WO2016091705A1 - Method for synthesizing quinolines in liquid phase - Google Patents

Abstract

The invention relates to a method for preparing quinoline in the liquid phase from glycerol in the presence of an acid and superheated water, said method being carried out in a continuous flow.

Description

 PROCESS FOR PRODUCING QUINOLINE IN THE LIQUID PHASE

Technical area

 The invention relates to a process for producing quinolines in the liquid phase. More particularly, the invention relates to the production of quinolines from glycerol and an aromatic organic compound in the presence of environmentally friendly medium and operating conditions.

Technological background of the invention

 Quinoline compounds are an important class of heterocycles involved in the synthesis of many products, especially as synthesis intermediates for therapeutic agents such as chloroquine, mefloquine or quinine for the treatment of malaria. The quinoline motif is also a basic synthon for the preparation of materials for the electronics sector.

 US 3,705,163 discloses the production of quinolines from nitrobenzene or derivatives thereof and an olefin in the presence of catalysts comprising a Group IV-A, IV-B, VB, VI-B or Vll-metal. B.

 The most commonly used quinoline synthesis route involves the reaction of aniline with glycerol. This reaction is known as the Skraup reaction. Other synthetic routes have also been described in the literature, such as, for example, the Friedlander reaction for the preparation of quinolines from 2-aminobenzaldehydes and a ketone or the Combes reaction carried out from aniline and of a diketone (Vladimir et al., Current Organic Chemistry, 2005, 9, 141).

 No. 6,103,904 discloses a process for the synthesis of quinolines by the Skraup reaction in the presence of an oxidizing agent such as AS2O5 or ferric salts. The process is carried out in the liquid phase under particular operating conditions, that is to say under reduced pressure and a temperature of between 130 ° C. and 150 ° C. The use of toxic oxidizing agents is a hindrance to the development of this type of process on an industrial scale. The recycling of the waste resulting from these reactions represents an additional operating cost and particular handling conditions for these reagents.

Also known by Reddy et al. (Journal of Molecular Catalysis A: chemical, 2000, 151, 289) the preparation of quinolines in the gaseous phase in the presence of glycerol, aniline and oxygen. The process is carried out continuously in presence of a catalyst consisting of mixed oxides of CuO-ZnO / Al2O3 type. The process is carried out at a very low gas flow (3-4 mL / h) preventing efficient industrial operation thereof.

 Finally, Saggadi et al. (RSC Adv., 2014, 4, 21456-21464) the preparation of quinolines by reaction between glycerol and aniline under microwave irradiation. It has also been described by Saggadi et al. (Catalysis Communications, 2014, 44, 15-18) the preparation of 6-hydroxyquinoline by reaction between glycerol and nitrobenzene under microwave irradiation. Although reactions under microwave irradiation are commonly used in the laboratory, their industrialization requires the replacement of existing industrial facilities and the establishment of complex production lines to allow the implementation of large quantities of reagents.

 There is therefore a need for a process for producing quinolines that is efficient from an industrial point of view and respectful of the environment.

Summary of the invention

 The present invention overcomes at least in part the obstacles of the conventional technique and may offer other unobserved advantages with conventional methods.

 The present invention relates to a process for the production of quinolines in the liquid phase of formula (I)

(I)

 in which

R ¹ , R ² , R ³ and R ⁴ independently of one another are hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 6 -C 20 aryl, 5 to 10-membered heteroaryl, 5 to 10-membered heterocycle. C 2 -C 20 alkenyl, C2-C20 alkynyl, -OR ^a , -SR ^a , -C (O) -R ^a , -C (O) -O-R ^a , -OC (O) -R ^a , -F, -Cl, -Br, -I, -NR ^a R ^b , -CN, -NO ₂ or -CF ₃ ; or R ¹ and R ² or R ² and R ³ or R ³ and R ⁴ together with the carbon atoms to which they are attached form a six-membered heteroaryl comprising a nitrogen atom;

R ^a and R ^b are independently selected from hydrogen, C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, five to ten-membered heteroaryl, five to ten membered heterocycle, C2-C20 alkenyl or C2-C20 alkynyl substituted or unsubstituted with -OR ^x , -SR ^X , -C (O) -R ^x , -C (O) -O-R ^x , -OC (O) -R ^x, -F, -Cl, -Br, -I, -NR ^x R ^y, -CN, -NO 2 or CF ₃ wherein R ^x and R ^y are independently selected from each other from hydrogen unsubstituted C1-C20 alkyl, unsubstituted C3-C20 cycloalkyl, unsubstituted C6-C20 aryl, five to ten-membered heteroaryl, five to ten-membered heterocycle, unsubstituted C 2 -C 20 alkenyl or C 2 -C 2 alkynyl -C20 unsubstituted,

 by reaction between glycerol and an aromatic organic compound of formula (II)

R ⁵

(he)

 in which

NR represents N H2, a salt thereof or a protecting group thereof

R ⁵ , R ⁶ , R ⁷ , R ⁸ independently of one another are hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C ⁶ -C ²⁰ aryl, five to ten membered heteroaryl, five to ten heterocycle. C 2 -C 20 alkenyl, C2-C20 alkynyl, -OR ^a , -SR ^a , -C (O) -R ^a , -C (O) -O-R ^a , -OC (O) -R ^a -F, -Cl, -Br, -I, -NR ^a R ^b , -NO 2, -CN or -CF ₃ ; R ^a and R ^b being as defined above;

 in the presence of an acid and water in a subcritical state, and characterized in that the process is carried out in continuous flow.

