Process for fluorination and / or cyclization of amino olefins or alkynes in continuous stream and apparatus for carrying out process

Abstract

The present invention relates to a process for fluorination and / or cyclization of amino olefins or alkynes in a continuous flow microreactor. The invention also relates to a device for carrying out such a process.

Description

Technical Field

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

[0002] In superacid medium, H 0 The acidity value is below -12, and as such all molecules, even simple alkanes, react as bases. Therefore, superacid systems are of great interest because they offer a specific type of reactivity involving multiply protonated molecules. In recent years, many processes have been developed in superacid media and can be envisioned for both laboratory and industrial scale syntheses.

[0003] For example, Michelet et al. describe a method for using superacid HF / SbF 5 Process for fluorinating aminoalkenes or alkynes (J. Fluorine Chem. 2018, 214, 68-79). This transformation is of particular interest because it allows access to fluoroamine units sought in medicinal chemistry. In addition, WO 95 / 03312 shows that vinorelbine can be fluorinated in superacid HF / SbF 5 In the presence of

[0004] However, these systems have many disadvantages that limit their use. In particular, the reagents that generate the peracid medium, 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 makes it impossible to control the outcome of the reactions: cascade reactions and polyfluorination reactions may be observed.

[0005] Therefore, there is a real need to develop a process that facilitates the handling of super acids and allows better control of their reactivity, most particularly when they are in contact with aminoalkynes or alkenes.

[0006] In this context, the Applicant has demonstrated that the use of microfluidics and more specifically continuous flow microreactors allows these limitations to be overcome. More specifically, it has been shown that, surprisingly, the use of continuous flow microreactors allows the preparation of fluorinated or cyclized compounds that are difficult or even impossible to obtain 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. Summary of the invention

[0007] The present invention therefore relates to a process for fluorinating and / or cyclizing an amino olefin or alkyne comprising:

[0008] a) providing a first phase comprising an amino olefin or an alkyne and a second phase comprising a super acid reagent,

[0009] b) placing the first phase and the second phase in contact in a continuous flow microreactor, and

[0010] c) recovering the fluorination and / or cyclization product of the aminoalkene or alkyne.

[0011] In a specific embodiment, the residence time of the first phase and the second phase in the continuous flow microreactor in step (b) is between 2 seconds and 400 seconds.

[0012] In a specific embodiment, the flow rate of the first phase and the flow rate of the second phase in step (b) are independently between 0.1 mL / min and 3.5 mL / min, such as between 0.25 mL / min and 3.0 mL / min.

[0013] In a specific embodiment, the continuous flow microreactor comprises a micromixer and a tubular tube, wherein the tubular tube preferably has:

[0014] - a length between 20 cm and 800 cm, and

[0015] An internal diameter of between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm and better still between 0.7 mm and 1.2 mm.

[0016] In a specific embodiment, the contacting is performed at a temperature between -70°C and 25°C in a continuous flow microreactor.

[0017] In a specific embodiment, the process according to the invention is carried out in an apparatus comprising:

[0018] - a storage unit (1) for a first phase comprising an aminoolefin or an alkyne,

[0019] - a storage unit (1') for a second phase containing a superacid reagent,

[0020] - a first phase continuous feeding device (3) connected to the first phase storage unit (1) and the first phase balancing tubular pipe (4),

[0021] - a second phase continuous feeding device (3') connected to the second phase storage unit (1') and the second phase balancing tubular pipe (4'),

[0022] - a continuous flow microreactor (2) comprising a micromixer (21) comprising two inlets and one outlet, and a tubular tube (22) comprising one inlet and one outlet, wherein the inlet of the tubular tube (22) is connected to the outlet of the micromixer (21),

[0023] wherein the first phase balancing tubular tube (4) is connected to a first inlet of the micromixer (21), and the second phase balancing tubular tube (4') is connected to a second inlet of the micromixer (21), and

[0024] - A collecting unit (5) connected to the outlet of the tubular tube (22) of the microreactor (2).

[0025] In a specific embodiment, the superacid reagent is selected from HF / MF 5 and HSO 3 F / MF 5 , wherein M is Sb, As, P, Ta or Nb; preferably, the superacid reagent is HF / SbF 5 .

