Method for preparing acyl derivatives

Abstract

The present invention relates to a process for the preparation of aromatic acyl derivatives of formula (I) using methanesulfonic acid. The present invention further relates to a process for the preparation of bioactive ingredients such as paracetamol. JPEG2024540120000023.jpg45170

Description

[Technical field]

[0001] The present invention relates to the field of organic chemistry, and more particularly to an improved process for the preparation of aromatic acyl derivatives which are useful as intermediates in the synthesis of bioactive ingredients such as paracetamol and ibuprofen. [Background technology]

[0002] One of the most important reactions from the industrial synthesis point of view to obtain bioactive compounds is the acylation of aromatic substrates. This electrophilic aromatic substitution is generally carried out in the presence of large amounts of inorganic salts, which is accompanied by the generation of large amounts of toxic and corrosive waste products. In most cases, toxic solvents (chlorinated, aromatic, or both) must be used.

[0003] For example, acylation reactions typically use Lewis acids such as AlCl3, FeCl3, SnCl4, and rare earth triflates. However, these Lewis acids must be used in large quantities, are expensive, toxic, and cannot be recycled. Acylation reactions can also be carried out using Bronsted acids such as hydrofluoric acid, trifluoroacetic acid, and trifluoromethanesulfonic acid. However, like Lewis acids, these fluorinating agents are expensive, toxic, and dangerous to handle. Summary of the Invention [Problem to be solved by the invention]

[0004] In order to obtain several important intermediates for the industrial synthesis of pharmaceuticals, there remains a need to improve acylation reactions that are suitable for industrial scale with high yields, high selectivity, and low environmental impact, taking into account economics, environmental impact, safety, etc. [Means for solving the problem]

[0005] Therefore, the present inventors have researched and developed new methods for preparing aromatic acyl derivatives. Unexpectedly, the present inventors have shown that aromatic acyl derivatives can be obtained in high yield and high selectivity by using methanesulfonic acid in the acylation reaction. The use of methanesulfonic acid in this way is compatible with industrial approaches because it is easily available, has a simple and less hazardous operation compared to fluoric acid and Lewis acids, is cost-effective, and does not require expensive starting materials or large amounts of reagents that have a significant impact on the environment. These acylation methods can be used in the synthesis of bioactive ingredients. For example, the present inventors have carried out an acylation reaction using methanesulfonic acid to prepare paracetamol. The present inventors have further improved the method for preparing paracetamol using hydroquinone as a starting material.

[0006] Thus, the present invention provides a compound of formula (I): [ka] (In the formula, R1 is - a hydroxy group, - (C1~C 18 ) alkyl group, - (C1-C6) alkoxy groups, and - Halogen groups is a radical selected from the group consisting of: R2 is - (C1~C 18 ) alkyl group, - phenyl optionally substituted with at least one hydroxy group, and - (C1-C6) alkoxy group is a radical selected from the group consisting of A method for preparing a compound of formula (I) comprising the steps of: a) a compound of formula (II): [ka] (wherein R1 is defined above). with methanesulfonic acid and a compound of formula (III): [ka] (In the formula, R2 is defined above, R3 is a radical selected from the group consisting of a hydroxy group, a -O-CO-CH3 group, a (C1-C6) alkoxy group, and chlorine. with a compound of the formula: b) recovering the compound of formula (I). The present invention relates to a method comprising the steps of:

[0007] Preferably, R2 is - (C1~C 18 ) alkyl group, - phenyl groups, and - (C1-C6) alkoxy group is a radical selected from the group consisting of:

[0008] In certain embodiments, the reaction in step a) is carried out at a temperature between 30° C. and 130° C., preferably between 40° C. and 60° C., more preferably at about 50° C. In further certain embodiments, 1 to 5 equivalents, preferably 1 to 3 equivalents, more preferably 1 to 2.5 equivalents, even more preferably 1, 1.5, or 2.5 equivalents of the compound of formula (III) relative to the compound of formula (II) are used in step a).

[0009] In a preferred embodiment, in the compound of formula (I), R1 is a hydroxy group and R2 is a methyl group, in the compound of formula (II), R1 is a hydroxy group, and in the compound of formula (III), R2 is a methyl group and R3 is a hydroxy group.

[0010] Thus, a preferred method of the present invention comprises the steps of: a) reacting phenol with methanesulfonic acid and acetic acid at a temperature of about 50° C. using 1 to 5 equivalents, preferably 1 to 3 equivalents, more preferably 1 to 2.5 equivalents, and even more preferably 1, 1.5, or 2.5 equivalents of acetic acid relative to the phenol; and b) recovering 4-hydroxyacetophenone Includes.

[0011] Another object of the present invention is to provide a method for producing a cellular endothelial cell comprising the steps of: a)-b) carrying out the method as described above; c) reacting 4-hydroxyacetophenone with formic acid and hydrogen peroxide; d) reacting the mixture obtained in step c) with ammonium acetate and acetic acid; and e) recovering the paracetamol A process for preparing paracetamol comprising the steps of:

[0012] Preferably, the process for preparing paracetamol comprises the following steps: a) reacting phenol with methanesulfonic acid and acetic acid at a temperature of about 50° C. using 2.5 equivalents of acetic acid relative to the phenol; b) recovering 4-hydroxyacetophenone; c) reacting 4-hydroxyacetophenone with formic acid and hydrogen peroxide; d) reacting the mixture obtained in step c) with ammonium acetate and acetic acid; and e) recovering the paracetamol Includes.

[0013] In certain embodiments, such process for preparing paracetamol further comprises purifying the mixture obtained in step c) and recovering hydroquinone.