The present process therefore makes it possible to produce quinolines which may or may not be substituted from glycerol under operating conditions which make it possible to obtain a yield that may be greater than 55%. The process also carried out in the liquid phase and in continuous flow allows efficient industrialization. Advantageously, the present process comprises the steps of:

 a) implementing a solution (A) comprising said acid, said aromatic organic compound of formula (II), water and glycerol, b) continuously passing a stream of said solution (A) from the step a) through a reaction zone under conditions allowing the conversion of at least a portion of the aromatic organic compound of formula (II) to a quinoline of formula (I),

 said conversion conditions including:

 i) a temperature in the reaction zone of from 100 ° C to 374 ° C, preferably from 200 ° C to 374 ° C,

 ii) a pressure in the reaction zone of between 1.6 MPa and 22.6 MPa;

 c) recovering a solution (B) comprising said quinoline of formula (I) and optionally the aromatic organic compound of formula (II) and glycerol that has not been converted.

Brief description of the drawings

 Fig. 1 shows the evolution of the quinoline yield as a function of the hourly space velocity according to particular embodiments of the invention in which the acid is respectively methanesulfonic acid and sulfuric acid.

Detailed description of the invention

 According to a first aspect of the invention, a process for producing quinolines in the liquid phase is provided for obtaining quinolines of formula (I)

(I)

 in which

R ¹ , R ² , R ³ and R ⁴ independently of one another are hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 6 -C 20 aryl, 5 to 10-membered heteroaryl, 5 to 10-membered heterocycle. membered alkenyl C ₂ -C ₂₀ alkynyl, C ₂ -C ₂₀ alkyl, -OR ^a, -SR ^a, -C (0) -R ^a, -C (0) ^-0-R, - OC (0) - R ^a , -F, -Cl, -Br, -I, -NR ^a R ^b , -CN, -NO ₂ or CF ₃ ; or R ¹ and R ² or R ² and R ³ or R ³ and R ⁴ together with the carbon atoms to which they are attached form a six-membered heteroaryl comprising a nitrogen atom;

R ^a and R ^b are independently selected from each other from hydrogen, alkyl Ci-C ₂ o, C3-C ₂ o, C6-C ₂ o, heteroaryl of five to ten membered heterocycle from five to ten members, C ₂ -C ₂₀ alkenyl or C ₂ -C _{2 2} alkynyl, optionally substituted with a group -OR ^x , -SR ^X , -C (O) -R ^x , -C (O) -0-R ^x, -OC (0) -R ^x, -F, -Cl, -Br, -I, -NR ^x R ^y, -CN, -N0 ₂ or -CF ₃ wherein R ^x and R ^y are independently selected from each other from hydrogen, alkyl Ci-C ₂ o unsubstituted, C3-C ₂ o unsubstituted C6-C ₂ o unsubstituted heteroaryl, five to ten membered , heterocycle with five to ten membered, alkenyl C ₂ -C ₂ o unsubstituted alkynyl or C ₂ -C ₂ o unsubstituted.

The quinoline compounds of formula (I) above can be obtained by reaction between the glycerol of formula HOCH ₂ CH (OH) CH ₂ OH and an aromatic organic compound of formula (II)

(he)

 in which

NR is NH ₂ , a salt thereof or a protecting group thereof, or NO ₂ ;

R ^5, R ^6, R ^7, R ⁸ independently from each other hydrogen, alkyl Ci-C ₂ o, C3-C ₂ o, C6-C ₂ o, heteroaryl of five to ten-membered , heterocycle with five to ten membered, alkenyl C ₂ -C ₂₀ alkynyl, C ₂ -C ₂₀ alkyl, -OR ^a, -SR ^a, -C (0) -R ^a, -C (0) -0-R ^a , - OC (O) -R ^a , -F, -Cl, -Br, -I, -NR ^a R ^b , -NO ₂ , -CF ₃ or -CN; R ^a and R ^b being as defined above. Said reaction between the glycerol and the aromatic compound of formula (II) can be carried out in the presence of an acid and water in subcritical state. In addition, the process according to the present invention is carried out in continuous flow.

 The term "substituted" as used in the present invention means that one or more hydrogen of the group to which the term "substituted" refers is replaced by one of the named substituents provided that the normal valence of the atom over which the substitution occurs. is considered not exceeded and the substitution results in a stable chemical compound, i.e. a compound sufficiently robust to be isolated from a reaction mixture.

The term "alkyl" refers to linear or branched hydrocarbon chains containing the specified number of carbon atoms. For example, C1-C6 alkyl means a linear or branched alkyl group containing at least 1, and at most 6 carbon atoms. The term "aryl" refers to an aromatic hydrocarbon ring containing the specified number of carbon atoms. For example, aryl may be phenyl, naphthyl, anthracyl or phenanthryl. The term "alkenyl" refers to linear or branched hydrocarbon chains containing the specified number of carbon atoms and at least one double bond. For example, C2-C6 alkenyl means a linear or branched alkenyl group containing at least 2, and at most 6 carbon atoms and containing at least one double bond. The term "alkynyl" refers to linear or branched hydrocarbon chains containing the specified number of carbon atoms and at least one triple bond. For example, C2-C6 alkynyl means a linear or branched alkynyl group containing at least 2, and at most 6 carbon atoms and containing at least one triple bond. The term "cycloalkyl" refers to a non-aromatic hydrocarbon ring having the specified number of carbon atoms. For example, cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The term "heteroaryl" refers to a fused monocyclic or fused polycyclic aromatic hydrocarbon ring having the specified number of members, wherein at least one of the carbon atoms is replaced by a phosphorus, sulfur, nitrogen or oxygen atom. . For example, heteroaryl includes, but is not limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, pyridine, pyridazine, pyrazine, indole, and the like. and indazole. The term "heterocycle" refers to a fused monocyclic or fused polycyclic non-aromatic hydrocarbon ring having the specified number of members, wherein at least one of the carbon atoms is replaced by a phosphorus, sulfur, nitrogen, or nitrogen atom. oxygen. For example, heterocycle includes, but is not limited to, tetrahydrofuran, dihydropyran, tetrahydropyran, pyran, piperidine and dioxane.

