WO2017023123A1

WO2017023123A1 - Novel method for preparing chromanone derivative

Info

Publication number: WO2017023123A1
Application number: PCT/KR2016/008579
Authority: WO
Inventors: 김은선; 고동현; 권재홍; 김영주; 이성아; 최광도; 허승평; 이지윤
Original assignee: 씨제이헬스케어 주식회사
Priority date: 2015-08-04
Filing date: 2016-08-03
Publication date: 2017-02-09
Also published as: CN107848943A; KR20170016754A; JP2020097607A; JP2018523662A; JP6948419B2; JP2020180134A; JP6770057B2

Abstract

The present invention relates to a novel method for preparing a 5,7-difluorochroman-4-one derivative. The preparation method according to the present invention allows industrial mass production by using a generally usable reagent and solvent requiring no separate refinement process, having low production costs, and being under no environmental regulation and thus allows a 5,7-difluorochroman-4-one derivative to be efficiently produced.

Description

Novel Method for Preparing Chromanone Derivatives

This specification claims the benefit of the filing date of Korean Patent Application No. 10-2015-0110245 filed with the Korea Intellectual Property Office on August 4, 2015, the entire contents of which are incorporated herein.

The present invention relates to a novel process for the preparation of 5,7-difluorochroman-4-one derivatives.

Chromanone derivatives are substances that are used in medicine and chemistry in a variety of ways, such as the substance itself, or material synthesis process. However, despite the importance of chromanone derivatives, many methods for easily synthesizing them have not been reported.

International publication WO 2009/156072 describes a method for preparing 5,7-difluorochroman-4-one using 3,5-difluorophenol as starting material. In this patent, O-alkylation of 3,5-difluorophenol and 3-chloro-1-propanol is carried out, followed by oxidation using chromium (VI) as a reagent, and finally oxalyl chloride. And a method of producing 5.7-difluorochroman-4-one in a total 60% yield by carrying out a cyclization reaction with and aluminum trichloride as a reagent.

However, the production method described in the above patent requires column chromatography purification on silica gel at each step, which is not suitable for industrial mass synthesis processes. In addition, in the process of preparing 3- (3,5-difluorophenoxy) propanoic acid through an oxidation reaction using a chromium oxide (VI) reagent, heavy metal oxidant chromium oxide (VI) is used. This process is very inadequate for mass production. In addition, the solvent used in the reaction has a problem that additional cost due to waste liquid treatment after the reaction about 150 times compared to the starting material. That is, according to the method described in WO 2009/156072, there is a problem of using heavy metals with high manufacturing costs and severe environmental regulations, which is not a suitable process for mass production.

In addition, a process for producing 5,7-difluorochroman-4-one using 3,5-difluorophenol and acrylonitrile as starting materials is described in International Publication WO 2005/016896. The patent carried out a Michael reaction with 3,5-difluorophenol and acrylonitrile to prepare 3- (3,5-difluorophenoxy) propionitrile in a yield of 35%. Next, hydrolysis was carried out with concentrated hydrochloric acid to prepare 3- (3,5-difluorophenoxy) propionic acid in a yield of 76%, and finally cyclized with thionyl chloride to give 5,7-di Fluorochroman-4-one was prepared in a yield of 73%. However, the process described in this patent is also purified by column chromatography on silica gel and is generally not suitable for industrial mass synthesis processes. In addition, there is a problem that can not be applied to the actual production because it requires a process to cool to -65 in the last process.

As a result, 5,7-difluoro, a drug-specific molecular group that is very important in the pharmaceutical and chemical industries that can be industrially mass-produced and environmentally regulated, using low production costs and commercially available reagents and solvents There is a need for a new manufacturing method for mass production of chromoman-4-one.

[Preceding technical literature]

[Patent Documents]

International Publication No. 2009/156072

International Publication No. 2005/016896

The present invention does not require a separate purification process, has a low manufacturing cost, and can be industrially mass-produced using commercially available reagents and solvents. Provided is a method for preparing a man-4-one derivative.

The present invention

Preparing a compound represented by formula (II) from a compound represented by formula (I); And

It provides a process for the preparation of a compound represented by the formula (III) comprising the step of preparing a compound represented by the formula (III) by cyclizing the compound represented by the formula (II):

[Formula I]

[Formula II]

[Formula III]

The preparation method of the present invention does not require a separate purification process, has a low manufacturing cost, and uses 5,7-difluorochroman-4-one derivatives using commercially available reagents and solvents that are not regulated by the environment. Can mass produce effectively.

