Method for fluorinating and / or cyclizing aminoalkenes or alkynes in a continuous stream and equipment for carrying out the method - Patent Application 20070122999

Abstract

The present invention relates to a process for the fluorination and / or cyclization of aminoalkenes or alkynes in a continuous stream microreactor. The present invention also relates to an apparatus for carrying out such a process.

Description

[Technical Field]

[0001] The present invention relates to a process for fluorinating and / or cyclizing aminoalkenes or alkynes in a continuous stream microreactor. The present invention also relates to an apparatus for carrying out such a process. [Background technology]

[0002] In superacid solvents, the acidity value of H0 is lower than -12, so all molecules, even simple alkanes, react as bases. Therefore, superacid systems are of great interest because they provide access to specific types of reactivity, including multiply protonated molecules. In recent years, many methods have been developed in superacid solvents, and both laboratory-scale and industrial-scale synthesis can be envisioned.

[0003] For example, Michelet et al. describe a method for fluorinating aminoalkenes or alkynes using the superacid HF / SbF5 (J. Fluorine Chem. 2018, 214, 68-79). This transformation is of particular interest because it provides access to the highly sought-after fluoroamine unit in medicinal chemistry. Furthermore, WO 95 / 03312 shows that vinorelbine can be converted to the anticancer drug Javlor® via a gem-difluorination reaction in the presence of the superacid HF / SbF5.

[0004] However, these systems have many drawbacks that limit their use. In particular, reagents that generate superacid solvents, such as HF, are toxic, corrosive, and dangerous to handle. In addition, many solvents and nucleophiles are incompatible with these media. Finally, the high reactivity of these systems does not allow for control of the reaction products, and cascade reactions and polyfluorination can be observed. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO 95 / 03312 [Non-patent literature]

[0006] [Non-Patent Document 1] J. Fluorine Chem. 2018, 214, 68-79 [Non-patent document 2] 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., published by John Wiley & Sons, Inc., Hoboken, New Jersey, 2009, 1-10) [Non-patent document 3] 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., published by John Wiley & Sons, Inc., Hoboken, New Jersey, 2009) Summary of the Invention [Problem to be solved by the invention]

[0007] Thus, there is a real need to develop methods that allow easier handling of superacids and better control of their reactivity, most specifically, more control over their reactivity when contacted with aminoalkynes or alkenes. [Means for solving the problem]

[0008] In this regard, the Applicant has shown that the use of microfluidics, and more specifically the use of continuous flow microreactors, makes it possible to overcome these limitations. More specifically, it has surprisingly been shown that the use of continuous flow microreactors makes it possible to prepare fluorinated or cyclized compounds that are difficult or even inaccessible via equivalent reactions under static (or "batch") conditions. It has also been shown that the productivity of these reactions under flow conditions is much higher than that obtained under static conditions.

[0009] Therefore, the present invention provides a) providing a first phase comprising an aminoalkene or alkyne and a second phase comprising a superacid reagent; b) contacting the first phase with the second phase in a continuous flow microreactor; c) recovering the aminoalkene or alkyne fluorination and / or cyclization product; The present invention relates to a method for fluorinating and / or cyclizing an aminoalkene or alkyne, comprising:

[0010] In a specific embodiment, the residence time of the first and second phases in the continuous flow microreactor in step (b) is between 2 and 400 seconds.

[0011] In a specific embodiment, the flow rates of the first phase and 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.

[0012] In a specific embodiment, the continuous flow microreactor comprises a micromixer and a tubular pipe, the tubular pipe preferably comprising: - Length between 20cm and 800cm, - has an internal diameter of between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and even better between 0.7 mm and 1.2 mm.

[0013] In a specific embodiment, the contacting with the continuous flow microreactor is carried out at a temperature between -70°C and 25°C.

[0014] In a specific embodiment, the method according to the present invention comprises: - a storage unit (1) for a first phase containing an aminoalkene or alkyne, - a storage unit (1') for the second phase containing the superacid reagent, - a continuous supply means (3) of the first phase connected to the storage unit (1) of the first phase and to the balancing tubular pipe (4) of the first phase; - a continuous supply means (3') of the second phase connected to the storage unit (1') of the second phase and to the balancing tubular pipe (4') of the second phase; - a continuous flow microreactor (2) comprising a micromixer (21) with two inlets and one outlet, and a tubular pipe (22) with one inlet and one outlet, the inlet of the tubular pipe (22) being connected to the outlet of the micromixer (21); a continuous flow microreactor (2), in which the equilibration tubular pipe (4) for the first phase is connected to a first inlet of a micromixer (21), and the equilibration tubular pipe (4') for the second phase is connected to a second inlet of the micromixer (21); and a recovery unit (5) connected to the outlet of the tubular pipe (22) of the microreactor (2); The test is carried out in a facility equipped with

[0015] In a specific embodiment, 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.

[0016] In a specific embodiment, the first phase is a solution of an aminoalkene or alkyne in HF, preferably at a concentration between 0.5 and 1.0 mol / L.

[0017] The aminoalkene or alkyne may specifically be an allyl or propargylamine. In a specific embodiment, the aminoalkene or alkyne is an aminoalkene of formula (Ia):

[0018] [ka]

[0019] In the formula, R1, R2, R3, R4, R5, R6, and R7 are independently hydrogen, halogen, C1 to C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C1-C 12 Heteroalkyl, C3-C 12 Cycloalkyl, C2-C 12 Heterocycloalkyl, aryl, heteroaryl, the group -S(O)2-R8 and the group -C(O)-R9, where R8 and R9 are independently C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C1-C 12 Heteroalkyl, C3-C 12 Cycloalkyl, C2-C 12 heterocycloalkyl, aryl, and heteroaryl; Alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted; Or, each of two groups selected from R1, R2, R3, R4, R5, R6 and R7, together with the atoms to which they are attached, is an aminoalkene that may otherwise form an optionally substituted 3- to 12-membered ring.

[0020] Specifically, the aminoalkene of formula (Ia) is R1 and R2 are independently hydrogen, C2 to C 12 alkenyl, [optionally substituted with C1-C6 alkyl, nitro, or a fluoro group selected from -CF3, -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', and -SCF(R')2 (wherein each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl)]aryl, -S(O)2-R8, and -C(O)-R9 wherein R8 and R9 are independently selected from aryl optionally substituted with C1-C6 alkyl, nitro, or a fluoro group selected from -CF3, -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', and -SCF(R')2, where each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl; or R1 and R2 together with the atoms to which they are attached form a piperidine or piperazine optionally substituted with aryl or acetyl; R3 and R4 are hydrogen; R5, R6 and R7 are independently selected from hydrogen and halogen (preferably at least two of R5, R6 and R7 are hydrogen); It may be something.

[0021] In another specific embodiment, the aminoalkene or alkyne is an aminoalkyne of formula (Ib):

[0022] [ka]

[0023] In the formula, R1, R2, R3, R4, and R5 are independently hydrogen, halogen, C1 to C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C1-C 12 Heteroalkyl, C3-C 12 Cycloalkyl, C2-C 12 Heterocycloalkyl, aryl, heteroaryl, the group -S(O)2-R8 and the group -C(O)-R9, where R8 and R9 are independently C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C1-C 12 Heteroalkyl, C3-C 12 Cycloalkyl, C2-C 12 heterocycloalkyl, aryl, and heteroaryl; alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted; Or, each of two groups selected from R1, R2, R3, R4, and R5, together with the atoms to which they are attached, may separately form an optionally substituted 3- to 12-membered ring, an aminoalkyne.

[0024] Specifically, the aminoalkene of formula (Ib) is R1 and R2 are independently hydrogen, C2 to C 12alkenyl, [optionally substituted with C1-C6 alkyl, nitro, or a fluoro group selected from -CF3, -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', and -SCF(R')2 (wherein each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl)]aryl, -S(O)2-R8, and -C(O)-R 9, wherein R and R are independently aryl optionally substituted with C-C alkyl, nitro, or a fluoro group selected from -CF, -OCF, -SCF, -OCFR', -OCF(R'), -SCFR', and -SCF(R'), wherein each R' independently represents hydrogen, halogen, C-C alkyl, C-C alkenyl, C-C alkynyl, or C-C cycloalkyl; or R1 and R2 together with the atoms to which they are attached form a piperidine or piperazine optionally substituted with aryl or acetyl; R3, R4 and R5 are hydrogen It may also be something.

[0025] In a preferred embodiment, the aminoalkene or alkyne is

[0026] [ka]

[0027] is selected from.

[0028] In one embodiment, the aminoalkene or alkyne is

[0029] [ka]

[0030] is selected from.

[0031] The present invention provides - a storage unit (1) for a first phase containing an aminoalkene or alkyne, - a storage unit (1') for the second phase containing the superacid reagent, - a continuous supply means (3) of the first phase connected to the storage unit (1) of the first phase and to the balancing tubular pipe (4) of the first phase; - a continuous supply means (3') of the second phase connected to the storage unit (1') of the second phase and to the balancing tubular pipe (4') of the second phase; - a continuous flow microreactor (2) comprising a micromixer (21) with two inlets and one outlet, and a tubular pipe (22) with one inlet and one outlet, The inlet of the tubular pipe (22) is connected to the outlet of the micromixer (21), A continuous flow microreactor (2), in which the equilibration tubular pipe (4) for the first phase is connected to a first inlet of a micromixer (21), and the equilibration tubular pipe (4') for the second phase is connected to a second inlet of the micromixer (21), and a recovery unit (5) connected to the outlet of the tubular pipe (22) of the microreactor (2); It also relates to an installation for carrying out the method defined in the present patent application, characterized in that it comprises:

[0032] The tubular pipe (22) of the continuous flow microreactor (2) preferably comprises: - Length between 20cm and 800cm, - Inner diameter between 0.5mm and 2.5mm, preferably between 0.7mm and 1.2mm It has.

[0033] Preferably, the facility comprises: a three-way valve (6) providing the connection between the first phase continuous supply means (3), the first phase storage unit (1) and the first phase balancing tubular pipe (4), and / or - a three-way valve (6') providing the connection between the second phase continuous supply means (3'), the second phase storage unit (1') and the second phase balancing tubular pipe (4'); Also includes. [Brief explanation of the drawings]

[0034] [Figure 1] 1 illustrates a method according to one embodiment of the present invention and an exemplary schematic installation for carrying out such a method. [Figure 2] 1 shows a method according to one embodiment of the present invention and an exemplary schematic installation for carrying out such a method, including a washing unit. DETAILED DESCRIPTION OF THE INVENTION

[0035] definition Unless otherwise specified, when a range is expressed using the phrase "between," the limiting values ​​are included within the stated range.

[0036] The term "alkyl" means a saturated, straight-chain or branched aliphatic hydrocarbon-based group. 12 "Alkyl" is an alkyl containing 1 to 12 carbon atoms. Alkyl (or C1-C 12 Specific examples of alkyl are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, or dodecyl. Preferably, C1-C 12 Alkyl is C1-C6 alkyl (for example: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl).

[0037] The term "alkenyl" means a straight-chain or branched, unsaturated aliphatic hydrocarbon-based group containing at least one carbon-carbon double bond. 12 "Alkenyl" is an alkenyl containing 2 to 12 carbon atoms. Alkenyl (or C2-C 12Specific examples of alkenyl include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, and dodecenyl. Preferably, C2 to C6 12 Alkenyl is C2-C6 alkenyl (for example: ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, or hexenyl).