[0014] Furthermore, the object of the present invention is a process for preparing paracetamol comprising the following steps: - reacting hydroquinone with ammonium acetate or acetamide and water at a temperature ranging from 240° C. to 300° C. for a reaction time ranging from 1 minute to 12 hours, using 1 to 50 equivalents of acetic acid or acetamide and water relative to hydroquinone, in the absence of acetic acid; and - Paracetamol recovery process The method includes:

[0015] In a particular embodiment, hydroquinone and ammonium acetate are reacted at a temperature of about 260° C. for about 1 hour using 10 equivalents of ammonium acetate relative to hydroquinone.

[0016] In a particular embodiment, hydroquinone, acetamide and water are reacted at a temperature of about 260° C. for about 1 hour using 10 equivalents of acetamide and 10 equivalents of water relative to hydroquinone.

[0017] In a further preferred embodiment, the method for preparing the compound of formula (I) comprises the steps of: in the compound of formula (I), R1 is a (C1-C6) alkyl group, preferably an isobutyl group, and R2 is a methyl group; in the compound of formula (II), R1 is a (C1-C6) alkyl group, preferably an isobutyl group; and in the compound of formula (III), R2 is a methyl group, and R3 is a -O-CO-CH3 group.

[0018] Thus, a preferred method of the present invention comprises the steps of: a) reacting 4-isobutylbenzene with methanesulfonic acid and acetic anhydride at a temperature of about 50° C. using 2 equivalents of acetic anhydride relative to the 4-isobutylbenzene; and b) recovering preferably 1-(4-isobutylphenyl)ethanone Includes.

[0019] Another object of the present invention is a method for preparing ibuprofen comprising the following steps: a) preparing 1-(4-isobutylphenyl)ethanone by the method described above; and b) obtaining ibuprofen from the 1-(4-isobutylphenyl)ethanone intermediate in step a) The method includes:

[0020] In another preferred embodiment, the process for preparing the compound of formula (I) is as follows: the compound of formula (I) is such that R1 is a radical selected from the group consisting of hydroxy, methoxy and chlorine, R2 is a radical selected from the group consisting of octyl and phenyl optionally substituted with at least one hydroxy group, preferably three hydroxy groups, the compound of formula (II) is such that R1 is a radical selected from the group consisting of hydroxy, methoxy and chlorine; The compounds of formula (III) are those in which R2 is a radical selected from the group consisting of octyl and phenyl optionally substituted with at least one hydroxy group, preferably three hydroxy groups, and R3 is hydroxy or chlorine. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] definition According to the present invention, the following terms have the following meanings: For example, C1~C 18 Terms described herein having a prefix such as 12 A lower number of carbon atoms, such as C1-C6, or C1-C2, can also be used. For example, the term C1-C 12 is used, it means that the corresponding hydrocarbon chain may be composed of 1 to 12 carbon atoms, in particular 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. For example, when the term C1-C6 is used, it means that the corresponding hydrocarbon chain may be composed of 1 to 6 carbon atoms, in particular 1, 2, 3, 4, 5, or 6 carbon atoms. For example, when the term C1-C3 is used, it means that the corresponding hydrocarbon chain may be composed of 1 to 3 carbon atoms, in particular 1, 2, or 3 carbon atoms.

[0022] The term "alkyl" means a saturated, linear or branched aliphatic group. 12The term "(C1-C6)alkyl" more specifically means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, heptyl, hexyl, nonyl, decyl, undecyl, or dodecyl. The term "(C1-C6)alkyl" more specifically means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, or hexyl.

[0023] The term "alkoxy" or "alkyloxy" corresponds to the above alkyl groups bonded to the molecule by an -O- (ether) bond. (C1-C6)alkoxy includes methoxy or methyloxy, ethoxy or ethyloxy, propoxy or propyloxy, isopropoxy or isopropyloxy, butoxy or butyloxy, isobutoxy or isobutyloxy, pentoxy or pentyloxy, isopentoxy or isopentyloxy, and hexoxy or hexyloxy.

[0024] The term "halogen" corresponds to a fluorine, chlorine, bromine or iodine atom, preferably chlorine.

[0025] The phrases "a radical substituted with one" and "a radical substituted with at least" mean that the radical is substituted with one or several of the groups listed. For example, the phrase "phenyl substituted with at least one hydroxy group" can include phenyl substituted with 1, 2, 3, 4, and 5 hydroxy groups, preferably 3 hydroxy groups.

[0026] As used herein, the terms "active ingredient", "active ingredient", "active pharmaceutical ingredient", "bioactive ingredient", and "drug" are synonymous and refer to a component of a pharmaceutical composition that has a therapeutic effect. Examples include paracetamol and ibuprofen.

[0027] As used herein, the term "about" will be understood by those of ordinary skill in the art to which the invention pertains and will vary to some extent depending on the context in which it is used. If there is a usage that is not clear to a person of ordinary skill in the art to which the invention pertains from the context in which the term is used, "about" will mean up to plus or minus 20% of the particular term, preferably up to 10%.

[0028] Acylation The present invention provides a process for the preparation of aromatic acyl derivatives which comprises reacting an aromatic derivative with methanesulfonic acid.

[0029] More specifically, the present invention relates to a compound of formula (I): [ka] (In the formula, R1 is - a hydroxy group, - (C1~C 18 ) alkyl group, preferably (C1-C 12 ) alkyl group, more preferably (C1-C 12 ) alkyl group, - (C1-C6) alkoxy groups, and - Halogen groups is a radical selected from the group consisting of: R2 is - (C1~C 18 ) alkyl group, preferably (C1-C 12 ) alkyl group, - phenyl optionally substituted with at least one hydroxy group, and - (C1-C6) alkoxy group is a radical selected from the group consisting of The present invention provides a method for preparing a compound of formula (I), comprising the steps of: a) a compound of formula (II): [ka] (wherein R1 is defined above). with methanesulfonic acid and a compound of formula (III): [ka] (In the formula, R2 is defined above, R3 is a radical selected from the group consisting of a hydroxy group, a -O-CO-CH3 group, a (C1-C6) alkoxy group, and chlorine. with a compound of the formula: b) recovering the compound of formula (I). Includes.

