Process for the fluorination and / or cyclization of an alkene or alkyne amino in continuous flow and installation for implementing the process

Abstract

The present invention relates to a process for the fluorination and / or cyclization of an alkene or amino alkyne in a continuous flow microreactor. It also relates to an installation for implementing such a process.

Description

Title of the invention: Process for the fluorination and / or cyclization of an alkene or amino alkyne in continuous flow and installation for implementing the process

[0001] SUBJECT OF THE INVENTION

[0002] The present invention relates to a process for the fluorination and / or cyclization of an alkene or amino alkyne in a continuous flow microreactor. It also relates to an installation for implementing such a process.

[0003] BACKGROUND OF THE INVENTION

[0004] In a superacid medium, the Ho acidity values are less than -12, so that all molecules, even simple alkanes, react as bases. Superacid systems are therefore of great interest because they provide access to a singular reactivity involving polyprotonated molecules. Many processes in a superacid medium have been developed in recent years, and have been considered both in a synthesis on a laboratory scale and on an industrial scale.

[0005] For example, Michelet et al. describes processes for fluorinating amino alkenes or alkynes using the superacid HF / SbF5 (J. Fluorine Chem. 2018, 214, 68-79). This transformation is particularly interesting because it provides access to fluorinated amino units that are sought after in medicinal chemistry. WO 9503312 also shows that vinorelbine can be converted into the anticancer drug Javlor® via a gem-difluorination reaction in the presence of the superacid HF / SbF5

[0006] However, these systems have several drawbacks that limit their use. In particular, reagents generating a superacid medium, such as HF, are toxic, corrosive, and dangerous to handle. In addition, many solvents and nucleophiles are not compatible with these media. Finally, the high reactivity of these systems does not allow for good control of the outcome of the reactions: cascade reactions and polyfluorination can be observed.

[0007] There therefore remains a real need to develop a process facilitating the handling of superacids and allowing better control of their reactivity, particularly when they are placed in the presence of an alkyne or amino alkene.

[0008] In this context, the Applicant has shown that the use of microfluidics, and more precisely of a continuous flow microreactor, makes it possible to overcome these limitations. More precisely, it has been demonstrated, surprisingly, that the use of a continuous flow microreactor makes it possible to prepare fluorinated or cyclized compounds, which are difficult to access or even inaccessible by an equivalent reaction in static (or “batch”) conditions. It has also been shown that the flow productivity for these reactions was much higher than that obtained in static conditions. Summary of the invention

[0009] The invention therefore relates to a process for the fluorination and / or cyclization of an amino alkene or alkyne, comprising:

[0010] a) providing a first phase comprising an amino alkene or alkyne and a second phase comprising a superacid reagent,

[0011] b) bringing the first and second phases into contact in a continuous flow microreactor, and

[0012] c) the recovery of the fluorination and / or cyclization product of said alkene or amino alkyne.

[0013] In a particular embodiment, the residence time of the first phase and the second phase in the continuous flow microreactor in step (b) is between 2 seconds and 400 seconds.

[0014] In a particular embodiment, the flow rate of the first phase and the flow rate of the second phase in step (b) are independently between 0.1 mL / min and 3.5 mL / min, for example between 0.25 mL / min and 3.0 mL / min.

[0015] In a particular embodiment, the continuous flow microreactor comprises a micro-mixer and a tubular conduit, in which the tubular conduit preferably has:

[0016] - a length between 20 cm and 800 cm, and

[0017] - an internal diameter between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and better between 0.7 mm and 1.2 mm.

[0018] In a particular embodiment, the contacting in the continuous flow microreactor is carried out at a temperature between -70°C and 25°C.

[0019] In a particular embodiment, the method according to the invention is implemented in an installation comprising:

[0020] - a storage unit (1) of a first phase comprising an alkene or alkyne amine,

[0021] - a storage unit (1') of a second phase comprising a superacid reagent,

[0022] - a means for continuously supplying the first phase (3) connected to the unit of storage of the first phase (1), and to a tubular pipe for balancing the first phase (4),

[0023] - a means for continuously supplying the second phase (3') connected to the unit of storage of the second phase (1'), and to a tubular balancing pipe of the second phase (4'),

[0024] - a continuous flow microreactor (2) comprising a micro-mixer (21) comprising two inlets and one outlet, and a tubular conduit (22) comprising one inlet and one outlet, wherein the inlet of the tubular conduit (22) is connected to the outlet of the micro-mixer (21),

[0025] where the first phase balancing tubular conduit (4) is connected to the first inlet of the micro-mixer (21) and the second phase balancing tubular conduit (4') is connected to the second inlet of the micro-mixer (21), and

[0026] - a collection unit (5), connected to the outlet of the tubular conduit (22) of the micro-mixer (21). croreactor (2).

[0027] In a particular embodiment, the superacid reagent is selected from HF / MF 5 and HSO3F / MF5, where M is Sb, As, P, Ta, or Nb, preferably the superacid reagent is HF / SbF5.

[0028] In a particular embodiment, the first phase is a solution of said alkene or alkyne amino in HF, preferably in a concentration of between 0.5 and 1.0 mol / L.

[0029] Said alkene or alkyne amino group may in particular be an allylic or pro-pargylic amine. In a particular embodiment, said alkene or alkyne amino group is an alkene amino group of formula (Ia):

[0030] [Chem.l] Ru \ / Ê «KM '"'FL HAS

[0031] in which:

[0032] Rb R2, R3, R4, R5, R6 and R7 are independently selected from hydrogen, halogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 heteroalkyljun C3-C12 cycloalkyl, C2-C12 heterocycloalkyl, aryl, heteroaryl, -S(O)2-R8 and -C(O)-R9, wherein R8 and R9 are independently selected from C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 heteroalkyljun C3-C12 cycloalkyl, C2-C12 heterocycloalkyl, aryl, and heteroaryl,

[0033] said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups being optionally substituted, or

[0034] two groups each chosen from Rb R2, R3, R4, R5, R6 and R7 which can alternately form together with the atom(s) to which they are linked a cycle having 3 to 12 links, optionally substituted.

[0035] In particular, the amino alkene of formula (Ia) may be such that:

[0036] - Ri and R2 are independently chosen from hydrogen, C2-Ci2 alkenyl, an aryl [optionally substituted by C1-C6 alkyl, nitro, or a fluorinated group selected from -CF3, -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', and -SCF(R')2where each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl], -S(O)2-R8 and -C(O)-R9, wherein R8 and R9 are independently an aryl optionally substituted by C1-C6 alkyl, nitro, or a fluorinated group selected from -CF3, -OCF3, -SCF3, -OCF2 R', -OCF(R')2, -SCF2R', and -SCF(R')2where each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl,

[0037] or alternatively Ri and R2 form with the atom to which they are linked, a piperidine or a piperazine, optionally substituted by an aryl or an acetyl,

[0038] - R3 and R4 are hydrogens, and

[0039] - R5, R6 and R7 are independently selected from hydrogen and halogen (of preferably, at least two of R5, R6 and R7 are hydrogen).

[0040] In another particular embodiment, said alkene or amino alkyne is an amino alkyne of formula (Ib):

[0041] [Chem.2] FC? R* .X. L "

[0042] in which:

[0043] R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from hydrogen, halogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 12 heteroalkyl, C 3 -C 12 cycloalkyl, C 2 -C 12 heterocycloalkyl, aryl, heteroaryl, -S(O)2-R 8 and -C(O)-R 9, wherein R 8 and R 9 are independently selected from C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 12 heteroalkyl, C 3 -C 12 cycloalkyl, C 2 -C 12 heterocycloalkyl, aryl, and heteroaryl,

[0044] said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups being optionally substituted, or

[0045] two groups each chosen from Rb R2, R3, R4, and R5 which can alternately form together with the atom(s) to which they are linked a cycle having 3 to 12 links which is optionally substituted.

[0046] In particular, the alkene amino group of formula (Ib) may be such that:

[0047] - Ri and R2 are independently chosen from hydrogen, C2-Ci2 alkenyl, an aryl [optionally substituted by a C1-C6 alkyl, a nitro, or a fluorinated group selected from -CF3, -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', and -SCF(R')2where each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl], -S(O)2-R8 and -C(O)-Rc), where R8 and R9 are independently an aryl optionally substituted by a C1-C6 alkyl, a nitro, or a fluorinated group selected from -CF3, -OCF3, -SCF3, -OCF2 R', -OCF(R')2, -SCF2R', and -SCF(R')2where each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl.

[0048] or alternatively Ri and R2 form, with the atom to which they are attached, a piperidine or a piperazine, optionally substituted by an aryl or an acetyl, and

[0049] - R3, R4 and R5 are hydrogens.

[0050] In a preferred embodiment, said alkene or alkyne amino is chosen from:

[0051] [Chem.3]

[0052] It further relates to an installation for implementing the method as defined in the present application, characterized in that it comprises:

[0053] - a storage unit (1) of a first phase comprising an alkene or alkyne amine,

[0054] - a storage unit (1') of a second phase comprising a superacid reagent,

[0055] - a means for continuously supplying the first phase (3) connected to the unit of storage of the first phase (1), and to a tubular pipe for balancing the first phase (4),

[0056] - a means for continuously supplying the second phase (3') connected to the unit of storage of the second phase (1'), and to a tubular balancing pipe of the second phase (4'),

[0057] - a continuous flow microreactor (2) comprising a micro-mixer (21) comprising two inlets and one outlet, and a tubular conduit (22) comprising one inlet and one outlet, wherein the inlet of the tubular conduit (22) is connected to the outlet of the micro-mixer (21),

[0058] where the balancing tubular conduit of the first phase (4) is connected to the first inlet of the micro-mixer (21) and the balancing tubular conduit of the second phase (4') is connected to the second inlet of the micro-mixer (21), and

[0059] - a collection unit (5), connected to the outlet of the tubular conduit (22) of the mi croreactor (2).

[0060] The tubular conduit (22) of the continuous flow microreactor (2) preferably has

[0061] - a length between 20 cm and 800 cm, and

[0062] - an internal diameter between 0.5 mm and 2.5 mm, preferably between 0.7 and 1.2 mm.

[0063] Preferably, said installation further comprises:

[0064] - a 3-way valve (6) ensuring the connection between the supply means in continuous in the first phase (3), the storage unit of the first phase (1), and the balancing tubular pipe of the first phase (4), and / or

[0065] - a 3-way valve (6') ensuring the connection between the supply means in continuous in the second phase (3'), the storage unit of the second phase (1') and the balancing tubular pipe of the second phase (4'). FIGURES

[0066] [Fig. 1] is a diagram illustrating the method according to one embodiment of the invention, as well as a particular schematic installation for implementing such a method.

[0067] [Fig.2] is a diagram illustrating the method according to one embodiment of the invention, as well as a particular schematic installation for implementing such a method, further comprising washing units. DETAILED DESCRIPTION

[0068] Definitions

[0069] Unless otherwise indicated, when a range is expressed using the expression "between", the limit values are included within the range described.

[0070] By “alkyl” is meant a saturated, linear or branched. A “C1-C12 alkyl” is an alkyl having from 1 to 12 carbon atoms. Examples of alkyl (or C1-C12 alkyl) include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, or dodecyl. Preferably, the C1-C12 alkyl is a C1-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, or hexyl).

[0071] By "alkenyl" is meant an unsaturated, linear or branched aliphatic hydrocarbon group comprising at least one carbon-carbon double bond. A "C2-Ci2 alkenyl" is an alkenyl having from 2 to 12 carbon atoms. Examples of alkenyl (or C2-Ci2 alkenyl) include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, or dodecenyl. Preferably, the C2-Ci2 alkenyl is a C2-C6 alkenyl (e.g., ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, or hexenyl).