[0038] The term "alkynyl" means a straight-chain or branched, unsaturated aliphatic hydrocarbon-based group containing at least one carbon-carbon triple bond. 12 "Alkynyl" is an alkynyl containing 2 to 12 carbon atoms. Alkynyl (or C2-C 12 Specific examples of alkynyl include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, and dodecynyl. Preferably, C2 to C6 12 Alkynyl is C2-C6 alkynyl (for example: ethynyl, propynyl, butynyl, pentynyl, or hexynyl).

[0039] The term "heteroalkyl" refers to an alkyl as defined above, wherein the carbon chain contains and / or is interrupted by at least one heteroatom, such as O, N, P, Se, or S, at one and / or the other of the carbon chain termini (specifically, the terminus attached to the remainder of the molecule). Examples of heteroalkyl are, specifically, alkoxy (-O-alkyl), alkylthio (-S-alkyl), alkylamino (-NH(alkyl) or -N(alkyl)2), organoline (-P(O)(alkyl)2), and organoselenide (-Se(alkyl)2 or -Se(O)(alkyl)NR or -Se(O)(alkyl)2). "C1-C 12 "Heteroalkyl" is a heteroalkyl containing 1 to 12 carbon atoms. Preferably, C1-C 12 Heteroalkyl is C1-C6 heteroalkyl.

[0040] Examples of heteroalkyl (or C1-C 12 or C1-C6 heteroalkyl) is specifically 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, propylphospho, isopropylphospho, butylphospho, isobutylphospho, tert-butylphospho, pentylphospho, hexylphospho, methylseleno, ethylseleno, propylseleno, isopropylseleno, butylseleno, isobutylseleno, tert-butylseleno, pentylseleno, or hexylseleno.

[0041] The term "cycloalkyl" means an optionally unsaturated (preferably saturated) aliphatic monocyclic or polycyclic hydrocarbon-based group, which may be fused, bridged and / or spiro-linked. 12 "Cycloalkyl" is a cycloalkyl containing 3 to 12 carbon atoms. C3-C 12 Or, specific examples of C3-C6 cycloalkyl are cyclopropyl, cyclopentyl or cyclohexyl.

[0042] The term "heterocycloalkyl" means a cycloalkyl as defined above that also contains at least one heteroatom such as N, S, P, Se, or O. 12 "Heterocycloalkyl" is a cycloalkyl containing 2 to 12 carbon atoms and at least one heteroatom. Preferably, C2-C 12Heterocycloalkyl is preferably C2-C6 heterocycloalkyl. Specific examples of heterocycloalkyl include 3-dioxolane, benzo-[1,3]-dioxolyl, azetidinyl, oxetanyl, pyrazolinyl, pyranyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1,4-dioxanyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl, 1,4-dithianyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, 7-oxabicyclo[2,2,1]heptanyl, cycloalkylphosphine, and tetrahydrothiophenyl.

[0043] The term "aryl" refers to a monocyclic or polycyclic aromatic carbocyclic group, preferably a monocyclic or polycyclic aromatic carbocyclic group containing 6 to 20 ring members. Examples of aryl groups are phenyl, biphenyl, and naphthyl, preferably phenyl. Aryl groups, particularly phenyl, are optionally substituted with one or more (preferably only one) groups selected from C1-C6 alkyl (e.g., methyl), -NO2, -CF3, and other fluoro substituents such as -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', or -SCF(R')2 (wherein 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 with one or more (preferably only one) groups selected from C1-C6 alkyl (eg, methyl), -NO2 and -CF3.

[0044] The term "heteroaryl" refers to an aromatic, monocyclic, or polycyclic group preferably containing from 5 to 20 carbon atoms and also containing at least one heteroatom such as N, O, P, Se, or S. Specific 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, quinolidinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnamyl, and cinnamyl. nyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, benzothienyl, benzothiazolyl, isatinyl, dihydropyridyl, pyrimidinyl, s-triazinyl, oxazolyl, arylphosphine, indole, indoline, phosphindoline or thiofuranyl.

[0045] The term "halogen" means chlorine, fluorine, bromine or iodine. Preferably, halogen is chlorine or fluorine, more preferably chlorine.

[0046] Alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups as defined in this patent application are optionally substituted. The term "optionally substituted" means unsubstituted or substituted with one or more (e.g., 1, 2, 3, or 4, preferably 1 or 2, or even only 1) substituents.

[0047] Specific examples of the substituents include trifluoromethyl (-CF3) and other fluoro substituents such as -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', or -SCF(R')2 (wherein each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl), nitro (-NO2), cyano (-CN), -S03H, -OH, -SH, -NH2, -COOH, halogen, , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, 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.

[0048] In this patent application, the abbreviation "Ac" means "acetyl" (i.e., -C(O)-CH3).

[0049] The method according to the present invention is a method for fluorinating and / or cyclizing a substrate that is an aminoalkene or alkyne. The step of contacting the substrate with a superacid reagent allows for the introduction of one or more fluorine atoms (usually one or two, more specifically only one) onto the substrate and / or the intramolecular cyclization of the substrate to form a ring. Generally, the method according to the present invention allows for one or the other of fluorination and cyclization of the aminoalkene or alkyne. In a specific embodiment, the fluorination reaction is hydrofluorination, which involves the incorporation of one or more fluorine atoms and one or more hydrogen atoms.

[0050] The method according to the present invention comprises step (a) which comprises providing a first phase comprising an aminoalkene or alkyne, and providing a second phase comprising a superacid reagent.

[0051] In particular embodiments, the aminoalkene or alkyne is an aminoalkene.

[0052] The term "aminoalkene" refers to an organic compound containing at least one alkene functional group and at least one amine functional group. The term "alkene" refers to an organic compound containing at least one alkene functional group, i.e., at least one carbon-carbon double bond. The term "amine functional group" refers to the functional group:

[0053] [ka]

[0054] wherein

[0055] [ka]

[0056] means a functional group representing a bond to the rest of the molecule. Each of the alkene and amine functional groups may independently be cyclic (i.e., contained in a ring, such as an endocyclic alkene or piperidine, or directly attached to a ring, such as an exocyclic alkene or cycloalkylamine) or acyclic. The aminoalkene may be aromatic or aliphatic. Preferably, the aminoalkene contains 2 to 60 carbon atoms and / or has a molecular weight between 50 and 1000 g / mol. It goes without saying that the aminoalkene may contain groups or functional groups other than the alkene and amine functional groups, such as, but not limited to, halogens, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C1-C 12 Heteroalkyl, C3-C 12 Cycloalkyl, C2-C 12 Heterocycloalkyl, aryl, heteroaryl, -CF3 and other fluoro substituents (such as -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', or -SCF(R')2 (wherein each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl)), -NO2, -CN, -S03H, -OH, -SH, and -COOH may also be included. In particular, the amine functional group may be adjacent to other chemical groups or functional groups, such as a -C(O)- or -S(O)2- group, collectively forming an amide or sulfonamide, respectively.

[0057] In a specific embodiment, the aminoalkene is an allylamine. The term "allylamine" refers to a compound in which an amine functional group is separated from an alkene functional group by a carbon atom.

[0058] In more specific embodiments, the aminoalkene is a compound of formula (Ia):

[0059] [ka]

[0060] In the formula, R1, R2, R3, R4, R5, R6, and R7 are independently hydrogen, halogen, C1 to C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C1-C 12 Heteroalkyl, C3-C 12 Cycloalkyl, C2-C 12 Heterocycloalkyl, aryl, heteroaryl, the group -S(O)2-R8 and the group -C(O)-R9, where R8 and R9 are independently C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C1-C 12 Heteroalkyl, C3-C 12 Cycloalkyl, C2-C 12 heterocycloalkyl, aryl, and heteroaryl; alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted; Or, a compound in which each of two groups selected from R1, R2, R3, R4, R5, R6 and R7 (e.g., R1 and R2) together with the atoms to which they are attached may separately form an optionally substituted 3- to 12-membered ring.

[0061] The compound of formula (Ia) is preferably R3 and R4 are hydrogen; R5, R6 and R7 are independently selected from hydrogen and halogen (preferably at least two of R5, R6 and R7 are hydrogen); The preferred halogen is chlorine.

[0062] In specific embodiments, compounds of Formula (Ia) are those in which R and R, together with the atoms to which they are attached, form an optionally substituted 3- to 12-membered ring, preferably a 5- to 7-membered ring, such as an optionally substituted piperidine or piperazine. In such embodiments, the ring may be substituted, for example, with an optionally substituted aryl or acetyl.

[0063] In another specific embodiment, the compound of formula (Ia) is R1 is hydrogen, - R2 is optionally substituted aryl It is something.

[0064] In another specific embodiment, the compound of formula (Ia) is R1 is hydrogen, R2 is -S(O)2-R8, where R8 is optionally substituted aryl. It is something.

[0065] In another specific embodiment, the compound of formula (Ia) is R1 is a —CH2—CH═CH2 group, - R2 is -C(O)-R9, wherein R9 is optionally substituted aryl. It is something.

[0066] In the above embodiments, the optionally substituted aryl group may be substituted with one or more (preferably only one) groups selected from, for example, C1-C6 alkyl (e.g., methyl), -NO2, -CF3, and other fluoro substituents, such as -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', or -SCF(R')2 (wherein 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 with one or more (preferably only one) groups selected from C1-C6 alkyl (e.g., methyl), -NO2, and -CF3.

[0067] In another specific embodiment, the compound of formula (Ia) is R1 and R2 are independently hydrogen, C2 to C 12 alkenyl, [C1-C6 alkyl, nitro, or fluoro groups selected from -CF3, -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', and -SCF(R')2 (wherein each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl)]aryl, -S(O)2-R8, and -C(O)- R9, where R8 and R9 are independently aryl optionally substituted with C1-C6 alkyl, nitro, or a fluoro group selected from -CF3, -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', and -SCF(R')2, where each R' independently represents hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl; or alternatively, R1 and R2 together with the atoms to which they are attached form a piperidine or piperazine optionally substituted with aryl or acetyl; R3 and R4 are hydrogen; R5, R6 and R7 are independently selected from hydrogen and halogen (preferably at least two of R5, R6 and R7 are hydrogen); It is something.

[0068] In another specific embodiment, the compound of formula (Ia) is R1 and R2 are independently hydrogen, C2 to C 12 alkenyl; C1-C6 alkyl, nitro, or aryl optionally substituted with -CF3, -S(O)2-R8, and -C(O)-R9, where R8 and R9 are independently aryl optionally substituted with C1-C6 alkyl, nitro, or trifluoromethyl; or alternatively R1 and R2 together with the atoms to which they are attached form a piperidine or piperazine optionally substituted with aryl or acetyl; R3 and R4 are hydrogen; R5, R6 and R7 are independently selected from hydrogen and halogen (preferably at least two of R5, R6 and R7 are hydrogen); It is something.

[0069] In a preferred embodiment, the aminoalkene is the following compound:

[0070] [ka]

[0071] is selected from.