 The method may include the steps of:

 a) implementing a solution (A) comprising said acid, said aromatic organic compound of formula (II), water and glycerol, b) continuously passing a stream of said solution (A) from the step a) through a reaction zone under conditions allowing the conversion of at least a portion of the aromatic organic compound of formula (II) to quinoline of formula (I),

 said conversion conditions including:

 i) a temperature in the reaction zone of from 100 ° C to 374 ° C, preferably from 200 ° C to 374 ° C,

 ii) a pressure in the reaction zone of between 1.6 MPa and 22.6 MPa

 c) recovering a solution (B) comprising said quinoline of formula

(I) and optionally the aromatic organic compound of formula (II) and / or glycerol which has not been converted.

 The term "subcritical water" refers to water maintained in the liquid state by the application of pressure in a temperature range between its boiling point (100 ° C) and its critical temperature (374 ° C).

 In particular, the operating conditions i) and ii) mentioned above make it possible to obtain water in a subcritical state in said reaction zone.

 Advantageously, said aromatic organic compound of formula (II) is soluble in solution (A), preferably said aromatic organic compound of formula (II) is soluble in water. Thus, the aromatic organic compound may be chosen from aromatic organic compounds of formula (II) soluble in solution (A), that is to say soluble in a medium comprising water, glycerol and acid; advantageously, the aromatic organic compound is selected from aromatic organic compounds of formula (II) soluble in water. In particular, the solubility of said aromatic organic compound of formula (II) in solution (A) is greater than 0.1 g / l at ambient temperature, more particularly the solubility of said aromatic organic compound of formula (II) in water is greater than 0.1 g / L at room temperature.

Said method may also comprise a step d) of separating the components contained in the solution (B). Thus, step d) may include separating said quinoline of formula (I) from reagents which may not have reacted, that is to say aromatic organic compound of formula (II) and / or glycerol. Solution (B) may also contain by-products of the reaction which are also separated from said quinoline of formula (I) in step d). The separation of step d) can be carried out by chemical or physical separation. Physical separation may include vacuum or atmospheric distillation, crystallization or selective precipitation in various components contained in solution (B), or liquid chromatography. The chemical separation may comprise a solid-liquid or liquid-liquid extraction in an acidic or basic medium depending on the components contained in the solution (B). Thus, said quinoline of formula (I) can be separated from glycerol and / or aromatic compound of formula (II) by fractional distillation. For example, said quinoline of formula (I) may be separated from glycerol and / or aromatic compound of formula (II) by high performance liquid chromatography. Alternatively, said quinoline of formula (I) may be separated from the glycerol and / or the aromatic compound of formula (II) by liquid-liquid extraction. The glycerol and / or the aromatic compound of formula (II) may be recycled and reused for the implementation of solution (A) of step a) after extraction or separation thereof from said quinoline of formula (I). Thus, the present process may comprise a step e) of recycling said organic aromatic compound of formula (II) and glycerol separated in step d) for the implementation of step (a) of the present process.

 The acid used in the present process may have a pKa of less than 2.5 as measured in water at ambient temperature and pressure. Ambient pressure refers to the atmospheric pressure. Ambient temperature refers to a temperature of 25 ° C.

Advantageously, said acid contained in solution (A) may be selected from the group consisting of H1, HBr, H ₂ SO ₄ , H ₃ PO ₄ , HClO ₄ , HNO ₃ , H ₂ PO ₃ , HClO ₂ , H ₂ SO ₃ , CF ₃ CO ₂ H , HO 2 CCO ₂ H, CH ₃ SO ₃ H, CH 3 CH ₂ SO ₃ H, CH 3 (CH ₂ ) ₂ SO ₃ H, CCI ₃ CO ₂ H, NH ₂ SO ₃ H, (NO ₂ ) 3 C ₆ H ₂ OH and HI ₃ ; advantageously from H ₁ , HBr, H ₂ SO ₄ , H ₃ PO ₄ , HCl ₄ , H 3 NO ₃ , H ₂ PO ₃ , HClO ₂ , H ₂ SO ₃ , CF ₃ CO ₂ H, HO ₂ COO ₂ H, CH ₃ SO ₃ H, CH ₃ CH ₂ SO ₃ H, CH ₃ (CH ₂ ) ₂ SO ₃ H; preferably from CH3SO3H, hci0 _4, H ₂ S0 _4, Hl, HBr, HN0 _3, in particular the acid may be CH3SO3H or H2S0 _4. Optionally said acid can be supported. According to a preferred embodiment, the acid may be selected from the acids mentioned above having a pKa of less than 1, advantageously a pKa of less than 0 in water at ambient temperature and pressure.

 According to a preferred embodiment of the invention, the glycerol may be of plant origin resulting from the fermentation of biomass or the gasification of biomass or the production of biodiesel or the transesterification of triglycerides. Alternatively, glycerol may be derived from the treatment of fossil resources.

 Said conversion conditions mentioned in step b) of the present process preferably comprise:

 i) a temperature in the reaction zone of between 250 ° C and

350 ° C, advantageously between 275 ° C and 325 ° C

 ii) a pressure in the reaction zone of between 5 MPa and 15 MPa, advantageously between 8 and 12 MPa.

In addition, said conversion conditions may comprise: iii) a hourly space velocity of the solution (A) of between 0.1 h ^-1 and 20 h ^-1 , advantageously between 1 and 10 h ^-1 , preferably between 2 and 8 h ^"1, in particular from 2.5 to 3.5 ^{h" 1.} the hourly space velocity of the solution (A) in the range of values mentioned above improves the conversion efficiency of the aromatic compound formula (II) and glycerol to quinolines of formula (I) The hourly space velocity corresponds to the rate at which the solution (A) is injected into the reaction zone.

