Method for preparing chromanone derivatives

Abstract

The present invention relates to a novel method for preparing 5,7-difluorochroman-4-one derivatives. The preparation method of the present invention uses commonly available reagents and solvents, does not require a separation or purification process, has low industrial costs, is free of environmental regulations, and is suitable for industrial large-scale production. Therefore, it can be used for the efficient preparation of 5,7-difluorochroman-4-one derivatives.

Description

[0001] This application claims the benefit of Korean Patent Application No. 10-2015-0110245 filed on August 4, 2015, in the Korean Intellectual Property Office, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0002] The present invention relates to a novel method for preparing 5,7-difluorochroman-4-one derivatives. Background Art

[0003] Chromanone derivatives have a variety of applications in the pharmaceutical and chemical fields, either by themselves or as raw materials for synthesis processes. However, despite their importance in many fields, a simple and feasible method for preparing chromanone derivatives has not yet been reported.

[0004] International Publication WO 2009 / 156072 describes a method for preparing 5,7-difluorochroman-4-one using 3,5-difluorophenol as a starting material. This patent describes a method for preparing 5,7-difluorochroman-4-one with a 60% overall yield. The method involves an O-alkylation reaction of 3,5-difluorophenol with 3-chloro-1-propanol, followed by oxidation with chromium(VI) oxide, and finally a ring-closure reaction using oxalyl chloride and aluminum chloride.

[0005] However, each step in the preparation method described in the aforementioned patent requires silica gel column chromatography separation and purification, making it unsuitable for industrial mass production. Furthermore, the oxidation of 3-(3,5-difluorophenoxy)propionic acid with chromium (VI) oxide is not suitable for large-scale production because the chromium (VI) oxide used is a heavy metal oxidant subject to strict environmental regulations. Furthermore, the amount of solvent used in the above reaction is 150 times that of the starting material, which also leads to expensive subsequent waste liquid treatment costs. In other words, due to the increased preparation costs and the heavy metal issues that are strictly regulated by environmental regulations, the method disclosed in WO 2009 / 156072 is not suitable for large-scale production.

[0006] Furthermore, International Publication WO 2005 / 016896 describes a method for preparing 5,7-difluorochroman-4-one using 3,5-difluorophenol and acrylonitrile as starting materials. In this patent, 3,5-difluorophenol and acrylonitrile undergo a Michael reaction to produce 3-(3,5-difluorophenoxy)propionitrile in a 35% yield. This addition product is hydrolyzed in concentrated hydrochloric acid to yield 3-(3,5-difluorophenoxy)propionic acid in a 76% yield. This hydrolysis product is then cyclized in the presence of thionyl chloride to yield 5,7-difluorochroman-4-one in a 73% yield. However, the method described in this patent requires silica gel column chromatography for separation and purification, making it unsuitable for conventional large-scale industrial production. Furthermore, the final reaction step requires cooling to -65°C, which limits its practical industrial application.

[0007] In this context, as an important pharmacophore in the pharmaceutical and chemical fields, it is necessary to research and develop a novel batch preparation method for 5,7-difluorochroman-4-one with low production cost and using commonly available reagents and solvents, so as to facilitate its industrial large-scale production and be environmentally friendly.

[0008] [Prior art]

[0009] [Patent Document]

[0010] WO 2009 / 156072

[0011] WO 2005 / 016896 Summary of the Invention

[0012] Technical issues

[0013] The present invention provides a method for preparing an excellent 5,7-difluorochroman-4-one derivative, which avoids additional purification process, has low industrial cost, and uses conventional reagents and solvents, thus being environmentally friendly and suitable for industrial production.

[0014] Technical Solution

[0015] The present invention provides a method for preparing a compound as shown in Formula III, which comprises the following steps:

[0016] Prepare the compound shown in formula II by using the compound shown in formula I; and

[0017] The compound of formula III is prepared by cyclizing the compound of formula II:

[0018] [Formula I]

[0019]

[0020] [Formula II]

[0021]

[0022] [Formula III]

[0023]

[0024] The preparation method of the present invention not only has the advantages of avoiding the purification process, low industrial cost, conventionally available reagents and solvents, and being environmentally friendly, but also is highly efficient and suitable for industrial production.