[0026] In a specific embodiment, the first phase is a solution of the aminoolefin or alkyne in HF, preferably at a concentration between 0.5 and 1.0 mol / L.

[0027] The aminoalkene or alkyne may in particular be allylamine or propargylamine. In a specific embodiment, the aminoalkene or alkyne is an aminoalkene of formula (Ia):

[0028]

[0029] in:

[0030] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, halogen, C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, C 1 -C 12 Heteroalkyl, C 3 -C 12 Cycloalkyl, C 2 -C 12 Heterocycloalkyl, aryl, heteroaryl, group -S(O) 2 -R 8 and the group -C(O)-R9 , where R 8 and R 9 Independently selected from C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, C 1 -C 12 Heteroalkyl, C 3 -C 12 Cycloalkyl, C 2 -C 12 Heterocycloalkyl, aryl and heteroaryl,

[0031] The alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted, or

[0032] Each selected from R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 The two groups of may alternatively be taken together with the atoms to which they are attached to form an optionally substituted 3 to 12-membered ring.

[0033] In particular, aminoolefins of formula (Ia) allow:

[0034] -R 1 and R 2 are independently selected from hydrogen, C 2 -C 12 Alkenyl, aryl [optionally C 1 -C 6 Alkyl, nitro, or selected from -CF 3 、-OCF 3 、-SCF 3 、-OCF 2 R', -OCF(R') 2 、-SCF 2 R' and -SCF(R') 2 substituted with a fluorinated group, wherein each R' independently represents hydrogen, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl or C 3 -C 6 Cycloalkyl], -S(O) 2 -R 8and -C(O)-R 9 , where R 8 and R 9 are independently optionally C 1 -C 6 Alkyl, nitro, or selected from -CF 3 、-OCF 3 、-SCF 3 、-OCF 2 R', -OCF(R') 2 、-SCF 2 R' and -SCF(R') 2 A fluorinated aromatic group substituted with a fluorinated group, wherein each R' independently represents hydrogen, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl or C 3 -C 6 Cycloalkyl,

[0035] Or alternatively R 1 and R 2 together with the atoms to which they are attached form a piperidine or piperazine optionally substituted with an aryl or acetyl group,

[0036] -R 3 and R 4 is hydrogen, and

[0037] -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 which are hydrogen).

[0038] In another specific embodiment, the aminoalkene or alkyne is an aminoalkyne of formula (Ib):

[0039]

[0040] in:

[0041] R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, halogen, C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C12 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 , where R 8 and R 9 Independently selected from C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, C 1 -C 12 Heteroalkyl, C 3 -C 12 Cycloalkyl, C 2 -C 12 Heterocycloalkyl, aryl and heteroaryl,

[0042] The alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted, or

[0043] Each selected from R 1 , R 2 , R 3 , R 4 and R 5 The two groups of may alternatively be taken together with the atoms to which they are attached to form an optionally substituted 3 to 12-membered ring.

[0044] In particular, aminoolefins of formula (Ib) allow:

[0045] -R 1 and R 2 are independently selected from hydrogen, C 2 -C 12 Alkenyl, aryl [optionally C 1 -C 6 Alkyl, nitro, or selected from -CF 3 、-OCF 3 、-SCF 3 、-OCF 2 R', -OCF(R') 2 、-SCF 2 R' and -SCF(R') 2 substituted with a fluorinated group, wherein each R' independently represents hydrogen, halogen, C 1 -C 6Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl or C 3 -C 6 Cycloalkyl], -S(O) 2 -R 8 and -C(O)-R 9 , where R 8 and R 9 are independently optionally C 1 -C 6 Alkyl, nitro, or selected from -CF 3 、-OCF 3 、-SCF 3 、-OCF 2 R', -OCF(R') 2 、-SCF 2 R' and -SCF(R') 2 A fluorinated aromatic group substituted with a fluorinated group, wherein each R' independently represents hydrogen, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl or C 3 -C 6 Cycloalkyl,

[0046] Or alternatively R 1 and R 2 together with the atoms to which they are attached form piperidine or piperazine optionally substituted with aryl or acetyl, and

[0047] -R 3 , R 4 and R 5 For hydrogen.

