Process for the preparation of para-aminophenol and its derivatives

Abstract

Process for the preparation of para-aminophenol and its derivatives The present invention relates to a process for the preparation of a compound of formula (I): wherein X represents CR23 or N, Y represents CR24 or N, R1 represents H or a COR3 group, R21, R22, R23 and R24 independently represent hydrogen, halogen, nitro, cyano, CF3, (C1-C6)-alkyl, COOH, COR4, COOR5 or CONR6R7, R3, R4 and R5 independently represent (C1-C6)-alkyl, and R6 and R7 independently represent hydrogen or a (C1-C6)-alkyl group. Figure for abstract: none

Description

Title of the invention: Process for the preparation of para-aminophenol and its derivatives

[0001] The present invention relates to a process for the preparation of p-aminophenol derivatives from a nitrobenzene derivative.

[0002] p-Aminophenol or para-aminophenol (PAP) is a widely used compound in the pharmaceutical industry. This molecule is particularly involved in the production of paracetamol, a chemical compound that is an analgesic and antipyretic and is one of the most widely consumed drugs in the world.

[0003] p-Aminophenol can be obtained by hydrogenation of nitrobenzene catalyzed by metals and in the presence of sulfuric acid followed by a Bamberger-type rearrangement. However, this process requires the use of rare metals such as platinum as a catalyst, considered a critical raw material in Europe, and by-products such as aniline are generated in large quantities. Industrially, this process requires access to pure hydrogen in workshops specifically designed to manage potentially explosive gases.

[0004] Patent application CN 114957035 describes a step for reducing nitrobenzene photochemically, but with nitrobenzene concentrations so low that they are not viable from an industrial point of view. Furthermore, this application does not describe a rearrangement of phenylhydroxylamine into p-aminophenol.

[0005] There is therefore a need for a process for preparing p-aminophenol derivatives which can be carried out on an industrial scale, is inexpensive, does not use potentially explosive gas and generates few undesirable by-products or waste to be specifically reprocessed such as metals.

[0006] To this end, the present invention relates to a process for preparing a compound of the following formula (I):

[0007] [Chem.l] OH (|)

[0008] in which:

[0009] X represents CR23 or N, preferably CR23,

[0010] Y represents CR24 or N, preferably CR24,

[0011] R1 represents H or a COR3 group,

[0012] R21, R22, R23 and R24 independently represent hydrogen, halogen, nitro group, a cyano group, a CF3 group, a (Ci-C6)-alkyl group, a COOH, COR4, COOR5 or CONR6R7 group,

[0013] R3, R4 and R5 independently represent a (C1-C6)-alkyl, and

[0014] R6 and R7 independently represent a hydrogen or a (Ci-C6)-alkyl group,

[0015] the method comprising:

[0016] a) the photochemical reduction of a compound of formula (II):

[0017] [Chem.2]

[0018] in which X, Y, R21 and R22 are as defined above,

[0019] in the presence of a secondary alcohol,

[0020] whereby a compound of formula (III) is formed:

[0021] [Chem.3]

[0022] b) bringing the compound obtained in the previous step into contact with an acid, whereby a rearrangement takes place, whereby the compound of formula (I) is formed,

[0023] the process further comprising, when R1 is a COR3 group, an additional step b') of Y-acylation by an acylating agent carrying a COR3 group.

[0024] Preferably, X and Y do not both represent N.

[0025] Step b) corresponds to a Bamberger-type rearrangement and makes it possible to obtain a compound of formula (I) which comprises an NHR1 group and an OH group in positions (1,4) on the ring.

[0026] As (Ci-C6)-alkyl group, preferred are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl and n-hexyl groups, preferably groups methyl, ethyl, n-propyl, z-isopropyl, and t-butyl.

[0027] In the compound of formula (I), (II) and (III), R21, R22, R23 and R24 independently represent a hydrogen, a halogen, a nitro group, a cyano group, a CF3 group, a (Ci-C6)-alkyl group, a COOH, COR4 or COOR5 or CONR6R7 group.

[0028] In particular, X represents CR23, Y represents CR24 and R21, R22, R23 and R24 independently represent a hydrogen, a halogen, a nitro group, a CF3 group, a (Ci-C6)-alkyl group, a COOH group, preferably one of the groups chosen from R21, R22, R23 and R24 represents a hydrogen, a halogen, a nitro group, a CF3 group, a (Ci-C6)-alkyl group, a COOH group and the other remaining groups from R 21, R22, R23 and R24 represent a hydrogen.