[0072] In another preferred embodiment, the aminoalkene is vinorelbine, which may be represented as follows:

[0073] [ka]

[0074] In another specific embodiment, the aminoalkene or alkyne is an aminoalkyne.

[0075] The term "aminoalkyne" refers to an organic compound containing at least one alkyne functional group and at least one amine functional group. The term "alkyne" refers to an organic compound containing at least one alkyne functional group, i.e., at least one carbon-carbon triple bond. Each of the alkyne and amine functional groups may independently be cyclic (i.e., contained in a ring, such as an endocyclic alkyne or piperidine, or directly attached to a ring, such as a cycloalkylamine) or acyclic. The aminoalkyne may be aromatic or aliphatic. Preferably, the aminoalkyne contains 2 to 60 carbon atoms and / or has a molecular weight between 50 and 1000 g / mol. It goes without saying that the aminoalkyne may contain groups or functional groups other than the alkyne and amine functional groups, such as, but not limited to, halogens, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C1-C 12 Heteroalkyl, C3-C 12 Cycloalkyl, C2-C 12 They may also include heterocycloalkyl, aryl, heteroaryl, -CF3 and other fluoro groups (-OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R' or -SCF(R')2 (wherein each R' is independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl)), -NO2, -CN, -S03H, -OH, -SH, -COOH. In particular, the amine functionality may be adjacent to other groups, such as a -C(O)- or -S(O)2- group, to form, in the aggregate, an amide or sulfonamide, respectively.

[0076] In a specific embodiment, the aminoalkyne is propargylamine. The term "propargylamine" refers to a compound in which an amine functional group is separated from an alkyne functional group by a carbon atom.

[0077] In another more specific embodiment, the aminoalkyne is a compound of formula (Ib):

[0078] [ka]

[0079] In the formula, R1, R2, R3, R4, and R5 are independently hydrogen, halogen, C1 to C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C1-C 12 Heteroalkyl, C3-C 12 Cycloalkyl, C2-C 12 Heterocycloalkyl, aryl, heteroaryl, the group -S(O)2-R8 and the group -C(O)-R9, where R8 and R9 are independently C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C1-C 12 Heteroalkyl, C3-C 12 Cycloalkyl, C2-C 12 heterocycloalkyl, aryl, and heteroaryl; alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted; Or alternatively, a compound in which each of two groups selected from R1, R2, R3, R4 and R5 (e.g., R1 and R2) together with the atoms to which they are attached may form an optionally substituted 3- to 12-membered ring.

[0080] Preferred compounds of formula (Ib) are those in which R3, R4 and R5 are hydrogen.

[0081] In specific embodiments, R and R, together with the atoms to which they are attached, form an optionally substituted 3- to 12-membered ring, preferably a 5- to 7-membered ring, such as an optionally substituted piperidine or piperazine. In such embodiments, the ring is optionally substituted, for example, with an optionally substituted aryl or acetyl.

[0082] According to another specific embodiment, the compound of formula (Ib) is R1 and R2 are independently hydrogen, C2 to C 12 alkenyl, aryl [optionally substituted with C1-C6 alkyl, nitro, or a fluoro group selected from -CF3, -OCF3, -SCF3, -OCF2R', -OCF(R')2, -SCF2R', and -SCF(R')2 (wherein 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)-R 9, wherein R and R are independently aryl optionally substituted with a C-C alkyl, nitro, or a fluoro group selected from -CF, -OCF, -SCF, -OCFR', -OCF(R'), -SCFR', and -SCF(R'), wherein each R' independently represents hydrogen, halogen, C-C alkyl, C-C alkenyl, C-C alkynyl, or C-C cycloalkyl; or alternatively, R1 and R2 together with the atoms to which they are attached form a piperidine or piperazine optionally substituted with aryl or acetyl; R3, R4 and R5 are hydrogen It is something.

[0083] In another specific embodiment, the compound of formula (Ib) is R1 and R2 are independently hydrogen, C2 to C 12 selected from alkenyl, aryl [optionally substituted with C-C alkyl, nitro, or -CF], -S(O)-R, and -C(O)-R, wherein R and R are independently aryl optionally substituted with C-C alkyl, nitro, or trifluoromethyl; or alternatively, R1 and R2 together with the atoms to which they are attached form a piperidine or piperazine optionally substituted with aryl or acetyl; R3, R4 and R5 are hydrogen It is something.

[0084] In a preferred embodiment, the aminoalkyne is the following compound:

[0085] [ka]

[0086] is selected from.

[0087] In another embodiment, the aminoalkyne is the following compound:

[0088] [ka]

[0089] is selected from.

[0090] The term "superacid reagent" refers to a reagent whose Hammett acidity value or acidity function H is less than -12, preferably less than or equal to -14. Several methods allow the Hammett constant H to be measured using weak bases, in particular spectroscopically (NMR), kinetically, thermodynamically or in conjunction with 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., published by John Wiley & Sons, Inc., Hoboken, New Jersey, 2009, 1-10).

[0091] The superacid reagent may be an acid, advantageously fluorinated, or a mixture of acids, at least one of which is advantageously fluorinated. Superacids are specifically described in the following references: 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., published by John Wiley & Sons, Inc., Hoboken, New Jersey, 2009).

[0092] The superacid reagent may specifically be a Lewis superacid (e.g., SbF5, AsF5, PF5, TaF5), a protic superacid or a Bronsted superacid (e.g., HF, CF3SO3H, (CF3SO2)2NH, HSO3F), or a combination thereof (e.g., HF / SbF5, HSO3F / AsF5, H2SO4 / SO3, HCl / AlCl3).

[0093] Examples of superacids and their acidity constants are given below. - Fluorosulfuric acid HSO3F, H0=-15.1; - Trifluoromethanesulfonic acid CF3SO3H, H0 = -14.1; - Hydrofluoric acid HF, H0 = -15.2; - HF / SbF5 mixture, H0=-23 / -24.

[0094] According to a specific embodiment, the superacid reagent is: a protic superacid selected from HF, CF3SO3H and HSO3F, Lewis superacids of formula MF5, where M is Sb, As, P, Ta or Nb, and - Combination of one protic superacid and one Lewis superacid is selected from.

[0095] In a specific embodiment, the superacid reagent is HF or HSO3F.

[0096] In another specific aspect, the superacid reagent is HF / MF5, where M is Sb, As, P, Ta, or Nb, and HSO3F / MF5 (wherein M is Sb, As, P, Ta or Nb) is selected from.

[0097] Preferably, the superacid reagent is HSO3F / SbF5 or HF / SbF5. More preferably, the superacid reagent is HF / SbF5.

[0098] 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 amount of the HF+SbF5 or HSO3F+SbF5 mixture, respectively. Of course, the value 0% is excluded from the range of "less than or equal to 50%".

[0099] The first phase in step (a) is preferably a liquid. The first phase, specifically the aminoalkene or alkyne, may be undiluted or may consist of a solution in a solvent. Preferably, the first phase is a solution of the aminoalkene or alkyne in a solvent, such as HF, an alcoholic solvent (e.g., methanol, ethanol, or isopropanol), a fluoroalcoholic solvent (e.g., hexafluoropropan-2-ol (HFIP) and its derivatives), or a polyfluorinated or perfluorinated aromatic solvent (e.g., pentafluorobenzene or 1,2,3,4-tetrafluorobenzene).

[0100] Preferably, the solvent is HF. The concentration of aminoalkene or alkyl 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.

[0101] The first phase may be stored in a storage unit such as a tank.

[0102] In a specific embodiment, the first phase is maintained in the storage unit at a temperature between -70°C and 25°C, preferably between -50°C and 5°C, and even more preferably between -50°C and -20°C.

[0103] The second phase in step (a) is preferably liquid. The second phase advantageously consists of undiluted superacid reagent. The second phase may be stored in a storage unit, for example in a tank.

[0104] In a specific embodiment, the second phase is maintained in the storage unit at a temperature between -70°C and 25°C, preferably between -50°C and 5°C, and even more preferably between -50°C and -20°C.

[0105] Step (b) of the method according to the invention comprises contacting the first phase with the second phase in a continuous flow microreactor.

[0106] The term "continuous flow microreactor" refers to a reactor of micrometer or millimeter dimensions, allowing the continuous flow of one or more fluid phases, preferably liquids. A continuous flow microreactor typically comprises a tubular pipe with an inlet and an outlet, the internal diameter of which is of micrometer or millimeter dimensions. For those skilled in the art of microfluidics, it is clear that the term "microreactor" refers to a reactor whose dimensions (more specifically, its internal diameter) are of micrometer dimensions, but which may also be of millimeter dimensions, as long as this does not affect the fluid properties of this millimeter-sized microreactor, in particular those related to the behavior of the fluids flowing through it.

[0107] The length of the tubular pipe may be on the order of a few centimetres to several metres.

[0108] The term "size in micrometers" means a size between 1 μm and 1000 μm, preferably between 100 μm and 1000 μm, and even more preferably between 300 μm and 1000 μm (excluding the value 1000 μm).

[0109] The term "millimeter size" means a size between 1 mm and 10 mm, preferably between 1 mm and 5 mm.

[0110] In a specific embodiment, the tubular pipe of the continuous flow microreactor has the following dimensions: - 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 - an internal diameter between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and even better between 0.7 mm and 1.2 mm It has.

[0111] The outer diameter of the tubular pipe may for example be between 0.8 mm and 3.2 mm, such as between 0.8 mm and 1.0 mm, between 1.0 mm and 2.0 mm, or between 1.6 mm and 3.2 mm.

[0112] In a specific embodiment, the tubular pipe of the continuous flow microreactor comprises: - inner diameter between 0.5mm and 1.5mm, - Preferably with an outer diameter between 1.0 and 2.0 mm It has.

[0113] The tubular pipe is typically arranged in a snake or coil shape over all or part of its length, although other arrangements are also contemplated.

[0114] Advantageously, the continuous flow microreactor also comprises a micromixer. The term "micromixer" means a mixer of micrometer or millimeter dimensions. The micromixer advantageously comprises two inlets and one outlet, and is usually T- or Y-shaped. The internal diameter of the micromixer is of micrometer or millimeter dimensions, advantageously between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and even more preferably between 0.7 mm and 1.2 mm. In a specific embodiment, the continuous flow microreactor comprises: a micromixer with two inlets and one outlet, and - a tubular pipe with one inlet and one outlet, The inlet of the tubular pipe is connected to the outlet of the micromixer. In such an embodiment, the means for continuously supplying the first phase is connected to the first inlet of the micromixer, and the means for continuously supplying the second phase is connected to the second inlet of the micromixer.

[0115] The continuous feeding means refers to any component or set of components that allows the continuous transfer of the first and second phases to the continuous flow microreactor, for example a pump or a syringe that may be equipped with a syringe pump.

[0116] Components are said to be "connected" when they are connected to each other directly or, in some cases, by tubular pipes or other equivalent components, the characteristics of which (e.g., materials, dimensions such as length and diameter) can be chosen in a judicious manner by those skilled in the art. For example, the tubular pipes of a micromixer and a continuous flow microreactor are preferably connected directly.

