WO2020060011A1

WO2020060011A1 - Novel preparation method for citalopram and escitalopram using carbonates

Info

Publication number: WO2020060011A1
Application number: PCT/KR2019/008035
Authority: WO
Inventors: 이영근; 오영선; 김정진; 차영남; 오기범
Original assignee: (주)유케이케미팜
Priority date: 2018-09-17
Filing date: 2019-07-02
Publication date: 2020-03-26
Also published as: KR102134179B1; KR20200032281A

Abstract

The present invention relates to a method for preparing citalopram and escitalopram, and addition salts using same. In the preparation of citalopram and escitalopram, intermediate compounds are not separately obtained before a cyclization process, and 4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile represented by chemical formula 3 or (S)-(-)-4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrile represented by chemical formula 3a is cyclized using carbonate compounds without subsequent treatment processes, such as separation and concentration, of intermediate compounds, thereby preparing citalopram and escitalopram with high purity and high yield.

Description

New method for manufacturing citalopram and escitalopram using carbonate

The present invention is 1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofuran carbonitrile represented by the following Chemical Formula 1 having antidepressant activity S-enantiomers of (aka citalopram) and citalopram, i.e., (S)-(+)-1- [3- (dimethylamino) propyl] -1- (4-formula 1a) Fluorophenyl) -1,3-dihydro-5-isobenzofuran carbonitrile (aka escitalopram) and its acid addition salt are related to a process for preparing the salt.

The present invention provides a new method for preparing citalopram or escitalopram and salts thereof using various carbonate compounds.

Citalopram compounds are first disclosed in U.S. Patent No. 4,136,193, and escitalopram compounds are disclosed in U.S. Patent No. 4,943,590.

Escitalopram is the active component of the product citalopram, a racemic mixture of R- and S-enantiomers, and has antidepressant activity as an active serotonin (5-hydroxytryptamine; 5HT) reuptake inhibitor.

In U.S. Patent No. 4,650,884, racemic diols that undergo a cyclization reaction under the condition of sulfuric acid to form citalopram represented by the following Chemical Formula 1, namely, 4- [4- (dimethylamino) represented by the following Chemical Formula 3 The use of -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (hydroxymethyl) benzonitrile is disclosed (see Scheme 1 below).

U.S. Patent No. 4,943,590 describes Formula 3a as an enantiomer diol compound.

That is, using (S) -4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (hydroxymethyl) -benzonitrile Disclosed is the preparation of escitalopram, a compound of Formula 1a.

U.S. Patent No. 4,943,590 discloses a configuration for producing escitalopram by generating methanesulfonyl ester as an intermediate (Formula 6).

This intermediate is a decomposable derivative that is not separated in the presence of a base for removal of acid generated as a by-product, but is cyclized directly to form escitalopram, but when it is cyclized, it generates optical isomer impurities that have low optical purity. Causes (Scheme 2 below).

The prior art as described above cyclizes the diol under acidic conditions and high temperatures to obtain citalopram, or derivatizes with susceptible sulfonyl intermediates, etc., and undergoes a cyclization reaction in the presence of a base to remove by-product acids. Escitalopram is obtained.

The conventional method has the following problems when increasing the production scale for industrial use.

First, cyclization of diols at high temperatures under acidic conditions results in the formation of impurities.

The cyclization reaction in preparing escitalopram requires the use of a reactive compound of a good leaving group, such as methanesulfonyl chloride, which can produce dimers and thus lead to the formation of impurities. You can.

Second, for example, an organic base compound such as triethylamine and pyridine is used for removing the by-product acid, but it is not easy to completely remove after completion of the reaction and acts as a factor that prevents crystal formation when remaining.

Also, in the production process, recovery is difficult and economic efficiency is poor.

On the other hand, the enantiomer diol compound of formula 3a, namely (S) -4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- ( Hydroxymethyl) -benzonitrile is reacted with 2,5-dichloronitrobenzene represented by the following formula (8) in the presence of a base, a novel ether compound, ie 4- [4- (represented by the following formula (7) Escitalop by using dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (2-nitro-4-chlorophenoxymethyl) -benzonitrile The contents of producing lamb are disclosed in International Publication No. WO 20O6 / 021971 (Scheme 3 below).

According to International Publication No. WO 20O6 / 021971, in preparing an ether compound of Formula 7 using a compound of Formula 8, a long reaction time of 10 to 15 hours is required in the presence of a strong base such as a butoxide compound. In order to prepare the ether compound of 7 in high purity, an uneconomical method, such as involving column chromatography purification, has been used, and thus there is a limit in industrial application.

And Korean Patent Publication No. 10-2017-0048878 discloses a method for producing citalopram and escitalopram using a novel intermediate having the following formula.