[0048] In a preferred mode, the aminoalkene or alkyne is selected from:

[0049]

[0050] In one embodiment, the aminoalkene or alkyne is selected from:

[0051]

[0052] The invention also relates to an apparatus for carrying out the process as defined in the present patent application, characterised in that the apparatus comprises:

[0053] - a storage unit (1) for a first phase comprising an aminoolefin or an alkyne,

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

[0055] - a first phase continuous feeding device (3) connected to the first phase storage unit (1) and the first phase balancing tubular pipe (4),

[0056] - a second phase continuous feeding device (3') connected to the second phase storage unit (1') and the second phase balancing tubular pipe (4'),

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

[0058] wherein the first phase balancing tubular tube (4) is connected to a first inlet of the micromixer (21), and the second phase balancing tubular tube (4') is connected to a second inlet of the micromixer (21), and

[0059] - A collecting unit (5) connected to the outlet of the tubular tube (22) of the microreactor (2).

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

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

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

[0063] Preferably, the device further comprises:

[0064] - a three-way valve (6) providing a connection between the first phase continuous feeding device (3), the first phase storage unit (1) and the first phase balancing tubular pipe (4), and / or

[0065] - A three-way valve (6') providing connection between the second phase continuous feeding device (3'), the second phase storage unit (1') and the second phase balancing tubular pipe (4'). BRIEF DESCRIPTION OF THE DRAWINGS

[0066] Figure 1 is a diagram illustrating a process according to one embodiment of the present invention, and certain schematic apparatus for carrying out such a process.

[0067] Figure 2 A diagram illustrating a process according to one embodiment of the present invention, and a specific schematic apparatus for carrying out such a process, which also includes a washing unit. DETAILED DESCRIPTION

[0068] definition

[0069] Unless otherwise stated, when the expression "between" is used to express a range, the limit values ​​are included in the range.

[0070] The term "alkyl" means a group based on a saturated, linear or branched aliphatic hydrocarbon. 1 -C 12 "Alkyl" is an alkyl group containing 1 to 12 carbon atoms. Alkyl (or C 1 -C 12 Examples of C alkyl) are in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl. Preferably, C 1 -C 12 Alkyl is C 1 -C 6 Alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl).

[0071] The term "alkenyl" means a linear or branched unsaturated aliphatic hydrocarbon-based group containing at least one carbon-carbon double bond. 2 -C 12 "Alkenyl" is an alkenyl group containing 2 to 12 carbon atoms. Alkenyl (or C 2 -C 12 Examples of alkenyl) are in particular ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl or dodecenyl. Preferably, C 2 -C 12 Alkenyl is C 2 -C 6 Alkenyl (for example, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl or hexenyl).

[0072] The term "alkynyl" means a linear or branched unsaturated aliphatic hydrocarbon-based group containing at least one carbon-carbon triple bond. 2 -C 12 "Alkynyl" is an alkynyl group containing 2 to 12 carbon atoms. Alkynyl (or C 2 -C 12 Examples of C alkynyl) are in particular ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl or dodecynyl. Preferably, C 2 -C 12 Alkynyl is C 2 -C 6 Alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl or hexynyl).

[0073] The term "heteroalkyl" means an alkyl group as defined above, wherein the carbon chain comprises at least one heteroatom at one and / or the other of its termini (in particular the termini connected to the rest of the molecule) and / or is interrupted by at least one heteroatom, such as O, N, P, Se or S. Examples of heteroalkyl groups are in particular alkoxy (-O-alkyl), alkylthio (-S-alkyl), alkylamino (-NH(alkyl) or -N(alkyl) 2 )、Organophosphorus (-P(O)(alkyl) 2 ) and organic selenium (-Se(alkyl) 2 or -Se(O)(alkyl)NR or -Se(O)(alkyl) 2 ). “C 1 -C 12 "Heteroalkyl" is a heteroalkyl group containing 1 to 12 carbon atoms. Preferably, C 1 -C 12 Heteroalkyl is C 1 -C 6 Heteroalkyl.