[0072] By "alkynyl" is meant an unsaturated, linear or branched aliphatic hydrocarbon group comprising at least one carbon-carbon triple bond. A "C2-C12 alkynyl" is an alkynyl having from 2 to 12 carbon atoms. Examples of alkynyl (or C2-C12 alkynyl) include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, or dodecynyl. Preferably, the C2-C12 alkynyl is a C2-C6 alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl).

[0073] By "heteroalkyl" is meant an alkyl as defined above, in which the carbon chain comprises at one and / or the other of its ends (in particular the end attached to the rest of the molecule), and / or is interrupted by, at least one heteroatom, such as O, N, P, Se or S. Examples of heteroalkyl are in particular alkoxy (-O-alkyl), alkylthio (-S-alkyl), alkylamino (-NH(alkyl) or -N(alkyl)2), organophosphorus (-P(O)(alkyl)2) and organoselenium (-Se(Alkyl)2 or -Se(O)(alkyl)NR or - Se(O)(alkyl)2). A "CrCi2 heteroalkyl" is a heteroalkyl having from 1 to 12 carbon atoms. Preferably, a CrCi2 heteroalkyl is a C1-C6 heteroalkyl.

[0074] Examples of heteroalkyl (or C1-C6 heteroalkyl) include methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy, pentyloxy, hexyloxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, hexylamino, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, methylphospho, ethylphospho, pro-pylphospho, isopropylphospho, butylphospho, isobutylphospho, tert-butylphospho, pentylphospho, hexylphospho, methylseleno, ethylseleno, propylseleno, isopro-pylseleno, butylseleno, isobutylseleno, tert-butylseleno, pentylseleno, or hexylseleno.

[0075] By "cycloalkyl" is meant an aliphatic mono- or polycyclic hydrocarbon group, optionally unsaturated (preferably saturated), and which may be condensed, bridged, and / or spiro-connected. A "C3-Ci2 cycloalkyl" is a cycloalkyl having 3 to 12 carbon atoms. Examples of C3-Ci2 or C3-C6 cycloalkyl include cyclopropyl, cyclopentyl, or cyclohexyl.

[0076] By "heterocycloalkyl" is meant a cycloalkyl as defined above, further comprising at least one heteroatom, such as N, S, P, Se or O. A "C2-C[2] heterocycloalkyl" is a cycloalkyl having 2 to 12 carbon atoms and at least one heteroatom. Preferably, a C2-C[2] heterocycloalkyl is a C2-C6 heterocycloalkyl. Examples of heterocycloalkyl include: 3-dioxolane, benzo-[l,3]-dioxolyl, azetidinyl, oxetanyl, pyrazolinyl, pyranyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1,4-dioxanyl, imida-zolinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl, 1,4-dithianyl, oxozolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, 7-oxabicyclo[2,2,l]heptanyl, cycloalkylphosphine and tetrahydrothiophenyl.

[0077] By "aryl" is meant an aromatic, mono- or polycyclic carbocyclic group, preferably having from 6 to 20 members. Examples of aryl groups are phenyl, biphenyl, and naphthyl, preferably phenyl. The aryl group, in particular phenyl, is optionally substituted, for example by one or more (preferably a single) groups selected from C1-C6 alkyl (eg methyl), -NO2, -CF3, and other fluorinated substituents such as -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', or -SCF(R')2 where each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl. Preferably, the aryl group is unsubstituted or substituted by one or more (preferably a single) groups selected from C1-C6 alkyl (eg methyl), -NO2, and -CF3.

[0078] By "heteroaryl" is meant an aromatic, mono- or polycyclic group preferably having 5 to 20 carbon atoms and further comprising at least one heteroatom such as N, O, P, Se or S. Examples of heteroaryl include: pyridinyl, thiazolyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, triazinyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, indazolyl, purinyl, quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, oxazolidinyl, benzotriazolyl, benzoisoxazolyl, oxindolyl, benzoxazolinyl, benzothienyl, benzothiazolyl, isatinyl, dihydropyridyl, pyrimidinyl, s-triazinyl, oxazolyl, aryl-phosphine, indole, indoline, phosphindoline or thiofuranyl.

[0079] By "halogen" is meant chlorine, fluorine, bromine or iodine. Preferably, a halogen is chlorine or fluorine, more preferably chlorine.

[0080] Said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups as defined in the present application are optionally substituted. By "optionally substituted" is meant unsubstituted or substituted by one or more (for example, one, two, three or four, preferably one or two, more preferably only one) substituents.

[0081] Examples of substituents include trifluoromethyl (-CF3) and other fluorinated substituents (such as -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', or -SCF(R')2where each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl), nitro (-NO2), cyano (-CN), -SO3H, -OH, -SH, -NH2, -COOH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl C2-C6, aryl, heteroaryl, -S(O) 2-R and -C(O)-R, where R is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, aryl, and heteroaryl.

[0082] In the present application, the abbreviation “Ac” means “acetyl” (i.e. -C(O)-CH3).

[0083] The process according to the invention is a process for the fluorination and / or cyclization of a substrate which is an alkene or alkyne amino group. Contacting the substrate with a superacid reagent allows the incorporation of one or more fluorine atoms (generally one or two, and more particularly only one) on the substrate, and / or the formation of a cycle by intramolecular cyclization of the substrate. In general, the process according to the invention allows either the fluorination or the cyclization of said alkene or alkyne amino group. In a particular embodiment, the fluorination reaction is a hydrofluorination, which consists of incorporating one or more fluorine atoms and one or more hydrogen atoms.

[0084] The method according to the invention comprises a step (a) comprising providing a first phase comprising an amino alkene or amino alkyne, and providing a second phase comprising a superacid reagent.

[0085] In a particular embodiment, said alkene or amino alkyne is an amino alkene.

[0086] By "alkene amino" is meant an organic compound having at least one alkene function and at least one amine function. By "alkene" is meant an organic compound having at least one alkene function, i.e., at least one carbon-carbon double bond. By "amine function" is meant a function:

[0087] [Chem.4] . 4. 4 v W - i -NHs, h or

[0088] where

[0089] [Chem.5]

[0090] denotes a bond to the rest of the molecule. Each of the alkene and amine functions may independently be cyclic (i.e., included in a ring, such as an endocyclic alkene or a piperidine, or directly linked to the ring, such as an exocyclic alkene or a cycloalkylamine) or acyclic. The aminated alkene may be aromatic or aliphatic. Preferably, the aminated alkene has from 2 to 60 carbon atoms and / or has a molecular weight of between 50 and 1000 g / mol.It is understood that the alkene amino group may further comprise other groups or functions than the alkene function(s) and the amine function(s), for example, halogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 heteroalkyl, C3-C12 cycloalkyl, C2-C12 heterocycloalkyl, aryl, heteroaryl, -CF3 and other fluorinated substituents (such as -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', or -SCF(R')2 where each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, or C1-C12 heteroalkyl. C2-C6, or a C3-C6 cycloalkyl), -NO2, -CN, -SO3H, -OH, -SH, -COOH, without this list being limiting. In particular, the amine function may be adjacent to other chemical groups or functions, such as a -C(O)- or -S(O)2- group so that the whole constitutes an amide or a sulfonamide respectively.

[0091] In a particular embodiment, said alkene amino is an allylic amine. By "allyl amine" is meant a compound in which an amine function is separated from an alkene function by a carbon atom.

[0092] In a more particular embodiment, said alkene amino is a compound of formula (Ia):

[0093] [Chem.6]

[0094] in which:

[0095] Rb R2, R3, R4, R5, R6 and R7 are independently selected from hydrogen, halogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 heteroalkyljun C3-C12 cycloalkyl, C2-C12 heterocycloalkyl, aryl, heteroaryl, -S(O)2-R8 and -C(O)-R9, wherein R8 and R9 are independently selected from C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 heteroalkyljun C3-C12 cycloalkyl, C2-C12 heterocycloalkyl, aryl, and heteroaryl,

[0096] said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups being optionally substituted, or

[0097] two groups each chosen from Rb R2, R3, R4, R5, R6 and R7 (for example, Ri and R2) which can alternatively form together with the atom(s) to which they are linked a cycle having 3 to 12 links which is optionally substituted.

[0098] It is preferred that the compound of formula (Ia) is such that:

[0099] - R3 and R4 are hydrogens, and

[0100] - R5, R6 and R7 are independently selected from hydrogen and halogen (of preferably, at least two of R5, R6 and R7 are hydrogen). A preferred halogen is chlorine.

[0101] In a particular embodiment, the compound of formula (Ia) is such that R1 and R2 form, with the atom to which they are attached, a ring having 3 to 12 optionally substituted members, preferably having 5 to 7 members, such as an optionally substituted piperidine or piperazine. In such an embodiment, said ring may for example be substituted by an optionally substituted aryl or an acetyl.

[0102] In another particular embodiment, the compound of formula (Ia) is such that:

[0103] - Riest a hydrogen, and

[0104] - R2 is an optionally substituted aryl.

[0105] In another particular embodiment, the compound of formula (Ia) is such that:

[0106] - Riest a hydrogen, and

[0107] - R2 is -S(O)2-R8, where R8 is an optionally substituted aryl.

[0108] In another particular embodiment, the compound of formula (Ia) is such that:

[0109] - Riest a group -CH2-CH=CH2, and

[0110] - R2 is -C(O)-R9, where R9 is an optionally substituted aryl.

[0111] In the embodiments described above, the optionally substituted aryl group may, for example, be substituted by one or more (preferably, a single) groups selected from C1-C6 alkyl (e.g., methyl), -NO2, -CF3, and other fluorinated substituents such as -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', or -SCF(R')2, where each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl. Preferably, the aryl group is unsubstituted or substituted by one or more (preferably, a single) groups selected from C1-C6 alkyl (e.g., methyl), -NO2, and -CF3.

[0112] In another particular embodiment, the compound of formula (Ia) is such that:

[0113] - Ri and R2 are independently chosen from hydrogen, C2-Ci2 alkenyl, an aryl [optionally substituted by C1-C6 alkyl, nitro, or a fluorinated group selected from -CF3, -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', and -SCF(R')2where each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl], -S(O)2-R8 and -C(O)-R9, wherein R8 and R9 are independently an aryl optionally substituted by C1-C6 alkyl, nitro, or a fluorinated group selected from -CF3, -OCF3, -SCF3, -OCF2 R', -OCF(R')2, -SCF2R', and -SCF(R')2where each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl,

[0114] or alternatively Ri and R2 form, with the atom to which they are attached, a piperidine or a piperazine, optionally substituted by an aryl or an acetyl,

[0115] - R3 and R4 are hydrogens, and

[0116] - R5, R6 and R7 are independently selected from hydrogen and halogen (of preferably, at least two of R5, R6 and R7 are hydrogen).

[0117] In another particular embodiment, the compound of formula (Ia) is such that:

[0118] - Ri and R2 are independently chosen from hydrogen, C2-Ci2 alkenyl, an aryl optionally substituted by a C1-C6 alkyl, a nitro or -CF3, -S(O)2-R8 and -C(O)-R9, where R8 and R9 are independently an aryl optionally substituted by a C1-C6 alkyl, a nitro or a trifluoromethyl,

[0119] or alternatively Ri and R2 form, with the atom to which they are attached, a piperidine or a piperazine, optionally substituted by an aryl or an acetyl,

[0120] - R3 and R4 are hydrogens, and

[0121] - R5, R6 and R7 are independently selected from hydrogen and halogen (of preferably, at least two of R5, R6 and R7 are hydrogen).