 In solution (A), the molar ratio between said acid and glycerol is between 0.1 and 10, advantageously between 0.5 and 5. In addition, the molar ratio between said acid and said aromatic organic compound of formula ( II) can be between 0.1 and 20, advantageously between 0.5 and 10.

The concentration of the aromatic organic compound of formula (II) in solution (A) can be between 0.001 mol.L ^"1 and 5 mol.L ^{" 1} , advantageously between 0.001 mol.L ^"1 and 1 mol.L ^{" 1} preferably between 0.01 mol.L-1 and 1 mol.L-1, in particular between 0.01 mol.L- ¹ and 0.5 mol.L- ¹ .

 In the solution (A), the ratio by weight of the glycerol and the water may be between 0.005 and 9, advantageously between 0.01 and 5, preferably between 0.01 and 1.

 Preferably, said quinoline may be of formula (I) in which:

R ¹ , R ² , R ³ and R ⁴ independently of one another are hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, five to seven membered heteroaryl, five to seven membered heterocycle, C2-C10 alkenyl, C2-C10 alkynyl, -OR ^a , -SR ^a , -C (O) -R ^a , -C (O) -O-R ^a , -OC ( 0) -R ^a , -F, -Cl, -Br, -I, -NR ^a R ^b , -CN, -NO ₂ or CF ₃ ; or R ¹ and R ² or R ² and R ³ or R ³ and R ⁴ together with the carbon atoms to which they are attached form a six-membered heteroaryl comprising a nitrogen atom;

R ^a and R ^b are independently selected from hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, five to seven-membered heteroaryl, five to seven-membered heterocycle, C2-C10 alkenyl, C2-C10 alkynyl substituted or unsubstituted by an OR ^x group, -SR ^X , -C (O) -R ^x , -C (O) -O-R ^x , -OC (O) - R ^x , -F, -Cl, -Br, -I, -NR ^x R ^y , -CN, -CF 3 or -NO 2 wherein R ^x and R ^y are selected independently of each other from hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, five to seven-membered heteroaryl, five to seven-membered heterocycle, C2-C10 alkenyl or unsubstituted C2-C10 alkynyl.

 Preferably, said quinoline may be of formula (I) in which:

R ¹ , R ² , R ³ and R ⁴ independently of one another are hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, five or six membered heteroaryl, five to six membered heterocycle. C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -OR ^a , -SR ^a , -C (O) -R ^a , -C (O) -O-R ^a , -OC (O) -R ^a -F, -Cl, -NR ^a R ^b , -CN, -NO ₂ or -CF ₃ ; or R ¹ and R ² or R ² and R ³ or R ³ and R ⁴ together with the carbon atoms to which they are attached form a six-membered heteroaryl comprising a nitrogen atom;

R ^a and R ^b are independently selected from hydrogen, C1-C3 alkyl, C6-C10 aryl.

In a preferred manner, said quinoline may be of formula (I) in which: R ¹ , R ² , R ³ and R ⁴ are selected independently of each other from -H, -OH, -OCH 3, -SH, -SCH ₃ , -NH2, F, Cl, -CH3, -CHMe ₂ , -COCH ₃ , -C0 ₂ H, -CN, -NO2 and -CF ₃ .

In particular, the quinoline produced according to the present process may be monosubstituted and of formula (I) in which R ¹ , R ² , R ³ and R ⁴ are selected from -H, -OH, -OCH ₃ , -SH, -SCH ₃ , -NH ₂ , F, Cl, -CH ₃ , -CHMe ₂ , -COCH 3, -C ₂ H, -CN, -NO 2 and -CF 3 with the proviso that three of the groups R ¹ , R ² , R ³ and R ⁴ simultaneously represent a hydrogen. Alternatively, the quinoline produced according to the present process may be disubstituted and of formula (I) in which R ¹ , R ² , R ³ and R ⁴ are selected from -H, -OH, -OCH ₃ , -SH, -SCH ₃ , -NH ₂ , -F, -Cl, -CH ₃ , -CHMe ₂ , -COCH ₃ , -CO ₂ H, -CN, -NO 2 and -CF ₃ with the proviso that two of the groups R ¹ , R ² , R ³ and R ⁴ simultaneously represent hydrogen.

Advantageously, the aromatic organic compound is of formula (II) in which: NR is N H 2, a salt thereof or a protecting group thereof, or NO 2 R ⁵ , R ⁶ , R ⁷ , R ⁸ independently of one another are hydrogen, C 1 -C 10 alkyl, cycloalkyl, C3-C10, C6-C10 aryl, five to seven-membered heteroaryl, five to seven-membered heterocycle, C2-C10 alkenyl, C2-C10 alkynyl, -OR ^a , - SR ^a , -C (O) - R ^a , -C (O) -O-R ^a , -OC (O) -R ^a , -F, -Cl, -Br, -I, -NR ^a R ^b , -NO 2, -CN, or -CF ₃ ; R ^a and R ^b are independently selected from hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, five to seven-membered heteroaryl, five to seven-membered heterocycle, C2-C10 alkenyl, C2-C10 alkynyl substituted or unsubstituted with -OR ^x , -SR ^X , -C (O) -R ^x , -C (O) -O-R ^x , -OC (O) R ^x , F, Cl, Br, I, NR ^x R ^y , -CN, -CF 3 or -NO 2 in which R ^x and R ^y are selected independently of one another from hydrogen, C 1-4 alkyl; C10, C3-C10 cycloalkyl, C6-C10 aryl, five to seven-membered heteroaryl, five to seven-membered heterocycle, C2-C10 alkenyl, C2-C10 alkynyl.

 The functional group N H2 of the aromatic organic compound (II) may be protected by a protecting group commonly used and well known to those skilled in the art. The functional group N H2 can in particular be protected in the form of imides, amides, carbamates, imines, enamines, sulfonylated, N-sulfenylated, N-alkylated or N-silylated derivatives.