[0074] Examples of heteroalkyl groups (or C 1 -C 12 or C 1 -C 6 heteroalkyl) is particularly methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, 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.

[0075] The term "cycloalkyl" means a radical based on an optionally unsaturated (preferably saturated) aliphatic monocyclic or polycyclic hydrocarbon, which may be fused, bridged and / or spiro-connected. 3 -C 12 "Cycloalkyl" is a cycloalkyl radical containing 3 to 12 carbon atoms. 3 -C 12 or C 3 -C 6 Examples of cycloalkyl are in particular cyclopropyl, cyclopentyl or cyclohexyl.

[0076] The term "heterocycloalkyl" means a cycloalkyl group as defined above, which further comprises at least one heteroatom, such as N, S, P, Se or O. 2 -C 12 "Heterocycloalkyl" is a cycloalkyl group containing 2 to 12 carbon atoms and at least one heteroatom. Preferably, C 2 -C 12 The heterocycloalkyl group is preferably C 2 -C 6 Heterocycloalkyl. Examples of heterocycloalkyl are in particular: 3-dioxolane, benzo-[1,3]-dioxolyl, azetidinyl, oxetanyl, pyrazolinyl, pyranyl, thiomorpholinyl, pyrazolidinyl, piperidinyl, 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 tetrahydrothienyl.

[0077] The term "aryl" means a monocyclic or polycyclic aromatic carbocyclic group, preferably containing 6 to 20 ring members. Examples of aryl are phenyl, biphenyl and naphthyl, preferably phenyl. Aryl, especially phenyl, is optionally substituted, for example, by one or more (preferably only one) substituents selected from the following: C 1 -C 6 Alkyl (e.g. methyl), -NO 2 , -CF 3 and other fluorinated substituents, such as -OCF 3 、-SCF 3 、-OCF 2 R', -OCF(R') 2 、-SCF 2 R' or -SCF(R') 2 , wherein each R' independently represents hydrogen, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl or C 3 -C 6 Preferably, the aryl group is unsubstituted or substituted by one or more (preferably only one) selected from C 1 -C 6 Alkyl (e.g. methyl), -NO 2 and -CF 3 The group is substituted.

[0078] The term "heteroaryl" means an aromatic monocyclic or polycyclic group preferably containing 5 to 20 carbon atoms and further containing at least one heteroatom such as N, O, P, Se or S. Examples of heteroaryl are in particular: pyridyl, thiazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, benzofuryl, thianaphthalenyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, triazinyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, indazolyl, purinyl, quinazolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthroline, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, hydroxyindolyl, benzoxazolinyl, benzothienyl, benzothiazolyl, isatinyl, dihydropyridyl, pyrimidinyl, s-triazinyl, oxazolyl, arylphosphine, indole, indoline, phosphindoline, or thiolanyl.

[0079] The term "halogen" means chlorine, fluorine, bromine or iodine. Preferably, the halogen is chlorine or fluorine, more preferably chlorine.

[0080] The alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl as defined in this patent application are optionally substituted. The term "optionally substituted" means unsubstituted or substituted by one or more (e.g., one, two, three or four, preferably one or two, more preferably only one) substituents.

[0081] Examples of substituents are in particular trifluoromethyl (-CF 3 ) and other fluorine-containing substituents (e.g., -OCF 3 , -SCF 3 , -OCF 2 R’, -OCF(R’) 2 , -SCF 2 R’ or -SCF(R’) 2 , where each R’ independently represents hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C6 Alkynyl or C 3 -C 6 Cycloalkyl), nitro (-NO 2 ), cyano (-CN), -SO 3 H, -OH, -SH, -NH 2 , -COOH, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Heteroalkyl, C 3 -C 6 Cycloalkyl, C 2 -C 6 Heterocycloalkyl, aryl, heteroaryl, -S(O) 2 -R and -C(O)-R, wherein R is independently selected from C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Heteroalkyl, C 3 -C 6 Cycloalkyl, C 2 -C 6 Heterocycloalkyl, aryl and heteroaryl.

[0082] In this patent application, the abbreviation "Ac" means "acetyl" (i.e., -C(O)-CH 3 ).