In the above patent, an alkali or alkaline earth metal hydroxide, carbonate, bicarbonate, or amine base is used as a base used when converting the hydrochloric acid generated during intermediate formation and the acid addition salt generated during cyclization into a free base, and the intermediate It has the same problems as the prior art, such as the process of separating the.

The present invention, in order to solve the problems of the prior art, in the preparation of citalopram and escitalopram, the intermediate compound is not separately obtained before the cyclization reaction process, and is represented by the formula [4-] 4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (hydroxymethyl) benzonitrile, or (S) -4- represented by Formula 3a [4- (Dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (hydroxymethyl) -benzonitrile using a carbonate compound to separate an intermediate compound The present invention relates to a method of preparing citalopram and escitalopram of high purity and high yield by subjecting a cyclization reaction without subsequent treatment such as concentration, and using the same to prepare an addition salt.

The present invention is to provide a manufacturing method that is economical and capable of mass production by a significantly shorter process and reaction time than the prior art.

In order to solve the problems occurring in the above-mentioned prior art, the present inventors fundamentally prevent the formation of impurities generated during the cyclization process of the compounds of Formulas 3 and 3a, thereby eliminating the need to use a base and achieving the cyclization process in one step. After a long study of possible methods, it was possible to complete the present invention using a carbonate compound of Formula 4.

This is presumed to be because the carbonate compound of Formula 4, the methane, ethane, and benzene compounds produced by the reaction with the hydroxyl groups of Formulas 3 and 3a do not affect other side reactions in a stable state, and the resulting intermediate is The cyclization reaction proceeds rapidly to a transition state, and the by-products generated after the cyclization reaction are easily separated with sodium carbonate, thereby obtaining a high purity citalopram compound.

In the present invention, by reacting a compound of Formula 3a and a carbonate compound of Formula 4, the intermediate is cyclized in a one-step reaction without separation and purification to prepare a compound of Formula 1a and an acid addition salt therefrom. It relates to a method (see Scheme 4 below).

In addition, the present invention is 4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (hydroxymethyl) benzonitrile represented by Chemical Formula 3 As a starting material, it reacts with a carbonate compound to dramatically improve the method via an intermediate in the form of an ester and ether, which has a conventional disadvantage, and is very economical, high purity, and high yield of 1- [3- (dimethylamino) ) Propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofuran carbonitrile (Formula 1) is prepared, and a method for preparing a salt therefrom (Scheme 5 below) Reference).

In particular, by using a carbonate compound from Formula 3 or 3a, a cyclization process is performed in 1 step to prepare a compound of Formula 1, citalopram (Formula 1) or escitalopram (Formula 1a) in an economical process. can do.

The present invention is in the synthesis of a compound represented by Formula 1 or 1a, that is, citalopram or escitalopram, and after synthesizing a conventional ether compound, an ether compound is obtained as an intermediate and purified by separating it. While the two-step chemical reaction proceeds, the cyclization reaction is carried out in one step using a carbonate compound from Formula 3 or 3a, and the process of separating and purifying the intermediate is omitted and has only one step of chemical reaction. Alternatively, since the production process time is shortened because the compound of 1a can be obtained, this has an effect of manufacturing the compound of Formula 1 or 1a, that is, citalopram or escitalopram, at a lower production cost than the conventional one.

Hereinafter, the present invention will be described in more detail through examples.

By reacting the compound of Formula 3 or 3a with the compound of Formula 4 to cyclize, a compound of Formula 1 or 1a and an acid addition salt thereof are obtained.

Preferred examples of the carbonate compound of the present invention formula 4 are dimethyl carbonate, diethyl carbonate or diphenyl carbonate, and most preferably diphenyl carbonate.

The acid addition salt of the compound of Formula 1 is, for example, a salt form of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like, or an organic acid such as oxalic acid, citric acid, succinic acid, cinnamic acid, p-toluenesulfonic acid and the like.

The cyclization reaction can be carried out in any suitable solvent.

Examples of solvents that can be used are bipolar aprotic solvents such as dimethylsulfoxide, ether solvents such as dioxane, amide solvents such as dimethylformamide, dimethylacetamide, and nitrile solvents such as acetonitrile, preferably It is acetonitrile.

The reaction can be carried out in a suitable solvent at a temperature ranging from room temperature to the reflux temperature of the selected solvent.

For example, when the solvent is acetonitrile, the reaction temperature is 70 to 80 ° C.

As a base for the cyclization reaction, it is a compound containing a hydroxyl group such as sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, methoxide lithium, methoxide sodium, methoxide potassium or methoxide, ethoxide, and tert butoxide groups. Sodium methoxide is used.