[0030] In a preferred embodiment, the present invention provides a compound of formula (I): [ka] (In the formula, R1 is - a hydroxy group, - (C1~C 18 ) alkyl group, preferably (C1-C 12 ) alkyl group, more preferably (C1-C 12 ) alkyl group, - (C1-C6) alkoxy groups, and - Halogen groups is a radical selected from the group consisting of: R2 is - (C1~C 18 ) alkyl group, preferably (C1-C 12 ) alkyl group, - phenyl groups, and - (C1-C6) alkoxy group is a radical selected from the group consisting of The present invention provides a method for preparing a compound of formula (I), comprising the steps of: a) a compound of formula (II): [ka] (wherein R1 is defined above). with methanesulfonic acid and a compound of formula (III): [ka] (In the formula, R2 is defined above, R3 is a radical selected from the group consisting of a hydroxy group, a -O-CO-CH3 group, a (C1-C6) alkoxy group, and chlorine. with a compound of the formula: b) recovering the compound of formula (I). Includes.

[0031] In a preferred embodiment, R2 is - (C1~C 18 ) alkyl group, - (C1-C6) alkoxy group is a radical selected from the group consisting of:

[0032] In a particular embodiment, the reaction in step a) is carried out at a temperature between 30°C and 130°C, preferably between 40°C and 60°C, more preferably at about 50°C.

[0033] In a further particular embodiment, the reaction in step a) is carried out with 1 to 5 equivalents, preferably 1 to 3 equivalents, more preferably 1 to 2.5 equivalents, even more preferably 1, 1.5 or 2.5 equivalents of a compound of formula (III) relative to the compound of formula (II).

[0034] In a further preferred embodiment, in the compound of formula (I), R1 is a hydroxy group and R2 is a methyl group, in the compound of formula (II), R1 is a hydroxy group, and in the compound of formula (III), R2 is a methyl group and R3 is a hydroxy group.

[0035] In this preferred embodiment, the method comprises the steps of: a) reacting phenol with methanesulfonic acid and acetic acid at a temperature of about 50° C. using 1 to 5 equivalents, preferably 1 to 3 equivalents, more preferably 1 to 2.5 equivalents, and even more preferably 1, 1.5, or 2.5 equivalents of acetic acid relative to the phenol; and b) recovering 4-hydroxyacetophenone Includes.

[0036] In a further preferred embodiment, in the compound of formula (I), R1 is a (C1-C6) alkyl group, preferably an isobutyl group, and R2 is a methyl group; in the compound of formula (II), R1 is a (C1-C6) alkyl group, preferably an isobutyl group; and in the compound of formula (III), R2 is a methyl group, and R3 is a -O-CO-CH3 group.

[0037] Thus, a preferred process comprises the steps of: a) reacting 4-isobutylbenzene with methanesulfonic acid and acetic anhydride at a temperature of about 50° C. using 1 to 5 equivalents, preferably 1 to 3 equivalents, more preferably 2 equivalents of acetic anhydride relative to 4-isobutylbenzene; and b) recovering 1-(4-isobutylphenyl)ethanone; Includes.

[0038] In a further preferred embodiment, in the compound of formula (I), R1 is a hydroxy group and R2 is an octyl group, in the compound of formula (II), R1 is a hydroxy group, and in the compound of formula (III), R2 is an octyl group and R3 is a hydroxy group.

[0039] Thus, a preferred method comprises the steps of: a) reacting phenol with methanesulfonic acid and nonanoic acid at a temperature of about 50° C. using 1 to 5 equivalents, preferably 1 to 3 equivalents, more preferably 1 to 2.5 equivalents, even more preferably 1, 1.5, or 2.5 equivalents of nonanoic acid relative to the phenol; and b) recovering 1-(4-hydroxyphenyl)nonan-1-one; Includes.

[0040] In a further preferred embodiment, in the compound of formula (I), R1 is a hydroxy group and R2 is a phenyl group, in the compound of formula (II), R1 is a hydroxy group, and in the compound of formula (III), R2 is a phenyl group and R3 is a hydroxy group.

[0041] Thus, a preferred method comprises the steps of: a) reacting phenol with methanesulfonic acid and benzoic acid at a temperature of about 60° C. using 1 to 5 equivalents, preferably 1 to 3 equivalents, more preferably 1 to 2.5 equivalents, even more preferably 1, 1.5, or 2.5 equivalents of benzoic acid relative to the phenol; and b) recovering 4-hydroxybenzophenone Includes.

[0042] In a further preferred embodiment, in the compound of formula (I), R1 is a methoxy group and R2 is a phenyl group, in the compound of formula (II), R1 is a methoxy group, and in the compound of formula (III), R2 is a phenyl group and R3 is a hydroxy group.

[0043] Thus, a preferred method comprises the steps of: a) reacting anisole with methanesulfonic acid and benzoic acid at a temperature of about 60° C. using 1 to 5 equivalents, preferably 1 to 3 equivalents, more preferably 1 to 2.5 equivalents, even more preferably 1, 1.5, or 2.5 equivalents of benzoic acid relative to the anisole; and b) recovering 4-methoxybenzophenone Includes.

[0044] In further preferred embodiments, the compound of formula (I) has R1 being a hydroxy group and R2 being a phenyl group substituted with three hydroxy groups (i.e., gallic acid), the compound of formula (II) has R1 being a hydroxy group and the compound of formula (III) has R2 being a phenyl group substituted with three hydroxy groups and R3 being a hydroxy group.