[0083] The process according to the present invention is the process of condensation and / or cyclization of substrate, and the substrate is aminoolefin or alkyne.The substrate is placed in contact with superacid reagent to allow one or more fluorine atoms (generally one or two, and more particularly only one) to be incorporated into the substrate, and / or to form a ring by the intramolecular cyclization of the substrate. Usually, the process according to the present invention allows one or another of the fluorination and cyclization of the aminoolefin or alkyne. In a specific mode, the fluorination reaction is hydrofluorination, which includes the incorporation of one or more fluorine atoms and one or more hydrogen atoms.

[0084] The process according to the invention comprises a step (a) which involves providing a first phase comprising an amino olefin or an alkyne, and providing a second phase comprising a super acid reagent.

[0085] In a specific embodiment, the aminoalkene or alkyne is an aminoalkene.

[0086] The term "aminoolefin" means an organic compound containing at least one olefin functional group and at least one amine functional group. The term "olefin" means an organic compound containing at least one olefin functional group, i.e., at least one carbon-carbon double bond. The term "amine functional group" means a functional group as follows:

[0087]

[0088] where

[0089]

[0090] represents a bond to the rest of the molecule. The olefin and amine functional groups can each independently be cyclic (i.e., included in a ring, such as a cycloolefin or piperidine, or directly attached to a ring, such as an exocyclic olefin or cycloalkylamine) or acyclic. The aminoolefin can be aromatic or aliphatic. Preferably, the aminoolefin contains 2 to 60 carbon atoms and / or has a molecular weight between 50 and 1000 g / mol. Needless to say, the aminoolefin can also contain groups or functional groups other than the olefin functional group and the amine functional group, such as 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, -CF 3 and other fluorine-containing substituents (such as -OCF 3 、-SCF 3 、-OCF 2 R’, -OCF(R’) 2 、-SCF 2 R’ or -SCF(R’) 2 where each R’ independently represents hydrogen, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl), -NO 2 、-CN、-SO 3 H, -OH, -SH, -COOH, but this list is not restrictive. In particular, the amine functional group can be adjacent to other chemical groups or functional groups, such as -C(O)- or -S(O)2 -group, so that the whole constitutes an amide or a sulfonamide, respectively.

[0091] In a specific embodiment, the aminoolefin is allylamine.The term "allylamine" means a compound in which the amine functional group is separated from the olefin functional group by a carbon atom.

[0092] In a more specific embodiment, the aminoolefin is a compound of formula (Ia):

[0093]

[0094] in:

[0095] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, halogen, C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, C 1 -C 12 Heteroalkyl, C 3 -C 12 Cycloalkyl, C 2 -C 12 Heterocycloalkyl, aryl, heteroaryl, group -S(O) 2 -R 8 and the group -C(O)-R 9 , where R 8 and R 9 Independently selected from C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, C 1 -C 12 Heteroalkyl, C 3 -C 12 Cycloalkyl, C 2 -C 12 Heterocycloalkyl, aryl and heteroaryl,

[0096] The alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted, or

[0097] Each selected from R 1 , R 2, R 3 , R 4 and R 5 Two groups (such as R 1 and R 2 ) may alternatively be taken together with the atoms to which they are attached to form an optionally substituted 3 to 12-membered ring.

[0098] The compound of formula (Ia) is preferably such that:

[0099] -R 3 and R 4 is hydrogen, and

[0100] -R 5 , R 6 and R 7 independently selected from hydrogen and halogen (preferably R 5 , R 6 and R 7 At least two of the halogens are hydrogen). The preferred halogen is chlorine.

[0101] In a particular mode, the compound of formula (Ia) is such that R 1 and R 2 Together with the atoms to which they are attached they 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 a pattern, the ring may be substituted, for example, by an optionally substituted aryl or acetyl group.

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

[0103] -R 1 is hydrogen, and

[0104] -R 2 is optionally substituted aryl.

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

[0106] -R 1 is hydrogen, and

[0107] -R 2 -S(O) 2 -R 8 , where R 8 is an optionally substituted aryl group.

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

[0109] -R 1 -CH 2 -CH=CH 2group, and

[0110] -R 2 -C(O)-R 9 , where R 9 is an optionally substituted aryl group.