The reaction time can be terminated in 4 to 78 hours, preferably 4 to 10 hours, depending on the solvent selected.

In the present invention, the compound of Formula 4 and the sodium methoxide in the compound of Formulas 3 and 3a are dimethyl sulfoxide, dioxane, dimethylformamide, dimethylacetamide, and acetonitrile. After refluxing and stirring for 4 to 78 hours within the reflux temperature range of the solvent, it is filtered and concentrated, and then ethyl acetate and purified water are injected and stirred to separate the layers.

The separated organic layer was concentrated under reduced pressure to obtain compounds of Formula 1 and 1a.

After dissolving the obtained compounds of Formula 1 and 1a in a solvent such as acetone or ethyl acetate, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or organic acids such as oxalic acid, citric acid, succinic acid, cinnamic acid, and p-toluenesulfonic acid The addition salts of the formulas 1 and 1a are prepared by adding the selected acid.

The above manufacturing method refers to the contents described in the prior art, and if it is a person skilled in the art, description thereof will be omitted since there is no difficulty in specifying the content, temperature and reaction time of the manufacturing process.

Conventional methods synthesize an ether compound from Formula 3 or 3a as an intermediate, while obtaining an ether compound, followed by a cyclization reaction, while the present invention proceeds directly to the cyclization reaction 1 step without separating the intermediate from Formula 3 or 3a. Thus, by forming citalopram or escitalopram, the manufacturing process is industrially simple, and the manufacturing time can be shortened and costs can be reduced.

Hereinafter, examples and comparative examples of the present invention (Public Patent No. 10-2017-0048878) will be described in detail for the present invention.

[Example 1]

Synthesis of 1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3 dihydro-5-isobenzofuran carbonitrile and hydrobromide salt (citalopram bromate)

50 mL of acetonitrile was added to 4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (hydroxymethyl) benzonitrile (11.8mmol). It was dissolved by injection, and diphenyl carbonate (47.2 mmol) and sodium methoxide (26 mmol) were added to the reaction mixture, followed by stirring at 74 ° C to 76 ° C for 8 hours.

After filtration and concentration, 50 ml of ethyl acetate and 100 ml of purified water were injected and stirred to separate the layers.

The separated organic layer was concentrated to obtain 3.3 g of citalopram.

After dissolving 3.3 g of the obtained citalopram by injecting 50 mL of acetone, 0.8 g of hydrogen bromide was injected to give (1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) in the form of a white powder. ) -1,3 dihydro-5-isobenzofuran carbonitrile 3.88 g of hydrobromide was obtained (overall yield: 81%, purity 99.6%).

[Example 2]

((S)-(+)-1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofuran carbonitrile and oxalate salt Synthetic (escitalopram oxalate)

To (S) -4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (hydroxymethyl) -benzonitrile (4.66mmol) Acetonitrile 50 mL was injected to dissolve, and diphenyl carbonate (14 mmol) and sodium methoxide (5.13 mmol) were added to the reaction mixture, followed by stirring at 79 ° C to 80 ° C for 4 hours.

After filtration and concentration, 100 ml of ethyl acetate and 50 ml of purified water were injected and stirred to separate the layers.

The separated organic layer was concentrated to obtain 2.72 g of escitalopram.

After dissolving 100 mL of ethyl acetate in 2.72 g of the obtained escitalopram, dissolving it, inject 1.2 g of oxalic acid dihydrate, refluxing for 3 hours, stirring and cooling to room temperature, followed by filtration to form a white-white powder (S) -4- 3.02 g of [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (4-nitrobenzoyloxymethyl) -benzonitrile oxalate was obtained ( overall yield 82.4%, purity 99.87%).

[Example 3]

((S)-(+)-1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofuran carbonitrile and oxalate salt synthesis

To (S) -4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (hydroxymethyl) -benzonitrile (4.66 mmol) 50 mL of acetonitrile was injected to dissolve, and diphenyl carbonate (14 mmol) and sodium hydroxide (5.13 mmol) were added to the reaction mixture, followed by stirring at 79 ° C to 80 ° C for 4 hours.

The separated organic layer was concentrated to obtain 2.85 g of escitalopram.

After dissolving 50 mL of ethyl acetate in 2.85 g of the obtained escitalopram, and dissolving it, 1.2 g of oxalic acid dihydrate was injected to give (S) -4- [4- (dimethylamino) -1- (4) in the form of a white powder. -Fluorophenyl) -1-hydroxy-1-butyl] -3- (4-nitrobenzoyloxymethyl) -benzonitrile 2.87 g of oxalate was obtained (overall yield: 76%, purity 99.1%).