[0029] In particular, X represents N, Y represents CR24 and R21, R22 and R24 independently represent a hydrogen, a halogen, a nitro group, a CF3 group, a (C i-C6)-alkyl group, a COOH group, preferably one of the groups chosen from R21, R22 and R24 represents a hydrogen, a halogen, a nitro group, a CF3 group, a (Ci-C6)-alkyl group, a COOH group and the other remaining groups from R21, R22 and R24 represent a hydrogen.

[0030] In particular, X represents CR23, Y represents N and R21, R22 and R23 independently represent a hydrogen, a halogen, a nitro group, a CF3 group, a (C i-C6)-alkyl group, a COOH group, preferably R21, R22 and R23 represent a hydrogen or one of the groups chosen from R21, R22 and R23 represents a hydrogen, a halogen, a nitro group, a CF3 group, a (Ci-C6)-alkyl group, a COOH group and the other remaining groups from R21, R22 and R23 represent a hydrogen.

[0031] Preferably, R22 represents hydrogen, halogen, nitro or (C1-C6)alkyl, or R21 represents hydrogen or CF3.

[0032] Preferably, R22 represents a halogen or a nitro group.

[0033] Alternatively, X represents CR23, Y represents CR24 and R21, R22, R23 and R24 represent H.

[0034] Alternatively, X represents N, Y represents CR24 and R21, R22 and R24 represent H.

[0035] Alternatively, X represents CR23, Y represents N and R21, R22 and R23 represent H.

[0036] Preferably, R1 represents H or a COMe, COEt or COnPr group. In particular, R1 represents H or a COMe group.

[0037] In particular, the compound of formula (II) is nitrobenzene. Thus, the compound of formula (III) is phenylhydroxylamine and the compound of formula (I) is para-aminophenol when R1 represents H and paracetamol when R1 represents COCH3.

[0038] The process comprises a step a) of photochemical reduction of a compound of formula (II) as defined above in the presence of a secondary alcohol, whereby a compound of formula (III) as defined above is formed.

[0039] Step a) is a photochemical reduction and therefore takes place in the presence of a source of light emitting in the visible or ultraviolet range. Preferably, step a) is carried out at a wavelength of 320 nm to 410 nm, preferably 340 nm to 405 nm, more preferably 350 to 400 nm.

[0040] Step a) can be carried out continuously or discontinuously.

[0041] The duration of step a) depends on the surface area of exposure of the reaction medium to the light source.

[0042] Preferably, the photochemical reduction of step a) takes place under an inert atmosphere, for example under nitrogen or under argon.

[0043] Preferably, the reaction of step a) takes place at a temperature of from 0°C to 100°C, preferably from 3°C to 90°C, preferably from 5°C to 80°C.

[0044] Step a) is preferably carried out in the presence of water, preferably in the presence of 1 to 500 equivalents of water relative to the compound of formula (II), preferably in the presence of 2 to 300 equivalents of water, preferably in the presence of 3 to 200 equivalents of water, preferably in the presence of 4 to 160 equivalents of water.

[0045] Preferably, in step a), the secondary alcohol is chosen from isopropanol, 3-pentanol, 2-butanol and a mixture thereof, preferably isopropanol.

[0046] Preferably, the secondary alcohol is generally useful as both a reactant and a solvent.

[0047] Typically, the solvent is secondary alcohol, or a mixture of secondary alcohols, this solvent being able to contain water (in particular in the quantities indicated above), or be free of it.

[0048] According to one embodiment, step a) is carried out without water.

[0049] Typically, step a) does not include any solvent other than the secondary alcohol.

[0050] During step a), the concentration of the compound of formula (II) in the secondary alcohol is from 0.01 M to 5 M, preferably from 0.05 M to 2 M, preferably from 0.03 M to 1 M, preferably from 0.04 M to 0.8 M, preferably from 0.05 M to 0.5 M. In particular, it is greater than 0.05 M, preferably greater than 0.1 M, preferably greater than or equal to 0.2 M.

[0051] Advantageously, the acetone formed in step a) can be removed from the reaction medium, for example by continuous distillation or by discontinuous distillation.

[0052] Step a) may optionally be followed by a step of purification of the compound of formula (III) as defined above. For example, the compound of formula (III) is purified by chromatography on silica gel, by crystallization, by recrystallization or by distillation.

[0053] Preferably, the process according to the invention is free from isolation of the compound of formula (III).

[0054] Preferably, in step b), the acid has a pKa of less than 3, preferably less than 1.