[0122] In a preferred embodiment, said alkene amino is chosen from the following compounds:

[0123] [Chem.7]

[0124] In another preferred embodiment, said alkene amino acid is vinorelbine, which can be represented as follows:

[0125] [Chem.8]

[0126] In another particular embodiment, said alkene or amino alkyne is an amino alkyne.

[0127] By "amino alkyne" is meant an organic compound having at least one alkyne function and at least one amine function. By "alkyne" is meant an organic compound having at least one alkyne function, i.e., at least one carbon-carbon triple bond. Each of the alkyne and amine functions may independently be cyclic (i.e., included in a ring, such as an endocyclic alkyne or a piperidine, or directly connected to the ring, such as a cycloalkylamine) or acyclic. The amino alkyne may be aromatic or aliphatic. Preferably, the amino alkyne has from 2 to 60 carbon atoms and / or has a molecular weight of between 50 and 1000 g / mol.It is understood that the amino alkyne may further comprise other groups or functions than the alkyne function(s) and the amine function(s), for example a halogen, a C1-C12 alkyl, a C2-C12 alkenyl, a C2-C12 alkynyl, a C1-C12 heteroalkyl, a C3-C12 cycloalkyl, a C2-C12 heterocycloalkyl, .

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136] an aryl, a heteroaryl, -CF3and other fluorinated groups selected from -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', or -SCF(R')2where each R' independently represents a hydrogen, a halogen, a C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, or a C3-C6 cycloalkyl), -NO2, -CN, -SO3H, -OH, -SH, -COOH, without this list being limiting. In particular, the amine function may be adjacent to other groups such as a -C(O)- or -S(O)2- group so that the whole constitutes an amide or a sulfonamide respectively. In a particular embodiment, said amino alkyne is a pro-pargylic amine. By "pro-pargylic amine" is meant a compound in which an amine function is separated from an alkyne function by a carbon atom. In another more particular embodiment, said amino alkyne is a compound of formula (Ib): [Chem.9] in which: R1, R2, R3, R4, and R5 are independently selected from hydrogen, halogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 heteroalkyl, C3-C12 cycloalkyl, C2-C12 heterocycloalkyl, aryl, heteroaryl, -S(O)2-R8 and -C(O)-R9, wherein R8 and R9 are independently selected from C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 heteroalkyl, C3-C12 cycloalkyl, C2-C12 heterocycloalkyl, aryl, and heteroaryl, said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups being optionally substituted, or two groups each chosen from Rb R2, R3, R4, and R5 (for example Ri and R2) which can alternatively form together with the atom(s) to which they are linked a cycle having 3 to 12 links which is optionally substituted. It is preferred that the compound of formula (Ib) is such that R3, R4 and R5 are hydrogen. In a particular embodiment, R 1 and R 2 form, with the atom to which they are attached, a ring having 3 to 12 optionally substituted members, preferably having 5 to 7 members, such as an optionally substituted piperidine or piperazine. In such an embodiment, said ring may for example be substituted by an optionally substituted aryl or an acetyl.

[0137] In another particular embodiment, the compound of formula (Ib) is such that:

[0138] - Ri and R2 are independently chosen from hydrogen, C2-Ci2 alkenyl, an aryl [optionally substituted by C1-C6 alkyl, nitro, or a fluorinated group selected from -CF3, -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', and -SCF(R')2where each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl], -S(O)2-R8 and -C(O)-R9, wherein R8 and R9 are independently an aryl optionally substituted by C1-C6 alkyl, nitro, or a fluorinated group selected from -CF3, -OCF3, -SCF3, -OCF2 R', -OCF(R')2, -SCF2R', and -SCF(R')2where each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl],

[0139] or alternatively Ri and R2 form, with the atom to which they are attached, a piperidine or a piperazine, optionally substituted by an aryl or an acetyl, and

[0140] - R3, R4 and R5 are hydrogens.

[0141] In another particular embodiment, the compound of formula (Ib) is such that:

[0142] - Ri and R2 are independently chosen from hydrogen, C2-Ci2 alkenyl, an aryl [optionally substituted by a C1-C6 alkyl, a nitro, or a -CF3], -S(O)2 -R8 and -C(O)-R9, where R8 and R9 are independently an aryl optionally substituted by a C1-C6 alkyl, a nitro or a trifluoromethyl,

[0143] or alternatively Ri and R2 form, with the atom to which they are attached, a piperidine or a piperazine, optionally substituted by an aryl or an acetyl, and

[0144] - R3, R4 and R5 are hydrogens.

[0145] In a preferred embodiment, said amino alkyne is chosen from the following compounds:

[0146] [Chem. 10]

[0147] By "superacid reagent" is meant a reagent having an acidity value or Hammett acidity function Ho, less than -12, preferably less than or equal to -14. Several techniques make it possible to determine this Hammett constant Ho, in particular using weak bases with spectroscopic (NMR), kinetic, thermodynamic or molecular modeling methods (Hammett LP, Deyrup AJ, J. Am. Chem. Soc., 1932, 54 (7), 2721 - 2739; Superacid chemistry, Second edition, Olah GA, Prakash GKS, Molnar A., Sommer J., Edition John Wiley & Sons, Inc., Hoboken, New Jersey, 2009, 1 - 10).

[0148] The superacid reagent may consist of an acid, advantageously fluorinated, or a mixture of several acids, at least one of which is advantageously fluorinated. Superacids are notably described in the following documents: Hwang, JP; Surya Prakash, GK; Olah, GA Tetrahedron 2000, 56 (37), 7199-7203; Culmann, J.-C.; Fauconet, M.; Jost, R.; Sommer, J. New J. Chem. 1999, 23 (8), 863-867; Esteves, PM; Ramirez-Solis, A.; Mota, CJAJ Am. Chem. Soc. 2002, 124 (11), 2672-2677; Superacid chemistry, Second edition, Olah GA, Prakash GKS, Molnar A., Sommer J., Edition John Wiley & Sons, Inc., Hoboken, New Jersey, 2009).

[0149] The superacid reagent may in particular be a Lewis superacid (such as SbF5, AsF 5, PF5, TaF5), a protic or Brpnsted superacid (such as HF, CF3SO3H, (CF3SO2)2 NH, HSO3F) or a combination thereof (such as HF / SbF5, HSO3F / AsF5, H2SO4 / SO3, HC1 / A1C13).

[0150] Examples of superacids and their acidity constant are provided below:

[0151] - fluorosulfuric acid HSO3F, Ho= -15.1;

[0152] - trifluoromethanesulfonic acid CF3SO3H, Ho= -14.1;

[0153] - hydrofluoric acid HF, Ho= -15.2;

[0154] - the HF / SbF5 mixture, Ho = -23 / -24.

[0155] In a particular embodiment, the superacid reagent is chosen from:

[0156] - a protic superacid chosen from HF, CF3SO3H, and HSO3F,

[0157] - a Lewis superacid of formula MF5, where M is Sb, As, P, Ta, or Nb, and

[0158] - a combination of one of said protic superacids and one of said superacids of Lewis.

[0159] In a particular embodiment, the superacid reagent is HF or HSO3F.

[0160] In another particular embodiment, the superacid reagent is chosen from:

[0161] - HF / MF5, where M is Sb, As, P, Ta, or Nb; and

[0162] - HSO3F / MF5, where M is Sb, As, P, Ta, or Nb.

[0163] Preferably, the superacid reagent is HSO3F / SbF5 or HF / SbF5. More preferably, the superacid reagent is HF / SbF5

[0164] When the superacid reagent is HF / SbF5 or HSO3F / SbF5, the molar percentage of SbF5 is advantageously less than or equal to 50%, preferably between 2 and 22%, relative to the molar quantity of the mixture HF+SbF5 or HSO3F+SbF5 respectively. It is understood that the value 0% in the range “less than or equal to 50%” is excluded.

[0165] Said first phase in step (a) is preferably liquid. The first phase may in particular consist of said alkene or alkyne amino, undiluted or in solution in a solvent. It is preferred that the first phase is a solution of said alkene or alkyne amino in a solvent, such as HF, an alcohol-type solvent (e.g. methanol, ethanol, or isopropanol), a fluoroalcohol-type solvent (such as hexafluoropropan- 2-ol (HFIP) and its derivatives), or a polyfluorinated or perfluorinated aromatic solvent (such as pentafluorobenzene or 1,2,3,4-tetrafluorobenzene).

[0166] Preferably, said solvent is HF. The concentration of said alkene or alkyne amino in the solvent is advantageously between 0.02 mol / L and 2.0 mol / L, preferably between 0.5 mol / L and 1.0 mol / L.

[0167] The first phase may be stored in a storage unit, such as a tank.

[0168] In a particular mode, said first phase is maintained at a temperature between -70°C and 25°C, preferably between -50°C and 5°C, more preferably between -50°C and -20°C, in the storage unit.

[0169] Said second phase in step (a) is preferably liquid. The second phase advantageously consists of the superacid reagent, undiluted. The second phase may be stored in a storage unit, such as a tank.

[0170] In a particular embodiment, said second phase is maintained at a temperature between -70°C and 25°C, preferably between -50°C and 5°C, better still between -50°C and -20°C, in the storage unit.

[0171] Step (b) of the method according to the invention comprises bringing the first and second phases into contact in a continuous flow microreactor.

[0172] By "continuous flow microreactor" is meant a reactor of micrometric or millimetric size, allowing a continuous flow of one or more fluid phases, preferably liquids. A continuous flow microreactor typically comprises a tubular conduit, comprising an inlet and an outlet, and whose internal diameter is of micrometric or millimetric size. It is clear that, for the person skilled in the art, a specialist in the microfluidic field, the term "microreactor" designates a reactor whose size (more particularly, that of its internal diameter) is micrometric, but can also be millimetric to the extent that this millimetric size does not affect the microfluidic properties of the microreactor, in particular with regard to the behavior of the fluid flowing therein.

[0173] The length of the tubular conduit can be of the order of a few centimeters to several meters.

[0174] By “micrometric size” is meant a size between 1 pm and 1000 pm, preferably between 100 pm and 1000 pm, better still between 300 pm and 1000 pm (the value of 1000 pm being excluded).

[0175] By “millimeter size” is meant a size between 1 mm and 10 mm, preferably between 1 mm and 5 mm.

[0176] In a particular embodiment, the tubular conduit of the continuous flow microreactor has the following dimensions:

[0177] - a length between 20 cm and 800 cm, for example between 30 cm and 150 cm or between 200 cm and 600 cm, and / or

[0178] - an internal diameter between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and better between 0.7 mm and 1.2 mm.

[0179] The external diameter of the tubular conduit may for example be between 0.8 mm and 3.2 mm, for example between 0.8 mm and 1.0 mm, between 1.0 and 2.0 mm, or between 1.6 mm and 3.2 mm.

[0180] In a particular embodiment, the tubular conduit of the continuous flow microreactor has:

[0181] - an internal diameter of between 0.5 mm and 1.5 mm, and

[0182] - preferably an external diameter between 1.0 and 2.0 mm.

[0183] The tubular conduit is generally arranged in a coil or coil, over all or part of its length. Other arrangements may however be envisaged.

[0184] Advantageously, the continuous flow microreactor further comprises a micromixer. By "micromixer" is meant a mixer of micrometric or millimetric size. The micromixer advantageously comprises two inlets and one outlet, typically giving it a T or Y shape. The internal diameter of the micromixer is of micrometric or millimetric size, and is advantageously between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and better still between 0.7 mm and 1.2 mm. In a particular embodiment, the continuous flow microreactor comprises:

[0185] - a micro-mixer comprising two inputs and one output, and

[0186] - a tubular conduit comprising an inlet and an outlet,

[0187] where the inlet of the tubular conduit is connected to the outlet of the micro-mixer. In such a mode, a means for continuously supplying said first phase is connected to the first input of the micro-mixer and a means for continuously supplying said second phase is connected to the second input of the micro-mixer.