[0045] Thus, a preferred method comprises the steps of: a) reacting phenol with methanesulfonic acid and 3,4,5-trihydroxybenzoic acid at a temperature of about 120° C. using 1 to 5 equivalents, preferably 1 to 3 equivalents, more preferably 1 to 2.5 equivalents, even more preferably 1, 1.5, or 2.5 equivalents of 3,4,5-trihydroxybenzoic acid relative to the phenol; and b) recovering (4-hydroxyphenyl)-(3,4,5-trihydroxyphenyl)methanone; Includes.

[0046] In a further preferred embodiment, the compound of formula (I) has R1 being chlorine and R2 being a phenyl group, the compound of formula (II) has R1 being chlorine, and the compound of formula (III) has R2 being a phenyl group and R3 being chlorine.

[0047] Thus, a preferred method comprises the steps of: a) reacting chlorobenzene with methanesulfonic acid and benzoyl chloride at a temperature of about 120° C. using 1 to 5 equivalents, preferably 1 to 3 equivalents, more preferably 1 to 2.5 equivalents, even more preferably 1, 1.5, or 2.5 equivalents of benzoyl chloride relative to chlorobenzene; and b) recovering 4-chlorobenzophenone Includes.

[0048] In particular, the aromatic acyl derivatives are prepared in a single chemical step without any recovery steps being taken into account, and therefore the process of the present invention is more suitable for industrial scale than the process using the Fries rearrangement for preparing 2-hydroxyacetophenone, which requires a prior step for preparing acetylbenzene, for example according to Hocking (J. Chem. Tech. Biotechnol. 1980, 30, 626-641).

[0049] In this specification, the term "comprising" (and other similar terms) is "open ended" and may generally be interpreted to include all of the specifically recited features as well as any additional and unspecified features. According to certain embodiments, unless otherwise specified, the phrase "consisting essentially of" may be interpreted to include the specified features and any additional and unspecified features that do not materially affect the basic and novel characteristics of the claimed invention, and the phrase "consisting of" may be interpreted to include only the specified features.

[0050] Thus, the object of the present invention is to provide a compound of formula (I): [ka] (In the formula, R1 is - a hydroxy group, - (C1~C 18 ) alkyl group, preferably (C1-C 12 ) alkyl group, more preferably (C1-C 12 ) alkyl group, - (C1-C6) alkoxy groups, and - Halogen groups is a radical selected from the group consisting of: R2 is - (C1~C 18 ) alkyl group, preferably (C1-C 12 ) alkyl group, - phenyl, preferably phenyl, optionally substituted with at least one hydroxy group, and - (C1-C6) alkoxy group is a radical selected from the group consisting of A method for preparing a compound of formula (I) comprising the steps of: a) Formula (II) [ka] (wherein R1 is defined above). with methanesulfonic acid and a compound of formula (III): [ka] (In the formula, R2 is defined above, R3 is a radical selected from the group consisting of a hydroxy group, a -O-CO-CH3 group, a (C1-C6) alkoxy group, and chlorine. with a compound of the formula: b) recovering the compound of formula (I). and all specific and preferred embodiments as disclosed herein.

[0051] As defined above and illustrated in the examples below, the inventors have developed a novel method for the preparation of aromatic acyl derivatives using methanesulfonic acid, which can be used as intermediates in the synthesis of a large number of aryl ketone derivatives of potential biological or therapeutic interest, such as, for example, paracetamol (IUPAC name: N-(4-hydroxyphenyl)acetamide) and ibuprofen (IUPAC name: (RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid).

[0052] Paracetamol Therefore, an object of the present invention is a method for preparing paracetamol comprising the following steps: a) a compound of formula (II): [ka] (wherein R1 is a hydroxy group). with methanesulfonic acid and a compound of formula (III): [ka] (wherein R2 is a methyl group and R3 is a hydroxy group). with a compound of formula (I); b) Formula (I): [ka] (wherein R1 is a hydroxy group and R2 is a methyl group). recovering the compound; c) reacting the compound of formula (I) with formic acid and hydrogen peroxide; d) reacting the mixture obtained in step c) with ammonium acetate and acetic acid; and e) recovering the paracetamol Includes.

[0053] Thus, the method for preparing such paracetamol comprises the following steps: a) reacting phenol with methanesulfonic acid and acetic acid; b) recovering 4-hydroxyacetophenone; c) reacting 4-hydroxyacetophenone with formic acid and hydrogen peroxide; d) reacting the mixture obtained in step c) with ammonium acetate and acetic acid; and e) recovering the paracetamol Includes.

[0054] In this method, step c) corresponds to a reaction using "Bayer-Villiger" conditions. In a particular embodiment, 4-hydroxyacetophenone is reacted with formic acid and hydrogen peroxide at room temperature. Preferably, 2 to 10 equivalents, more preferably 3 to 7 equivalents, even more preferably 5 equivalents of formic acid relative to 4-hydroxyacetophenone are used. In a further embodiment, 1 to 2 equivalents, preferably 1 to 1.2 equivalents of formic acid relative to 4-hydroxyacetophenone are used.

[0055] Step d) corresponds to a nucleophilic substitution reaction with ammonium acetate and acetic acid. In a particular embodiment, the mixture obtained in step c) is reacted with ammonium acetate and acetic acid at a temperature between 200 and 250° C., preferably at about 230° C.

[0056] In a preferred embodiment, the method for preparing paracetamol comprises the following steps: a) reacting phenol with methanesulfonic acid and acetic acid at a temperature of about 50° C. using 2.5 equivalents of acetic acid relative to the phenol; b) recovering 4-hydroxyacetophenone; c) reacting 4-hydroxyacetophenone with formic acid and hydrogen peroxide; d) reacting the mixture obtained in step c) with ammonium acetate and acetic acid; and e) recovering the paracetamol Includes.