[0025] The present invention provides a method for preparing a compound as shown in Formula II, comprising the following steps:

[0026] The compound of formula V is prepared by reacting the compound of formula I with the compound of formula IV; and

[0027] The compound shown in Formula II is prepared by reacting the compound shown in Formula V with 2-iodobenzoic acid and potassium peroxymonosulfate:

[0028] [Formula IV]

[0029]

[0030] [Formula V]

[0031]

[0032] In the compound of formula IV, X may be a halogen selected from F, Cl or I.

[0033] In the step 1 of preparing the compound of formula V by reacting the compound of formula I with the compound of formula IV, the reaction is an O-alkylation reaction.

[0034] In the O-alkylation reaction, tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), etc., alone or in mixtures thereof, can be used as the organic solvent, preferably N,N-dimethylformamide.

[0035] In addition, the O-alkylation reaction can use potassium hydride, sodium hydride, lithium hydride, potassium tert-butoxide, etc. as a base, preferably sodium hydride.

[0036] In the presence of the above organic solvent, the compound represented by formula I and the base can be stirred below 10°C, preferably 0-10°C, and then mixed with the compound represented by formula VI to carry out O-alkylation reaction at 60-90°C.

[0037] In the compound represented by formula IV, X is preferably Cl.

[0038] In step 2 of preparing the compound of formula II by reacting the compound of formula V with 2-iodobenzoic acid and potassium peroxymonosulfate, the reaction is carried out in a polar solvent, such as water, methanol, acetonitrile or a mixed solvent thereof.

[0039] In the presence of a polar solvent, the compound represented by formula V can be reacted with 2-iodobenzoic acid and potassium peroxymonosulfate at 60-90°C.

[0040] Unlike known reactions, the above reaction uses 2-iodobenzoic acid and potassium peroxymonosulfate, which does not have regulatory issues caused by environmental pollution and does not have feeding hazards. Therefore, the reaction is suitable for large-scale production processes and has a high production yield.

[0041] The present invention provides a method for preparing a compound as shown in Formula II, comprising the following steps:

[0042] Step 1: preparing a compound represented by Formula VI by reacting a compound represented by Formula I with acrylonitrile in the presence of a base; and

[0043] Step 2: Prepare the compound shown in Formula II by hydrolyzing the compound shown in Formula VI:

[0044] [Formula VI]

[0045]

[0046] Wherein, the alkali described in step 1 is copper hydroxide.

[0047] In step 1 of preparing the compound of Formula VI by reacting the compound of Formula I with acrylonitrile in the presence of copper hydroxide as a base, the reaction is a Michael addition reaction using copper hydroxide as a base. In the present invention, using copper hydroxide as a base in this Michael addition reaction significantly improves the reaction yield compared to using other bases.

[0048] The step of preparing the compound of formula VI is preferably carried out at 75-85°C.

[0049] In step 2 of preparing the compound of Formula II by hydrolyzing the compound of Formula VI, the compound of Formula II is synthesized by hydrolysis in the presence of an acid or a base. The acid can be selected from sulfuric acid, hydrochloric acid, or phosphoric acid, preferably sulfuric acid. The base can be selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.

[0050] The step of preparing the compound represented by formula II is preferably carried out at 40-60° C. in the presence of an acid, and is preferably carried out under reflux conditions in the presence of a base.

[0051] The present invention provides a method for preparing a compound as shown in Formula III, which comprises the following steps:

[0052] Step 1: preparing a compound represented by Formula V by reacting a compound represented by Formula I with a compound represented by Formula IV;

[0053] Step 2: preparing a compound of Formula II by reacting a compound of Formula V with 2-iodobenzoic acid and potassium peroxymonosulfate; and

[0054] Step 3: Prepare the compound represented by Formula III by subjecting the compound represented by Formula II to a ring-closure reaction.