[0188] Said continuous supply means designate any element or set of elements making it possible to continuously transfer the first and second phases into the continuous flow microreactor, for example a pump or a syringe possibly associated with a syringe pump.

[0189] Elements are said to be "connected" when they are connected to each other, directly or possibly via a tubular conduit or another equivalent element, the characteristics of which (e.g. material, dimensions such as length and diameter) can be judiciously chosen by a person skilled in the art. For example, the micro-mixer and the tubular conduit of the continuous flow microreactor are preferably connected directly.

[0190] The contacting step (b) may comprise the transfer of the first phase included in a first phase storage unit, to the continuous flow microreactor, and more particularly into the micro-mixer of the flow microreactor continuous (even more particularly, in a first inlet of the micro-mixer) via a means for continuously feeding said first phase, and transferring the second phase included in a storage unit of the second phase, to the continuous flow microreactor, and more particularly into the micromixer of the continuous flow microreactor (even more particularly, in a second inlet of the micro-mixer) via a means for continuously feeding said second phase.

[0191] The means for continuous supply in the first and second phases may for example be a first and a second syringe (possibly associated with a syringe pump) respectively, or a first and a second pump respectively.

[0192] In a more particular embodiment, the first phase contained in a storage unit (for example, a reservoir) of the first phase is sampled, typically by means of a first syringe or pump, and the second phase contained in a storage unit (for example, a reservoir) of the second phase is sampled, typically by means of a second syringe or pump, and each of the first and second phases is injected into the continuous flow microreactor, and more particularly into the micro-mixer of the continuous flow microreactor (even more particularly, the first phase in a first inlet of the micro-mixer and the second phase in a second inlet of the micro-mixer).A first 3-way valve connected to the first phase storage unit, a first syringe or pump and the flow-through microreactor (in particular, to a first inlet of the micro-mixer of the microreactor), and / or a second 3-way valve connected to the second phase storage unit, a second syringe or pump and the flow-through microreactor (in particular, to a second inlet of the micro-mixer of the microreactor) may be used to facilitate the withdrawal and injection of the first and second phases. The internal diameter of the 3-way valves is micrometric or millimetric in size, and may for example be between 0.8 mm and 1.6 mm. The withdrawal and injection of the first and second phases may be implemented using a computer-controlled syringe pump or pump.The temperature of the syringes or pumps is generally maintained at a temperature between -70°C and 25°C, preferably between -50°C and 5°C, more preferably between -50°C and -20°C. The temperature of the storage units is generally maintained at a temperature between -70°C and 25°C, preferably between -50°C and 5°C, more preferably between -50°C and -20°C.

[0193] The flow rate of the first phase and that of the second phase in step (b) are independently between 0.1 mL / min and 3.5 mL / min, for example between 0.25 mL / min and 3.0 mL / min. The total flow rate may be between 0.5 mL / min and 4.5 mL / min, for example example between 1.0 mL / min and 3.0 mL / min.

[0194] Adjusting the dimensions of the microreactor, in particular the diameter and length of a tubular conduit, and the flow rate of the first and second phases in the microreactor, makes it possible to control and fix a residence time of the first and second phases in the microreactor. It is preferred that the residence time of the first and second phases brought into contact in the microreactor in step (b) is between 2 seconds and 400 seconds. For example, this residence time may be between 2 and 30 seconds, between 30 and 60 seconds, or between 60 seconds and 400 seconds.

[0195] The contacting of the first and second phases in the continuous flow microreactor is generally carried out at a temperature (called "contacting temperature") of between -70°C and 25°C, preferably between -50°C and 5°C, better still between -50°C and -20°C. When the temperature of the first and / or second phase in step (a) is different from the contacting temperature in the microreactor in step (b), an equilibration step may be implemented before the contacting. This equilibration aims to bring and stabilize the first and / or second phases at the contacting temperature, before the contacting. A first equilibration tubular conduit and / or a second equilibration tubular conduit, maintained at the contacting temperature, may be used for this equilibration.Preferably, said first balancing tubular conduit and / or said second balancing tubular conduit are connected respectively: .

[0196] - between the continuous feed means in the first phase and the microreactor at continuous flow (more particularly the micro-mixer of the continuous flow microreactor, even more particularly, a first inlet of the micro-mixer), and / or

[0197] - between the means for continuous feeding in the second phase and the microreactor continuous flow (more particularly the micro-mixer of the continuous flow microreactor, even more particularly, a second inlet of the micro-mixer).

[0198] The internal diameter of the balancing tubular conduits is of micrometric or millimetric size, and can independently be between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and better still between 0.7 mm and 1.2 mm. The length of the balancing tubular conduits can independently be between 25 cm and 100 cm. The value can in particular be chosen so as to allow efficient cooling at a given flow rate. The balancing tubular conduits are generally arranged in a coil or coil, over all or part of their length. Other arrangements can however be envisaged.

[0199] The first and second phases brought into contact in the microreactor may together form one or more phases, preferably a single phase generally. liquid.

[0200] Step (c) of the process according to the invention comprises the recovery (or equivalently, “collection”) of the fluorination and / or cyclization product of said alkene or alkyne amino acid. The recovery of the product is carried out at the outlet of the continuous flow microreactor (in particular, at the outlet of its tubular conduit), which is typically connected to a collection unit, such as a flask. The recovered product is generally recovered in a mixture with reaction by-products and / or superacid reagent residues. To neutralize the superacid reagent residues, a neutralizing agent may be brought into contact with the mixture recovered in the collection unit.This neutralizing agent may be, for example, a mixture of water, a base such as sodium carbonate, sodium hydroxide, potassium hydroxide, or other bases in resin form such as Amberlyst A26 hydroxide form, and possibly one or more organic solvents such as acetone, methanol, or ammoniacal methanol. The amount of neutralizing agent to be used should be adjusted according to the amount of residual superacid reagent.

[0201] Given the corrosive nature of superacids, the elements used for implementing the method of the invention, such as the continuous flow microreactor (in particular the tubular conduit and the micromixer that it comprises), the balancing tubular conduits, the storage units, the collection units, the syringes, and / or the 3-way valves, are advantageously made of materials that resist this corrosive nature. Examples of materials that may be mentioned are fluoropolymers such as polytetrafluoroethylene and poly(ethylene-co-tetrafluoroethylene) and certain metal alloys such as Hastelloy® nickel alloys. In any event, a person skilled in the art will be able to judiciously choose the appropriate material for each element of the assembly.

[0202] The installation used for implementing the method of the invention constitutes another object of the invention. [Fig.l] is a diagram illustrating the method according to one embodiment of the invention, as well as the installation which can be used to implement this method.

[0203] The installation according to the invention comprises the following elements:

[0204] - a storage unit (1) of a first phase comprising an alkene or alkyne amine,

[0205] - a storage unit (1') of a second phase comprising a superacid reagent,

[0206] - a continuous flow microreactor (2), preferably comprising a micro-mixer (21) and a tubular conduit (22),

[0207] - a means of continuous supply in the first phase (3),

[0208] - a means of continuous supply in the second phase (3'),

[0209] - a tubular balancing pipe for the first phase (4),

[0210] - a tubular balancing pipe for the second phase (4'), and

[0211] - a collection unit (5).

[0212] More particularly, the installation according to the invention comprises:

[0213] - a storage unit (1) of a first phase comprising an alkene or alkyne amine,

[0214] - a storage unit (1') of a second phase comprising a superacid reagent,

[0215] - a means for continuously supplying the first phase (3) connected to the unit of storage of the first phase (1), and to a tubular pipe for balancing the first phase (4),

[0216] - a means for continuously supplying the second phase (3') connected to the unit of storage of the second phase (1'), and to a tubular balancing pipe of the second phase (4'),

[0217] - a continuous flow microreactor (2) comprising a micro-mixer (21) comprising two inlets and one outlet, and a tubular conduit (22) comprising one inlet and one outlet, wherein the inlet of the tubular conduit (22) is connected to the outlet of the micro-mixer (21),

[0218] where the first phase balancing tubular conduit (4) is connected to the first inlet of the micro-mixer (21) and the second phase balancing tubular conduit (4') is connected to the second inlet of the micro-mixer (21), and

[0219] - a collection unit (5), connected to the outlet of the tubular conduit (22) of the micro-mixer (21). croreactor (2).

[0220] The connection between the continuous supply means in the first phase (3), the storage unit of the first phase (1), and the balancing tubular conduit of the first phase (4) can be ensured by means of a 3-way valve (6). The connection between the continuous supply means in the second phase (3'), the storage unit of the second phase (1') and the balancing tubular conduit of the second phase (4') can be ensured by means of a 3-way valve (6'). The valves (6) and (6') can be computer-controlled.

[0221] In a particular embodiment, the installation according to the invention further comprises one or more washing units comprising a washing solvent. [Fig. 2] is a diagram illustrating the method according to one embodiment of the invention, as well as the installation that can be used to implement this method, further comprising washing units. A first washing unit (7) and a second washing unit (7') can be connected respectively to the means for continuously feeding the first phase (3) and to the means for continuously feeding the second phase (3'), so that the washing solvent can circulate in the continuous flow microreactor. 3-way valves (8, 8') can be used to alternate the injection of the first and second phases, and the injection of the washing solvent. Such 3-way valves are installed so that they connect:

[0222] - on the one hand, the storage unit of the first phase (1), a first unit of washing (7), and the means of continuous supply in the first phase (3) (or the 3-way valve (6)), and

[0223] - on the other hand, the storage unit of the second phase (1'), a second unit of washing (7'), and the means of continuous supply in the second phase (3') (or the 3-way valve (6')).

[0224] A waste collection unit (9) may be used to collect the washing solvents after circulation in the installation. A 3-way valve (10) may be used to connect the outlet of the tubular conduit (22) with the collection unit (5) and the waste collection unit (9).

[0225] The washing solvent may in particular be water, optionally comprising a base (such as sodium carbonate, sodium hydroxide, or potassium hydroxide) and / or one or more suitable organic solvents, such as acetone. In a particular embodiment, several successive washing solvents are used, for example, water, then a basic aqueous solution then acetone.

[0226] The 3-way valves described in the present application (such as valves (6), (6'), (8), and (8') may for example be manually or automatically switching valves. The automatically switching 3-way valves may be computer controlled.

[0227] In a particular embodiment, the tubular conduit (22) of the continuous flow microreactor (2) has the following dimensions:

[0228] - a length between 20 cm and 800 cm, for example between 30 cm and 150 cm or between 200 cm and 600 cm, and / or

[0229] - an internal diameter between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and better between 0.7 mm and 1.2 mm.

[0230] The external diameter of the tubular conduit (22) may for example be between 0.8 mm and 3.2 mm, for example between 0.8 mm and 1.0 mm, between 1.0 and 2.0 mm, or between 1.6 mm and 3.2 mm.

[0231] In a particular mode, the tubular conduit (22) of the continuous flow microreactor (2) has:

[0232] - an internal diameter between 0.5 mm and 1.5 mm, and

[0233] - preferably an external diameter between 1.0 and 2.0 mm.

[0234] The tubular conduit (22) is generally arranged in a coil or coil, over all or part of its length. Other arrangements can however be envisaged.

[0235] The micro-mixer (21) typically has a T or Y shape. The internal diameter of the micro-mixer (21) is of micrometric or millimetric size, and is advantageously between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and better between 0.7 mm and 1.2 mm.