[0117] The contacting step (b) may comprise the steps of transferring a first phase contained in a storage unit of the first phase to the continuous flow microreactor, specifically to a micromixer of the continuous flow microreactor (even more specifically to a first inlet of the micromixer) via a means for continuously supplying the first phase, and transferring a second phase contained in a storage unit of the second phase to the continuous flow microreactor, more specifically to a micromixer of the continuous flow microreactor (even more specifically to a second inlet of the micromixer) via a means for continuously supplying the second phase.

[0118] The means for continuously supplying the first and second phases may be, for example, a first syringe and a second syringe, respectively (which may comprise syringe pumps), or a first pump and a second pump, respectively.

[0119] In more specific embodiments, the first phase contained in the storage unit for the first phase (e.g., a tank) is typically drawn up by a first syringe or pump, and the second phase contained in the storage unit for the second phase (e.g., a tank) is typically drawn up by a second syringe or pump, and each of the first and second phases is injected into a continuous flow microreactor, more specifically into a micromixer of the continuous flow microreactor (even more specifically, the first phase into a first inlet of the micromixer and the second phase into an inlet of a second micromixer). A first three-way valve connected to the storage unit for the first phase, the first syringe or pump, and the continuous-flow microreactor (specifically, to the first inlet of the micromixer of the microreactor), and / or a second three-way valve connected to the storage unit for the second phase, the second syringe or pump, and the continuous-flow microreactor (specifically, to the second inlet of the second micromixer of the microreactor) can be used to facilitate the uptake and injection of the first and second phases. The inner diameter of the three-way valve can be in the order of micrometers or millimeters, for example, between 0.8 mm and 1.6 mm. The first and second phases can be uptaken and injected using a syringe pump or a computer-controlled pump. The temperature of the syringe or pump is typically maintained between -70°C and 25°C, preferably between -50°C and 5°C, and even more preferably between -50°C and -20°C. The temperature of the storage unit is typically maintained at a temperature between -70°C and 25°C, preferably between -50°C and 5°C, and even more preferably between -50°C and -20°C.

[0120] The flow rates of the first and second phases 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, and the total flow rate may be between 0.5 mL / min and 4.5 mL / min, for example between 1.0 mL / min and 3.0 mL / min.

[0121] Adjusting the dimensions of the microreactor, specifically the diameter and length of the tubular pipe, and the flow rates of the first and second phases into the microreactor allows for controlling and fixing the residence time of the first and second phases in the microreactor. In step (b), the residence time of the contacted first and second phases in the microreactor is preferably between 2 and 400 seconds. For example, this residence time may be between 2 and 30 seconds, between 30 and 60 seconds, or between 60 and 400 seconds.

[0122] The step of contacting the first and second phases in the continuous flow microreactor is generally carried out at a temperature (also referred to as the "contact temperature") between -70°C and 25°C, preferably between -50°C and 5°C, and even more preferably between -50°C and -20°C. If the temperature of the first and / or second phase in step (a) is different from the contact temperature in the microreactor in step (b), an equilibration step may be carried out before the contacting step. The purpose of this equilibration is to bring the first and / or second phases to the contact temperature and stabilize them before the contacting step. A first equilibration tubular pipe and / or a second equilibration tubular pipe maintained at the contact temperature can thus be used for this equilibration. Preferably, the first equilibration tubular pipe and / or the second equilibration tubular pipe, respectively, are between the means for continuous supply of the first phase and the continuous flow microreactor (more particularly the micromixer of the continuous flow microreactor, even more particularly the first inlet of the micromixer), and / or - between the means for continuous supply of the second phase and the continuous flow microreactor (more specifically the micromixer of the continuous flow microreactor, even more specifically the second inlet of the micromixer); is connected to.

[0123] The inner diameter of the balancing tubular pipe may be measured in micrometers or millimeters and may independently be between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and even between 0.7 mm and 1.2 mm. The length of the balancing tubular pipe may independently be between 25 cm and 100 cm. The value may be specifically selected to allow efficient cooling at a given flow rate. The balancing tubular pipe is typically arranged in a snake or coil shape over all or part of its length, although other arrangements are also contemplated.

[0124] The first and second phases contacted within the microreactor may together form one or more phases, preferably a single, usually liquid, phase.

[0125] Step (c) of the process according to the present invention involves the recovery (or "collection") of the fluorination and / or cyclization products of the aminoalkene or alkyne. The products are recovered at the outlet of the continuous flow microreactor (specifically, at the outlet of its tubular pipe), which is usually connected to a recovery unit such as a flask. The recovered products are generally recovered in admixture with reaction by-products and / or residual superacid reagent. To neutralize the residual superacid reagent, a neutralizing agent may be contacted with the mixture recovered in the recovery unit. This neutralizing agent may be, for example, a mixture of water, sodium carbonate, sodium hydroxide, potassium hydroxide, or other base in resin form, e.g., Amberlyst A26 hydroxide form, and, optionally, one or more organic solvents such as acetone, methanol, or ammonia-methanol solution. The amount of neutralizing agent used is adjusted according to the amount of residual superacid reagent.

[0126] Due to the corrosiveness of superacids, the components used to carry out the process of the present invention, such as the continuous flow microreactor (particularly the tubular pipes and micromixers it comprises), the equilibration tubular pipes, the storage unit, the recovery unit, the syringes and / or the three-way valves, are advantageously made of materials that are resistant to this corrosiveness. Examples of materials that may be mentioned include fluoropolymers, such as polytetrafluoroethylene and poly(ethylene-co-tetrafluoroethylene), and certain metal alloys, such as Hastelloy® nickel alloy. In any case, those skilled in the art can judiciously select suitable materials for each component of the assembly.

[0127] Another subject of the invention is the equipment used to carry out the method of the invention. Figure 1 is a diagram illustrating the method according to one embodiment of the invention and also an equipment that can be used to carry out this method.

[0128] The installation according to the invention comprises the following components: - a storage unit (1) for a first phase containing an aminoalkene or alkyne, - a storage unit (1') for the second phase containing the superacid reagent, - a continuous flow microreactor (2), preferably comprising a micromixer (21) and a tubular pipe (22), - means (3) for continuously supplying the first phase, - means (3') for continuously supplying the second phase, - balancing tubular pipe for the first phase (4), - a balancing tubular pipe (4') for the second phase, and - Recovery Unit (5) Equipped with.

[0129] More specifically, the installation according to the invention comprises: - a storage unit (1) for a first phase containing an aminoalkene or alkyne, - a storage unit (1') for the second phase containing the superacid reagent, - a continuous supply means (3) of the first phase connected to the storage unit (1) of the first phase and to the balancing tubular pipe (4) of the first phase; - a continuous supply means (3') of the second phase connected to the storage unit (1') of the second phase and to the balancing tubular pipe (4') of the second phase; - a continuous flow microreactor (2) comprising a micromixer (21) with two inlets and one outlet, and a tubular pipe (22) with one inlet and one outlet, The inlet of the tubular pipe (22) is connected to the outlet of the micromixer (21), a continuous flow microreactor (2), in which the equilibration tubular pipe (4) for the first phase is connected to a first inlet of a micromixer (21), and the equilibration tubular pipe (4') for the second phase is connected to a second inlet of the micromixer (21); and a recovery unit (5) connected to the outlet of the tubular pipe (22) of the microreactor (2); Equipped with.

[0130] The connections between the first phase continuous supply means (3), the first phase storage unit (1) and the first phase equilibration tubular pipe (4) may be provided by a three-way valve (6). The connections between the second phase continuous supply means (3'), the second phase storage unit (1') and the second phase equilibration tubular pipe (4') may be provided by a three-way valve (6'). Valves (6) and (6') may be computer-controlled.

[0131] In a specific embodiment, the installation according to the invention further comprises one or more washing units containing a washing solvent. Figure 2 illustrates a method according to one embodiment of the invention further comprising a washing unit, and also an installation that can be used to carry out the method. The first washing unit (7) and the second washing unit (7') can be connected to the means for continuous supply of the first phase (3) and the means for continuous supply of the second phase (3'), respectively, so that the washing solvent can circulate in the continuous flow microreactor. Three-way valves (8, 8') can be used to alternate between the injection of the first and second phases and the injection of the washing solvent. The three-way valves - on the one hand, a storage unit (1) for the first phase, a first washing unit (7), a continuous supply means (3) for the first phase (or a three-way valve (6)), and - on the other hand, a storage unit (1') for the second phase, a second washing unit (7') and a continuous supply means (3') for the second phase (or a three-way valve (6')). can be attached to connect

[0132] A waste recovery unit (9) may be used to recover the wash solvent after it has circulated through the facility. A three-way valve (10) may be used to connect the outlet of the tubular pipe (22) to the recovery unit (5) and the waste recovery unit (9).

[0133] The wash solvent may specifically be water and / or one or more suitable organic solvents, such as acetone, optionally containing a base (e.g., sodium carbonate, sodium hydroxide, or potassium hydroxide). In a specific embodiment, several successive wash solvents are used, such as water, followed by a basic aqueous solution, then acetone.

[0134] The three-way valves described in this patent application (e.g., valves (6), (6'), (8), and (8')) may be, for example, manual switching valves or automatic switching valves. Automatic switching three-way valves may be computer-controlled.

[0135] In a specific embodiment, the tubular pipe (22) of the continuous flow microreactor (2) has the following dimensions: - 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 - an internal diameter between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and even better between 0.7 mm and 1.2 mm It has.

[0136] The outer diameter of the tubular pipe (22) may be, for example, between 0.8 mm and 3.2 mm, such as between 0.8 mm and 1.0 mm, between 1.0 mm and 2.0 mm, or between 1.6 mm and 3.2 mm.

[0137] In a specific embodiment, the tubular pipe (22) of the continuous flow microreactor (2) comprises: - an inner diameter between 0.5 mm and 1.5 mm, and - Preferably with an outer diameter between 1.0 and 2.0 mm It has.

[0138] The tubular pipe 22 may typically be arranged in a snake or coil shape over all or part of its length, although other arrangements are also contemplated.

[0139] The micromixer (21) is usually T-shaped or Y-shaped. The internal diameter of the micromixer (21) is measured in micrometers or millimeters, advantageously between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and even more preferably between 0.7 mm and 1.2 mm.

[0140] The continuous feeding means (3, 3') represents any component or set of components making it possible to continuously transfer the first and / or second phase into the continuous flow microreactor (2), preferably a pump or a syringe which may be equipped with a syringe pump.

[0141] The internal diameters (4, 4') of the balancing tubular pipes may be measured in micrometers or millimeters and may independently be between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and even between 0.7 mm and 1.2 mm. The lengths (4, 4') of the balancing tubular pipes may independently be between 25 cm and 100 cm. The balancing tubular pipes (4, 4') are typically arranged in a snake or coil shape over all or part of their length, although other arrangements may also be envisaged.

[0142] The present invention can be understood in light of the following examples, which are given by way of illustration only and are not intended to limit the scope of the invention as defined in the appended claims. [Example]

[0143] Example 1: Fluorination and / or cyclization of aminoalkenes or alkynes by the method of the present invention

[0144] The methods for fluorinating and / or cyclizing aminoalkenes or alkynes were carried out according to the general procedures described below.