[0055] In the method, step 1 and step 2 are as described above.

[0056] In step 3 of subjecting the compound of Formula II to a ring-closure reaction to prepare the compound of Formula III, the ring-closure reaction can be carried out in the presence of an acid. The acid can be selected from sulfuric acid, hydrochloric acid, or phosphoric acid, preferably sulfuric acid. The reaction in the presence of an acid is preferably carried out at a temperature of 40-60°C.

[0057] The present invention provides a method for preparing a compound as shown in Formula III, which comprises the following steps:

[0058] Step 1: preparing a compound represented by Formula VI by reacting a compound represented by Formula I with acrylonitrile in the presence of a base;

[0059] Step 2: preparing a compound of Formula II by hydrolyzing a compound of Formula VI; and

[0060] Step 3: Prepare the compound shown in Formula III by subjecting the compound shown in Formula II to a ring-closure reaction.

[0061] The base is copper hydroxide.

[0062] In the method, step 1 and step 2 are as described above.

[0063] In step 3 of preparing the compound represented by formula III by subjecting the compound represented by formula II to a ring-closure reaction, the ring-closure reaction can be carried out in the presence of an acid.

[0064] The contents of step 3 of preparing the compound of formula III by ring-closing the compound of formula II can be applied to the reaction conditions. The reaction of formula VI to formula III can be carried out by in-situ reaction.

[0065] For example, the method for preparing the compound of Formula III according to the present invention can be represented by the following reaction formula I.

[0066] [Reaction Formula 1]

[0067]

[0068] As shown in Reaction Formula I, the compound shown in Formula I can be subjected to an O-alkylation reaction with the compound shown in Formula IV, and the resulting compound can be oxidized with 2-iodobenzoic acid and potassium peroxymonosulfate to produce the compound shown in Formula II. Alternatively, the compound shown in Formula I can be reacted with acrylonitrile, and the resulting compound can be hydrolyzed to produce the compound shown in Formula II.

[0069] The compound represented by Formula II can be added in the presence of an acid and then subjected to a ring-closure reaction to prepare the compound represented by Formula III.

[0070] The method for preparing the compound of Formula II of the present invention can be represented by the following reaction formula II-1.

[0071] [Reaction formula II-1]

[0072]

[0073] As shown in Reaction Formula II-1, the compound shown in Formula I is reacted with sodium hydride in DMF and then subjected to O-alkylation with the compound shown in Formula IV to prepare the compound shown in Formula V. The prepared compound shown in Formula V is reacted with 2-iodobenzoic acid and potassium peroxymonosulfate to prepare the compound shown in Formula II.

[0074] The method for preparing the compound of Formula II of the present invention can be represented by the following reaction formula II-2.

[0075] [Reaction formula II-2]

[0076]

[0077] As shown in Reaction Formula II-2, the compound of Formula I reacts with acrylonitrile in the presence of copper hydroxide to produce the compound of Formula VI. The prepared compound of Formula VI is hydrolyzed under acidic conditions to produce the compound of Formula II.

[0078] The method for preparing the compound represented by Formula III of the present invention can preferably be represented by the following reaction formula I-1.

[0079] [Route I-1]

[0080]

[0081] As shown in Reaction Formula I-1, the compound of Formula I is reacted with sodium hydride in the presence of N,N-dimethylformamide, and then O-alkylated with the compound of Formula IV to produce the compound of Formula V. The prepared compound of Formula V is reacted with 2-iodobenzoic acid and potassium peroxymonosulfate to produce the compound of Formula II. The compound of Formula II is then added to sulfuric acid to produce the compound of Formula III through a ring-closure reaction.

[0082] The method for preparing the compound of Formula III according to the present invention can preferably be represented by the following reaction formula I-2.

[0083] [Route I-2]

[0084]

[0085] As shown in Reaction Formula I-2, the compound of Formula I is reacted with acrylonitrile in the presence of copper hydroxide to produce the compound of Formula VI. The prepared compound of Formula VI is hydrolyzed and ring-closed under acidic conditions to produce the compound of Formula III. Here, the reaction with sulfuric acid can be carried out in situ.