[0055] According to a first alternative, R1 represents H. The process is then free of step b') of yV-acylation by an acylating agent carrying a COR3 group. The process according to the invention is then illustrated by the following scheme:

[0056] [Chem.4]

[0057] According to this alternative, the method comprises:

[0058] a) the photochemical reduction of a compound of formula (II) as defined above in the presence of a secondary alcohol, whereby a compound of formula (III) is formed,

[0059] b) bringing the compound (III) obtained in the previous step into contact with an acid, whereby a rearrangement takes place, whereby the compound of formula (I) as defined above and in which R1 represents H is formed.

[0060] Preferably, during step b) of this first alternative, the acid has a pKa of less than 3, preferably less than 1.

[0061] The acid can be organic or inorganic.

[0062] Sulfuric acid is an example of a usable inorganic acid.

[0063] In particular, during step b) according to this first alternative, the acid is chosen from organic acids, preferably organic acids carrying at least one halogen, a sulfonic group or a salt thereof, optionally supported on a solid support. Among the organic acids carrying at least one usable halogen, trifluoromethanesulfonic acid (TfOH), trifluoroacetic acid (TFA), Br2CHCOOH, CCl3COOH and C12CHCOOH may be mentioned. p-Toluenesulfonic acid (TsOH) and sulfonic acid-based ion exchange resins, such as Amberlyst™ 15 or SPEEK, are examples of organic acids carrying at least one sulfonic group or a salt thereof.

[0064] Preferably, the acid is chosen from H2SO4, TsOH and TFA.

[0065] The reaction of step b) is preferably carried out for at least 2 hours, preferably for at least 3 hours, preferably for at least 4 hours.

[0066] The reaction of step b) is preferably carried out at a temperature of at least 50°C, preferably at least 60°C, preferably at least 70°C.

[0067] According to this alternative, the compound of formula (I) obtained can be purified by for example by chromatography on silica, by crystallization, by recrystallization or by distillation.

[0068] Preferably, steps a) and b) are carried out in a single-pot manner. Preferably, the reactants of steps a) and b), namely the secondary alcohol and the acid, are brought into contact with the compound of formula (II), and the reactions of steps a) and b) take place successively without isolating the compound of formula (III) (intermediate product). In this case, the irradiation of step a) takes place in the presence of the acid of step b). Thus, as soon as the compound of formula (III) is formed, it reacts with the acid to form the compound of formula (I). Typically, the secondary alcohol and the acid are added simultaneously to the compound of formula (II).

[0069] When steps a) and b) are carried out in a single-step and successive manner, without isolating the compound of formula (III), step b) is preferably carried out in the presence of 1 to 4 equivalents of acid relative to the compound of formula (II) (and therefore in the presence of 1 to 4 equivalents of acid relative to the compound of formula (III) when the conversion of step a) is complete).

[0070] By "monotopic" is meant that the compound of formula (II) undergoes several successive reactions, namely steps a) and b), in a single container or reactor.

[0071] However, a person skilled in the art would be dissuaded from carrying out steps a) and b) in a monotopic manner by bringing the reactants of steps a) and b), namely the secondary alcohol and the acid, into contact with the compound of formula (II) and without isolating the compound of formula (III), for fear of polymerization and / or degradation of the reaction medium. Indeed, it is then necessary to add acid (required for step b) to a medium comprising a secondary alcohol (required for step a). The inventor observed that the two reactions could be carried out in a monotopic manner without any degradation being observed. A monotopic reaction saves time, because the reaction intermediate of formula (III) is not isolated. Advantageously, a monotopic reaction makes it possible to reduce the quantities of solvents used, and to improve the overall chemical yield.

[0072] According to a second alternative, R1 represents a COR3 group in which R3 is as defined above, preferably R3 is methyl or ethyl.

[0073] According to this second alternative, the method comprises:

[0074] a) the photochemical reduction of a compound of formula (II) as defined above in the presence of a secondary alcohol, whereby a compound of formula (III) is formed,

[0075] b) bringing the compound (III) obtained in the previous step into contact with an acid, whereby a rearrangement takes place, whereby the compound of formula (I) as defined above is formed, and

[0076] b') a step of A-acylation by an acylating agent carrying a COR3 group.