[0111] In the above embodiments, the optionally substituted aryl group may be substituted, for example, by one or more (preferably only one) groups selected from the following: 1 -C 6 Alkyl (e.g. methyl), -NO 2 , -CF 3 and other fluorinated substituents such as -OCF 3 、-SCF 3 、-OCF 2 R', -OCF(R') 2 、-SCF 2 R', or -SCF(R') 2 , wherein each R' independently represents hydrogen, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl or C 3 -C 6 Preferably, the aryl group is unsubstituted or substituted by one or more (preferably only one) selected from C 1 -C 6 Alkyl (e.g. methyl), -NO 2 and -CF 3 The group is substituted.

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

[0113] -R 1 and R 2 are independently selected from hydrogen, C 2 -C 12 Alkenyl, aryl [optionally C 1 -C 6 Alkyl, nitro, or selected from -CF 3 、-OCF 3 、-SCF 3 、-OCF 2 R', -OCF(R') 2 、-SCF 2 R' and -SCF(R') 2 substituted with a fluorinated group, wherein each R' independently represents hydrogen, halogen, C 1 -C 6 Alkyl, C2 -C 6 Alkenyl, C 2 -C 6 Alkynyl or C 3 -C 6 Cycloalkyl], -S(O) 2 -R 8 and -C(O)-R 9 , where R 8 and R 9 independently is optionally C 1 -C 6 Alkyl, nitro, or selected from -CF 3 、-OCF 3 、-SCF 3 、-OCF 2 R', -OCF(R') 2 、-SCF 2 R' and -SCF(R') 2 A fluorinated aromatic group substituted with a fluorinated group, wherein each R' independently represents hydrogen, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl or C 3 -C 6 Cycloalkyl,

[0114] Or alternatively, R 1 and R 2 together with the atoms to which they are attached form a piperidine or piperazine optionally substituted with an aryl or acetyl group,

[0115] -R 3 and R 4 is hydrogen, and

[0116] -R 5 , R 6 and R 7 independently selected from hydrogen and halogen (preferably R 5 , R 6 and R 7 at least two of which are hydrogen).

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

[0118] -R 1 and R 2 are independently selected from hydrogen, C 2 -C 12 Alkenyl, optionally C 1 -C 6 Alkyl, nitro or -CF3 Substituted aryl, -S(O) 2 -R 8 and -C(O)-R 9 , where R 8 and R 9 independently is optionally C 1 -C 6 alkyl, nitro or trifluoromethyl substituted aryl,

[0119] Or alternatively, R 1 and R 2 together with the atoms to which they are attached form a piperidine or piperazine optionally substituted with an aryl or acetyl group,

[0120] -R 3 and R 4 is hydrogen, and

[0121] -R 5 , R 6 and R 7 independently selected from hydrogen and halogen (preferably R 5 , R 6 and R 7 at least two of which are hydrogen).

[0122] In a preferred embodiment, the aminoolefin is selected from the following compounds:

[0123]

[0124] In another preferred embodiment, the aminoolefin is vinorelbine (vinorelbine), which can be represented as follows:

[0125]

[0126] In another specific embodiment, the aminoalkene or aminoalkyne is an aminoalkyne.

[0127] The term "aminoalkyne" means an organic compound containing at least one alkyne functional group and at least one amine functional group. The term "alkyne" means an organic compound containing at least one alkyne functional group, i.e. at least one carbon-carbon triple bond. The alkyne and amine functional groups may each independently be cyclic (i.e. included in a ring, such as endocyclic alkynes or piperidines, or directly attached to a ring, such as cycloalkylamines) 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 also contain groups or functional groups other than the alkyne functional group and the amine functional group, such as halogens, C 1 -C 12 Alkyl, C2 -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, -CF 3 and other fluorine-containing groups (selected from -OCF 3 、-SCF 3 、-OCF 2 R', -OCF(R') 2 、-SCF 2 R' or -SCF(R') 2 , wherein each R' independently represents hydrogen, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl or C 3 -C 6 Cycloalkyl), -NO 2 、-CN、-SO 3 H, -OH, -SH, -COOH, this list is not limiting. In particular, the amine functional group can be combined with other groups such as -C(O)- or -S(O) 2 - groups are adjacent so that the whole constitutes an amide or a sulfonamide, respectively.