 Preferably, the aromatic organic compound may be of formula (II) in which:

NR is NH 2, a salt thereof or a protecting group thereof, or NO 2 R ⁵ , R ⁶ , R ⁷ , R ⁸ independently of one another are hydrogen, C 1 -C 6 alkyl, cycloalkyl, C3-C6, C6-C10 aryl, five- or six-membered heteroaryl, five- or six-membered heterocycle, C2-C6 alkenyl, C2-C6 alkynyl, -OR ^a , -SR ^a , -C (O) - R ^a , -C (O) -O-R ^a , -OC (O) -R ^a , -F, -Cl, -Br, -I, -NR ^a R ^b , -NO 2, -CN, or -CF ₃ ;

R ^a and R ^b are independently selected from hydrogen, C1-C3 alkyl or C6-C10 aryl.

 In particular, the aromatic organic compound may be of formula (II) in which:

NR is N H2, a salt thereof, or a protecting group thereof;

R ^5, R ^6, R ^7, R ⁸ independently of one another -H, -OH, -OCH3, -SH, - SCH _3, -N H2, -F, -Cl, -CH3, -CHMe _2, -COCH ₃ , -C0 ₂ H, -CN, -NO 2 or -CF ₃ .

According to a preferred embodiment of the invention, the aromatic organic compound is monosubstituted and of formula (II) in which NR represents N H 2, a salt thereof or a protective group thereof; R ⁵ , R ⁶ , R ⁷ and R ⁸ are selected from -H, -OH, -OCH ₃ , -SH, -SCH ₃ , -NH ₂ , -F, -Cl, -CH ₃ , -CHMe ₂ , -COCH ₃ , -CO ₂ H, -CN, -CF 3 and NO 2 with the proviso that three of the groups R ⁵ , R ⁶ , R ⁷ and R ⁸ simultaneously represent hydrogen. Alternatively, the aromatic organic compound is disubstituted and of formula (II) wherein NR is NH 2, a salt thereof or a protecting group thereof; R ⁵ , R ⁶ , R ⁷ and R ⁸ are selected from -H, -OH, -OCH ₃ , -SH, -SCH ₃ , -NH ₂ , -F, -Cl, -CH ₃ , -CHMe ₂ , - COCH ₃ , -C0 ₂ H, -CN, -CF 3 and -NO 2 with the proviso that two of the groups R ⁵ , R ⁶ , R ⁷ and R ⁸ simultaneously represent hydrogen.

According to a first particular embodiment, the aromatic organic compound of formula (II) may be nitrobenzene to produce a quinoline of formula (I) in which R ¹ , R ² , R ⁴ are hydrogen and R ^{3 is} an OH group.

According to a second particular embodiment, the aromatic organic compound may be of formula (II) in which NR is N H 2 or a salt thereof or a protective group thereof; one of the groups R ⁵ , R ⁶ , R ⁷ or R ⁸ is -NO 2, the other groups being a hydrogen to produce the quinoline of formula (I) in which R ¹ and R ² or R ² and R ³ or R ³ and R ⁴ together with the carbon atoms to which they are attached form a six-membered heteroaryl comprising a nitrogen atom. Thus, when R ⁷ is -NO 2, and R ⁵ , R ⁶ , R ⁸ are respectively hydrogen, the quinoline produced is of formula (I) in which R ¹ , R ² are hydrogen and R ³ and R ⁴ together form with the carbon atoms to which they are attached a six-membered heteroaryl comprising a nitrogen atom. Alternatively, when R ⁵ is -NO 2, and R ⁶ , R ⁷ , R ⁸ are respectively hydrogen, the quinoline produced is of formula (I) in which R ³ , R ⁴ are hydrogen and R ¹ and R ² together form with the carbon atoms to which they are attached a six-membered heteroaryl comprising a nitrogen atom. Alternatively, when R ⁶ is -NO 2, and R ⁵ , R ⁷ , R ⁸ are respectively hydrogen, the quinoline produced is of formula (I) in which R ¹ , R ⁴ are hydrogen and R ² and R ³ together form with the carbon atoms to which they are attached a six-membered heteroaryl comprising a nitrogen atom. Thus, this second particular embodiment allows the production of phenanthroline.

According to a third particular embodiment of the invention, the substituents R ⁵ , R ⁶ , R ⁷ and R ⁸ of the aromatic organic compound of formula (II) used as reagent in the process correspond respectively to the substituents R ¹ , R ² , R ³ and R ⁴ of the quinoline of formula (I) produced at the end of said present process. Thus, the present invention can provide a process for producing quinolines of formula (I)

(L)

in which

R ¹ , R ² , R ³ and R ⁴ independently of one another are hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 6 -C 20 aryl, 5 to 10-membered heteroaryl, 5 to 10-membered heterocycle. C 2 -C 20 alkenyl, C2-C20 alkynyl, -OR ^a , -SR ^a , -C (O) -R ^a , -C (O) -O-R ^a , -OC (O) -R ^a , -F, -Cl, -Br, -I, -NR ^a R ^b , -CN, -NO 2 or CF ₃ ; or R ¹ and R ² or R ² and R ³ or R ³ and R ⁴ together with the carbon atoms to which they are attached form a six-membered heteroaryl comprising a nitrogen atom;

R ^a and R ^b are independently selected from hydrogen, C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, five to ten-membered heteroaryl, five to ten membered heterocycle, C2-C20 alkenyl or C2-C20 alkynyl substituted or unsubstituted with -OR ^x , -SR ^X , -C (O) -R ^x , -C (O) -O-R ^x , -OC (O) -R ^x, -F, -Cl, -Br, -I, -NR ^x R ^y, -CN, -CF3, -NO2 or wherein R ^x and R ^y are independently of one another selected from hydrogen C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, five to ten membered heteroaryl, five to ten membered heterocycle, C2-C20 alkenyl or unsubstituted C2-C20 alkynyl,

by reaction, in the presence of an acid and water in a subcritical state, between glycerol and an aromatic organic compound of formula (II)