[0077]

[0078] According to this second alternative, two reaction pathways are possible depending on the order between steps b) and b'). These two pathways are illustrated in the following reaction scheme. [Chem. 5] mht

[0079]

[0080] According to a first route of this second alternative, step b) takes place before step b'). The following reaction scheme illustrates this first route. [Chem. 6] HO. acid TRACK 1 aqent acy ta ot OH

[0081]

[0082]

[0083] The process then includes: (a) the photochemical reduction of a compound of formula (II) as defined above in the presence of a secondary alcohol, whereby a compound of formula (III) as defined above is formed, b) bringing the compound (III) obtained in the previous step into contact with an acid, whereby a rearrangement takes place and a compound of the following formula (VI) is formed:

[0084] [Chem.7]

[0085] in which X, Y, R21 and R22 are as defined above, then

[0086] b') the V-acylation of the compound of formula (VI) with the acylating agent bearing a group COR3, whereby the compound of formula (I) in which R1 represents COR3 is formed.

[0087] In the first route of this second alternative, step b) is preferably carried out in the presence of at least 1 equivalent, preferably in the presence of at least 1.5 equivalents, preferably in the presence of at least 5 equivalents, preferably in the presence of at least 8 equivalents, preferably in the presence of at least 10 equivalents, of acid relative to the compound of formula (III).

[0088] Step b) is preferably carried out at a temperature of at least 50°C, preferably at least 60°C, preferably at least 65°C, preferably at least 70°C. In particular, the reaction of step b) is, in this first route, carried out for at least 2 hours, preferably for at least 3 hours, preferably for at least 4 hours.

[0089] In this first route, the compound of formula (VI) obtained can be purified, for example by chromatography on silica, by crystallization, by recrystallization or by distillation.

[0090] Preferably, in the first route of this second alternative, steps a) and b) are carried out in a monotopic manner. Preferably, the reactants of steps a) and b), namely the secondary alcohol and the acid, are brought into contact with the compound of formula (II), and the reactions of steps a) and b) take place successively without isolating the compound of formula (III) (intermediate product). In this case, the irradiation of step a) takes place in the presence of the acid of step b). Thus, as soon as the compound of formula (III) is formed, it reacts with the acid to form the compound (VI). Typically, the secondary alcohol and the acid are added simultaneously to the compound of formula (II).

[0091] When steps a) and b) are carried out in a single-step and successive manner, without isolating the compound of formula (III), step b) is preferably carried out in the presence of 1 to 4 equivalents of acid relative to the compound of formula (II) (and therefore in the presence of 1 to 4 equivalents of acid relative to the compound of formula (III) when the conversion of step a) is complete).

[0092]

[0093] According to a second route of this second alternative, step b') takes place before step b). The following reaction scheme illustrates this second route. [Chem. 8]

[0094]

[0095]

[0096]

[0097] The process then includes: (a) the photochemical reduction of a compound of formula (II) as defined above in the presence of a secondary alcohol, whereby a compound of formula (III) as defined above is formed, b') the yV-acylation of the compound of formula (III) with the acylating agent bearing a COR3 group, whereby a compound of the following formula (VII) is formed: [Chem.9] O

[0098]

[0099]

[0100] in which X, Y, R21 and R22 are as defined above and R3 represents a (CrC 6)-alkyl, then b) contacting the compound of formula (VII) with an acid, whereby a rearrangement takes place and the compound of formula (I) in which R1 represents COR3 is formed. The compound of formula (VII) as described above, formed during step b'), can then be recovered by liquid-liquid extraction and purified for example by crystal lization, by recrystallization, or by chromatography on silica. For example, the aqueous phase of the reaction mixture can be extracted with a suitable solvent, such as a polar aprotic solvent such as ethyl acetate, then the organic phase comprising the recovered compound of formula (VII) can be dried, for example over an anhydrous salt such as MgSO4, concentrated under reduced pressure and the residue is recrystallized from toluene, or purified by chromatography on silica gel.

[0101] In the second route of this second alternative, steps a) and b') can be carried out sequentially. In this case, the reaction of step a) is first carried out, then the acylating agent of step b') is added to the solution comprising the compound of formula (III) obtained at the end of step a).

[0102] When steps a) and b') are carried out sequentially, step b') is preferably carried out at a temperature below 10°C, preferably below 5°C, preferably below 2°C, preferably below 1°C. Preferably, the duration of step b') is at least 60 min, preferably at least 90 min, preferably at least 120 min.