[0145] The equipment consists of two pumps or syringe pumps with two high-pressure metal syringes, each connected to an automatic valve. These syringes are connected to a fluid reservoir through metal tubing. The syringes are cooled by a chamber containing dry ice, which cools the liquid inside the syringe by thermal conduction. The components in contact with the superacid mixture were designed to accommodate the corrosive solvent by selecting materials compatible with this type of solvent (i.e., inside the syringes, the three-way valve, and the metal connector tubing (inside diameter 1 mm, outside diameter 1.6 mm) for transporting the fluid).

[0146] Fluid 1 (HF / SbF5 superacid) and Fluid 2 (dissolved substrate) were placed in tanks immersed in a cold bath (acetone / water, T = -35 °C), respectively, and connected to the system by tubing (inner diameter = 0.8 mm, outer diameter = 1.6 mm).

[0147] The three-way valve module is a motorized ball valve that allows the flow paths to be opened, closed, or switched. Thus, once the syringes are filled with fluids 1 and 2, the process of contacting the fluids can be initiated automatically through software that controls the distribution of a small volume V of each fluid at a given flow rate ratio F1 and F2. Thus, the pump and valve control limits the operator's contact with the superacid during the reaction. The fluids are then sent to a T-mixer (inner diameter 1 mm) through an equilibration loop with a length determined to reach the desired reaction temperature (here, V = 0.25 mL for L = 50 cm), which is itself connected to a tubing with a variable length L (inner diameter 0.8 mm, outer diameter 1.6 mm), and the residence time (t) of each reaction is measured. R The recovery is visually confirmed in a flask containing a solution to neutralize the residual acid, and the product is extracted with dichloromethane or a suitable solvent, washed with water, and dried over MgSO4. The crude residue is purified by silica chromatography, followed by 1 H, 13 C and 19 The compounds are analyzed by FNMR and compared to results previously obtained in the laboratory. The compounds are analyzed by one or more of these methods: 1 H, 13 C and 19 Identified by FNMR, HSQC, HMBC, and HRMS.

[0148] A wash tank (base / water, then acetone / water, then acetone) also connected to a manual valve allows washes to be performed at the end of the experiment.

[0149] [ka]

[0150] 1-(4-(2-fluoropropyl)piperazin-1-yl)ethanone 1a was immersed in a bath maintained at -20°C for a length L = 47 cm (t RThis was achieved by following the standard flow-through procedure using a tubular reactor with a flow rate of 8.2 s. The flow rate ratio of a 1:1 HF / SbF5 superacid mixture (F1 = 1 mL / min) to the HF solution of 1-(4-allylpiperazin-1-yl)ethan-1-one substrate 1 (F2 = 1 mL / min, c = 0.5 mol / L) was adjusted to produce SbF5 with a final acidity of 8.3 mol%. The reaction mixture was collected for 1 min (0.43 mmol used, 73 mg). Purification by silica chromatography (98 / 2 CHCl / MeOH) afforded 61.2 mg of product 1a (75%). 1 H NMR (400 MHz, CDCl3, ppm) δ: 1.42 (dd, CH3, J = 23.8 Hz, J = 6.3 Hz), 3.28 (m, CH2), 3.98 (bs, 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). 13 C NMR (100 MHz, CDCl3, ppm) δ: 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. 19 F{ 1 H} NMR (CDCl3, 376 MHz, ppm) δ: - 180.0.

[0151] [ka]

[0152] 4,6-Dimethyl-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide 2a was immersed in a bath maintained at -20°C for a length L = 130 cm (t RThis was achieved by following the standard flow-through procedure using a tubular reactor with a flow rate of 52.3 s. The flow rate ratio of the HF / SbF5 superacid mixture (F1 = 0.25 mL / min) to the N-allyl-4-methylbenzenesulfonamide substrate 2 in HF (c = 0.5 mol / L) with F2 = 0.5 mL was adjusted to produce SbF5 with a final acidity of 5.1 mol%. The reaction mixture was collected for 2 min (0.887 mmol used, 187.8 mg). Purification by silica chromatography (98 / 2 CHCl / MeOH) afforded 171.2 mg of product 2a (76%). 1 H NMR (400 MHz, CDCl3, ppm) δ: 1.34 (d, J = 7.2 Hz, 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). 13 C NMR (100 MHz, CDCl3, ppm) δ: 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.

[0153] [ka]

[0154] N-(2-fluoropropyl)-4-methylbenzenesulfonamide 2b was immersed in a bath maintained at -20°C for a length L = 78.2 cm (t RThis was achieved by following the standard flow-through procedure using a tubular reactor with a flow rate of 9.2 s. The flow rate ratio of a 1:1 v / v HF / SbF5 superacid mixture (F1 = 1 mL / min) to the HF solution of N-allyl-4-methylbenzenesulfonamide substrate 2 (F2 = 2 mL / min, c = 1 mol / L) was adjusted to produce SbF5 with a final acidity of 1.9 mol%. The reaction mixture was collected for 30 s (0.852 mmol used, 180 mg). Purification by silica chromatography (98 / 2 CHCl / MeOH) afforded 147.7 mg of product 2b (75%). 1 H NMR (400 MHz, CDCl3, ppm) δ: 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, J H-F = 45 Hz, 1H), 4.84 (s, 1H), 7.35 (d, J = 8 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H). 13 C NMR (100 MHz, CDCl3, ppm) δ: 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). 19 F{ 1 H} NMR CDCl3, 376 MHz, ppm) δ: -180.2. HRMS (ESI): calculated for C10H14FNO2S: 231.0729; found: 232.080241 [M+H] + and 254.062169 [M+Na] + .

[0155] [ka]

[0156] N-(2-fluoropropyl)-4-nitrobenzenesulfonamide 3b was immersed in a bath maintained at -20°C for a length L = 78.2 cm (t R This was achieved by following the standard flow-through procedure using a tubular reactor with a RT = 13.6 s. The flow rate ratio of a 1:1 v / v HF / SbF5 superacid mixture (F1 = 1 mL / min) to the HF solution of N-allyl-4-nitrobenzenesulfonamide substrate 3 (F2 = 1 mL / min, c = 1 mol / L) was adjusted to produce SbF5 with a final acidity of 8.4 mol%. The reaction mixture was collected for 1 min (0.867 mmol used, 120 mg). Purification by silica chromatography (98 / 2 CHCl / MeOH) afforded 190 mg of product 3b (84%). 1 H NMR (400 MHz, CDCl3, ppm) δ: 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, J =9.1 Hz, 2H). 13 C NMR (100 MHz, CDCl3, ppm) δ: 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). 19 F{ 1 H} NMR (CDCl3, 376 MHz, ppm) δ: - 180.2

[0157] [ka]

[0158] N-(2-fluoropropyl)-4-(trifluoromethyl)benzenesulfonamide 4b was immersed in a bath maintained at −20° C. for a length L=78.2 cm (t R This was achieved by following the standard flow-through procedure using a tubular reactor with a RT = 35.7 s. The flow rate ratio of a 1:1 v / v HF / SbF5 superacid mixture (F1 = 0.25 mL / min) to the HF solution of N-allyl-4-trifluorobenzenesulfonamide substrate 4 (F2 = 0.5 mL / min, c = 0.49 mol / L) was adjusted to produce SbF5 with a final acidity of 5.2 mol%. The reaction mixture was collected for 2 min (0.398 mmol used, 105.6 mg). Purification by silica chromatography (98 / 2 CHCl / MeOH) afforded 90.8 mg of product 4b (80%).

[0159] No trace of the cyclized product 4a was observed under the conditions studied. 1 H NMR (400 MHz, CDCl3, ppm) δ: 1.29 (dt, J = 23.8, 6.3 Hz, 3H), 3.34 - 2.97 (m, 2H), 4.71 (dm, J = 49 Hz, 1H), 5.24 (brs, NH), 7.78 (d, J = 8.3 Hz, 2H), 8.00 (d, J = 8.2 Hz, 2H). 19 F{ 1 H} NMR (CDCl3, 376 MHz, ppm) δ: - 179.8.

[0160] [ka]

[0161] 1-(4-(2-chloro-2-fluoropropyl)piperazin-1-yl)ethan-1-one 5a was immersed in a bath maintained at -20°C for a length L = 200 cm (t RThis was achieved by following the standard flow-through procedure using a tubular reactor with a chromatographic time of 60.3 seconds. The flow rate of a 1:1 v / v HF / SbF5 superacid mixture (F1 = 0.5 mL / min) to the HF solution containing the 1-(4-(2-chloroallyl)piperazin-1-yl)ethan-1-one substrate 5 (F2 = 0.5 mL / min, c = 0.5 mol / L) was adjusted to produce SbF5 with a final acidity of 6.4 mol%. The reaction mixture was collected for 2 minutes (0.499 mmol used, 111.1 mg). Purification by silica chromatography (99 / 1 CHCl / MeOH) afforded 77 mg of product 5a (70%). 1 H NMR (400 MHz, CDCl3, ppm) δ: 1.93 (d, J = 19.4 Hz, 3H), 2.06 (s, 3H), 2.57 (m, 4H), 2.78 (dd, J= 24.2 Hz, J = 14.3 Hz, 1H), 2.94 (dd, J = 14.3 Hz, J = 14.3 Hz, 1H), 3.42 and 3.57 (2m, 4H). 13 C NMR (100 MHz, CDCl3, ppm) δ: 21.7 (s, CH3), 28.4 (d, J = 25 Hz, CH3), 41.9 and 46.8 (2s, 2CH2), 54.4 and 54.6 (s, CH2), 67.8 (d, J = 22 Hz, CH2), 114.3 (d, J = 243 Hz, 1C), 169.3 (s). 19 F{ 1 H} NMR (CDCl3, 376 MHz, ppm) δ: - 98.9.

[0162] [ka]

[0163] Route A (starting from compound 5): 1-(4-(2,2-difluoropropyl)piperazin-1-yl)ethan-1-one 5b was immersed in a bath maintained at 0° C. for a length L=600 cm (t R This was obtained by following the standard flow-through procedure using a tubular reactor with a chromatographic time (T = 274 s). The flow rate of a 1:1 v / v HF / SbF5 superacid mixture (F1 = 0.5 mL / min) to the HF solution containing 1-(4-(2-chloroallyl)piperazin-1-yl)ethan-1-one substrate 5 (F2 = 0.25 mL / min, c = 0.499 mol / L) was adjusted to produce SbF5 with a final acidity of 12.1 mol%. The reaction mixture was collected for 2 min (0.215 mmol used, 44.3 mg). Purification by silica chromatography (from 100% CHCl2 to 98 / 2 CHCl2 / MeOH) afforded 38 mg of product 5b (74%).

[0164] Route B (starting from compound 9): 1-(4-(2,2-difluoropropyl)piperazin-1-yl)ethan-1-one 5b was immersed in a bath maintained at −40° C. for a length L=400 cm (t R Separately, 5b was obtained by following the standard flow-through procedure using a tubular reactor with a flow rate of 136 s. The flow rate ratio of a 3:1 v / v HF / SbF5 superacid mixture (F1 = 0.5 mL / min) to the HF solution containing 1-(4-(prop-2-yn-1-yl)piperazin-1-yl)ethan-1-one substrate 9 (F2 = 0.5 mL / min, c = 0.5 mol / L) was adjusted to produce SbF5 with a final acidity of 2.65 mol%. The reaction mixture was collected for 30 s (0.50 mmol used, 85.8 mg). Purification by silica chromatography (from 100% CHCl2 to 98 / 2 CHCl2 / MeOH) afforded 73 mg of product 5b (71%). 1H NMR (400 MHz, CDCl3, ppm) δ: 3.66 - 3.59 (m, 2H), 3.47 (dd, J = 12.4, 7.3 Hz, 2H), 2.70 (t, J = 13.5 Hz, 2H), 2.58 (ddd, J = 21.2, 13.1, 8.0 Hz, 4H), 2.09 (d, J = 2.6 Hz, 3H), 1.66 (t, J = 18.7 Hz, 3H). 19 F{ 1 H} NMR (CDCl3, 376 MHz, ppm) δ: - 92.2.