 (II)

in which

NR is NH 2, a salt thereof, or a protecting group thereof; R ¹ , RR ³ , R ⁴ being as defined for the quinoline of formula (I) above; said procedure being carried out in continuous flow. Advantageously, according to this third particular embodiment, the quinoline and the aromatic organic compound are respectively of formula (I) and of formula (II) in which:

R ¹ , R ² , R ³ and R ⁴ independently of one another are hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, five to seven membered heteroaryl, five to seven membered heterocyclic rings; C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, -OR ^a , -SR ^a , -C (O) -R ^a , -C (O) -O-R ^a , -OC (O) -R ^a -F, -Cl, -Br, -I, -NR ^a R ^b , -CN, -NO 2 or -CF ₃ ; preferably, R ¹ , R ² , R ³ , R ⁴ independently of one another represent hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, five or six membered heteroaryl, heterocycle with five or six members, C2-C6 alkenyl, C2-C6 alkynyl, -OR ^a , -SR ^a , -C (O) -R ^a , -C (O) -O-R ^a , -OC (O) -R ^a , -F, -Cl, -NR ^a R ^b , -CN, -NO ₂ or -CF ₃ ; and

R ^a and R ^b are independently selected from hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, five to seven-membered heteroaryl, five to seven-membered heterocycle, C2-C10 alkenyl, C2-C10 alkynyl substituted or unsubstituted by a group OR ^x , -SR ^X , -C (O) -R ^x , -C (O) -O-R ^x , -OC (O) - R ^x , -F, -Cl, -Br, -I, -NR ^x R ^y , -CN, -CF ₃ or -NO 2 in which R ^x and R ^y are selected independently of each other from hydrogen C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, five to seven-membered heteroaryl, five to seven-membered heterocycle, C2-C10 alkenyl or unsubstituted C2-C10 alkynyl; preferably, R ^a and R ^b are independently selected from hydrogen, C1-C3 alkyl, C6-aryl,

Preferably, in this third particular embodiment, the aromatic organic compound of formula (II) may be monosubstituted R ¹ , R ² , R ³ and R ⁴ being selected independently of each other from -H, -OH, -OCH 3 , -SH, -SCH3, -NH ₂ , -F, -Cl, -CH3, -CHMe ₂ , -COCH ₃ , -C0 ₂ H, -CN, -NO 2 and -CF ₃ with the proviso that three of the groups R ¹ , R ² , R ³ and R ⁴ simultaneously represent hydrogen to produce the corresponding quinoline of formula (I) monosubstituted; or being disubstituted R ¹ , R ² , R ³ and R ⁴ being independently selected from -H, -OH, -OCH ₃ , -SH, -SCH ₃ , -NH ₂ , -F, -Cl, - CH ₃ , -CHMe ₂ , -COCH ₃ , -C0 ₂ H, -CN, -NO 2, -CF 3 with the proviso that two of the groups R ¹ , R ² , R ³ and R ⁴ simultaneously represent a hydrogen to produce quinoline corresponding formula of formula (I) disubstituted. The expression "corresponding quinoline of formula (I)" means that the substituents R ¹ , R ² , R ³ and R ⁴ of the quinoline of formula (I) are respectively identical to the substituents R ¹ , R ² , R ³ and R ⁴ of the aromatic organic compound of formula (II). When the aromatic organic compound of formula (II) is substituted, in the meta position with respect to the NR group, by one of the groups mentioned above with the exception of hydrogen, a mixture of two quinolines of formula (I ) can be obtained in which either R ² or R ⁴ corresponds to the group initially present in the meta position with respect to the NR group in said aromatic organic compound of formula (II).

Examples

Example 1

To a solution of 0.91 ml of aniline (10.0 mmol, 1.0 equiv), of formula (II) in which NR is Nhb, R ⁵ , R ⁶ , R ⁷ , R ⁸ are hydrogen, in 200 ml of water were added at room temperature, 4.31 mL (60.0 mmol, 6.0 eq) of glycerol and 1.97 mL (30 mmol, 3.0 eq) of methanesulfonic acid. The solution was stirred at room temperature for 10 minutes and then was injected with an hourly space velocity of 3.1 h ^"1 in a reaction zone having a temperature of 300 ° C and a pressure of 10 MPa. The solution was continuously injected into the reaction zone for 50 minutes The solution recovered continuously contained the corresponding quinoline of formula (I) wherein R ¹ , R ² , R ³ , R ⁴ are hydrogen, as confirmed by the NMR data Below, at the end of the experiment, a volume of 100 ml was recovered, 10 ml of a saturated aqueous NaHCO 3 solution were added and then the solution was diluted with methanol to a volume of 400 ml The solution was injected with HPLC (Pervail C18 column, methanol / water 80/20 at 1 ml / min) and the yield was determined using a calibration curve previously carried out (retention time of quinoline = 5.063 minutes) The yield was 40 %.

¹ H NMR (400 MHz, CDCl ₃ ), δ (ppm), J (Hz):

8.84 (d, J = 2.8 Hz, 1H, H1); 8.1 (d, J = 8.40 Hz, 1H, H ₈ ); 7.99 (d, J = 8.4 Hz, 1H, H ₃ ); 7.67 (d, J = 8 Hz, 1H, H ₅ ); 7.63 (d, J = 8 Hz, 1H, H ₇ ); 7.44 (t, 1H, H ₆ ); 7.25 (t, 1H, H ₂ ).

¹³ C NMR (100 MHz, CDC):

150.0 (Ci); 148.1 (C _ar ); 135.7 (C _ar ); 129.2 (2C _ar ); 128.0 (C _ar ); 127.6 (C _ar ); 126.3 (Car,);

Example 2 Example 1 is repeated substituting methanesulfonic acid with sulfuric acid. A 38% yield of quinoline was obtained.