[0103] In the second route of this second alternative, steps a) and b') can be carried out in a monotopic manner. Preferably, the reactants of steps a) and b'), namely the secondary alcohol and the acylating agent, are brought into contact with the compound of formula (II), and the reactions of steps a) and b') take place successively without isolating the compound of formula (III) (intermediate product). In this case, the irradiation of step a) takes place in the presence of the acylating agent of step b') and step b') takes place in the presence of a secondary alcohol. Thus, as soon as the compound of formula (III) is formed, it reacts with the acylating agent to form the compound of formula (VII). Typically, the secondary alcohol and the acylating agent are added simultaneously to the compound of formula (II).

[0104] In the case where steps a) and b') are carried out in a monotopic manner, preferably, the reaction takes place at room temperature (20°C).

[0105] When steps a) and b') are carried out in a single-step manner, the compound of formula (VII) formed can then be purified, for example, by chromatography on silica, by crystallization, by recrystallization or by distillation.

[0106] This second alternative comprises, in the first route and the second route, a step b') of V-acylation, by an acylating agent carrying a COR3 group.

[0107] Preferably, the acylating agent is chosen from the compounds of formula (IV) or (V):

[0108] [Chem 10]

[0109] R3-CO-R8 (IV)

[0110] in which R3 is as defined above and R8 is a halogen, in particular a bromine atom or a chlorine atom, a mesylate, a tosylate or a triflate [YES] or

[0112] [Chem 11]

[0113] R3-CO-O-CO-R3 (V)

[0114] wherein R3 is as defined above.

[0115] Preferably, R3 represents a methyl or ethyl group.

[0116] Preferably, the acylating agent is chosen from acetyl chloride or acetic anhydride.

[0117] During step b'), the acylating agent can be introduced in the form of a solution in a preferably organic solvent, for example in diethyl ether.

[0118] Step b') may take place in isopropanol. Isopropanol may be the solvent for the A-acylation reaction, particularly when step a) and step b') are carried out in a one-pot manner.

[0119] In particular, step b') takes place in the presence of 0.1 to 4 equivalents, preferably 0.5 to 2 equivalents of acylating agent relative to the compound of formula (II).

[0120] Preferably, step b') takes place at a temperature below 110°C, preferably below 100°C, preferably below 90°C.

[0121] Preferably, step b') takes place at room temperature (20°C).

[0122] The duration of step b') is typically at least 30 min, preferably at least 45 min, preferably at least 60 min, at least 90 min, preferably at least 120 min.

[0123] Step b') can also take place without an acylating agent as described above, but in the presence of an excess of acetic acid at high temperature under conditions usual for those skilled in the art.

[0124] Preferably, during step b) of routes 1 and 2 of this second alternative, the acid has a pKa of less than 3, preferably less than 1.

[0125] The acid can be organic or inorganic.

[0126] Sulfuric acid is an example of a usable inorganic acid.

[0127] In particular, during step b) of this second alternative, for routes 1 and 2, the acid is chosen from organic acids, preferably organic acids carrying at least one halogen, a sulfonic group or a salt thereof, optionally supported on a solid support. Among the organic acids carrying at least one halogen that can be used, mention may be made of trifluoromethanesulfonic acid (TfOH), trifluoroacetic acid (TFA), CCl3COOH, Br2CHCOOH and C12CHCOOH. p-Toluenesulfonic acid (TsOH) and sulfonic acid-based ion exchange resins, such as Amberlyst™ 15, are examples of organic acids carrying at least one sulfonic group or a salt thereof.

[0128] Preferably, during step b) of routes 1 and 2 of this second alternative, the acid is chosen from TfOH, TsOH, TFA and CC13COOH.

[0129] Preferably, during step b) of route 2 of this second alternative, the acid is chosen from TFA and CCI3COOH.

[0130] Preferably, the methods according to the first or second alternative are carried out continuously.

[0131] Advantageously, the first two steps of the processes according to the first or second alternative (i.e. steps a) and b) for the first alternative and route 1 of the second alternative, and steps a) and b') for route 2 of the second alternative) are carried out in a single-pot and successive manner, without isolating the compound of formula (III). Preferably, the reactants of these first two steps (i.e. the secondary alcohol and the acid for carrying out steps a) and b) are brought into contact with the compound of formula (II) for the first alternative and route 1 of the second alternative, and the secondary alcohol and the acylating agent are brought into contact with the compound of formula (II) for carrying out steps a) and b') for route 2 of the second alternative), and the reactions of these first two steps take place successively without isolating the compound of formula (III) (intermediate product).

[0132] The term “equivalent” or “eq.” means molar equivalent.