[Comparative example]

S) Synthesis of-(+)-1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofuran carbonitrile and oxalate salt ( S)-(-)-4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (hydroxymethyl) -benzonitrile (186.71 mmol) was dissolved by injecting 400 mL of methylene chloride, and 65 mL of triethylamine was injected.

A mixture of 4-nitrobenzoyl chloride (224.05 mmol) and methylene chloride (100 mL) was slowly injected into the reaction mixture at 30 ° C. or lower, followed by stirring at room temperature for 2 hours.

600 mL of sodium hydrogen carbonate aqueous solution was injected into the reaction mixture, followed by stirring to separate the layers.

After concentrating the separated organic layer, 400 mL of acetone is injected to dissolve it, cooled, and 35% hydrochloric acid is injected to form (S) -4- [4- (dimethylamino) -1- (4-fluoro) as a white-white powder. Hydrochloride (intermediate) of phenyl) -1-hydroxy-1-butyl] -3- (4-nitrobenzoyloxymethyl) -benzonitrile was obtained (yield: 91%).

(S) -4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (4-nitrobenzoyloxymethyl) -benzonitrile obtained Into hydrochloride (164.78 mmol), 445 mL of ethyl acetate and 890 mL of aqueous sodium hydrogen carbonate solution were added and stirred to separate the layers.

After concentrating the separated organic layer, 250 mL of dimethyl sulfoxide was injected to dissolve it, and the temperature was raised to 90 ° C.

48.93 g of potassium carbonate was added to the reaction mixture, followed by stirring at 100 ° C for 2 hours.

After the reaction was cooled to 20 ° C., 330 mL of ethyl acetate and 745 mL of sodium hydroxide aqueous solution were injected and stirred to separate the layers, and the separated organic layers were combined, washed with brine, and concentrated to S)-(+)-1- [3- (Dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofuran carbonitrile was obtained.

The obtained S)-(+)-1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofuran carbonitrile concentrated residue oxalic acid (S)-(+)-1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbo in the form of an off-white powder. Nitrile oxalate was obtained (yield: 82%, overall yield: 74.6%).

As described above, the comparative example, which is a conventional technique, undergoes a three-step process by preparing an intermediate, preparing escitalopram, and preparing a salt thereof, so that the intermediate synthesis yield from the starting material is 91%, and the target yield from the intermediate. Since the final yield (overall yield) of this 82% is 74.6%, it can be seen that the process is longer and the yield is lower than the present invention, and the present invention can economically produce superior quality citalopram or escitalopram. It is.

Preparation of the compound of Formula 1 or 1a and a salt thereof according to an embodiment of the present invention can be cyclized in one step without separation of an intermediate compared to the comparative example to produce Formula 1, 1a and an acid addition salt thereof, and the final yield (overall yield) Also, according to the simplification of the process, a compound of Formula 1 or 1a, that is, citalopram or escitalopram and its acid addition salt can be economically prepared at a lower manufacturing cost than the existing technology.

On the other hand, the present invention has been described with reference to examples, but this is only exemplary, and those skilled in the art will understand that various modifications and equivalent examples are possible therefrom. The true scope of technical protection should be defined by the appended claims.

Claims

In the method for producing citalopram and S-enantiomer escitalopram and salts thereof,

4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (hydroxymethyl) benzonitrile of the following Chemical Formula 3, or ( S)-(-)-4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (hydroxymethyl) -benzonitrile compound, By reacting the carbonate compound of 4 and the presence of a solvent and a base, the compound of Formula 3 or 3a is cyclized without the process of separating the intermediate to prepare the following Formula 1 or 1a compound, and the compound of Formula 1 or 1a is concentrated under reduced pressure. After the addition of an acid to this, characterized in that to prepare a salt Formula 1 or 1a compound and a method for producing an acid addition salt thereof:

Where X is selected from methyl, ethyl and phenyl.
According to claim 1,

A compound of Formula 4, wherein the compound of Formula 1 is diphenyl carbonate, or a method for preparing an acid addition salt thereof.
According to claim 1,

A method of preparing a compound of Formula 1 or 1a and an acid addition salt thereof, wherein the solvent is at least one selected from dimethyl sulfoxide, dioxane, dimethylformamide, dimethylacetamide and acetonitrile.
According to claim 1,

Formula 1 or 1a, characterized in that the base is a compound containing a hydroxyl group or a methoxide, ethoxide, or tert butoxide group such as sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, methoxide lithium, methoxide sodium, methoxide potassium, etc. Method for preparing compounds and acid addition salts thereof.
According to claim 1,

A compound represented by Formula 1 or 1a, wherein the acid is any one selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or oxalic acid, citric acid, succinic acid, cinnamic acid, and p-toluenesulfonic acid, and a method for preparing an acid addition salt thereof.