[0057] Starting from 4-hydroxyacetophenone, the "Baeyer-Villiger reaction" of step c) with hydrogen peroxide and formic acid can be carried out to obtain acetylhydroquinone as the main product and hydroquinone as a by-product. Hydroquinone can therefore be isolated by any purification method known to those skilled in the art. For example, hydroquinone can be isolated from the acetylhydroquinone / hydroquinone mixture by hydrolysis and distillation.

[0058] In a particular embodiment, the method for preparing paracetamol as defined above further comprises purifying the mixture obtained in step c) to recover hydroquinone.Preferably, hydroquinone is purified and isolated using hydrolysis and any distillation method currently used by those skilled in the art.Thus, the hydroquinone obtained from purifying the mixture obtained after step c) can be used as an intermediate to provide paracetamol in one chemical step.

[0059] Therefore, a further object of the present invention is a process for preparing paracetamol comprising the following steps: - reacting hydroquinone with ammonium acetate at a temperature ranging from 240 to 300°C for 1 minute to 12 hours using 1 to 50 equivalents of ammonium acetate relative to hydroquinone in the absence of acetic acid; and - Paracetamol recovery process Includes.

[0060] In a preferred embodiment, hydroquinone and ammonium acetate are reacted at a temperature in the range of 240° C. to 300° C. for 10 minutes to 2 hours using 5 to 30 equivalents of ammonium acetate relative to hydroquinone.

[0061] In a more preferred embodiment, hydroquinone and ammonium acetate are reacted at a temperature of about 280° C. for about 30 minutes using 20 equivalents of ammonium acetate relative to hydroquinone.

[0062] In a more preferred embodiment, hydroquinone and ammonium acetate are reacted at a temperature of about 260° C. for about 1 hour using 10 equivalents of ammonium acetate relative to hydroquinone.

[0063] A further object of the present invention is also a process for preparing paracetamol comprising the following steps: - reacting hydroquinone with acetamide and water at a temperature ranging from 240° C. to 300° C. for 1 minute to 12 hours using 1-50 equivalents of acetamide and 1-50 equivalents of water relative to hydroquinone in the absence of acetic acid; and - Paracetamol recovery process Includes.

[0064] In a preferred embodiment, hydroquinone, acetamide, and water are reacted at a temperature in the range of 240° C. to 300° C. for 10 minutes to 2 hours using 5 to 30 equivalents of acetamide and 5 to 30 equivalents of water relative to hydroquinone.

[0065] In a more preferred embodiment, hydroquinone, acetamide, and water are reacted at a temperature of about 260° C. for about 1 hour using 10 equivalents of acetamide and 10 equivalents of water relative to hydroquinone.

[0066] The above disclosed process for the preparation of paracetamol starting from hydroquinone using ammonium acetate or acetamide and water makes it possible to provide paracetamol with high selectivity (more than 95%, even 100%) and in a very short reaction time (less than 12 hours, even less than 1 hour).

[0067] In particular, such methods further include the step of recovering the ammonium acetate or acetamide for reuse.

[0068] In the method for preparing paracetamol from hydroquinone, the reaction is carried out in the absence of acetic acid. The absence of acetic acid can improve the conversion rate of paracetamol from hydroquinone, reduce impurities and reaction time. Therefore, such a method is well suited for industrial scale because it can be carried out in continuous reactors and small amounts of industrial materials.

[0069] Ibuprofen The method for preparing ibuprofen comprises the following steps: a) preparing 1-(4-isobutylphenyl)ethanone as described above; and b) obtaining ibuprofen from the 1-(4-isobutylphenyl)ethanone intermediate recovered in step a); Includes.

[0070] Therefore, an object of the present invention is a method for preparing ibuprofen comprising the following steps: a) a compound of formula (II): [ka] (wherein R1 is an isobutyl group). with methanesulfonic acid and a compound of formula (III): [ka] (wherein R2 is a methyl group and R3 is a -O-CO-CH3 group). with a compound of formula (I); b) Formula (I): [ka] (wherein R1 is an isobutyl group and R2 is a methyl group). recovering the compound of formula (I); and c) obtaining ibuprofen from the 1-(4-isobutylphenyl)ethanone intermediate recovered in step b); Includes.

[0071] Thus, the process for preparing such ibuprofen comprises the following steps: a) reacting 4-isobutylbenzene with methanesulfonic acid and acetic anhydride; b) recovering 1-(4-isobutylphenyl)ethanone; and c) obtaining ibuprofen from the 1-(4-isobutylphenyl)ethanone intermediate recovered in step b); Includes.

[0072] Preferably, such a method comprises the steps of: a) reacting 4-isobutylbenzene with methanesulfonic acid and acetic anhydride at a temperature of about 50° C. using 2 equivalents of acetic anhydride relative to the 4-isobutylbenzene; b) recovering 1-(4-isobutylphenyl)ethanone; and c) obtaining ibuprofen from the 1-(4-isobutylphenyl)ethanone intermediate recovered in step b); Includes.

[0073] The preparation of ibuprofen from the 1-(4-isobutylphenyl)ethanone intermediate is well known to those skilled in the art and can be accomplished using several methods, such as that disclosed by James Speight (Handbook of Industrial Hydrocarbon Processes, pp. 588-590). The two main chemical methods for obtaining ibuprofen from the 1-(4-isobutylphenyl)ethanone intermediate are the Boot process and the Hoechst process. Such a route involves the reduction of 1-(4-isobutylacetophenone) to the corresponding alcohol under hydrogen atmosphere using Raney nickel catalyst, followed by carbonylation using palladium catalyst, as disclosed in Scheme 3 of Kjonaas et al. (J. Chem. Educ., 2011, 88, 825-828).