The present invention

Preparing a compound represented by Chemical Formula V by reacting the compound represented by Chemical Formula I with the compound represented by Chemical Formula IV; And

Reaction of the compound represented by the formula (II) comprising the step of reacting the compound represented by the formula (V) with 2-iodobenzoic acid and potassium peroxymonosulfate (Potassium peroxymonosulfate) It provides a manufacturing method.

[Formula IV]

[Formula Ⅴ]

In Chemical Formula IV,

X may be selected from fluoro, chlorine or iodine with halogen atoms.

In a first step of preparing a compound represented by Formula V by reacting the compound represented by Formula I with the compound represented by Formula IV, the reaction is an O-alkylation reaction.

The O-alkylation reaction may be used alone or mixed with tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) as an organic solvent. Dimethylformamide can be preferably used.

In addition, as the base used in the O-alkylation reaction, potassium hydride, sodium hydride, lithium hydride, potassium t-butoxide or the like can be used, and preferably sodium hydride can be used.

The compound and base represented by the formula (I) under the organic solvent are stirred at 10 ° C. or lower, preferably 0 ° C. to 10 ° C., and then mixed with the compound represented by the formula to perform an O-alkylation reaction at 60 ° C. to 90 ° C. Can be.

In the compound represented by the above formula (IV), X is preferably chlorine.

In a second step of preparing a compound represented by Chemical Formula II by reacting 2-iodobenzoic acid and potassium peroxymonosulfate with potassium peroxymonosulfate, the reaction is a polar solvent, such as Water, methanol, acetonitrile or mixed solvents thereof are used.

The compound represented by the formula under a polar solvent may be reacted with 2-Iodobenzoic acid and potassium peroxymonosulfate at 60 ° C to 90 ° C.

Unlike the known reactions, the reaction is mass-produced by using 2-iodobenzoic acid and potassium peroxymonosulfate, which are generally available without risk, and are not regulatory reagents due to environmental pollution. It is suitable for the process and shows high production yield.

The present invention

Reacting a compound represented by the formula (I) with acrylonitrile under a base to prepare a compound represented by the following formula (VI); And

A second step of preparing a compound represented by formula II by hydrolyzing the compound represented by formula VI;

Provided is a method for preparing a compound represented by Formula II, wherein the base of the first step is copper hydroxide.

[Formula VI]

In the first step of preparing a chemical compound by reacting the compound represented by the formula (I) with acrylonitrile using copper hydroxide as a base, the reaction using copper hydroxide as a base in the Michael addition reaction (Michael addition reaction) The reaction is carried out. By using copper hydroxide in the Michael addition reaction, the present reaction can greatly improve the reaction yield compared to using other base sources.

Preparation of the compound represented by the formula (VI) is preferably carried out at 75 ℃ to 85 ℃.

In the second step of preparing a compound represented by the formula (II) by hydrolysis of the compound represented by the formula (VI), the compound represented by the formula (VI) is synthesized by hydrolysis in the presence of an acid or a base. The acid may be selected from sulfuric acid, hydrochloric acid or phosphoric acid, preferably the acid is sulfuric acid. The base may be selected from sodium hydroxide or potassium hydroxide, preferably the base is sodium hydroxide.

The step of preparing the compound represented by Formula (II) is preferably performed at 40 ° C. to 60 ° C. under acidic conditions, and under reflux under basic conditions.

The present invention

A first step of preparing a compound represented by Formula V by reacting the compound represented by Formula I with the compound represented by Formula IV;

A second step of preparing a compound of Formula II by reacting 2-iodobenzoic acid with potassium peroxymonosulfate with 2-Iodobenzoic acid; And

Provided is a method for preparing a compound represented by the formula (III) comprising a third step of preparing a compound represented by the formula (III) by cyclizing the compound represented by the formula (II).

In the above production process, the two preceding steps are as described above.

In the third step of preparing a compound represented by Formula III by cyclizing the compound represented by Formula II, the cyclization reaction may be performed under acidic conditions.

The acid may be selected from sulfuric acid, hydrochloric acid or phosphoric acid, preferably sulfuric acid. The reaction in the presence of an acid is preferably reacted at 40 ° C to 60 ° C.

The present invention

A first step of preparing a compound of formula by reacting a compound of formula (I) with acrylonitrile under a base;

A second step of preparing a compound represented by Chemical Formula II by hydrolyzing the compound represented by Chemical Formula VI; And

And a third step of preparing a compound represented by Chemical Formula III by cyclizing the compound represented by Chemical Formula II,

Provided is a method for preparing a compound represented by Formula III, wherein the base of the first step is copper hydroxide.