[0236] Said continuous supply means (3, 3') designate any element or set of elements making it possible to continuously transfer the first and second phases into the continuous flow microreactor (2), preferably a pump or a syringe possibly associated with a syringe pump.

[0237] The internal diameter of the balancing tubular conduits (4, 4') is of micrometric or millimetric size, and can independently be between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and better still between 0.7 mm and 1.2 mm. The length of the balancing tubular conduits (4, 4') can independently be between 25 cm and 100 cm. The balancing tubular conduits (4, 4') are generally arranged in a coil or coil, over all or part of their length. Other arrangements can however be envisaged.

[0238] The invention will be better understood in light of the following examples, which are given purely for illustrative purposes and are not intended to limit the scope of the invention, defined by the appended claims. EXAMPLES

[0239] Example 1: Fluorination and / or cyclization of amino alkenes or alkynes according to the process of the invention

[0240] The process of fluorination and / or cyclization of amino alkenes or alkynes was carried out according to the general procedure described below:

[0241] The installation is composed of two pumps or syringe pumps equipped with two high-pressure metal syringes, each connected to an automatic valve. The latter are connected, by a metal tube, to the fluid reservoirs. The syringes are cooled by an enclosure containing dry ice allowing cooling of the liquid in the syringe by thermal conduction. The parts in contact with the superacid mixture were designed and adapted to the corrosive environment by choosing a material compatible with this type of environment (i.e. the interior of the syringe, the interior of the 3-way valves, the metal connector tubes for transporting the fluids (internal diameter 1 mm, external diameter 1.6 mm).

[0242] Fluids 1 (HF / SbF5 superacid) and 2 (solubilized substrate) are respectively placed in the reservoirs immersed in a cold bath (acetone / water, T= -35 °C) and connected to the system by a tube (internal diameter = 0.8 mm, external diameter = 1.6 mm).

[0243] The 3-way valve module is a motorized ball valve, which allows the passage of fluids to be opened, closed or switched. Thus, once the syringes are filled with fluids 1 and 2, the contacting of the fluids can be initiated automatically by means of software which controls the dispensing of a small volume V of each fluid at given flow rates Fl and F2. Software control of the pumps and valves thus limits operator contact with the superacid during the reaction. The fluids are then conveyed to a T-shaped mixer (internal diameter 1 mm), via equilibration loops, of length determined to reach the desired reaction temperature (here, L = 50 cm with V = 0.25 mL), itself connected to a tube of variable length L (internal diameter 0.8 mm, external diameter 1.6 mm) allowing the residence time (tR) of each reaction to be modulated. Collection control is done manually in bottles containing a residual acid neutralization solution and the product is extracted with dichloromethane or suitable solvent, washed with water and dried over MgSO4. The crude residue is purified by silica chromatography then analyzed by *H, 13C and 19F NMR and then compared to the results previously obtained by the laboratory.The compounds are characterized by one or more of these techniques: 1H, 13C and 19F NMR, HSQC, HMBC, HRMS.

[0244] Washing tanks (base / water then acetone / water then acetone) also connected to the manual valves allow washing to be carried out at the end of the experiment.

[0245] [Chem. 11] Ac"

[0246] 1-(4-(2-fluoropropyl)piperazin-1-yl)ethanone 1a was obtained by following the general flow-through procedure using a tubular reactor of length L = 47 cm (tR = 8.2 s) immersed in a bath maintained at -20°C. Flow rates of superacid mixture HF / SbF5 1:1 v / v (Fi = 1 mL / min) and substrate l-(4-allylpiperazin-l-yl)ethan-l-one 1 (F2= 1 mL / min, c = 0.5 mol / L) in HF were set producing a final acidity of 8.3 mol% SbF5. The reaction mixture was collected for 1 min (0.43 mmol committed, 73 mg). Purification carried out by silica chromatography (98 / 2 CH2Cl2 / MeOH) allowed to obtain 61.2 mg of the product the (75%).

[0247] XH RMN (400 MHz, CDC13, ppm) ô: 1.42 (dd, CH3, J= 23.8 Hz, J = 6.3 Hz), 3.28 (m, CH2), 3.98 (si, NH).4.89 (dm, CH, J = 49.4 Hz), 6.64 (dd, 2CH, J = 8.5 Hz, J = 0.9 Hz), 6.74 (t, CH, J = 7.3 Hz), 7.19 (dd, 2CH, J = 8.4 Hz, J = 7.4 Hz).13C RMN (100 MHz, CDC13, ppm) ô: 18.8 (d, CH3, = 22 Hz), 49.6 (d, CH2, J= 21 Hz), 89.6 (d, CH, J = 167 Hz), 113.1 (2CH), 118.1 (1CH), 129.4 (2CH), 147.9.X9F{XH} RMN (CDC13, 376 MHz, ppm) ô: -180.0.

[0248] [Chem. 12]

[0249] 4,6-Dimethyl-3,4-dihydro-2H-benzo[e][l,2]thiazine 1,1-dioxide 2a was obtained by following the general flow-through procedure using a tubular reactor of length L = 130 cm (tR= 52.3 s) immersed in a bath maintained at -20°C. Flow rates of superacid mixture HF / SbF5l:l (Fi = 0.25 mL / min) and substrate N -allyl-4-methylbenzenesulfonamide 2 in HF (c = 0.5 mol / L) F2= 0.5 mL / min were set producing a final acidity of 5.1 mol% SbF5. The reaction mixture was collected for 2 min (0.887 mmol committed, 187.8 mg). Purification carried out by silica chromatography (98 / 2 CH2Cl2 / MeOH) allowed obtaining 171.2 mg of product 2a (76%).

[0250] XH RMN (400 MHz, CDC13, ppm) 0:1.34 (d, J = 7.2Hz, 3H), 2.37 (s, 3H), 2.98 (m, 1H), 3.41 (m, 1H), 3.82 (m, 1H), 4.89 (t, J = 7.7 Hz, 1H), 7.09 (s, 1H), 7.14 (d, J = 8.1Hz, 1H), 7.62 (d, J = 8.1Hz, 1H).13C RMN (100 MHz, CDC13, ppm) ô: 19.5 (CH3 ), 21.6 (CH3), 31.5 (CH), 48.2 (CH2), 124.0 (CH), 128.2 (CH), 129.0, 134.2, 140.2, 142.7.

[0251] [Chem. 13] HN—■ y'

[0252] N-(2-fluoropropyl)-4-methylbenzenesulfonamide 2b was obtained by following the general flow-through procedure using a tubular reactor of length L = 78.2 cm (tR= 9.2 s) immersed in a bath maintained at -20°C. Flow rates of superacid mixture HF / SbF5l:lv / v (Fi = 1 mL / min) and substrate N-allyl-4-methylbenzenesulfonamide 2 (F2= 2 mL / min, c = 1 mol / L) in HF were set producing a final acidity of 1.9 mol% SbF5. The reaction mixture was collected for 30 s (0.852 mmol committed, 180 mg). Purification carried out by silica chromatography (98 / 2 CH2Cl2 / MeOH) allowed obtaining 147.7 mg of product 2b (75%).

[0253] XH RMN (400 MHz, CDC13, ppm) ô: 1.32 (dd, J= 23.8, 6.3 Hz, 3H, CH3), 2.46 (s, 3H, CH3), 3.03 (dddd, J= 18.4, 13.8,7.6, 4.8 Hz, 1H), 3.23 (dddd, J= 28.4, 13.7, 8.1, 2.9 Hz, 1H), 4.84 - 4.62 (dm, JH.F = 45 Hz, 1H), 4.84 (s, 1H), 7.35 (d, J = 8 Hz, 2H), 7.77 (d, J= 8.3 Hz, 2H). X3C RMN (100 MHz, CDC13, ppm) ô: 143.8 (Cq), 136.94 (Cq), 129.9 (2CH), 127.16 (2CH), 89.3 (d, J= 167.6 Hz), 48.3 (CH2, d, J= 21.0 Hz), 21.7 (CH3), 18.2 (CH3, d, J = 21.8 Hz).19F{xH} RMN (CDC13, 376 MHz, ppm) ô: -180.2. HRMS (ESI): Cale pour C10H14FNO2S: 231.0729, trouvé : 232.080241 [M+H]+ et 254.062169 [M+Na]+.

[0254] [Chem. 14]

[0255] N-(2-fluoropropyl)-4-nitrobenzenesulfonamide 3b was obtained by following the general flow-through procedure using a tubular reactor of length L = 78.2 cm (tR= 13.6 s) immersed in a bath maintained at -20°C. Flow rates of superacid mixture HF / SbF5l:lv / v (Fi= 1 mL / min) and substrate N-allyl-4-nitrobenzenesulfonamide 3 (F2 = 1 mL / min, c = 1 mol / L) in HF were set producing a final acidity of 8.4 mol% SbF5. The reaction mixture was collected for 1 min (0.867 mmol committed, 120 mg). Purification carried out by silica chromatography (98 / 2 CH2Cl2 / MeOH) allowed obtaining 190 mg of product 3b (84%).

[0256] XH RMN (400 MHz, CDC13, ppm) ô: 1.32 (dd, J= 23.8 Hz, J = 6.3 Hz, 3H), 3.10 (m, 1H), 3.26 (dm, J = 28.1 Hz, 1H), 4.73 (dm, J= 48.9 Hz, 1H), 5.38 (1H, m, NH), 8.07 (d, J= 9.1 Hz, 2H), 8.38 (d, 7=9.1 Hz, 2H). 13C RMN (100 MHz, CDC13, ppm) ô: 18.0 (d, J =22 Hz, CH3), 48.2 (d, J = 21 Hz, CH2), 89.1 (d, J = 168 Hz, CH), 124.5 (s, 2CH), 128.3 (s, 2CH), 145.8 (s), 150.1 (s). 19F{XH} RMN (CDC13, 376 MHz, ppm) ô: -180.2

[0257] [Chem. 15] K \__ Z _ _ / / 'A , y

[0258] N-(2-fluoropropyl)-4-(trifluoromethyl)benzenesulfonamide 4b was obtained by following the general flow-through procedure using a tubular reactor of length L = 78.2 cm (tR=35.7s) immersed in a bath maintained at -20°C. Flow rates of HF / SbF5 1:1 v / v superacid mixture (Fi = 0.25 mL / min) and N-allyl-4-trifluorobenzenesulfonamide substrate 4 (F2= 0.5 mL / min, c = 0.49 mol / L) in HF were set producing a final acidity of 5.2 mol% SbF5. The reaction mixture was collected for 2 min (0.398 mmol committed, 105.6 mg). Purification carried out by silica chromatography (98 / 2 CH2Cl2 / MeOH) allowed obtaining 90.8 mg of product 4b (80%).

[0259] No trace of the cyclization product 4a was observed under the conditions studied.

[0260] XH RMN (400 MHz, CDC13, ppm) ô: 1.29 (dt, J = 23.8, 6.3 Hz, 3H), 3.34 - 2.97 (m, 2H), 4.71 (dm, J = 49), 7b Hz 5, N2H (d, J = 8.3 Hz, 2H), 8.00 (d, J = 8.2 Hz, 2H). 19F{XH} NMR (CDC13, 376 MHz, ppm) ô : -179.8.