[0165] [ka]

[0166] 1-(2,2-Difluoropropyl)-4-phenylpiperidine 6a was immersed in a bath maintained at -40°C for a length L = 200 cm (t R The reaction mixture was obtained by following the standard flow-through procedure using a tubular reactor with a flow rate of 2.7 s. The flow rate ratio of a 3:1 v / v HF / SbF5 superacid mixture (F1 = 0.5 mL / min) to the HF solution of 4-phenyl-1-(prop-2-yn-1-yl)piperidine substrate 6 (F2 = 1 mL / min, c = 0.5 mol / L) was adjusted to produce SbF5 with a final acidity of 2.41 mol%. The reaction mixture was collected for 30 s (0.232 mmol used, 46.25 mg). Purification by silica chromatography (from 100% CHCl2 to 98 / 2 CHCl2 / MeOH) afforded 40.7 mg of product 6a (88%). 1 H NMR (400 MHz, CDCl3, ppm) δ: 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).13 C NMR (100 MHz, CDCl3) δ: 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). 19 F{ 1 H} NMR (376 MHz, CDCl3, ppm) δ ppm: - 92.3.

[0167] [ka]

[0168] 1-(2-fluoroallyl)-4-phenylpiperidine 6b was immersed in a bath maintained at -40 °C for a length L = 30 cm (t R The reaction mixture was obtained by following the standard flow-through procedure using a tubular reactor with a flow rate of 2.3 s. The flow rate ratio of a 3:1 v / v HF / SbF5 superacid mixture (F1 = 1 mL / min) to the HF solution containing 4-phenyl-1-(prop-2-yn-1-yl)piperidine substrate 6 (F2 = 2 mL / min, c = 0.48 mol / L) was adjusted to produce SbF5 with a final acidity of 2.4 mol%. The reaction mixture was collected for 30 s (0.494 mmol used, 90.2 mg). Purification by silica chromatography (from 100% CHCl2 to 98 / 2 DCM / MeOH) afforded 27.3 mg of product 6a (25%). 1 H NMR (400 MHz, CDCl3, ppm) δ: 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).13 C NMR (100 MHz, CDCl3, ppm) δ: 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, CF), 59.1 (d, J = 27.6 Hz), 54.1 (CH2), 42.5 (CH), 33.4 (CH2). 19 F{ 1 H} NMR (CDCl3, 376 MHz, ppm) δ: -98.2. HRMS (ESI): calculated for C14H18NF: 219.1423; found: 220.1496 [M+H] + .

[0169] [ka]

[0170] 1-(4-(3-chloro-3-fluoropropyl)piperazin-1-yl)ethan-1-one 7a was immersed in a bath maintained at -20 °C for a length L = 400 cm (t R This was obtained by following the standard flow-through procedure using a tubular reactor with a pH of 1.0 (Eq. 120.7 s). The flow rate of a 1:1 v / v HF / SbF5 superacid mixture (F1 = 0.5 mL / min) to the HF solution of (Z / E)-1-(4-(3-chloroallyl)piperazin-1-yl)ethan-1-one substrate 7 (F2 = 0.5 mL / min, c = 0.5 mol / L) was adjusted to produce SbF5 with a final acidity of 8.4 mol%. The reaction mixture was collected for 1 min (0.271 mmol used, 40.4 mg). Purification by silica chromatography (100% CHCl2 to 98 / 2 CHCl2 / MeOH gradient) afforded 32.5 mg of product 7a (57%). 1H NMR (400 MHz, CDCl3, ppm) δ: 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, CHFCl). 19 F{ 1 H} NMR (CDCl3, 376 MHz, ppm) δ: - 117.08.

[0171] [ka]

[0172] 1-(4-(3,3-difluoropropyl)piperazin-1-yl)ethan-1-one 7b was immersed in a bath maintained at 0 °C for a length L = 600 cm (t R This was obtained by following the standard flow-through procedure using a tubular reactor with a chromatographic gradient (E = 241 s). The flow rate of a 1:1 v / v HF / SbF5 superacid mixture (F1 = 0.5 mL / min) to the HF solution of (Z / E)-1-(4-(3-chloroallyl)piperazin-1-yl)ethan-1-one substrate 7 (F2 = 0.25 mL / min, c = 0.5 mol / L) was adjusted to produce SbF5 with a final acidity of 12.1 mol%. The reaction mixture was collected for 2 min (0.218 mmol used, 44.8 mg). Purification by silica chromatography (100% CHCl2 to 98 / 2 CHCl2 / MeOH gradient) resulted in the isolation of 45 mg of product 7b (85%). 1 H NMR (400 MHz, CDCl3, ppm) δ: 2.05 - 1.92 (m, 2H, CH2), 2.06 (s, 3H, CH3), 2.41 (dt, J = 14.7, 5.0 Hz, 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). 13 C NMR (100 MHz, CDCl3, ppm) δ: 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). 19 F{ 1 H} NMR (CDCl3, 376 MHz, ppm) δ: - 117.1.

[0173] [ka]

[0174] N-(2-fluoropropyl)aniline 8a was immersed in a bath maintained at -50°C for a length L = 50 cm (t R The reaction mixture was obtained by following the standard flow-through procedure using a tubular reactor with a pH of 5.0 s. The flow rate of a 3:1 v / v HF / SbF5 superacid mixture (F1 = 1.5 mL / min) to the HF solution of N-allylaniline substrate 8 (F2 = 1.5 mL / min, c = 0.57 mol / L) was adjusted to produce SbF5 with a final acidity of 3.74 mol%. The reaction mixture was collected for 30 s (0.429 mmol used, 53.6 mg). Purification by silica chromatography (100% CHCl2 to 98 / 2 CHCl2 / MeOH gradient) isolated 43 mg of product 8a (66%). 1H NMR (400 MHz, CDCl3, ppm) δ: 1.43 (dd, J = 23.8, 6.3 Hz, 3H, CH3), 3.44 - 3.17 (m, 2H), 5.01 - 4.77 (dm, J = 49.56 Hz, 1H, CH-F), 6.64 (m, 2H, CH ar ), 6.75 (tt, J = 7.4, 1.0 Hz, 1H), 7.24 - 7.12 (m, 2H, CH). 19 F{ 1 H} NMR (CDCl3, 376 MHz, ppm) δ: - 179.9.

[0175] [ka]

[0176] 3-Methylindoline 8b and 1,2,3,4-tetrahydroquinoline 8c were immersed in a bath maintained at 0°C for a length L = 200 cm (t R The reaction mixture was obtained by following the standard flow-through procedure using a tubular reactor with a flow rate of 40 s. The flow rate ratio of a 1:1 v / v HF / SbF5 superacid mixture (F1 = 0.5 mL / min) to the HF solution of N-allylaniline substrate 8 (F2 = 1.0 mL / min, c = 0.74 mol / L) was adjusted to produce SbF5 with a final acidity of 5.2 mol%. The reaction mixture was collected for 30 s (0.429 mmol used, 53.6 mg). Purification by silica chromatography (CHCl / MeOH gradient) resulted in the isolation of 31.3 mg of product 8b (37%) and 35.9 mg of product 8c (42%).

[0177] 3-Methylindoline 8b 1H NMR (400 MHz, CDCl3, ppm) δ: 1.33 (d, J = 6.8 Hz, 1H), 3.12 (t, J = 8.6 Hz, 1H), 3.45 - 3.27 (m, 1H), 3.71 (t, J = 8.6 Hz, 1H), 6.66 (d, J = 7.7 Hz, 1H), 6.75 (td, J = 7.4, 0.9 Hz, 1H), 7.04 (ddd, J = 8.7, 2.0, 1.0 Hz, 1H), 7.12 - 7.08 (m, 1H), 1,2,3,4-Tetrahydroquinoline 8c 1 H NMR (400 MHz, CDCl3, ppm) δ: 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, J = 7.4, 1.1 Hz, 1H), 7.00 - 6.89 (m, 1H).

[0178] [ka]

[0179] N-(2-fluoropropyl)-4-nitroaniline 12b was immersed in a bath maintained at 0°C for a length L = 200 cm (t R The reaction mixture was obtained by following the standard flow-through procedure using a tubular reactor with a flow rate of 40 s. The flow rate ratio of a 1:1 v / v HF / SbF5 superacid mixture (F1 = 0.5 mL / min) to the N-allyl-4-nitroaniline substrate (F2 = 1 mL / min, c = 0.3 mol / L) in HF was adjusted to produce SbF5 with a final acidity of 5.1 mol%. The reaction mixture was collected for 1 min 21 s (0.448 mmol used, 79.8 mg). Purification by silica chromatography (CHCl / MeOH gradient) resulted in the isolation of 65 mg of product 12b (73%).

[0180] Tubular reactor L = 600 cm (t R = 241 sec), F1 = 0.25 mL / min to F2 = 0.5 mL / min, to give product 12b in 92% yield. 1 H NMR (400 MHz, CDCl3, ppm) δ: 1.44 (dd, J = 23.8, 6.3 Hz, 3H, CH3), 3.40 (m, 2H, CH2), 4.79 (bs, 1H, NH), 4.87 (dm, J = 49.1, 3 J H-H = 6.3 Hz, CFH), 6.57 (d, J = 9.3 Hz, 2-H, CH), 8.09 (d, J = 9.3 Hz, 2H, CH). 19 F{ 1 H} NMR (CDCl3, 376 MHz, ppm) δ: - 179.9

[0181] [ka]

[0182] 1-(4-(2-fluoroallyl)piperazin-1-yl)ethan-1-one 9b was immersed in a bath maintained at -40 °C for a length L = 30 cm (t R This was achieved by following the standard flow-through procedure using a tubular reactor with a flow rate of 2 s. The flow rate ratio of a 5:1 v / v HF / SbF5 superacid mixture (F1 = 1.5 mL / min) to the HF solution containing the 1-(4-(prop-2-yn-1-yl)piperazin-1-yl)ethan-1-one substrate 9 (F2 = 3 mL / min, c = 0.5 mol / L) was adjusted to produce SbF5 with a final acidity of 1.57 mol%. The reaction mixture was collected for 30 s (0.748 mmol used, 154.3 mg). Purification by silica chromatography (from 100% CHCl2 to 98 / 2 CHCl2 / MeOH) resulted in the isolation of 97.9 mg of product 9b (70%). 1H NMR (400 MHz, CDCl3, ppm) δ: 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). 13 C NMR (100 MHz, CDCl3, ppm) δ: 41.2 (CH2), 46.1 (CH2), 58.4 (d, J = Hz, CH2), 93.8 (CH2), 19 F{ 1 H} NMR (CDCl3, 376 MHz, ppm) δ: - 98.7. HRMS (ESI): C9H 15 Calculated for FNO: 186.1168; Found: 187.1241 [M+H] + .