Reaction conditions may be applied to the content of the third step of preparing a compound represented by the formula (III) by cyclizing the compound represented by the formula (II) described above. The reaction from formula (VI) to formula (III) may be carried out in an in-situ reaction.

For example, the method for preparing a compound represented by Formula III according to the present invention may be represented by the following Scheme I.

Scheme I

As in the above formula, the preparation of the compound represented by the formula (I) to the compound represented by the formula (II) is treated with the compound represented by the formula (IV) to the compound represented by the formula (I) after the O-alkylation reaction to 2-benzoic iodide ( 2-Iodobenzoic acid) and potassium peroxymonosulfate (Potassium peroxymonosulfate) may be treated to synthesize the compound represented by Formula II, or may be prepared by hydrolysis after performing a reaction with acrylonitrile.

Preparation of the compound represented by the formula (III) from the compound represented by the formula (II) can be prepared by adding a compound represented by the formula (II) in the presence of an acid, and then carrying out a cyclization reaction.

The method for preparing a compound represented by Formula (II) according to the present invention may be represented by the following Scheme -1.

Scheme II-1

As in Scheme II-1, a compound represented by Formula V is prepared by reacting a compound represented by Formula I with sodium hydride under dimethylformamide, and performing an O-alkylation reaction with a compound of Formula IV. The compound represented by the formula (V) is reacted with 2-iodic benzoic acid and potassium peroxymonosulfate to prepare the compound represented by the formula (II).

The method for preparing a compound represented by Formula II according to the present invention may be represented by the following Scheme II-2.

[Scheme II-2]

As in Scheme II-2, acrylonitrile is reacted under copper hydroxide to prepare a compound of formula VI, and hydrolysis is performed through acid treatment to prepare a compound represented by formula II.

The preparation method of the compound represented by the formula (III) according to the present invention may be preferably represented by the following reaction scheme (I-1).

Scheme I-1

As in Scheme I-1, a compound represented by Formula V is prepared by reacting a compound represented by Formula I with sodium hydride under dimethylformamide, and performing an O-alkylation reaction with a compound of Formula IV. The compound represented by formula (V) is reacted with 2-iodic benzoic acid and potassium peroxymonosulfate to prepare the compound represented by formula (II), and then the sulfuric acid is treated to prepare a compound represented by formula (III) through a cyclization reaction. do.

The preparation method of the compound represented by the formula (III) according to the present invention may be preferably represented by the following reaction scheme (I-2).

Scheme I-2

As in Scheme I-2, acrylonitrile is reacted under copper hydroxide to prepare a compound of formula VI, and hydrolysis is performed through acid treatment, followed by a cyclization reaction to prepare a compound of formula III. Here, the sulfuric acid treatment reaction may be carried out in the In-situ reaction.

The preparation method of the present invention does not require a separate purification process, has a low manufacturing cost, and effectively utilizes 5,7-difluorochroman-4-one using commercially available reagents and solvents that are not regulated by the environment. Can be mass produced industrially.

Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, the following Examples and Experimental Examples are provided to illustrate the present invention, and the scope of the present invention is not limited by these Examples and Experimental Examples.

The reagents and solvents mentioned below were purchased from Sigma Aldrich unless otherwise noted, and ¹ H-NMR was measured by Bruker NMR 400 MHz.

실시예 1: 3-(3,5-디플루오로페녹시)프로판-1-올의 제조Example 1: Preparation of 3- (3,5-difluorophenoxy) propan-1-ol

36 kg of sodium hydride and 439 kg of dimethylformamide were added to the reactor, and the mixture was cooled to 0 ° C. Separately, 116 kg of 3,5-difluorophenol was dissolved in 165 kg of dimethylformamide, and added dropwise to the reactor at 5 ° C. or lower, followed by stirring. In addition, 108 kg of 3-chloro-1-propanol was dissolved in 165 kg of dimethylformamide, added dropwise to the reactor, and the reaction was heated to 80 ° C. After the reaction was completed, the reaction mixture was cooled to 20 ° C, and 839 kg of diisopropyl ether and 530 kg of purified water were added thereto. Then 48 kg of concentrated hydrochloric acid was added dropwise and stirred. After separation of the layers, 5% aqueous sodium hydroxide solution (29 kg of sodium hydroxide + 579 kg of purified water) was added to the organic layer, followed by stirring. The organic layer was separated and concentrated in vacuo at 40 ° C. to give 3- (3,5-difluorophenoxy). Propan-1-ol (167 kg, 100%, in-situ) was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.84 (quint, 2H), 3.54 (dd, 2H), 4.06 (t, 2H), 4.57 (t, 1H)