Example 3

 Example 1 was repeated by varying the hourly space injection rate of solution in the reaction zone. The results are shown in Table 1 below and are illustrated in Figure 1.

Table 1 - Quinoline yield versus hourly space velocity

Example 3c, reproducing example 1 shows the best results with a yield of the order of 40%. However, very good results have also been obtained at higher or lower hourly space velocities. Thus yields of 33% and 34% were obtained at hourly space velocities respectively of 7.75h ^"1 and 1, 55h ^{" 1} .

Example 4

 Example 3 was repeated substituting methanesulfonic acid with sulfuric acid. The results are shown in Table 2 below and are illustrated in Figure 1.

Table 2 - Quinoline yield versus hourly space velocity

The realization of the process according to the present invention has made it possible to obtain good yields with sulfuric acid as with methanesulfonic acid. Example 5

 Example 1 was reproduced to prepare a solution containing 200 ml of water, 30 mmol of methanesulfonic acid, 60 mmol of glycerol and 10 mmol of aromatic organic compound of formula (II) as defined in the present application. The process is carried out continuously at 300 ° C and 10 MPa. The hourly space velocity and the quinoline yield of formula (I) are shown in Table 3 below.

Table 3 - Quinoline yield as a function of the hourly space velocity from different aromatic organic compound of formula (II) in the presence of CH ₃ SO ₃ H.

As shown in Example 5, good yields of quinoline are obtained for different substituted anilines.

Example 6

Example 5 is reproduced by substituting methanesulfonic acid with sulfuric acid and applying a space velocity of 3.1 h ^"1. The results are detailed in Table 4 below.

Table 4 - Quinoline yield as a function of hourly space velocity from various aromatic organic compound of formula (II) in the presence of C / 7-2SO4.

 Comp. Organic Speed Quinoline

 yield

Aromatic Examples of Spatial Formula (I)

(%) formula (II) hourly (h ^"1 )

 6a 4-chloroaniline 3,10 6-chloroquinoline 50%

6b 4-isopropylaniline 3,10 6-isopropylquinoline 56%

6c 4-methylaniline 3,10 6-methylquinoline 40% The present invention therefore proposes an innovative process for the production of quinolines for a wide variety of anilines under conditions improving the industrial efficiency of the process.

 The terms and descriptions used here are for illustrative purposes only and are not limitations. Those skilled in the art will recognize that many variations are possible within the spirit and scope of the invention as described in the following claims and equivalents thereof; in these, all terms must be understood in their broadest sense unless otherwise indicated.

Claims

claims 1. Process for the liquid phase production of quinolines of formula (I)

(I)  in which R ¹ , R ² , R ³ and R ⁴ independently of one another are hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 6 -C 20 aryl, 5 to 10-membered heteroaryl, 5 to 10-membered heterocycle. C 2 -C 20 alkenyl, C2-C20 alkynyl, -OR ^a , -SR ^a , -C (O) -R ^a , -C (O) -O-R ^a , -OC (O) -R ^a , -F, -Cl, -Br, -I, -NR ^a R ^b , -CN, -NO ₂ or -CF ₃ ; or R ¹ and R ² or R ² and R ³ or R ³ and R ⁴ together with the carbon atoms to which they are attached form a six-membered heteroaryl comprising a nitrogen atom; R ^a and R ^b are independently selected from hydrogen, C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, five to ten-membered heteroaryl, five to ten membered heterocycle, C2-C20 alkenyl or C2-C20 alkynyl substituted or unsubstituted by a group OR ^x , -SR ^X , -C (O) -R ^x , -C (O) -O-R ^x , -OC (O) - R ^x , -F, -Cl, -Br, -I, -NR ^x R ^y , -CN, -CF ₃ or -NO 2 in which R ^x and R ^y are selected independently of each other from hydrogen C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, five to ten membered heteroaryl, five to ten membered heterocycle, C2-C20 alkenyl or unsubstituted C2-C20 alkynyl, by reaction between glycerol and an aromatic organic compound of formula (II)