[0133] Other advantages and characteristics of the present invention will appear from the illustrative examples set out below. EXAMPLES

[0134] I. Step a): photochemical reduction of a nitrobenzene derivative in the presence of a secondary alcohol to obtain an aromatic hydroxylamine

[0135] General procedure:

[0136] A solution of compound of formula (II) at different concentrations in a suitable solvent (alcohol and optionally water) is injected at a flow rate of 0.54 mL.min 1 into a Corning® AFRTM G11F photoreactor (reactor volume: 10.8 mL, residence time: 20 min). Irradiation takes place at different wavelengths with a power of 140 mW.cm2, at different temperatures. After 20 min of reactor stabilization, the solution is collected in a flask under positive argon pressure.

[0137] For a second cycle, the collected solution is injected again into the reactor (0.54 mL.min *, residence time 20 min). After 20 min of reactor stabilization, the solution is collected in a bottle under positive argon pressure.

[0138] After irradiation, the collected solution is concentrated under reduced pressure to obtain a crude mixture. The crude mixture is analyzed by 'H NMR to evaluate the conversion rate of the compound of formula (II) to the corresponding compound of formula (III). In some cases the corresponding compound of formula (III) is purified by silica gel chromatography (for phenylhydroxylamine, the elution gradient is pentane / AcOEt = 1:0 to 8:2).

[0139] 1.1. Influence of alcohol

[0140] According to the general procedure, a solution of nitrobenzene in an alcohol ROH (c = 0.06 M) is irradiated at 20 °C according to the conditions described in Table 1 below. The results are shown in Table 1.

[0141] [Tables 1] ROH Input Wavelength (nm) Number of cycles (time in minutes) Conversion rate (%) 1 EtOH 365 1(20) 0 2 t-BuOH 365 1(20) 0 3 z'PrOH 365 1(20) 83 4 z'PrOH 385 2(40) 100 5 3-pentanol 385 2(40) 90 6 z'PrOH 405 2(40) 40

[0142] The reaction of step a) does not work with a primary alcohol or a tertiary alcohol. It is necessary to have a secondary alcohol.

[0143] Furthermore, the reaction works with a secondary alcohol at different wavelengths: 365 nm, 385 nm and 405 nm.

[0144] 1.2. Influence of water

[0145] According to the general procedure, a solution of nitrobenzene in isopropanol (c = 0.06 M) in the presence of water is irradiated at 385 nm, at 20°C for two cycles (2 x 20 min) according to the conditions described in Table 2 below. The results are shown in Table 2. The quantities of water are indicated in water equivalents relative to nitrobenzene.

[0146] [Tables2] Water inlet (eq.) Insulated efficiency (%) 1 0 65 2 20 73 3 200 90

[0147] The reaction works without water, but it is noted that the presence of water makes it possible to increase the yield.

[0148] 1.3. Influence of the nature of the compound of formula (II)

[0149] According to the general procedure, a solution of compound of formula (II) in iso- propanol (c = 0.06 M) in the presence of water (20 eq.) is irradiated at 385 nm, at 20 °C for two cycles (2 x 20 min) according to the conditions described in Table 3 below. The results are shown in Table 3.

[0150] [Tables3] Input XY R21 R22 Conversion rate (%) 1 CH CH H no2 100 2 CH CH H Cl 100 3 CH CH HF 98 4 CH CH cf3 H 60 5 CH CH H Me 80 6 N CH HH 80 7 CH NHH 100

[0151] 1.4. Influence of temperature

[0152] According to the general procedure, a solution of compound of formula (II) in isopropanol (c = 0.06 M) is irradiated at 385 nm at different temperatures for two cycles (2 x 20 min) according to the conditions described in Table 4 below. The results are shown in Table 4.

[0153] [Tables4] Input Temperature (°C) Conversion Rate (%) 1 5 90 2 20 100 3 60 100

[0154] II. Route 2 - Step b') Æ-acetylation of aromatic hydroxylamine

[0155] General procedure:

[0156] A solution of acetyl chloride (1.01 g, 13.75 mmol, 1.5 eq.) in Et2O (12 mL) is added dropwise to a solution of phenylhydroxylamine (1 g, 9.17 mmol) and NaHCO3 (1.21 g, 13.75 mmol, 1.5 eq.) in Et2O (40 mL) cooled to 0 °C. The reaction mixture is stirred for 2 hours at room temperature (20 °C). The reaction mixture is diluted with water. The aqueous phase is extracted twice with Et2O. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The residue is recrystallized from toluene to obtain N-acetylphenylhydroxylamine, a compound of formula (VII) in which R3 is Me, as a white solid (1.25 g, 8.23 mmol, 90%).