실시예Example 2: 32: 3 -(3,5--(3,5- 디플루오로페녹시Difluorophenoxy )) 프로파노익Propanoic 산의 제조 Manufacture of acid

167 kg of 3- (3,5-difluorophenoxy) propan-1-ol, 882 kg of acetonitrile and 552 kg of purified water were added to the reactor, followed by stirring. 11 kg of 2-iodic benzoic acid and potassium peroxymonosulfate were added. 227 kg were added and stirred at 80 ° C. After the reaction was completed, the mixture was cooled to 5 ° C. or lower, and 1201 kg of ethyl acetate and 1339 kg of purified water were added and stirred. The precipitated solid was filtered and washed with 300 kg of ethyl acetate and 335 kg of purified water. The filtrate was concentrated in vacuo at 40 ° C, 569 kg of heptanes were added, cooled to 20 ° C and stirred. After filtration, vacuum drying at 40 ° C. yielded 3- (3,5-difluorophenoxy) propanoic acid (142 kg, 79%).

¹ H-NMR (400 MHz, DMSO-d ₆ ): delta = 2.69 (t, 2H), 4.19 (t, 2H), 6.68-6.81 (m, 3H), 12.4 (s, 1H)

실시예 3: 5,7-디플루오로크로만-4-온의 제조Example 3: Preparation of 5,7-difluorochroman-4-one

345 kg of concentrated sulfuric acid was added to Reactor A, cooled to 10 ° C, and 142 kg of 3- (3,5-difluorophenoxy) propanoic acid was added dropwise. After stirring at 50 ° C., the reaction was cooled to 20 ° C. after completion of the reaction. 1421 kg of purified water was added to Reactor B, and it cooled to 0 degreeC. The reactant of Reactor A was slowly added dropwise to Reactor B while maintaining below 10 ° C., 1890 kg of dichloromethane was added and stirred. After separating the organic layer, 1421 kg of purified water was added and 5% aqueous sodium carbonate solution (sodium carbonate 14 kg + 284 kg purified water) to pH 7.5. The organic layer was separated, concentrated in vacuo at 40 ° C, and 483 kg of heptane was added and stirred. Vacuum drying at 40 ° C. after filtration gave 5,7-difluorochroman-4-one (109 kg, 84%).

¹ H-NMR (400 MHz, DMSO-d ₆ ): delta = 2.77 (t, 2H), 4.57 (t, 2H), 6.81-6.95 (m, 2H)

실시예 4: 3-(3,5-디플루오로페녹시)프로판니트릴의 제조Example 4: Preparation of 3- (3,5-difluorophenoxy) propanenitrile

13 kg of 3,5-difluorophenol and 21 kg of acrylonitrile were added to the reactor, followed by stirring. 5 kg of copper hydroxide was added thereto, and the mixture was refluxed at 80 ° C. for 48 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated at 50 ° C. 100 L of dichloromethane and 50 L of purified water were added and stirred. 50 L of purified water was added to the organic layer, followed by stirring to separate the organic layer. Thereafter, the mixture was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to yield 3- (3,5-difluorophenoxy) propanenitrile (11 kg, 60%).

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 2.87 (t, 2H), 4.19 (t, 2H), 6.44-7.54 (m, 3H)

실시예 5: 5,7-디플루오로크로만-4-온의 제조Example 5: Preparation of 5,7-difluorochroman-4-one

30 kg of concentrated sulfuric acid was added to Reactor A. 11 kg of 3- (3,5-difluorophenoxy) propanenitrile was added at 10-20 degreeC, it heated up at 50 degreeC, and stirred. After the reaction was completed, the reaction mixture was cooled to room temperature. 100 L of purified water was added to Reactor B, and it cooled to 0 degreeC. The reaction of Reactor A was introduced into Reactor B. 110 L of dichloromethane was added thereto, and the pH was adjusted to 7 using 5% aqueous sodium carbonate solution. After stirring, the organic layer was separated. After concentrating under reduced pressure, 55 L of heptane was added thereto, stirred, and filtered. The resultant was dried under vacuum at 40 ° C. to obtain 5,7-difluorochroman-4-one (9 kg, 80%).