[0086] Beneficial effects

[0087] The preparation method of the present invention not only has the advantages of avoiding the separation and purification process, low industrial cost, conventionally available reagents and solvents, and environmental friendliness, but also can efficiently and large-scale produce 5,7-difluorochroman-4-one derivatives. DETAILED DESCRIPTION

[0088] The present invention will be described more fully below with reference to the accompanying examples and experimental examples. However, the present invention can be implemented in many different forms and should not be limited to the scope of the embodiments described herein.

[0089] Unless otherwise stated, all reagents and solvents disclosed below were purchased from Sigma Aldrich. 1 H-NMR was measured by Bruker 400 MHz.

[0090] Example 1: Preparation of 3-(3,5-difluorophenoxy)-1-propanol

[0091] 36 kg of sodium hydride and 439 kg of N,N-dimethylformamide were added to a reactor and cooled to 0°C. Separately, 116 kg of 3,5-difluorophenol was dissolved in 165 kg of N,N-dimethylformamide and added dropwise to the reactor at a temperature below 5°C with stirring. 108 kg of 3-chloro-1-propanol was dissolved in 165 kg of N,N-dimethylformamide and added dropwise to the reactor, which was heated to 80°C for reaction. After the reaction, the mixture was cooled to 20°C, and 839 kg of isopropyl ether and 530 kg of purified water were added. 48 kg of concentrated hydrochloric acid was then added and stirred. After the layers were allowed to stand and separate, a 5% aqueous sodium hydroxide solution (29 kg of sodium hydroxide + 579 kg of purified water) was added to the organic layer and stirred. The organic layer was separated and concentrated in vacuo at 40°C to yield 3-(3,5-difluorophenoxy)-1-propanol (167 kg, 100%, in situ).

[0092] 1 H-NMR (400MHz, DMSO-d6): δ = 1.84 (quint, 2H), 3.54 (dd, 2H), 4.06 (t, 2H), 4.57 (t, 1H)

[0093] Example 2: Preparation of 3-(3,5-difluorophenoxy)-1-propionic acid

[0094] 167 kg of 3-(3,5-difluorophenoxy)-1-propanol, 882 kg of acetonitrile, and 552 kg of purified water were added to a reactor and stirred. 11 kg of 2-iodobenzoic acid and 227 kg of potassium peroxymonosulfate were added to the reactor and stirred at 80°C. After the reaction, the reaction mixture was cooled to below 5°C, and 1201 kg of ethyl acetate and 1339 kg of purified water were added with stirring. The precipitated solid was filtered and rinsed with 300 kg of ethyl acetate and 335 kg of purified water. The filtrate was concentrated under vacuum at 40°C, and 569 kg of n-heptane was added. The reaction mixture was cooled to 20°C and stirred. After filtration, the filtrate was concentrated under vacuum at 40°C to yield 3-(3,5-difluorophenoxy)-1-propionic acid (142 kg, 79%).

[0095] 1H-NMR (400MHz, DMSO-d6): δ = 2.69 (t, 2H), 4.19 (t, 2H), 6.68-6.81 (m, 3H), 12.4 (s, 1H)

[0096] Example 3: Preparation of 5,7-difluorochroman-4-one

[0097] 345 kg of concentrated sulfuric acid was added to Reactor A and cooled to 10°C. 142 kg of 3-(3,5-difluorophenoxy)-1-propionic acid was then added dropwise to Reactor A. The reaction mixture was stirred at 50°C. After the reaction was completed, the mixture was cooled to 20°C. 1421 kg of purified water was added to Reactor B and cooled to 0°C. While maintaining the temperature of Reactor A below 10°C, the reaction solution was slowly added dropwise to Reactor B. 1890 kg of dichloromethane was then added and stirred. The organic layer was separated, and 1421 kg of purified water was added to the mixture. The pH was adjusted to 7.5 with a 5% aqueous sodium bicarbonate solution (14 kg of sodium bicarbonate plus 284 kg of purified water). The organic layer was separated and concentrated under vacuum at 40°C. 483 kg of n-heptane was added and stirred. After filtration, the mixture was dried under vacuum at 40°C to yield 5,7-difluorochroman-4-one (109 kg, 84%).