[0261] [Chem. 16] r TX” V, JF Cl AC

[0262] The 1 -(4-(2-chloro-2-fluoropropyl)piperazine-1 -yl)ethane-1 -one 5a was obtained by following the general flow-through procedure using a tubular reactor of length L = 200 cm (tR = 60.3 s) immersed in a bath maintained at -20°C. Flow rates of superacid mixture HF / SbF5l:lv / v (Fi = 0.5 mL / min) and substrate l-(4-(2-chloroallyl)piperazin-l-yl)ethan-l-one 5 (F2 = 0.5 mL / min, c = 0.5 mol / L) in HF were set, producing a final acidity of 6.4 mol% SbF5. The reaction mixture was collected for 2 min (0.499 mmol committed, 111.1 mg). Purification by silica chromatography (99 / 1 CH2Cl2 / MeOH) yielded 77 mg of product 5a (70%).

[0263] XH RMN (400 MHz, CDC13, ppm) ô: 1.93 (d, J= 19.4 Hz, 3H), 2.06 (s, 3H), 2.57 (m, 4H), 2.78 (dd, J= 29.2 .2 Hz, J= J= 14.3 Hz, J= 14.3 Hz, 1H), 3.42 et 3.57 (2m, 4H).X3C NMR (100 MHz, CDC13, ppm) ô: 21.7 (s, CH3), 28.4 (d, J= 82 et 4, Hz4, 2CH2), 54.4 and 54.6 (s, CH2), 67.8 (d, J= 22 Hz, CH2), 114.3 (d, J= 243 Hz, IC), 169.3 (s).x'F{xH} RMN (CDC13, 378) MHz,

[0264] [Chem. 17]

[0265] Pathway A (from compound 5): The 1-(4-(2,2-Difluoropropyl)piperazin-l-yl)ethan-1-one 5b was obtained by following the general flow-through procedure using a tubular reactor of length L = 600 cm (tR= 274 s) immersed in a bath maintained at 0°C. Flow rates of superacid mixture HF / SbF5l:lv / v (Fi= 0.5 mL / min) and substrate l-(4-(2-chloroallyl)piperazin-l-yl)ethan-1-one 5 (F2= 0.25 mL / min, c = 0.499 mol / L) in HF were set producing a final acidity of 12.1 mol% SbF5. The reaction mixture was collected for 2 min (0.215 mmol committed, 44.3 mg). Purification carried out by silica chromatography (CH2C12 100% to 98 / 2 CH2Cl2 / MeOH) allowed 38 mg of product 5b (74%) to be obtained.

[0266] Route B (from compound 9): The 1-(4-(2,2-Difluoropropyl)piperazin-l-yl)ethan-1-one 5b was alternatively obtained by following the general flow-through procedure using a tubular reactor of length L = 400 cm (tR= 136 s) immersed in a bath maintained at -40°C. Flow rates of superacid mixture HF / SbF53:lv / v (Fi= 0.5 mL / min) and substrate l-(4-(prop-2-yn-l-yl)piperazin-l-yl)ethan-1-one 9 (F2= 0.5 mL / min, c = 0.5 mol / L) in HF were set leading to a final acidity of 2.65 mol% SbF5. The reaction mixture was collected for 30 s (0.50 mmol committed, 85.8 mg). Purification by silica chromatography (CH2C12 100% to 98 / 2 CH2Cl2 / MeOH) yielded 73 mg of product 5b (71%).

[0267] 8.0 Hz, 4H), 2.09 (d, J = 2.6 Hz, 3H), 1.66 (t, J = 18.7 Hz, 3H). X9F{XH} NMR (CDC13, 376 MHz, ppm) ô: -92.2.

[0268] [Chem. 18]

[0269] l-(2,2-Difluoropropyl)-4-phenylpiperidine 6a was obtained by following the general flow-through procedure using a tubular reactor of length L = 200 cm (tR = 2.7 s) immersed in a bath maintained at -40°C. Flow rates of superacid mixture HF / SbF53:lv / v (Fi = 0.5 mL / min) and substrate 4-phenyl-l-(prop-2-yn-l-yl)piperidine 6 (F2 = 1 mL / min, c = 0.5 mol / L) in HF were set producing a final acidity of 2.41 mol% SbF5. The reaction mixture was collected for 30 s (0.232 mmol committed, 46.25 mg). Purification carried out by silica chromatography (100% CH2Cl2 to 98 / 2 CH2Cl2 / MeOH) allowed obtaining 40.7 mg of product 6a (88%).

[0270] XH RMN (400 MHz, CDC13, ppm) ô: 7.33-7.17 (m, 5H), 3.05 (d, J = 10.8 Hz, 2H), 2.70 (t, J = 13.8 Hz, 2H), 2.45 (m, 1H), 2.30 (dd, J = 11.1 Hz, J = 3.6 Hz, 2H), 1.79 (m, 4H), 1.66 (t, J = 18.7 Hz, 3H). X3C RMN (100 MHz, CDC13) ô: 146.3, 128.4, 126.8, 126.1, 124.4 (t, J= 239 Hz), 63.0 (t, J= 28 Hz), 55.5, 42.2, 33.6, 22.0 (t, J= 27 Hz). X9F{XH} RMN (376 MHz, CDC13, ppm) ô ppm: -92.3.

[0271] [Chem. 19]

[0272]

[0273]

[0274] l-(2-Fluoroallyl)-4-phenylpiperidine 6b was obtained by following the general flow-through procedure using a tubular reactor of length L = 30 cm (tR = 2.3 s) immersed in a bath maintained at -40°C. Flow rates of superacid mixture HF / SbF53:lv / v (Fi = 1 mL / min) and substrate 4-phenyl-l-(prop-2-yn-l-yl)piperidine 6 (F2 = 2 mL / min, c = 0.48 mol / L) in HF were set, producing a final acidity of 2.4 mol% SbF5. The reaction mixture was collected for 30 s (0.494 mmol committed, 90.2 mg). Purification carried out by silica chromatography (CH2C12 100% at 98 / 2 DCM / MeOH) allowed obtaining 27.3 mg of product 6a (25%). XH RMN (400 MHz, CDC13, ppm) ô: 1.93-1.80 (m, 4H, 2CH2), 2.24-2.09 (m, 2H), 2.58-2.42 (m, 1H, CH), 3.12 - 3.04 (m, 2H), 3.15 (d, J= 16.9 Hz, 2H), 4.48 (dd, J = 49.0, 2.7 Hz, 1H), 4.73 (dd, J= 16.8, 2.7 Hz, 1H), 7.37 - 7.16 (m, 5H).13C RMN (100 MHz, CDC13, ppm) ô: 162.8 (Cq, d, J = 260.7 Hz), 146.3 (Cq), 128.44 (CH), 126.9 (CH), 126.2 (CH), 93.3 (d, J= 18.7 Hz, C-F), 59.1 (d, J= 27.6 Hz), 54.1 (CH2), 42.5 (CH), 33.4 (CfL).19F{’H} RMN (CDC13, 376 MHz, ppm) ô: 98.2. HRMS (ESI): Cale, pour C14H18NF: 219.1423, trouvé : 220.1496 [M+H]+. [Chem. 20]

[0275]

[0276]

[0277] 1-(4-(3-Chloro-3-fluoropropyl)piperazin-l-yl)ethan-l-one 7a was obtained by following the general flow-through procedure using a tubular reactor of length L = 400 cm (tR = 120.7 s) immersed in a bath maintained at -20°C. Flow rates of superacid mixture HF / SbF5l:lv / v (Fi = 0.5 mL / min) and substrate (Z / E )-l-(4-(3-chloroallyl)piperazin-l-yl)ethan-l-one 7 (F2 = 0.5 mL / min, c = 0.5 mol / L) in HF were set, producing a final acidity of 8.4 mol% SbF5. The reaction mixture was collected for 1 min (0.271 mmol committed, 40.4 mg). Purification carried out by silica chromatography (gradient 100% CH2Cl2 to 98 / 2 CH2Cl2 / MeOH) made it possible to obtain 32.5 mg of product 7a (57%). XH RMN (400 MHz, CDC13, ppm) ô: 2.07 (S, 3h, CH3), 2.24 (M, 2h, CH2), 2.39 (M, 4h, 2ch2), 3.65 - 3.55 (M, 2h), 3.50 - 3.39 (M, 2h), 2.54 (T, J = 6.9 Hz, 2H), 6.29 (dt, J= 50.9, 5.5 Hz, 1H, CHFC1). X9F{XH} NMR (CDC13, 376 MHz, ppm) ô: -117.08. [Chem.21]

[0278] 1-(4-(3,3-difluoropropyl)piperazin-l-yl)ethan-l-one 7b was obtained by following the general flow-through procedure using a tubular reactor of length L = 600 cm (tR = 241 s) immersed in a bath maintained at 0°C. Flow rates of superacid mixture HF / SbF5l:lv / v (Fi = 0.5 mL / min) and substrate (Z / E )-l-(4-(3-chloroallyl)piperazin-l-yl)ethan-l-one 7 in HF (F2 = 0.25 mL / min, c = 0.5 mol / L) were set producing a final acidity of 12.1 mol% SbF5. The reaction mixture was collected for 2 min (0.218 mmol committed, 44.8 mg). Purification carried out by silica chromatography (gradient 100% CH2C12 to 98 / 2 CH2Cl2 / MeOH) allowed the isolation of 45 mg of product 7b (85%).

[0279] XH RMN (400 MHz, CDC13, ppm) ô: 2.05 - 1.92 (m, 2H, CH2), 2.06 (s, 3H, CH3), 2.41 (dt, J = 14.7, 5.0Hz, 4H), 2.51 (t, J= 7.2 Hz, 2H), 3.44 (t, J = 5.0 Hz, 2H, CH2), 3.59(t, J= 5.1 Hz, 2H, CH2), 5.91 (tt, J= 56.7, J = 4.6 Hz, 1H, CHF2). 13C RMN (100 MHz, CDC13, ppm) ô: 168.8 (C=O), 116.2 (t, J = 238.6 Hz, CH), 53.1 (CH2), 52.5 (CH2), 51.1 (t, J= 6.3 Hz, CH2), 46.1 (CH2), 41.2 (CH2), 31.5 (t, J= 21.1 Hz, CH2), 21.1 (CH3). X9F{XH} RMN (CDC13, 376 MHz, ppm) ô: -117.1.

[0280] [Chem.22]

[0281] N-(2-fluoropropyl)aniline 8a was obtained by following the general flow-through procedure using a tubular reactor of length L = 50 cm (tR = 5.0 s) immersed in a bath maintained at -50°C. Flow rates of superacid mixture HF / SbF5 3:1 nIn (Fi = 1.5 mL / min) and substrate / V-allyl aniline 8 (F2 = 1.5 mL / min, c = 0.57 mol / L) in HF were set producing a final acidity of 3.74 mol% SbF5. The reaction mixture was collected for 30 s (0.429 mmol committed, 53.6 mg). Purification carried out by silica chromatography (gradient CH2Cl2100% to 98 / 2 CH2 Cl2 / MeOH) allowed the isolation of 43 mg of product 8a (66%).

[0282] 2H, CHJ, 6.75 (tt, J = 7.4, 1.0 Hz, 1H), 7.24 - 7.12 (m, 2H, CH} NMR (CDC13, 376 MHz, ppm) ô: -179.9.

[0283] [Chem.23] Sb 8c

[0284] 3-Methylindoline 8b and 1,2,3,4-tetrahydroquinoline 8c were obtained following the general flow-through procedure using a tubular reactor of length L = 200 cm (tR = 40 s) immersed in a bath maintained at 0°C. Flow rates of superacid mixture HF / SbF5l:lv / v (Fi = 0.5 mL / min) and substrate N-allylaniline 8 (F2 = 1.0 mL / min, c = 0.74 mol / L) in HF were set producing a final acidity of 5.2 mol% SbF5. The reaction mixture was collected for 30 s (0.429 mmol committed, 53.6 mg). Purification carried out by silica chromatography (CH2Cl2 / MeOH gradient) allowed the isolation of 31.3 mg of product 8b (37%) and 35.9 mg of product 8c (42%).