[0157] III. Path 2 - Steps a) and b') sequential or successive

[0158] III. 1. Sequential steps a) and b')

[0159] A solution of nitrobenzene (1 eq.) in isopropanol (c = 0.06 M) is injected at a flow rate of 0.54 mL.min 1 in a Corning® AFRTM G11F photoreactor (reactor volume: 10.8 mL, residence time: 20 min). Irradiation takes place at 385 nm with a power of 140 mW.cm2, at 20 °C. After 20 min of reactor stabilization, the solution is collected in a flask under positive argon pressure.

[0160] For a second cycle, the collected solution is injected again into the reactor (0.54 mL.min-1, residence time 20 min). After 20 min of reactor stabilization, the solution is collected in a bottle under positive argon pressure.

[0161] To the collected solution is added acetyl chloride (1.5 eq.) dropwise at 0 °C. The reaction mixture is stirred at 0 °C for 2 hours. The reaction mixture is then concentrated under reduced pressure to obtain V -acetylphenylhydroxylamine, compound of formula (VII) in which R3 represents a methyl (70%).

[0162] III.2. Successive steps a) and b')

[0163] A solution of nitrobenzene (60 mg, 0.48 mmol), acetic anhydride (40 mg, 0.48 mmol) and H2O (172 mg, 9.6 mmol) in degassed isopropanol (8 mL) is irradiated at 390 nm for 20 hours at 20 °C. The reaction mixture is concentrated under reduced pressure. The residue is then purified by chromatography on silica (elution gradient pentane / AcOEt 1:0 to 8:1) to obtain A-acetylphenylhydroxylamine, compound of formula (VII), as a white solid (36 mg, 0.24 mmol, 50%).

[0164] IV. Step b): rearrangement of aromatic hydroxylamine in the presence of an acid

[0165] IV. 1. according to the first alternative

[0166] To a solution of phenylhydroxylamine, compound of formula (III), in a degassed solvent is added an acid (2 eq.). The reaction medium is heated under argon at 70 °C for 4 hours. The reaction mixture is then cooled to room temperature (20 °C), neutralized by adding an aqueous solution of NaHCO3 to pH 8. The aqueous solution is extracted three times with AcOEt. The combined organic phases are dried over MgSO4, concentrated under reduced pressure. The residue is then purified by chromatography on silica (elution gradient CH2Cl2 / MeOH 1:0 to 9:1 to obtain p-aminophenol, compound of formula (I) in which R1 represents H.

[0167] The results are shown in Table 5.

[0168] [Tables5] Acid Solvent Input Yield (%) 1 z'PrOH / water 1:1 TfOH 70 2 z'PrOH / water 1:1 TsOH.H2O 70 3 z'PrOH / water 1:1 TFA 69 4 z'PrOH / water 1:1 Br2CHCOOH 55 5 z'PrOH / water 1:1 C12CHCOOH 30 6 h2o Amberlyst 15 nd (601)

[0169] 1 according to the crude H NMR ratio with 100% conversion.

[0170] IV.2. according to the second route of the second alternative

[0171] - In the presence of trifluoroacetic acid

[0172] α-Acetylphenylhydroxylamine is dissolved in trifluoroacetic acid (10 eq.) and the reaction mixture is refluxed for 4 hours. The reaction mixture is cooled to room temperature (20 °C) and the trifluoroacetic acid is removed under reduced pressure. The residue is purified by silica chromatography (elution gradient CH2Cl2 / MeOH 1:0 to 8:2) to obtain p-acetylaminophenol, compound of formula (I) (65%).

[0173] - In the presence of trichloroacetic acid

[0174] α-Acetylphenylhydroxylamine (1 eq.) and trichloroacetic acid (10 eq.) are mixed and heated at 70 °C for 4 hours. The reaction mixture is cooled to room temperature (20 °C), diluted with CH2Cl2 and neutralized with saturated aqueous NaHCO3 solution to pH 8. The aqueous phase is extracted 3 times with CH2Cl2. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica chromatography (elution gradient CH2Cl2 / MeOH 1:0 to 8:2) to obtain p-acetylaminophenol, a compound of formula (I) in which R1 represents a COR3 group (67%).

[0175] V. Successive steps a) and b) according to the first alternative

[0176] A solution of nitrobenzene, compound of formula (II), (1 eq.) in a mixture i PrOH / H2O and an acid solution (2 eq.) in a z'PrOH / H2O mixture is injected at a flow rate of 0.54 mL.min 1 into a Corning® AFRTM G11F photoreactor (reactor volume: 10.8 mL, residence time: 20 min). Irradiation takes place at 385 nm with a power of 140 mW.cm2, at 70 °C. After 20 min of reactor stabilization, the solution is collected in a flask under positive argon pressure.