[0098] 1 H-NMR (400MHz, DMSO-d6): δ = 2.77 (t, 2H), 4.57 (t, 2H), 6.81-6.95 (m, 2H)

[0099] Example 4: Preparation of 3-(3,5-difluorophenoxy)-1-propionitrile

[0100] 13 kg of 3,5-difluorophenol and 21 kg of acrylonitrile were added to a reactor and stirred. 5 kg of copper hydroxide was then added to the reactor and refluxed at 80°C for 48 hours. After the reaction, the mixture was cooled to room temperature and concentrated at 50°C. 100 L of dichloromethane and 50 L of purified water were added to the reactor and stirred. 50 L of purified water was then added to the organic layer, stirred, and the organic layer was separated. The mixture was then dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to yield 3-(3,5-difluorophenoxy)-1-propionitrile (11 kg, 60%).

[0101] 1 H-NMR (400MHz, CDCl3): δ = 2.87 (t, 2H), 4.19 (t, 2H), 6.44-7.54 (m, 3H)

[0102] Example 5: Preparation of 5,7-difluorochroman-4-one

[0103] 30 kg of concentrated sulfuric acid was added to reactor A. 11 kg of 3-(3,5-difluorophenoxy)-1-propionitrile was added to the reactor at 10-20 ° C, the temperature was raised to 50 ° C 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 cooled to 0 ° C. The reaction solution in reactor A was added to reactor B. 110 L of dichloromethane was added to reactor B, and the pH value was adjusted to 7 with 5% sodium bicarbonate aqueous solution. After stirring, the organic layer was separated. After concentration under reduced pressure, 55 L of n-heptane was added to the reactor and stirred and filtered. The mixture was vacuum dried at 40 ° C to obtain 5,7-difluorochroman-4-one (9 kg, 80%).

[0104] 1 H-NMR (400MHz, CDCl3): δ = 2.81 (t, 2H), 4.55 (t, 2H), 6.44-6.53 (m, 2H)

Claims

1. A method for preparing a compound as shown in Formula III, comprising the following steps: Step 1: preparing a compound represented by Formula V by reacting a compound represented by Formula I with a compound represented by Formula IV; Step 2: preparing a compound represented by Formula II by reacting a compound represented by Formula V with 2-iodobenzoic acid and potassium peroxymonosulfate in the presence of a mixture of water, methanol, and acetonitrile at a temperature of 60 to 90° C.; as well as Step 3: Prepare the compound represented by Formula III by subjecting the compound represented by Formula II to a ring-closure reaction at a temperature of 40-60° C. in the presence of sulfuric acid: [Formula I] [Formula II] [Formula III] [Formula IV] [Formula V] Wherein, X in the compound of formula IV is a halogen selected from F, Cl or I; In step 1, the compound represented by formula I is stirred with sodium hydride in dimethylformamide at a temperature of 0 to 10° C., and then mixed with the compound represented by formula IV, and an O-alkylation reaction is carried out at a temperature of 60 to 90° C.

2. The method according to claim 1, wherein The X is Cl.

3. A method for preparing a compound as shown in Formula III, comprising the following steps: Step 1: preparing a compound represented by Formula VI by reacting a compound represented by Formula I with acrylonitrile in the presence of a base, wherein the reaction is carried out at a temperature of 75 to 85° C.; Step 2: preparing a compound represented by Formula II by hydrolyzing a compound represented by Formula VI in the presence of sulfuric acid; as well as Step 3: Prepare the compound represented by Formula III by subjecting the compound represented by Formula II to a ring-closure reaction in the presence of sulfuric acid: Step 2 and step 3 are carried out by in-situ reaction at a temperature of 40-60°C; [Formula I] [Formula II] [Formula III] [Formula VI] Wherein, the alkali described in step 1 is copper hydroxide.

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