[0074] Thus, a preferred embodiment of the present invention is a method for preparing ibuprofen, said method comprising the steps of: a) preparing 1-(4-isobutylphenyl)ethanone by the methods described herein; b) reducing 1-(4-isobutylphenyl)ethanone with Raney nickel under a hydrogen atmosphere to give 1-(4-isobutylphenyl)ethanol; and c) performing a palladium-catalyzed carbonylation reaction of 1-(4-isobutylphenyl)ethanol; and d) recovering the ibuprofen Includes.

[0075] In the same paper, Kjonaas et al. further disclose an alternative four-step synthesis involving reduction of 1-(4-isobutylacetophenone) to the corresponding alcohol with sodium borohydride in acetic acid, followed by nucleophilic substitution to prepare the chlorine derivative, the Grignard reagent, and then carboxylation to prepare ibuprofen.

[0076] Thus, a preferred embodiment of the present invention is a method for preparing ibuprofen comprising the steps of: a) preparing 1-(4-isobutylphenyl)ethanone by the methods described herein; b) reducing 1-(4-isobutylphenyl)ethanone with borohydride in acetic acid to give 1-(4-isobutylphenyl)ethanol; c) reacting 1-(4-isobutylphenyl)ethanol in hydrochloric acid to obtain 1-(4-isobutylphenyl)chloroethane; e) reacting 1-(4-isobutylphenyl)chloroethane with magnesium to prepare a Grignard reagent; and f) reacting the Grignard reagent with carbon dioxide; and g) recovering the ibuprofen Includes.

[0077] Further aspects and advantages of the present invention are disclosed in the following examples, which should be considered as illustrative and not limiting the scope of the present application. EXAMPLES

[0078] Overview All reagents and solvents used in the synthesis were commercially available and were obtained from Sigma Aldrich.

[0079] All compounds were characterized by spectroscopic data. Nuclear magnetic resonance spectra were recorded on a Bruker DRX 300 or Bruker ALS 300 (1H: 300 MHz, 13C: 75 MHz). Measurements are given in parts per million (ppm). Chemical shifts δ are given in ppm. Chemical shifts are given with reference to the residual DMSO-d6 central peak: protons at 2.50 ppm, carbons at 39.52 ppm. Chemical shifts with reference to the residual CDCl3 central peak are protons at 7.26 ppm, carbons at 77.16 ppm. The abbreviations are defined as follows: s singlet, d doublet, dd doublet of doublets, t triplet, q quadruplet, qt hexuplet, hex hexuplet, hept heptuplet, m multiplet, br broad. The coupling constant J is expressed in Hertz (Hz).

[0080] Mass spectra were performed in positive ion mode using a hybrid quadrupole time-of-flight mass spectrometer (MicroTOFQ-II, Bruker Daltonics, Bremen) equipped with an electrospray ionization (ESI) ion source. The spray gas flow rate was 0.6 bar and the capillary voltage was 4.5 kV. Solutions dissolved in a mixed solvent (methanol / dichloromethane / water = 45 / 40 / 15) were injected at 180 μL / h. The mass range of the analysis was 50-1000 m / z, and calibration was performed with sodium formate.

[0081] 1. Acylation of various substrates

[0082] 1.1. Preparation of 4-hydroxyacetophenone A round-bottom flask was charged with 10 g of phenol (0.1 mol), 100 mL of methanesulfonic acid (1M), and 15 mL of acetic acid (0.25 mol). After 24 h of reaction at 50 °C, 100 mL of water was added at a temperature of 0 °C, the reaction mixture was extracted with butyl acetate (3 times with 100 mL), and then the organic phase was washed with water (3 times with 100 mL) until the pH reached 6 (control of the aqueous phase by HPLC). It was dried over Na2SO4 and concentrated under reduced pressure to obtain the desired product in 83% yield (average 75-88% yield). The HPLC conditions were as follows: column C18 (250 × 4.6 mm, particle size 0.5 μm), mobile phase: (water 60 + CH3CN 40) + 0.1% v / v H3PO4 isocratic, flow rate: 1.0 mL.min -1 , wavelength: 205 nm. 1 H NMR (300 MHz) was CDCl3: 7.93 (d, 2H), 6.90 (d, 2H), 2.58 (s, 3H).

[0083] 1.2.Preparation of 1-(4-isobutylphenyl)ethanone 1-(4-isobutylphenyl)ethanone was prepared according to the procedure described in 1.1 above using 4-isobutylbenzene (1 eq.) and acetic anhydride (2 eq.). The yield was 80%. 1 H NMR (CDCl3): d 7.8 (d, 2H, J=7.0 Hz), 7.22 (d, 2H, J=7.0 Hz), 2.50 (s, 3H), 2.45 (d, 2H, J=7.0 Hz), 1.80 (m, 1H), 0.83 (d, 6H, J=7.0 Hz). 13 C NMR (CDCl3): 197.8, 147.6, 135, 129.3, 128.3, 45.4, 30.1, 26.5, 22.3.

[0084] 1.3. Preparation of 1-(4-hydroxyphenyl)nonan-1-one 1-(4-Hydroxyphenyl)nonan-1-one was prepared from phenol and nonanoic acid according to the procedure described in 1.1 above in quantitative yield. 1 H(CDCl3): 7.84 (2H, d, J = 8.97 Hz), 6.87 (2H, d, J = 8.97 Hz), 2.86 (2H, t, J = 7.32 Hz), 1.65 (2H, m), 1.29 (10H, m), 0.79 (3H, t, J = 7.14 Hz); 13 C(CDCl3): 200.4, 161, 130.8, 129.5, 115.4, 38.4, 31.8, 29.4, 29.1, 24.9, 22.65, 14.09.

[0085] 1.4. Preparation of 4-hydroxybenzophenone 4-Hydroxybenzophenone was prepared according to the procedure described in 1.1 above using phenol and benzoic acid at a temperature of 60° C. The yield was 60%. 1 H NMR (300 MHz, CDCl3): δ = 7.71-7.65 (m, 4H), 7.56 (tt, J = 7.4, 1.7 Hz, 1H), 7.49-7.43 (m, 2H,), 6.88 (tt, J = 9.5, 2.4 Hz, 2H). 13 C NMR (75 MHz, CDCl3): δ = 197.8, 161.0, 138.0, 133.2, 132.2, 129.9, 129.4, 115.5.