[0285] 3-methylindoline 8b 6.66 (d, J = 7.7 Hz, 1H), 6.75 (td, 7=7.4, 0.9 Hz, 1H), 7.04 (ddd, J = 8.7, 2.0, 1.0 Hz, 1H), 7.12 - 7.08 (m, 1H),

[0286] 1,2,3,4-tetrahydroquinoline 8c XH NMR (400 MHz, CDC13, ppm) ô: 1.95 (dtd, J = 8.8, 6.4, 4.2 Hz, 1H), 2.77 (t, J = 6.4 Hz, 1H), 3.33 - 3.28 (m, 1H), 6.48 (d, J = 7.9 Hz, 1H), 3.78 (s, 1H), 6.61 (td, 7 = 7.4, 1.1 Hz, 1H), 7.00 - 6.89 (m, 1H).

[0287] [Chem.24]

[0288] N-(2-fluoropropyl)-4-nitroaniline 12b was obtained by following the general flow-through procedure using a tubular reactor of length L = 200 cm (tR = 40 s) immersed in a bath maintained at 0°C. Flow rates of superacid mixture HF / SbF5l:lv / v (Fi= 0.5 mL / min) and substrate N-allyl-4-nitroaniline (F2= 1 mL / min, c = 0.3 mol / L) in HF were set producing a final acidity of 5.1 mol% SbF5. The reaction mixture was collected for 1 min 21 s (0.448 mmol committed, 79.8 mg). Purification carried out by silica chromatography (CH2C12 / MeOH gradient) allowed the isolation of 65 mg of 12b (73%).

[0289] With a tubular reactor L = 600 cm (tR = 241 s), Fi = 0.25 mL / min and F2 = 0.5 mL / min a yield of 92% of the product 12b was obtained.

[0290] CFH), 6.57 (d, 7 = 9.3 Hz, 2-H, CH), 8.09 (d, 7 = 9.3 Hz, 2H, CH). X9F{XH} NMR (CDC13, 376 MHz, ppm) ô: -179.9

[0291] [Chem.25] H Ac—MH—H

[0292] l-(4-(2-fluoroallyl)piperazin-l-yl)ethan-l-one 9b was obtained by following the general flow-through procedure using a tubular reactor of length L = 30 cm (tR = 2 s) immersed in a bath maintained at -40°C. Flow rates of superacid mixture HF / SbF55:lv / v (Fi = 1.5 mL / min) and substrate l-(4-(prop-2-yn-l-yl)piperazin-l-yl)ethan-l-one 9 (F2 = 3 mL / min, c = 0.5 mol / L) in HF were set producing a final acidity of 1.57 mol% SbF5. The reaction mixture was collected for 30 s (0.748 mmol committed, 154.3 mg). Purification carried out by silica chromatography (CH2Cl2100% to CH2Cl2 / MeOH 98 / 2) allowed the isolation of 97.9 mg of product 9b (70%).

[0293] XH RMN (400 MHz, CDC13, ppm) ô: 2.09 (s, 3H, CH3), 2.50 (m, 4H, 2CH2), 3.11 (dd, J= 16.5 Hz, J = 2.7 Hz, CH2), 3.51 (m, 2H, CH2), 3.65 (m, 2H, CH2), 4.47 (dt, J = 48.8 Hz, J = 2.8 Hz, CH), 4.74 (dt, J= 16.6 Hz, J = 2.8 Hz, CH). 13C RMN (100 MHz, CDC13, ppm) ô: 41.2 (CH2), 46.1 (CH2), 58.4 (d, J= Hz, CH2), 93.8 (CH2), «FpH} RMN (CDC13, 376 MHz, ppm) ô: 98.7. HRMS (ESI): Cale pour C9H15FN2O: 186.1168, trouvé : 187.1241 [M+H]+.

[0294] [Chem.26]

[0295] (4-Fluoro-4-methylpiperidin-l-yl)(4-nitrophenyl)methanone 10a was obtained by following the general flow-through procedure using a tubular reactor of length L = 600 cm (tR= 104 s) immersed in a bath maintained at 0°C. Flow rates of superacid mixture HF / SbF5l:lv / v (Fi= 1 mL / min) and substrate N,N -diallyl-4-nitrobenzamide 10 (F2= 1 mL / min, c = 0.23 mol / L) in HF were set producing a final acidity of 8.4 mol% SbF5. The reaction mixture was collected for 1 min 53 s (0.353 mmol committed, 75.7 mg). Purification carried out by silica chromatography (petroleum ether / AcOEt 70 / 30) allowed the isolation of 43.1 mg of product 10a (46%).

[0296] 8.8 Hz, 2H, 2CH), 8.27 (d, J= 8.8 Hz, 2H, 2CH). X9F{XH} NMR (CDC13, 376 MHz, ppm) ô: -151.7.

[0297] [Chem.27]

[0298] 4-Fluoro-4-methyl-l-(4-nitrobenzyl)piperidine 16a was obtained by following the general flow-through procedure using a tubular reactor of length L = 600 cm (tR= 104 s) immersed in a bath maintained at 0°C. Flow rates of superacid mixture HF / SbF5l:lv / v (Fi= 1 mL / min) and substrate Af-allyl-iV -(4-nitrobenzyl)prop-2-en-l-amine 16 (F2= 1 mL / min, c = 0.34 mol / L) in HF were set producing a final acidity of 8.4 mol% SbF5. The reaction mixture was collected for 1 min (0.341 mmol committed, 88.4 mg). Purification carried out by silica chromatography (CH2Cl2 / MeOH 99 / 1) allowed the isolation of 37 mg of product 16a (47%).

[0299] 'H RMN (400 MHz, CDC13, ppm) ô: 1.35 (d, J = 21.6 Hz, CH3), 1.66 and 1.85 (m, 2CH), 2.26 (m, 2CH), 2.60 (m, 2CH), 3.62 (s, CH2), 7.52 (d, J = 8.8 Hz, 2CHJ, 8.17 (d, J = 8.8, 2CHJ. 13C RMN (100 MHz, CDC13, ppm) ô: 26.9 (d, J = 24 Hz, CH3), 36.6 (d, J= 22 Hz, 2CH2), 49.5 (d, J= 1.1 Hz, 2CH2), 62.1 (CH2), 91.9 (d, J= 167 Hz, C-F), 123.5 (2CH), 129.4 (2CH), 146.8 (Cq), 147.1 (Cq). 19F{XH} RMN (CDC13, 376 MHz, ppm) ô: -151.55. HRMS (ESI): Cale pour C13H18FN2O2: 252.1274, trouvé : 253.1346 [M+H]+.

[0300] [Chem.28]

[0301] 3-Fluoro-3-methyl-l-(4-nitrobenzyl)piperidine 16b was obtained by following the general flow-through procedure using a tubular reactor of length L = 600 cm (tR= 104 s) immersed in a bath maintained at -40°C. Flow rates of superacid mixture HF / SbF5l:lv / v (Fi= 1 mL / min) and substrate JV-allyl-iV -(4-nitrobenzyl)prop-2-en-l-amine 16 (F2= 1 mL / min, c = 0.34 mol / L) in HF were set producing a final acidity of 8.4 mol% SbF5. The reaction mixture was collected for 1 min (0.341 mmol committed, 88.4 mg). Purification by silica chromatography (CH2Cl2 / MeOH 99 / 1) allowed the isolation of 12 mg of 3-fluoro-3-methyl-l-(4-nitrobenzyl)piperidine 16b (35%).

[0302] XH RMN (400 MHz, CDC13, ppm) ô: 1.34 (d, J = 21.6 Hz, CH3), 1.53 (m, 2CH), 1.83 (m, 2CH), 2.22 (m, 2CH), 2.55(m, 2CH), 3.61 (s, CH2), 7.51 (d, J = 8.8 Hz, 2(¾ ), 8.16 (d, J= 8.7 Hz, 2CHJ. 13C RMN (100 MHz, CDC13, ppm) ô: 22.0 (d, J= 4 Hz, CH2), 25.0 (d, J = 24 Hz, CH3), 35.0 (d, J = 22.1 Hz, CH2), 53.1 (CH2), 61.8 (CH2), 62.1 (d, J = 23 Hz, CH2), 92.2 (d, J = 170 Hz, Cq), 123.5 (2CH), 129.3 (CH), 146.4 (Cq), 147.1 (Cq). «EpH} RMN (CDC13, 376 MHz, ppm) ô: 146.8. HRMS (ESI): Cale pour C13H18FN2O2: 252.1274, trouvé : 253.1346 [M+H]+.

[0303] [Chem.29] 18a

[0304] Vinflunine 18a was obtained following the general procedure using a tubular reactor of length L = 600 cm (tR = 603 s) immersed in a bath maintained at -40°C. The flow rates Fi = 0.2 or 0.3 mL / min of HF / SbF5 mixture 2:1 v / v and F2 = 0.2 or 0.3 mL / min of vinorelbine tartrate 18 solubilized in anhydrous chloroform (c = 0.03 mol / L) were applied. The reaction mixture was collected for 10 min, allowing 23 mg of crude residue to be collected. NMR and HPLC analysis of the crude mixture allowed the identification of vinflunine in the majority quantity with yields of the order of 3-15% (NMR yields) compared to the standard reference. Purification of the crude using a reverse phase C18 (ACN / TFA aq. 0.2% gradient peak of interest isolated at 30% ACN) allowed the isolation of enriched fractions (HPLC).

[0305] Example 2: Comparative study

[0306] 1) Productivity

[0307] The productivity of each reaction was calculated, giving access to the amount of product formed in a given time. Productivity is given relative to the reactor volume, so that reactors of different sizes or constructions can be compared with each other. Similarly, productivity can be calculated for a static reaction volume and compared to the reactor volume for a given time in flow chemistry. In English, we speak of Space-Time Yield (STY) in kg.m 3.h *.

[0308] STY = [Math.l] m of product (in g) reactor volume (mL) x reaction time (min)

[0309] [Chem.30] ?HF / SbFs; AC N Ac-N N —z there

[0310] For example, for compound 1, we can observe for the fluorination reaction an increase in mass productivity by a factor of 34 when moving from the static method to the process of the invention, which is in flow.

[0311] [Tables 1] Static Invention (flow) Yield (%) 69 75 Reaction time tRen min 10 0.14 Reaction volume (mL) 6 0.24 m product (g) 0.13 0.062 n product (mmol) 0.689 0.325 Productivity (mmol / min) 0.0698 2.32 Productivity (g / h) 0.78 26.6 STY (kg.mAh1) 130 110714

[0312] The productivities of the static process and of the process of the invention for each reaction product were calculated from the data summarized in the table below (Table 2). In general, the process according to the invention is much more efficient, in particular for reactions with a very short residence time (tR < 1 min), making it possible to obtain a mass productivity multiplied by a factor of up to 34 compared to the static process.

[0313] The acidity of the medium is an important parameter as mentioned previously. In flow also the exploitation of the variation of acidity has been studied and for several syntheses, the amount of SbF5 has been considerably reduced, while increasing the efficiency of the reaction and obtaining an increased productivity compared to the static process.