¹ H-NMR (400 MHz, CDCl ₃ ): delta = 2.81 (t, 2H), 4.55 (t, 2H), 6.44-6.53 (m, 2H)

Claims

A first step of preparing a compound represented by the formula (V) by reacting a compound represented by the formula (I) and a compound represented by the formula (IV); And

A compound represented by formula (II) comprising a second step of preparing a compound of formula (II) by reacting a compound represented by formula (V) with 2-iodobenzoic acid and potassium peroxymonosulfate Manufacturing method:

[Formula I]

[Formula II]

[Formula IV]

[Formula Ⅴ]

In formula (IV), X may be selected from fluoro, chlorine or iodine as the halogen atom.
The method of claim 1, wherein X is chlorine.
The O-alkylation according to claim 1, wherein the reaction in the first step of reacting the compound represented by Chemical Formula I with the compound represented by Chemical Formula IV to produce the compound represented by Chemical Formula V is performed under a base. A method for producing a compound represented by the formula (II) which is a reaction.
The method of claim 3, wherein the base is any one selected from potassium hydride, sodium hydride, lithium hydride or potassium t-butoxide.
According to claim 1, wherein the second step of reacting the compound represented by Formula V with 2-Iodobenzoic acid and potassium peroxymonosulfate (Potassium peroxymonosulfate) is carried out under a polar organic solvent The manufacturing method of the compound represented by II.
The method of claim 5, wherein the polar solvent is water, methanol, acetonitrile, or a mixture thereof.
A first step of preparing a compound represented by the following Chemical Formula VI by reacting a compound represented by the following Chemical Formula I with acrylonitrile under a base; And

A second step of preparing a compound represented by Chemical Formula II by hydrolyzing the compound represented by Chemical Formula VI,

Method for preparing a compound represented by the formula (II) wherein the base of the first step is copper hydroxide:

[Formula I]

[Formula II]

[Formula VI]

.
The process for preparing a compound represented by the formula (II) according to claim 7, wherein the second step of preparing the compound represented by the formula (II) by hydrolysis of the compound represented by the formula (VI) is performed in the presence of an acid.
The method of claim 8, wherein the acid is any one selected from sulfuric acid, hydrochloric acid, or phosphoric acid.
A first step of preparing a compound represented by the following Chemical Formula by reacting a compound represented by the following Chemical Formula with a compound represented by the following Chemical Formula;

A second step of preparing a compound of formula by reacting 2-iodobenzoic acid and potassium peroxymonosulfate with 2-iodobenzoic acid; And

Method for preparing a compound represented by the formula comprising a third step of preparing a compound represented by the formula by the cyclization reaction of the compound represented by the formula:

[Formula I]

[Formula II]

[Formula III]

[Formula IV]

[Formula Ⅴ]

In formula (IV), X may be selected from fluoro, chlorine or iodine as the halogen atom.
The method of claim 10, wherein X is chlorine.
The O-alkylation reaction according to claim 10, wherein the reaction in the first step of reacting the compound represented by Formula (I) with the compound represented by Formula (IV) to prepare the compound represented by Formula (V) is performed under a base. Process for producing a compound represented by the formula (III).
13. The method of claim 12, wherein the base is any one selected from potassium hydride, sodium hydride, lithium hydride or potassium t-butoxide.
The method of claim 10, wherein the second step of reacting the compound represented by the formula with 2-iodobenzoic acid and potassium peroxymonosulfate is performed under a polar organic solvent. Method for producing a compound represented by.
15. The method of claim 14, wherein the polar solvent is water, methanol, acetonitrile or a mixture thereof.
The process for preparing a compound represented by formula (III) according to claim 10, wherein the third step of preparing a compound represented by formula (III) by cyclizing the compound represented by formula (II) is performed under acidic conditions.
The method of claim 16, wherein the acid is any one selected from sulfuric acid, hydrochloric acid, or phosphoric acid.
A first step of preparing a compound of formula (VI) by reacting a compound represented by formula (I) with acrylonitrile under a base;

A second step of preparing a compound represented by Chemical Formula II by hydrolyzing the compound represented by Chemical Formula VI; And

And a third step of preparing a compound represented by Chemical Formula III by cyclizing the compound represented by Chemical Formula II,

Method for preparing a compound of Formula III wherein the base of the first step is copper hydroxide:

[Formula I]

[Formula II]

[Formula III]

[Formula VI]

.
19. The method of claim 18, wherein the second step of preparing a compound represented by Formula II by hydrolyzing the compound represented by Formula VI is carried out in the presence of an acid.
20. The method of claim 19, wherein the acid is any one selected from sulfuric acid, hydrochloric acid or phosphoric acid.
19. The process for preparing the compound represented by the formula (III) according to claim 18, wherein the third step of preparing a compound represented by the formula (III) by cyclizing the compound represented by the formula (II) is performed under acidic conditions.
The method of claim 21, wherein the acid is any one selected from sulfuric acid, hydrochloric acid or phosphoric acid.