[0086] 1.5.Preparation of 4-methoxybenzophenone 4-Methoxybenzophenone was prepared according to the procedure described in 1.1 above using anisole and benzoic acid at a temperature of 60° C. The yield was 65%. 1H NMR (CDCl3): δ = 7.83 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 7.5 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H). 13 C NMR (CDCl3): δ = 195.5, 163.1, 138.2, 132.5, 131.8, 130.0, 129.6, 128.1, 113.5, 55.4.

[0087] 1.6. Preparation of (4-hydroxyphenyl)-(3,4,5-trihydroxyphenyl)methanone (4-Hydroxyphenyl)-(3,4,5-trihydroxyphenyl)methanone was prepared according to the procedure described in 1.1 above using phenol and 3,4,5-trihydroxybenzoic acid at a temperature of 120° C. The yield was 55%. 1H NMR (MeOD): δ = 7.67 (d, J = 7.5Hz, 2H), 6.86 (d, J = 7.5 Hz, 2H), 6.82 (s, 2H).

[0088] 1.7. Preparation of 4-chlorobenzophenone 4-Chlorobenzophenone was prepared according to the procedure described in 1.1 above using chlorobenzene and benzoyl chloride at a temperature of 120° C. The yield was 63%. 1 H NMR (300 MHz, CDCl3): δ 7.78-7.75 (m, 4 H), 7.62-7.59 (m, 1 H), 7.51-7.46 (m, 4 H).

[0089] 2. Preparation of Paracetamol

[0090] 2.1. Step 1: Acylation of phenol 4-Hydroxyacetophenone was prepared according to the procedure described in 1.1. above.

[0091] 2.2. Step 2: Baeyer-Villiger reaction with 4-hydroxyacetophenone A 25 mL three-necked round bottom flask was charged with 10 g (74 mmol) of 4-hydroxyacetophenone and 14 mL (370 mmol; 5 equiv.) of formic acid. 5 mL (50% aqueous solution) of 1.2 equiv. of hydrogen peroxide (H2O2) was carefully added dropwise via syringe pump over 1 h at -10 °C. After complete addition of hydrogen peroxide, the reaction was allowed to warm slowly to room temperature over 15 h. After extraction with ethyl acetate, drying and concentration, the desired product was obtained in 86% yield. 1 H NMR of the product, 300 MHz, CDCl3: 6.94 (d, 2H), 6.78 (d, 2H), 2.29 (s, 3H). 13 C NMR: 171.3, 153.6, 143.5, 122.2, 116.1, 116.0, 20.9.

[0092] 2.3. Step 3: Nucleophilic substitution reaction Acetylhydroquinone / hydroquinone mixture (44.0 g, 0.4 mol, 1 equiv.), ammonium acetate (63.0 g, 0.8 mol, 2 equiv.), and acetic acid (114 mL, 2 mol, 5 equiv.) were added to a Parr Instrument 300 mL reaction vessel equipped with a thermometer and mechanical stirrer. The autoclave was purged with argon and heated to 160 °C (using a heating mantle) before stirring. The temperature was further increased to 230 °C and the mixture was stirred at this temperature for 15 h. The reaction vessel was cooled to room temperature and the homogenous mixture was transferred to a 250 mL flask (a sample was taken at this stage for HPLC analysis). A distillation apparatus was then installed and the acetic acid was evaporated under reduced pressure. A total of 98 mL was collected, which corresponds to a recovery of 85%. The reaction mixture was cooled to room temperature and the precipitate was filtered, washed with water (2 x 20 mL) and dried to give paracetamol (53.0 g, 88%) as a white solid with a purity of 99% by HPLC analysis. 1 13C NMR (CD3OD, 125 MHz): δ 171.3, 155.4, 131.7, 123.3, 116.2, 23.5.

[0093] 2.4. Acetic acid-free alternatives

[0094] Ammonium acetate Hydroquinone (5.5 g, 1 equiv.) and ammonium acetate (38.5 g, 10 equiv.) were added to a 100 mL Parr Instrument reaction vessel equipped with a temperature sensor and mechanical stirrer. The autoclave was heated to 260° C. The mixture was stirred at this temperature for 1 h. The observed pressure was 26 bar. At the end of the reaction, the conversion of hydroquinone was up to 90% with a selectivity of more than 95%.

[0095] Hydroquinone (2.75 g, 1 equiv.) and ammonium acetate (38.5 g, 20 equiv.) were added to a 100 mL Parr Instrument reaction vessel equipped with a temperature sensor and mechanical stirrer. The autoclave was heated to 280° C. The mixture was stirred at this temperature for 30 min. The observed pressure was 32 bar. At the end of the reaction, the conversion of hydroquinone was up to 95%. 1 13C NMR (CD3OD, 125 MHz): δ 171.3, 155.4, 131.7, 123.3, 116.2, 23.5.

[0096] 2.4.2. Acetamide / water mixture Hydroquinone (5.5 g, 1 equiv.) and acetamide (10 equiv.) and water (10 equiv.) were added into a 100 mL Parr Instrument reactor equipped with a temperature sensor and mechanical stirrer. The autoclave was heated to 260° C. The mixture was stirred at this temperature for 1 h. The observed pressure was 26 bar. At the end of the reaction, the conversion of hydroquinone was up to 90% and the selectivity was more than 95%.

[0097] Separation of the reaction mixture as described above gave paracetamol and also 9 equivalents of acetamide which could be reused in other syntheses.