[0183] [ka]

[0184] (4-Fluoro-4-methylpiperidin-1-yl)(4-nitrophenyl)methanone 10a was immersed in a bath maintained at 0° C. for a length L=600 cm (t R The reaction mixture was obtained by following the standard flow-through procedure using a tubular reactor with a flow rate of 104 s. The flow rate ratio of a 1:1 v / v HF / SbF5 superacid mixture (F1 = 1 mL / min) to the HF solution of N,N-diallyl-4-nitrobenzamide substrate 10 (F2 = 1 mL / min, c = 0.23 mol / L) was adjusted to produce SbF5 with a final acidity of 8.4 mol%. The reaction mixture was collected for 1 min 53 s (0.353 mmol used, 75.7 mg). Purification by silica chromatography (70 / 30 petroleum ether / EtOAc) isolated 43.1 mg of product 10a (46%). 1H NMR (400 MHz, CDCl3, ppm) δ: 1.41 (d, J = 21.4 Hz, 3H, CH3), 1.71 (m, 4H, 2CH2), 3.17 (m, 1H), 4.53 (m, 1H), 3.41 (m, 2H, CH2), 7.56 (d, J = 8.8 Hz, 2H, 2CH), 8.27 (d, J = 8.8 Hz, 2H, 2CH). 19 F{ 1 H} NMR (CDCl3, 376 MHz, ppm) δ: - 151.7.

[0185] [ka]

[0186] 4-Fluoro-4-methyl-1-(4-nitrobenzyl)piperidine 16a was immersed in a bath maintained at 0 °C for a length L = 600 cm (t R The reaction mixture was obtained by following the standard flow-through procedure using a tubular reactor with a RT = 104 s. The flow rate ratio of a 1:1 v / v HF / SbF5 superacid mixture (F1 = 1 mL / min) to the HF solution of N-allyl-N-(4-nitrobenzyl)prop-2-en-1-amine substrate 16 (F2 = 1 mL / min, c = 0.34 mol / L) was adjusted to produce SbF5 with a final acidity of 8.4 mol%. The reaction mixture was collected for 1 min (0.341 mmol used, 88.4 mg). Purification by silica chromatography (99 / 1 CHCl / MeOH) resulted in the isolation of 37 mg of product 16a (47%). 1 H NMR (400 MHz, CDCl3, ppm) δ: 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, 2CH ar ), 8.17 (d, J = 8.8, 2CH ar ).13 C NMR (100 MHz, CDCl3, ppm) δ: 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, CF), 123.5 (2CH), 129.4 (2CH), 146.8 (Cq), 147.1 (Cq). 19 F{ 1 H} NMR (CDCl3, 376 MHz, ppm) δ: - 151.55. HRMS (ESI): C 13 H 18 Calculated for FN2O2: 252.1274; Found: 253.1346 [M+H] + .

[0187] [ka]

[0188] 3-Fluoro-3-methyl-1-(4-nitrobenzyl)piperidine 16b was immersed in a bath maintained at -40°C for a length L = 600 cm (t R This was achieved by following the standard flow-through procedure using a tubular reactor with a RT = 104 s. The flow rate ratio of a 1:1 v / v HF / SbF5 superacid mixture (F1 = 1 mL / min) to the HF solution of N-allyl-N-(4-nitrobenzyl)prop-2-en-1-amine substrate 16 (F2 = 1 mL / min, c = 0.34 mol / L) was adjusted to produce SbF5 with a final acidity of 8.4 mol%. The reaction mixture was collected for 1 min (0.341 mmol used, 88.4 mg). Purification by silica chromatography (99 / 1 CHCl / MeOH) resulted in the isolation of 12 mg of 3-fluoro-3-methyl-1-(4-nitrobenzyl)piperidine 16b (35%). 1H NMR (400 MHz, CDCl3, ppm) δ: 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 = 8.8Hz, 2CH ar ), 8.16 (d, J = 8.7 Hz, 2CH ar ). 13 C NMR (100 MHz, CDCl3, ppm) δ: 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). 19 F{ 1 H} NMR (CDCl3, 376 MHz, ppm) δ: - 146.8. HRMS (ESI): C 13 H 18 Calculated for FN2O2: 252.1274; Found: 253.1346 [M+H] + .

[0189] [ka]

[0190] Vinflunine 18a was immersed in a bath maintained at -40°C for a length L = 600 cm (t RThe product was obtained by following the usual procedure using a tubular reactor with a flow rate of 603 s. Flow rates of a 2:1 v / v HF / SbF5 mixture at F1 = 0.2 or 0.3 mL / min and a solution of vinorelbine tartrate 18 in anhydrous chloroform (c = 0.03 mol / L) at F2 = 0.2 or 0.3 mL / min were applied. The reaction mixture was collected for 10 min, and 23 mg of crude residue was recovered. NMR and HPLC analysis of the crude mixture identified vinflunine in predominant amounts with yields of approximately 3 to 15% (NMR yield) relative to a reference standard. The enriched fraction (HPLC) was isolated by purification of the crude mixture using a C18 reversed phase (ACN / 0.2% TFA aqueous solution, peaks of which were isolated at 30% ACN in a gradient).

[0191] [ka]

[0192] N-(2-fluoropropyl)-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide 19a was immersed in a dry ice bath for a length L = 78 cm (t R This was obtained by following the standard flow-through procedure using a tubular reactor with a flow rate of 7.8 s. The flow ratio of the HF / SbF5 superacid mixture to N-allyl-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide 19 (c = 0.16 mol / L) was adjusted. The reaction mixture was collected for 30 s (0.156 mmol used, 65.6 mg). Purification by silica chromatography (PE / EtOAc gradient from 5% to 30% EtOAc) gave 50.2 mg of product 19a (72%). 1H NMR (400 MHz, CDCl3, ppm) δ: 1.29 (dd, J = 23.8, 6.3 Hz, 3H), 2.38 (s, 3H), 3.02 (m, 1H), 3.21 (m, 1H), 4.69 (dm, J = 49.2 Hz, 1H), 5.07 (bm, 1H), 6.75 (s, 1H), 7.10 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 7.54 - 7.43 (m, 1H), 7.91 - 7.79 (m, 1H). 13 C NMR (100 MHz, CDCl3, ppm) δ: 145.4, 144.2 (q, J = 38.5 Hz, CF3), 142.7, 139.9, 139.4, 129.87 (s), 128.8 (s), 128.1 (s), 125.7, 121.1 (q, J = 269.2 Hz, CF), 106.4, 89.8 (s), 88.5, 48.2 (d, J = 21.1 Hz, CF), 21.4, 18.2, 18.1. 19 F NMR (CDCl3, 376 MHz, ppm) δ: - 62.42 (CF3), - 179.9 (CF). HRMS (ESI): C 20 H 19 Calculated value of F4N3O2S: 441.1134; Measured value: C 20 H 19 F4N3O2S 442.1206 [M+H] + .

[0193] [ka]

[0194] 4-Fluoro-4-methyl-1-((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)piperidine 20a was immersed in an acetone / dry ice bath for a length L = 400 cm (t RThis was obtained by following the standard flow-through procedure using a tubular reactor with a flow rate of 4.1 s. The flow ratio of the HF / SbF5 superacid mixture to N-diallyl-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide 20 (c = 0.11 mol / L) was adjusted. The reaction mixture was collected for 2 min (0.076 mmol used, 37 mg). Purification by silica chromatography (PE / EtOAc gradient from 5% to 30% EtOAc) gave 7.2 mg of product 20a (20%). 1 H NMR (400 MHz, CDCl3, ppm) δ: 7.77 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 3.58 - 3.28 (m, 1H), 2.88 - 2.54 (m, 1H), 2.76 - 2.64 (m, 1H), 2.38 (s, 1H), 1.89 - 1.77 (m, 1H), 1.65 - 1.54 (m, 1H), 1.36 (d, J = 21.0 Hz, 1H). 13 C NMR (100 MHz, CDCl3, ppm) δ: 145.4, 144.2 (q, J = 38.5 Hz), 142.6, 139.9, 136.7, 129.8, 128.8, 128.7, 125.71, 122.2, 120.1, 106.3, 90.5 (d, J = 175.4 Hz), 53.9 (d, J = 25.7 Hz), 45.5, 34.5 (d, J = 22.6 Hz), 24.5 (d, J = 23.4 Hz), 21.4, 21.11 (d, J = 3.6 Hz). 19 F{ 1 H} NMR (CDCl3, 376 MHz, ppm) δ: - 62.44, - 150.01. HRMS (ESI): C 23 H 24Calculated for F4N3O2S [M+H] 482.151987; found 482.154140.

[0195] [ka]

[0196] N-(2-fluoroallyl)-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide 21a was immersed in an acetone / dry ice bath for a length L = 25 cm (t R This was obtained by following the standard flow-through procedure using a tubular reactor with a pH of 4.2 s. The flow ratio of the HF / SbF5 superacid mixture to N-(prop-2-yn-1-yl)-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide 21 (c = 0.11 mol / L) was adjusted. The reaction mixture was collected for 30 s (0.07 mmol used, 31 mg). Purification by silica chromatography (from 0% to 10% PE / EtOAc) afforded the fluorovinyl compound 21a in 29% yield. 1 H NMR (400 MHz, CDCl3, ppm) δ: 7.85 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.74 (s, 1H), 4.77 (t, J = 6.4 Hz, 1H), 4.61 (dd, J = 16.2, 3.5 Hz, 1H), 4.44 (dd, J = 47.9, 3.5 Hz, 1H), 3.76 (dd, J = 13.1, 6.3 Hz, 1H), 2.38 (s, 2H). 13C NMR (100 MHz, CDCl3, ppm) δ: 161.12, 159.07, 145.26, 144.13 (q, J = 39.0 Hz), 142.69, 139.83, 139.36, 129.77, 128.73, 128.14, 125.67, 125.64, 125.55, 106.38, 93.36 (d, J = 17.4 Hz), 43.45 (d, J = 32.6 Hz), 29.73, 21.37. 19 F{ 1 H} NMR (CDCl3, 376 MHz, ppm) δ: - 62.44 (s), - 104.12 - - 104.45 (m). HRMS (ESI): C 20 H 18 Calculated for F4N3O2S [M+H]: 440.105037; Found: 440.106449.