[0177] For a second cycle, the collected solution is injected again into the reactor (0.54 mL.min *, residence time 20 min). After 20 min of reactor stabilization, the solution is collected in a flask under positive argon pressure.

[0178] For a third cycle, the collected solution is injected again into the reactor (0.54 mL.min *, residence time 20 min). After 20 min of reactor stabilization, the solution is collected in a flask under positive argon pressure.

[0179] After irradiation, the collected solution is neutralized by adding a saturated aqueous NaHCO3 solution to pH 8. The aqueous solution is extracted three times with AcOEt. The combined organic phases are dried over MgSO4, concentrated under reduced pressure. The residue is then purified by chromatography on silica (elution gradient CH2Cl2 / MeOH 1:0 to 9:1 to obtain p-aminophenol, compound of formula (I) in which R1 represents H.

[0180] The results are shown in Table 6.

[0181] [Tableauxô] Acid input yield (%) 1 TFA 50 2 H2SO4 67

Claims

Claims

1. A process for the preparation of a compound of formula (I): [Chem. 12] in which: X represents CR23 or N, preferably CR23, Y represents CR24 or N, preferably CR24, R1 represents H or a COR3 group, R21, R22, R23 and R24 independently represent hydrogen, halogen, nitro, cyano, CF3, (Ci-C6)-alkyl, COOH, COR4, COOR5 or CONR6R7, R3, R4 and R5 independently represent (Ci-C6)-alkyl, and R6 and R7 independently represent hydrogen or a (Ci-C6)-alkyl group, the process comprising: a) the photochemical reduction of a compound of formula (II): [Chem. 13] H (M) in which X, Y, R21 and R22 are as defined above, in the presence of a secondary alcohol, whereby a compound of formula (III) is formed: [Chem. 14] HQ NH H (!H)

2.

3.

4.

5.

6.

7.

8.

9. b) bringing the compound obtained in the previous step into contact with an acid, whereby a rearrangement takes place, whereby the compound of formula (I) is formed, the process further comprising, when R1 is a COR3 group, an additional step b') of V-acylation by an acylating agent carrying a COR3 group. The method of claim 1, wherein X and Y are not both N. Process according to claim 1 or 2, wherein step a) is carried out in the presence of water, preferably in the presence of 1 to 500 equivalents of water relative to the compound of formula (II), preferably in the presence of 2 to 300 equivalents of water, preferably in the presence of 3 to 200 equivalents of water, preferably in the presence of 4 to 160 equivalents of water. Method according to any one of claims 1 to 3, wherein step a) is carried out at a wavelength of 320 nm to 410 nm, preferably of 340 nm to 405 nm, more preferably of 350 to 400 nm. A process according to any one of claims 1 to 4, wherein, in step a), the secondary alcohol is chosen from isopropanol, 3-pentanol, 2-butanol and a mixture thereof, preferably isopropanol. Method according to one of claims 1 to 5, in which, during step b), the acid has a pKa of less than 3, preferably less than 1. A method according to any one of claims 1 to 6, wherein R1 represents H. A method according to any one of claims 1 to 6, wherein R1 represents COR3. The method of claim 8, the method comprising: (b) bringing the compound of formula (III) into contact with an acid, whereby a rearrangement takes place and a compound of formula (VI) is formed [Chem. 15]

10.

11. wherein X, Y, R21 and R22 are as defined in claim 1, then b') Y-acylation of the compound of formula (VI) with the acylating agent bearing a COR3 group, whereby the compound of formula (I) in which R1 represents COR3 is formed. Method according to claim 9, wherein steps a) and b) are implemented in a monotopic manner. The method of claim 8, the method comprising: b') V-acylation of the compound of formula (III) with the acylating agent bearing a COR3 group, whereby a compound of formula (VII) is formed: [Chem. 16]

12.

13.

14. in which R3 represents a (Ci-C6)-alkyl, then b) contacting the compound of formula (VII) with an acid, whereby a rearrangement takes place and the compound of formula (I) in which R1 represents COR3 is formed. Method according to claim 11, wherein steps a) and b') are implemented in a monotopic manner. Method according to any one of the preceding claims, carried out continuously. A process according to any preceding claim, the process being free from isolation of the compound of formula (III).