[0098] 2.4.3. EP 2 860 172: Comparative Example (15 h, 220° C.). The same procedure using hydroquinone (1 equivalent) and ammonium acetate (10 equivalents) at 220° C. for 15 hours gives a conversion of 96% of hydroquinone, but only a selectivity of 79%.

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, R 1 teeth - a hydroxy group, - (C 1 ~C 18 ) alkyl groups, - (C 1 ~C 6 ) alkoxy groups, and - Halogen groups is a radical selected from the group consisting of: R 2 teeth - (C 1 ~C 18 ) alkyl groups, phenyl optionally substituted with at least one hydroxy group, and - (C 1 ~C 6 ) alkoxy group is a radical selected from the group consisting of 1. A method for preparing a compound of formula (I), comprising the steps of: a) Formula (II): 【Chemistry 2】 (In the formula, R 1 is defined above) with methanesulfonic acid and a compound of formula (III): 【Transformation 3】 (In the formula, R 2 is defined above, R 3 is a hydroxy group, -O-CO-CH 3 Group, (C 1 ~C 6 ) an alkoxy group, and chlorine. with a compound of formula (I); and b) recovering the compound of formula (I). A method comprising:

2. R 2 but - (C 1 ~C 18 ) alkyl groups, - a phenyl group, and - (C 1 ~C 6 ) alkoxy group 2. The method of claim 1, wherein the radical is selected from the group consisting of:

3. 2. The process according to claim 1, wherein the reaction in step a) is carried out at a temperature of from 30°C to 130°C, preferably from 40°C to 60°C, more preferably at about 50°C.

4. 2. The method according to claim 1, wherein in step a), 1 to 5 equivalents, preferably 1 to 3 equivalents, more preferably 1 to 2.5 equivalents, even more preferably 1, 1.5, or 2.5 equivalents of the compound of formula (III) are used relative to the compound of formula (II).

5. The compound of formula (I) is R 1 is a hydroxy group, and R 2 is a methyl group, and the compound of formula (II) is 1 is a hydroxy group, and the compound of formula (III) is 2 is a methyl group, and R 3 The method of claim 1 , wherein is a hydroxy group.

6. The following steps: a) reacting phenol with methanesulfonic acid and acetic acid at a temperature of about 50° C. using 1 to 5 equivalents, preferably 1 to 3 equivalents, more preferably 1 to 2.5 equivalents, and even more preferably 1, 1.5, or 2.5 equivalents of acetic acid relative to the phenol; and b) recovering 4-hydroxyacetophenone The method of claim 1 , comprising:

7. The following steps: a) - b) carrying out the method defined in claim 5; c) reacting 4-hydroxyacetophenone with formic acid and hydrogen peroxide; d) reacting the mixture obtained in step c) with ammonium acetate and acetic acid; and e) recovering the paracetamol 1. A method for preparing paracetamol, comprising:

8. The following steps: a) reacting phenol with methanesulfonic acid and acetic acid at a temperature of about 50° C. using 2.5 equivalents of acetic acid relative to the phenol; b) recovering 4-hydroxyacetophenone; c) reacting 4-hydroxyacetophenone with formic acid and hydrogen peroxide; d) reacting the mixture obtained in step c) with ammonium acetate and acetic acid; and e) recovering the paracetamol The method of claim 7, comprising:

9. 8. The method of claim 7, further comprising purifying the mixture obtained in step c) to obtain hydroquinone.

10. The following steps: - reacting hydroquinone with ammonium acetate or acetamide and water at a temperature ranging from 240°C to 300°C for 1 minute to 12 hours using 1 to 50 equivalents of ammonium acetate or acetamide relative to hydroquinone in the absence of acetic acid; and - Paracetamol recovery process 1. A method for preparing paracetamol, comprising:

11. 11. A process for preparing paracetamol as claimed in claim 10, wherein hydroquinone and ammonium acetate are reacted at a temperature of about 260°C for about 1 hour using 10 equivalents of ammonium acetate relative to hydroquinone.

12. 11. A process for preparing paracetamol according to claim 10, wherein hydroquinone, acetamide and water are reacted at a temperature of about 260°C for about 1 hour using 10 equivalents of acetamide and 10 equivalents of water relative to hydroquinone.

13. The compound of formula (I) is R 1 But (C 1 ~C 6 ) an alkyl group, preferably an isobutyl group, and R 2 is a methyl group, and the compound of formula (II) is 1 But (C 1 ~C 6 ) alkyl group, preferably an isobutyl group, and the compound of formula (III) is R 2 is a methyl group, and R 3 -O-CO-CH 3 The method of claim 1 , wherein the aryl group is a aryl group.

14. The following steps: a) reacting 4-isobutylbenzene with methanesulfonic acid and acetic anhydride at a temperature of about 50° C. using two equivalents of acetic anhydride relative to the 4-isobutylbenzene; and b) recovering 1-(4-isobutylphenyl)ethanone The method of claim 1 , comprising:

15. The following steps: a) preparing 1-(4-isobutylphenyl)ethanone by the method of claim 14; and b) obtaining ibuprofen from the 1-(4-isobutylphenyl)ethanone intermediate recovered in step a) 1. A method for preparing ibuprofen, comprising:

16. The compound of formula (I) is R 1 is a radical selected from the group consisting of hydroxy, methoxy, and chlorine; R 2 is a radical selected from the group consisting of octyl and phenyl optionally substituted with at least one hydroxy group, preferably phenyl substituted with three hydroxy groups, The compound of formula (II) is R 1 is a radical selected from the group consisting of hydroxy, methoxy, and chlorine; The compound of formula (III) is R 2 is a radical selected from the group consisting of octyl and phenyl optionally substituted with at least one hydroxy group, preferably phenyl substituted with three hydroxy groups, and R 3 The method of claim 1 , wherein is a hydroxy group or chlorine.

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