[0197] [ka]

[0198] N-(2,2-difluoropropyl)-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide 21b has a length L = 39 cm (t R This was obtained by following the standard flow-through procedure using a tubular reactor with a flow rate of 2 s. The flow ratio of the HF / SbF5 superacid mixture to N-(prop-2-yn-1-yl)-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide 21 was adjusted. The reaction mixture was collected for 15 s (0.118 mmol used, 49.5 mg). Purification by silica chromatography (PE / EtOAc gradient) gave 47.2 mg of product 21b (86%). 1H NMR (500 MHz, CDCl3, ppm) δ: 1.65 (t, J = 18.6, 3H), 2.40 (s, 3H), 3.35 (td, J = 13.0, 6.8 Hz, 2H), 5.08 (bs, 1H), 6.77 (s, 1H), 7.12 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 7.51 (m, 2H), 7.86 (m, 2H). 13 C NMR (126 MHz, CDCl3, ppm) δ: 145.3, 144.1 (q, J = 38.6 Hz, CF3), 142.7, 139.8, 139.2, 129.7, 128.7, 127.9, 125.6, 125.6, 123.3, 121.4, 121.0 (q, J = 269.2 Hz, CF2), 119.5, 106.4, 106.34 (s, J = 1.4 Hz), 48.15 (t, J = 30.9 Hz), 29.7, 21.4, 21.3, 21.2, 21.0. 19 F NMR (CDCl3, 376 MHz, ppm) δ: - 62.4 (s), - 96.6 (m). HRMS (ESI): C 20 H 18 Calculated value of F5N3O2S: 459.1040; Measured value: C 20 H 19 F5N3O2S 460.1112 [M+H] + .

[0199] Example 2: Comparative Study 1) Productivity The productivity of each reaction was calculated to provide access to the amount of product formed in a given time. Productivities are given relative to the reactor volume so that comparisons can be made between reactors of different sizes or configurations. Similarly, productivity can be calculated for the static reaction volume and compared to the reactor volume over a given time in flow chemistry. This is expressed in kg.m -3 .h -1 This is known as the space-time yield (STY) in units of

[0200]

number

[0201] [ka]

[0202] For example, in the case of compound 1, it is striking that the productivity of the fluorination reaction increases 34-fold when going from a static method to the flow process described in the present invention.

[0203] [Table 1]

[0204] The productivity of the static process and the process of the present invention for each reaction product was calculated from the data summarized in the table below (Table 2). In general, the process according to the present invention is advantageous, especially in that it has a very short residence time (t R <1 min) reactions, doubling productivity by up to 34-fold over static processes.

[0205] As mentioned above, the acidity of the solvent is an important parameter. The use of varying acidity has also been investigated in flow processes, and in some syntheses, the amount of SbF5 was significantly reduced, while at the same time the reaction efficiency was improved, resulting in higher productivity than in static processes.

[0206] [Table 2A]

[0207] [Table 2B]

[0208] 2) Selection rate While static application of the superacid reagent to compound 2 systematically produces only compound 2a, the method of the present invention makes it possible to selectively obtain compound 2a or compound 2b by adjusting the residence time and concentration of the superacid reagent.

[0209] [ka]

[0210] Furthermore, while static application of the superacid reagent to compound 9 systematically produces only the difluoro compound 5b, the method of the present invention allows for selectively obtaining compound 9b or compound 5b by adjusting the conditions.

[0211] [ka]

[0212] In this example, the preparation of the fluorovinyl product 21a of propargylated celecoxib 21 is only possible under the conditions of the present invention, which now allows for the capture of this reaction intermediate, which is inaccessible under batch conditions as in the case of 9b.

[0213] [ka]

[0214] While the static application of a superacid reagent to compound 5 produces difluoro compound 5b and, with great difficulty, compound 5a, the use of the method of the present invention makes it possible to selectively obtain compound 5a or compound 5b by adjusting the conditions.

[0215] [ka]

[0216] Finally, the equipment described in this invention allows for the super-electrophilic activity of celecoxib diallyl derivative 20, which, by the method of this invention requiring an assay for acidity, allows for a tandem cyclization / fluorination reaction that selectively produces compound 20a, a unit of pharmaceutical interest, which cannot be achieved under static conditions. Product 20a cannot be obtained by a similar reaction under batch conditions.

[0217] [ka] [Explanation of symbols]

[0218] 1 Phase 1 Storage Unit 1' Phase 2 Storage Unit 2. Continuous Flow Microreactor 3. Means for continuous supply of first phase 3' Second phase continuous supply means 4. First Phase Equilibration Tubular Pipe 4' Second Phase Equilibration Tubular Pipe 5 Recovery Unit 6 Three-way valve 6' three-way valve 7 First cleaning unit 7' Second cleaning unit 8 Three-way valve 8' three-way valve 9. Waste Collection Unit 10 Three-way valve 21 Micro Mixer 22 Tubular Pipe

Claims

1. a) providing a first phase comprising an aminoalkene or alkyne and a second phase comprising a superacid reagent; b) contacting the first phase with the second phase in a continuous flow microreactor; c) recovering the fluorination and / or cyclization products of the aminoalkene or alkyne; 1. A method for fluorinating and / or cyclizing an aminoalkene or alkyne, comprising:

2. - the residence time of the first and second phases in the continuous flow microreactor in step (b) is between 2 and 400 seconds; and / or - the flow rates of the first phase and the second phase in step (b) are independently between 0.1 mL / min and 3.5 mL / min, e.g., between 0.25 mL / min and 3.0 mL / min 2. The method according to claim 1 .

3. The continuous flow microreactor comprises a micromixer and a tubular pipe, and the tubular pipe is preferably - Lengths between 20cm and 800cm, and - an internal diameter between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and even better between 0.7 mm and 1.2 mm 3. The method according to claim 1 or 2, characterized in that it comprises:

4. - a storage unit (1) for a first phase containing an aminoalkene or alkyne, - a storage unit (1') for the second phase containing the superacid reagent, - a continuous supply means (3) of the first phase connected to said storage unit (1) of the first phase and to a first phase balancing tubular pipe (4); - second phase continuous supply means (3') connected to said second phase storage unit (1') and to a second phase balancing tubular pipe (4'); - a continuous flow microreactor (2) comprising a micromixer (21) with two inlets and one outlet, and a tubular pipe (22) with one inlet and one outlet, the inlet of the tubular pipe (22) being connected to the outlet of the micromixer (21); a continuous flow microreactor (2), in which the equilibration tubular pipe (4) for the first phase is connected to the first inlet of the micromixer (21), and the equilibration tubular pipe (4') for the second phase is connected to the second inlet of the micromixer (21); and a recovery unit (5) connected to the outlet of the tubular pipe (22) of the microreactor (2); 4. The method according to claim 1, wherein the method is carried out in a facility comprising:

5. The superacid reagent is HF / MF 5 and HSO 3 F / MF 5 where M is Sb, As, P, Ta, or Nb, and preferably the superacid reagent is selected from HF / SbF 5 5. The method according to claim 1, wherein

6. 6. The process according to claim 1, wherein the aminoalkene or the alkyne is an allyl or propargylamine.

7. The aminoalkene or the alkyne is an aminoalkene of formula (Ia): 【Chemical 1】 In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently 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, group -S(O) 2 -R 8 and the group -C(O)-R 9 (In the formula, R 8 and R 9 is independently 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; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted; Or R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 each of two groups selected from, together with the atom to which they are attached, may separately form an optionally substituted 3- to 12-membered ring; 7. The method according to claim 6, characterized in that the compound is an aminoalkene.

8. -R 1 and R 2 are independently hydrogen, C 2 ~C 12 alkenyl, [optionally C 1 ~C 6 Alkyl, nitro, or -CF 3 , -OCF 3 , -SCF 3 , -OCF 2 R', -OCF(R') 2 , -SCF 2 R' and -SCF(R') 2 (wherein each R' is independently hydrogen, halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl or C 3 ~C 6 aryl, -S(O) 2 -R 8 and -C(O)-R 9 (In the formula, R 8 and R 9 are independently and optionally, C 1 ~C 6 Alkyl, nitro or -CF 3 , -OCF 3 , -SCF 3 , -OCF 2 R', -OCF(R') 2 , -SCF 2 R' and -SCF(R') 2 (wherein each R' is independently hydrogen, halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl or C 3 ~C 6 cycloalkyl) Or, R 1 and R 2 together with the atoms to which they are attached form an optionally aryl- or acetyl-substituted piperidine or piperazine; -R 3 and R 4 is hydrogen, -R 5 , R 6 and R 7 are independently selected from hydrogen and halogen, preferably R 5 , R 6 and R 7 At least two of them are hydrogen 8. The method according to claim 7.

9. The aminoalkene or the alkyne is an aminoalkyne of formula (Ib): 【Chemistry 2】 In the formula, R 1 , R 2 , R 3 , R 4 and R 5 are independently 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, group -S(O) 2 -R 8 and the group -C(O)-R 9 (In the formula, R 8 and R 9 is independently 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; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted; Or R 1 , R 2 , R 3 , R 4 and R 5 each of two groups selected from, together with the atom to which they are attached, may separately form an optionally substituted 3- to 12-membered ring; 7. The method according to claim 6, characterized in that the compound is an aminoalkyne.

10. -R 1 and R 2 are independently hydrogen, C 2 ~C 12 alkenyl, [optionally C 1 ~C 6 Alkyl, nitro, or -CF 3 , -OCF 3 , -SCF 3 , -OCF 2 R', -OCF(R') 2 , -SCF 2 R' and -SCF(R') 2 (wherein each R' is independently hydrogen, halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl or C 3 ~C 6 aryl, -S(O) 2 -R 8 and -C(O)-R 9 (In the formula, R 8 and R 9 are independently and optionally, C 1 ~C 6 Alkyl, nitro or -CF 3 , -OCF 3 , -SCF 3 , -OCF 2 R', -OCF(R') 2 , -SCF 2 R' and -SCF(R') 2 (wherein each R' is independently hydrogen, halogen, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl or C 3 ~C 6 cycloalkyl) or alternatively, R 1 and R 2 together with the atoms to which they are attached form an optionally aryl- or acetyl-substituted piperidine or piperazine; -R 3 , R 4 and R 5 is hydrogen 10. The method according to claim 9.

11. The aminoalkene or the alkyne is 【Chemistry 3】 7. The method according to claim 6, characterized in that the compound is selected from the group consisting of:

12. - a storage unit (1) for a first phase containing an aminoalkene or alkyne, - a storage unit (1') for the second phase containing the superacid reagent, - a continuous supply means (3) of the first phase connected to said storage unit (1) of the first phase and to a first phase balancing tubular pipe (4); - second phase continuous supply means (3') connected to said second phase storage unit (1') and to a second phase balancing tubular pipe (4'); - a continuous flow microreactor (2) comprising a micromixer (21) with two inlets and one outlet, and a tubular pipe (22) with one inlet and one outlet, the inlet of the tubular pipe (22) being connected to the outlet of the micromixer (21); a continuous flow microreactor (2), in which the equilibration tubular pipe (4) for the first phase is connected to the first inlet of the micromixer (21), and the equilibration tubular pipe (4') for the second phase is connected to the second inlet of the micromixer (21); and a recovery unit (5) connected to the outlet of the tubular pipe (22) of the microreactor (2), The tubular pipe (22) of the continuous flow microreactor (2) is preferably - Length between 20cm and 800cm, - an internal diameter between 0.5 mm and 2.5 mm, preferably between 0.7 mm and 1.2 mm 12. An installation for carrying out the method according to any one of claims 1 to 11, characterized in that it comprises:

13. a three-way valve (6) providing the connection between the first phase continuous supply means (3), the first phase storage unit (1) and the first phase balancing tubular pipe (4), and / or - a three-way valve (6') providing the connection between the second phase continuous supply means (3'), the second phase storage unit (1') and the second phase balancing tubular pipe (4'); 13. The installation according to claim 12, further comprising:

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