[0314] [T ableaux2] Product t Process n Prod. mmol V reactor ml rpm min mol% SbFs Yield % P mass eg / h STY gm^.h1 ref la Inventio n 0.325 0.24 0.14 8.4 75 26.6 110714 - Static 0.689 6.0 10 3.8 69 0.78 130 i 2a Inventio n 0.810 0.39 0.87 5.2 76 11.8 30274 - Static 1.280 6.0 10 13.6 64 0.81 270 i 2b Inventio n 0.639 0.39 0.15 2.41 75 59.1 151487 - Static - - - - - - - - 3b Inventio n 0.728 0.39 0.23 8.4 84 49.8 127759 - Static 0.923 6.0 10 13.6 74 1.45 242 i 4b Inventio n 0.318 0.39 0.60 5.2 80 9.16 23478 - Static 0.830 3.0 10 3.8 84 1.43 476 ii 5a Inventio n 0.499 1.0 1 6.4 70 4.60 11787 - Static 0.740 3.0 10 3.8 74 0.98 130 iii 5b from 9 Inventio n 0.160 1.0 1 3.7 64 1.97 1968 - Inventio n 0.350 2.0 4.02 3.7 71 1.09 545 - Static - - - - - - - - 6a Inventio n 0.170 0.15 0.045 5.1 92 54.0 360000 - Static 1.316 7.5 10 12.6 87 1.89 252 iv 6b Inventio n 0.124 0.15 0.058 2.1 27 28.2 188276 - Static - - - - - - - - 8a Invention n 0.324 0.25 0.10 3.7 66 26.7 106639 0.057 Static 10.010.01 3.8 50 0.46 114 V 8b Inventio n 0.235 1.0 0.77 3.7 42 2.4 2439 - Static 0.367 4.0 10.0 21.6 39 0.30 74 V 8c Inventio n 0.269 7.37 37 2.8 2797 - Static 0.210 4.0 10.0 21.6 22 0.17 42 V 9b Inventio n 0.525 0.15 0.033 1.6 70 178.0 1186667 - Static - - - - - -

[0315] ' Sébastien Thibaudeau, Agnès Martin-Mingot, Marie-Paule Jouannetaud, Omar Karam, Fabien Zunino Chem. Commun 2007, 3198-3200.

[0316] ii Fei Liu, Agnès Martin-Mingot, Marie-Paule Jouannetaud, Fabien Zunino, Sébastien Thibaudeau Org. Lett. 2010,12(4), 868-871.

[0317] 1 Fei Liu, Agnès Martin-Mingot, Marie-Paule Jouannetaud, Christian Bachmann, Gilles Frapper, Fabien Zunino, Sébastien Thibaudeau J. Org. Chem. 2011, 76, 1460-1463.

[0318] iv Cantet, Anne-Céline; Carreyre, Helene; Gesson, Jean-Pierre; Jouannetaud, Marie-Paule; Renoux, Brigitte J. Org. Chem. 2008, 73(7), 2875-2878.

[0319] va) Guillaume Compain, Agnès Martin-Mingot, Gilles Frapper, Christian Bachmann, Marie-Paule Jouannetaud, Sébastien Thibaudeau Chem. Commun., 2012, 48, 5877-5879. b) Guillaume Compain, Céline Bonneau, Agnès Martin-Mingot, Sébastien Thibaudeau J. Org. Chem. 2013, 78, 4463-4472.

[0320] 2) Selectivity

[0321] The application of a superacid reagent to compound 2 in static mode systematically produces only compound 2a, while the method of the invention makes it possible to obtain compound 2a or 2b selectively by adjusting the residence time and the concentration of superacid reagent.

[0322] [Chem.31] 2a(75%J 4Jml% SbFS: t-Winue U 8 g / h Invention Ort 1J 2b (76%) ? 2 * Static 0 g(h Invention 59 1 g / h

[0323] Furthermore, the application of a superacid reagent to compound 9 in static mode systematically produces only the difluorinated compound 5b, while the method of the invention makes it possible to obtain compound 9b or 5b selectively by adjusting the conditions.

[0324] [Chem.32] ■4Ü'C 5b (54%) MSmmSbF5. t i» 60 s Stetw* 09 g / h 197 g / h ■4(10 1 "7 SbF5 ts 2 s StaUqu® û g / h Invention 178 g / h

[0325] Finally, the application of a superacid reagent to compound 5 in static mode produces the difluorinated compound 5b and very hardly the compound 5a, while the use of the process of the invention makes it possible to obtain compound 5a or 5b selectively by adjusting the conditions.

[0326] [Chem.33] 5b (74%) M.mom.SbFg 5 M md% SbF§ 5a (78%) M?3s MO® Ssaüquw 0 BS glt Invention 0 44 g / h Statique 0 98 ÿh lns.€’idlun 4 80 g / h

Claims

Claims

1. A process for the fluorination and / or cyclization of an amino alkene or alkyne, comprising: a) providing a first phase comprising an amino alkene or alkyne and a second phase comprising a superacid reagent, said superacid reagent being a fluorinated acid or a mixture of several acids of which at least one is fluorinated when the process is a fluorination process, b) contacting the first and second phases in a continuous flow microreactor, and c) recovering the fluorination and / or cyclization product of said amino alkene or alkyne, wherein said amino alkene or alkyne is an allylic or pro-pargylic amine.

2. Method according to claim 1, characterized in that: - the residence time of the first phase and the second phase in the continuous flow microreactor in step (b) is between 2 seconds and 400 seconds, and / or - the flow rate of the first phase and the flow rate of the second phase in step (b) are independently between 0.1 mL / min and 3.5 mL / min, for example between 0.25 mL / min and 3.0 mL / min.

3. Method according to claim 1 or 2, characterized in that the continuous flow microreactor comprises a micro-mixer and a tubular conduit, in which the tubular conduit preferably has: - a length of between 20 cm and 800 cm, and - an internal diameter of between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and better still between 0.7 mm and 1.2 mm.

4. Method according to any one of claims 1 to 3, characterized in that it is implemented in an installation comprising: - a storage unit (1) of a first phase comprising an alkene or alkyne amine, - a storage unit (1') of a second phase comprising a superacid reagent, - a means for continuously supplying the first phase (3) connected to the storage unit of the first phase (1), and to a tubular pipe for equilibrating the first phase (4), - a means for continuously supplying the second phase (3') connected to the storage unit of the second phase (1'), and to a tubular equilibration conduit of the second phase (4'), - a continuous flow microreactor (2) comprising a micro-mixer (21) comprising two inlets and one outlet, and a tubular conduit (22) comprising one inlet and one outlet, where the inlet of the tubular conduit (22) is connected to the outlet of the micro-mixer (21), where the tubular equilibration conduit of the first phase (4) is connected to the first inlet of the micro-mixer (21) and the tubular equilibration conduit of the second phase (4') is connected to the second inlet of the micro-mixer (21), and - a collection unit (5), connected to the outlet of the tubular conduit (22) of the microreactor (2).

5. A method according to any one of claims 1 to 4, characterized in that the superacid reagent is selected from HF / MF5 and HSO3F / MF5, where M is Sb, As, P, Ta, or Nb, preferably the superacid reagent is HF / SbF5.

6. A process according to any one of claims 1 to 5, characterized in that said alkene or amino alkyne is an amino alkene of formula (Ia): [Chem. 34] in which: R1, R2, R3, R4, R5, R6 and R7 are independently selected from hydrogen, halogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 heteroalkyl, C3-C12 cycloalkyl, C2-C12 heterocycloalkyl, aryl, heteroaryl, -S(O)2-R8 and -C(O)-R9, wherein R8 and R9 are independently selected from C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 heteroalkyl, C3-C12 cycloalkyl, C2-C12 heterocycloalkyl, aryl, and heteroaryl, said alkyl groups, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl being optionally substituted, or two groups each chosen from Rb R2, R3, R4, R5, R6 and R7 which may alternatively form together with the atom(s) to which they are linked a cycle having 3 to 12 links, possibly substituted.

7. Method according to claim 6, characterized in that: - R1 and R2 are independently selected from hydrogen, C2-C12 alkenyl, aryl [optionally substituted by C1-C6 alkyl, nitro, or a fluorinated group selected from -CF3, -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', and -SCF(R')2where each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl], -S(O)2-R8 and -C(O)-R9, wherein R8 and R9 are independently aryl optionally substituted by C1-C6 alkyl, nitro, or a fluorinated group selected from -CF3, -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', and -SCF(R')2where each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, or alternatively R1 and R2 form, with the atom to which they are attached, a piperidine or piperazine, optionally substituted by aryl or acetyl, - R3 and R4 are hydrogens, and - R5, R6 and R7 are independently selected from hydrogen and halogen, preferably at least two of R5, R6 and R7 are hydrogen.

8. A process according to any one of claims 1 to 5, characterized in that said alkene or amino alkyne is an amino alkyne of formula (Ib) [Chem. 35] R- .X " (IW. in which: R1, R2, R3, R4, and R5 are independently selected from hydrogen, halogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 heteroalkyl, C3-C12 cycloalkyl, C2-C12 heterocycloalkyl, aryl, heteroaryl, -S(O)2-R8 and -C(O)-R9, wherein R8 and R9 are independently selected from a C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C12 heteroalkyl, C3-C12 cycloalkyl, C2-C12 heterocycloalkyl, aryl, and heteroaryl, said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups being optionally substituted, or two groups each chosen from Rb R2, R3, R4, and R5 which may alternatively form together with the atom(s) to which they are attached a ring having 3 to 12 members which is optionally substituted.

9. Method according to claim 8, characterized in that: - R1 and R2 are independently selected from hydrogen, C2-C12 alkenyl, aryl [optionally substituted by C1-C6 alkyl, nitro, or a fluorinated group selected from -CF3, -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', and -SCF(R')2where each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl], -S(O)2-R8 and -C(O)-Rç), where R8 and R9 are independently aryl optionally substituted by C1-C6 alkyl, nitro, or a fluorinated group selected from -CF3, -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', and -SCF(R')2where each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl. or alternatively Ri and R2 form, with the atom to which they are attached, a piperidine or a piperazine, optionally substituted by an aryl or an acetyl, and - R3, R4 and R5 are hydrogens.

10. Process according to any one of claims 1 to 5, characterized in that said alkene or alkyne amino is chosen from: [Chem.36]

11. Installation for implementing the method according to one of claims 1 to 10, characterized in that it comprises: - a storage unit (1) of a first phase comprising an alkene or amino alkyne, - a storage unit (1') of a second phase comprising a superacid reagent, - a means for continuously supplying the first phase (3) connected to the storage unit of the first phase (1), and to a tubular pipe for balancing the first phase (4), - a continuous supply means for the second phase (3') connected to the storage unit of the second phase (1'), and to a tubular equilibration conduit of the second phase (4'), - a continuous flow microreactor (2) comprising a micro-mixer (21) comprising two inlets and one outlet, and a tubular conduit (22) comprising one inlet and one outlet, where the inlet of the tubular conduit (22) is connected to the outlet of the micro-mixer (21), where the tubular equilibration conduit of the first phase (4) is connected to the first inlet of the micro-mixer (21) and the tubular equilibration conduit of the second phase (4') is connected to the second inlet of the micro-mixer (21), and - a collection unit (5), connected to the outlet of the tubular conduit (22) of the microreactor (2), in which the tubular conduit (22) of the continuous flow microreactor (2) preferably presents: - a length between 20 cm and 800 cm, and - an internal diameter between 0.5 mm and 2.5 mm, preferably between 0.7 and 1.2 mm.

12. Installation according to claim 11, characterized in that it further comprises: - a 3-way valve (6) ensuring the connection between the continuous supply means in the first phase (3), the storage unit of the first phase (1), and the tubular balancing pipe of the first phase (4), and / or - a 3-way valve (6') ensuring the connection between the continuous supply means in the second phase (3'), the storage unit of the second phase (1') and the tubular balancing pipe of the second phase (4').

Images