulfonic acid or formic acid.

The cyclized haloacetal of formula V thus formed is reacted with a zinc halide, preferably zinc chloride or zinc bromide, to form the ester compound of formula VI. Thereafter, the ester compound of formula VI is hydrolyzed at room temperature to obtain a high purity dibenzothione derivative of formula I. At this time, the reaction temperature is preferably 20 to 30 ° C. In the hydrolysis process, an alcohol solvent may be used, and in this case, an alcohol having an alkyl group having 1 to 6 carbon atoms is preferable. More preferably the alcohol solvent is methanol or isopropanol.

Wherein, X is a halogen atom, R ₁ is C _{1 - 6} is alkyl, phenyl having a substituent selected from a _hydroxy-6 alkyl, phenyl, or hydrogen, halogen, C _1.

The present invention is explained in more detail by the following examples, but the present invention is not limited in any way by these.

Example 1: 2- (2-bromo-propionyl) -11 H - dibenzo [b, f] - thio Synthesis of pin-on -10

180 L of dichloromethane was added to the reactor, and 18.8 kg of 5-propionyl-2-thiophenyl-phenyl-acetic acid was added and dissolved under stirring. The resulting solution was cooled to 5 ° C., 10 kg of bromine (Br ₂ ) was added dropwise, the reaction solution was stirred for 1 hour, 180 L of water was added to the reaction solution, and the layers were separated after stirring. 100 L of water and 0.35 kg of sodium hydrosulfite were added to the organic layer, followed by stirring to separate the layers. The organic layer was concentrated, 100 L of dichloromethane, 26 kg of polyphosphoric acid, and 2.5 kg of methanesulfonic acid were added to the residue, and the mixture was heated with stirring to reflux for 4 hours. The reaction was cooled, 100 L of water was added, stirred for 1 hour, and the layers were separated. 100 L of water and 0.5 Kg of sodium hydroxide were added to the organic layer, the mixture was stirred for 1 hour, and layers were separated. The organic layer was concentrated and the residue was recrystallized from a mixture of ethyl acetate and hexane and dried to obtain the above 2- (2-bromo-propionyl) -11 H - dibenzo [b, f] - thio -10 pin on 18.6 kg Was obtained (yield: 82%, purity: 99.2%).

IR (KBr) ν max: 1682 (CO)

H ¹ NMR (CDCl ₃ ) ppm: 1.92 to 1.96 (t. 3H, BrCHCH ₃ ), 4.42 to 4.53 (t. 2H, COCH ₂ ), 5.26 to 5.31 (t. 1H, BrCHCH ₃ ), 7.30 to 7.41 (t 1H, aromatics), 7.50 ~ 7.51 (t. 1H, aromatics), 7.64 ~ 7.66 (d. 1H, aromatics), 7.79 ~ 7.81 (d. 1H, aromatics), 7.88 ~ 7.89 (d.1H, aromatics), 8.11-8.12 (s. 1H, aromatics), 8.24-8.26 (d. 1H, aromatics).

Example 2 Synthesis of 2- (10,11-dihydro-10-oxodibenzo [ b, f ] thipin-2-yl) propionic acid

Were charged to a 10-pin thio-on 18.6 kg - with stirring was added 100 L of methanol to the reaction vessel a 2- (2-bromo-propionyl) -11 H prepared in Example 1-dibenzo [b, f]. 31 kg of trimethyl orthoformate and 1.7 kg of methanesulfonic acid were added to the reaction solution, followed by heating to reflux. The reaction solution was concentrated under reduced pressure, and 100 L of toluene and 14 kg of zinc bromide were added to the residue. The reaction was allowed to warm to reflux for 3 hours. The reaction was cooled, 100 L of water was added thereto, stirred, and the layers were separated. The organic layer was concentrated, and 100 L of methanol was added to the residue. The reaction was cooled to 5 ° C., and 5 kg of sodium hydroxide was added thereto and stirred. It stirred for 4 hours and added 120L of water. After hydrochloric acid was added to acidify the solution, the crystals were filtered and dried to give a crude crystal. The crude crystals were recrystallized from 140 L of ethyl acetate and dried to obtain 11.5 kg of 2- (10,11-dihydro-10-oxodibenzo [ b, f ] thipin-2-yl) propionic acid. (Yield: 77%, Purity: 99.8%)

IR (KBr) ν max: 2978 (OH), 1682 (CO)

H ¹ NMR (CDCl ₃ ) ppm: 1.52 ~ 1.54 (d. 3H, CH ₂ CH ₃ ), 3.77 ~ 3.78 (q. 1H, CHCH ₃ ), 4.40 (s. 1H, CHCH ₃ ), 7.19 ~ 7.21 (d 1H, aromatics), 7.03 to 7.46 (m. 3H, aromatics), 7.62 to 7.63 (m. 2H, aromatics), 8.22 to 8.25 (d. 1H, aromatics).

According to the preparation method of the present invention, 2- (10,11-dihydro-10-oxodibenzo [ b, f ] chipin-2-yl) propionic acid, a propionic acid anti-inflammatory analgesic agent, is improved compared to the conventional method. The process can be used to provide benzothiene derivatives of high purity and high yield. In addition, compared to the conventional method, it is judged to be an industrially useful invention technology because it does not use reagents that are highly toxic, and thus industrially can be safely produced in large quantities, and the manufacturing process is simple to shorten the production time.

Claims (14)

(Iii) reacting propiophenone of formula II with bromine to convert it to a haloketone compound of formula III; (Ii) reacting the haloketone compound of formula III with polyphosphoric acid in the presence of methanesulfonic acid or sulfuric acid and then crystallizing to form a cyclized haloketone compound of formula IV below; (Iii) reacting the cyclized haloketone compound of formula IV with C _1-6 alkylorthoformate to form cyclized haloacetal of formula V: (Iii) reacting the cyclized haloacetal of formula V with a zinc halide to form an ester compound of formula VI: And (Iii) preparing a dibenzothione derivative of formula I by hydrolyzing the ester compound of formula VI, wherein the dibenzothiene derivative of formula I is prepared.

Wherein X is bromine and R ₁ is C _1-6 alkyl. The propiophenone of formula II is reacted with bromine to convert to a haloketone compound of formula III, then the haketone compound of formula III is reacted with polyphosphoric acid in the presence of methanesulfonic acid or sulfuric acid, followed by crystallization. A process for preparing a cyclized haloketone compound of formula IV:

Wherein X is bromine. delete delete delete delete delete The method of claim 1, wherein the zinc halide is zinc chloride or zinc bromide. The process of claim 1, wherein an alcohol solvent is used in the step of hydrolyzing an ester compound of formula VI to produce a dibenzothiefine derivative of formula I:

10. The method of claim 9, wherein the alcohol solvent is an alcohol having an alkyl group having 1 to 6 carbon atoms. 10. The method of claim 9, wherein the alcohol solvent is methanol or isopropanol. The method of claim 9, wherein the reaction temperature during the hydrolysis is characterized in that 20 ~ 30 ℃. delete The process according to claim 1 or 2, wherein the crystallization is carried out in ethyl acetate, hexane or a mixed solvent thereof.