(he)  in which NR represents N H2, a salt thereof or a protecting group thereof

R ⁵ , R ⁶ , R ⁷ , R ⁸ independently of one another are hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C ⁶ -C ²⁰ aryl, five to ten membered heteroaryl, five to ten heterocycle. C 2 -C 20 alkenyl, C2-C20 alkynyl, -OR ^a , -SR ^a , -C (O) -R ^a , -C (O) -O-R ^a , -OC (O) -R ^a -F, -Cl, -Br, -I, -NR ^a R ^b , -CF ₃ , -NO 2 or -CN; R ^a and R ^b being as defined above; in the presence of an acid and water in a subcritical state, and characterized in that the process is carried out in a continuous flow. Method according to the preceding claim, characterized in that it comprises the steps of:  a) implementing a solution (A) comprising said acid, said aromatic organic compound of formula (II), water and glycerol; advantageously, said aromatic organic compound of formula (II) is soluble in said solution (A);  b) continuously passing a stream of said solution (A) of step a) through a reaction zone under conditions allowing the conversion of at least a portion of the aromatic organic compound of formula (II) in quinolines of formula (I),  said conversion conditions including: i) a temperature in the reaction zone of from 200 ° C to 374 ° C, preferably from 250 ° C to 350 ° C, preferably from 275 ° C to 325 ° C, ii) a pressure in the reaction zone of between 1.6 MPa and 22.6 MPa, advantageously between 5 MPa and 15 MPa, preferably between 8 and 12 MPa,  c) recovering a solution (B) comprising said quinoline of formula (I) and optionally the aromatic organic compound of formula (II) and glycerol that has not been converted. Process according to any one of the preceding claims, characterized in that the acid has a pKa of less than 2.5 measured in water at ambient temperature and pressure, advantageously a pKa of less than 1, and preferably a pKa of less than 0. Process according to any one of Claims 2 or 3, characterized in that the said conversion conditions also comprise: iii) a hourly space velocity of the solution (A) of between 0.1 h ^-1 and 20 h ^-1 , advantageously between 1 and 10 h ^-1 , preferably between 2 and 8 h ^-1 . Process according to any one of Claims 2 to 4, characterized in that, in solution (A): the molar ratio between said acid and glycerol is between 0.1 and 10, advantageously between 0.5 and 5, or the molar ratio between said acid and said aromatic organic compound of formula (II) is between 0.1 and 20, advantageously between 0.5 and 10. Process according to any one of the preceding claims, characterized in that the quinoline is of formula (I) in which: R ¹ , R ² , R ³ and R ⁴ independently of one another are hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, five to seven membered heteroaryl, five to seven membered heterocyclic rings; C 2 -C 10 alkenyl, C2-C10 alkynyl, -OR ^a , -SR ^a , -C (O) -R ^a , -C (O) -O-R ^a , -OC (O) -R ^a , -F, -Cl, -Br, -I, -NR ^a R ^b , -CN, -NO ₂ or -CF ₃ ; or R ¹ and R ² or R ² and R ³ or R ³ and R ⁴ together with the carbon atoms to which they are attached form a six-membered heteroaryl comprising a nitrogen atom; R ^a and R ^b are independently selected from hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, five to seven-membered heteroaryl, five to seven-membered heterocycle, C2-C10 alkenyl, C2-C10 alkynyl substituted or unsubstituted by an OR ^x group, -SR ^X , -C (O) -R ^x , -C (O) -O-R ^x , -OC (O) - R ^x , -F, -Cl, -Br, -I, -NR ^x R ^y , -CN, -CF 3 or -NO 2 wherein R ^x and R ^y are independently selected from hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, five to seven-membered heteroaryl, five to seven-membered heterocycle, C2-C10 alkenyl or unsubstituted C2-C10 alkynyl; advantageously R ¹ , R ² , R ³ and R ⁴ independently of one another are hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, five or six membered heteroaryl, five or six membered heterocycle. membered alkenyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ alkyl, -OR ^a, -SR ^a, -C (0) -R ^a, -C (0) ^-0-R, - OC (0 ) -R ^a , -F, -Cl, -NR ^a R ^b , -CN, -NO ₂ or -CF ₃ ; preferably R ¹ , R ² , R ³ , R ⁴ represent independently of each other -H, -OH, -OCH 3, -SH, -SCH 3, -NH 2, -F, -Cl, -CH 3, -CHMe ₂ , -COCH 3 , -C0 ₂ H, -CN, -NO 2 or -CF ₃ . Process according to any one of the preceding claims, characterized in that the aromatic organic compound is of formula (I I) in which: R ⁵ , R ⁶ , R ⁷ , R ⁸ independently of one another are hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, five to seven-membered heteroaryl, five to seven-membered heterocycle. C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, -OR ^a , -SR ^a , -C (O) -R ^a , -C (O) -O-R ^a , -OC (O) -R ^a -F, -Cl, -Br, -I, -NR ^a R ^b , -NO 2, -CN, or -CF ₃ ; R ^a and R ^b are selected independently from each other from hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C2-C10 alkenyl, alkynyl, and the like; C2-C10 substituted or not with an OR ^x group, -SR ^X , -C (O) -R ^x , -C (O) -O-R ^x , -OC (O) -R ^x , -F, -Cl , -Br, -I, -NR ^X R ^X , -CN, CF ₃ , -NO 2 wherein R ^x is hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, C 3 heteroaryl -C10, C2-C10 alkenyl, C2-C10 alkynyl; advantageously R ⁵ , R ⁶ , R ⁷ , R ⁸ independently of one another are hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C ⁶ -C ¹⁰ aryl, five or six membered heteroaryl, five or six membered heterocycle. membered alkenyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ -0R ^a, -SR ^a, -C (0) -R ^a, -C (0) ^-0-R, - OC (0) - R ^a , -F, -Cl, -NR ^a R ^b , -CN, -NO ₂ or -CF ₃ ;  preferably R ^5, R ^6, R ^7, R ⁸ independently of one another -H, -OH, - OCH _3, -SH, -SCH _3, -NH _2, -F, -Cl, -CH _3, -CHMe ₂ , -COCH ₃ , -COR ₂ H, -CN, -NO ₂ or -CF ₃ . Process according to any one of the preceding claims, characterized in that it produces a quinoline of formula (I)

(I)  in which R ¹ , R ² , R ³ , R ⁴ are as defined in claim 1 or 7,  by reaction between glycerol and an aromatic organic compound of formula (he)

wherein NR is NH ₂ , a salt thereof or a protecting group thereof, and R ¹ , R ² , R ³ , R ⁴ are respectively identical to the substituents R ¹ , R ² , R ³ , R ⁴ as defined for quinoline of formula (I). Process according to any one of Claims 1 to 7, characterized in that the quinoline is of formula (I) in which R ¹ , R ² and R ⁴ are hydrogen, and R ³ is OH, and the aromatic organic compound is nitrobenzene. 10. Method according to any one of claims 1 to 7 characterized in that the quinoline is of formula (I) wherein R ¹ and R ² or R ² and R ³ or R ³ and R ⁴ together with the atoms of carbon to which they are attached a six-membered heteroaryl comprising a nitrogen atom, and the aromatic organic compound is of formula (II) wherein NR is Nhb or a salt thereof or a protecting group thereof; and one of the groups R ⁵ , R ⁶ , R ⁷ or R ⁸ is -NO 2, the remaining three other groups among R ⁵ , R ⁶ , R ⁷ or R ⁸ being a hydrogen.