[0128] In a specific embodiment, the aminoalkyne is propargylamine.The term "propargylamine" means a compound wherein an amine functional group is separated from an alkyne functional group by a carbon atom.

[0129] In another more specific embodiment, the aminoalkyne is a compound of formula (Ib):

[0130]

[0131] in:

[0132] R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, halogen, C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, C1 -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 , where R 8 and R 9 Independently selected from C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, C 1 -C 12 Heteroalkyl, C 3 -C 12 Cycloalkyl, C 2 -C 12 Heterocycloalkyl, aryl and heteroaryl,

[0133] The alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted, or

[0134] Each selected from R 1 , R 2 , R 3 , R 4 and R 5 Two groups (such as R 1 and R 2 ) may alternatively be taken together with the atoms to which they are attached to form an optionally substituted 3 to 12-membered ring.

[0135] The compound of formula (Ib) is preferably such that R 3 , R 4 and R 5 For hydrogen.

[0136] In a particular mode, R 1 and R 2 Together with the atoms to which they are attached they 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 a pattern, the ring may be substituted, for example, by an optionally substituted aryl or acetyl group.

[0137] According to another specific embodiment, the compound of formula (Ib) is such that:

[0138] -R 1 and R 2 are independently selected from hydrogen, C 2-C 12 Alkenyl, aryl [optionally C 1 -C 6 Alkyl, nitro or selected from -CF 3 、-OCF 3 、-SCF 3 、-OCF 2 R', -OCF(R') 2 、-SCF 2 R' and -SCF(R') 2 substituted with a fluorinated group, wherein each R' independently represents hydrogen, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl or C 3 -C 6 Cycloalkyl], -S(O) 2 -R 8 and -C(O)-R 9 , where R 8 and R 9 are independently optionally C 1 -C 6 Alkyl, nitro or selected from -CF 3 、-OCF 3 、-SCF 3 、-OCF 2 R', -OCF(R') 2 、-SCF 2 R' and -SCF(R') 2 A fluorinated aromatic group substituted with a fluorinated group, wherein each R' independently represents hydrogen, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl or C 3 -C 6 Cycloalkyl,

[0139] Or alternatively, R 1 and R 2 together with the atoms to which they are attached form piperidine or piperazine optionally substituted with aryl or acetyl, and

[0140] -R 3 , R 4 and R 5 For hydrogen.

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

[0142] -R 1 and R 2 are independently selected from hydrogen, C 2 -C 12 Alkenyl, aryl [optionally C 1 -C 6 Alkyl, nitro or -CF 3 Substitution], -S(O) 2 -R 8 and -C(O)-R 9 , where R 8 and R 9 independently is optionally C 1 -C 6 alkyl, nitro or trifluoromethyl substituted aryl,

[0143] Or alternatively, R 1 and R 2 together with the atoms to which they are attached form piperidine or piperazine optionally substituted with aryl or acetyl, and

[0144] -R 3 , R 4 and R 5 For hydrogen.

[0145] In a preferred embodiment, the aminoalkyne is selected from the following compounds:

[0146]

[0147] In another embodiment, the aminoalkyne is selected from the following compounds:

[0148]

[0149] The term "superacid" refers to the Hammett acidity value or acidity function H 0 A reagent with a value less than -12, preferably less than or equal to -14. Various techniques allow the determination of the Hammett constant H 0 , in particular using weak bases by spectroscopic (NMR), kinetic, thermodynamic or molecular simulation methods (Hammett LP, Deyrup AJ, J. Am. Chem. Soc., 1932, 54(7), 2721-2739; Superacid chemistry, 2nd edition, Olah GA, Prakash GKS, Molnar A., ​​Sommer J., published by John Wiley & Sons, Inc., Hoboken, New Jersey, 2009, 1-10).

[0150] The superacid reagent may consist of one acid, which is advantageously fluorinated, or a mixture of acids, at least one of which is advantageously fluorinated. Superacids are described in particular in the following literature: 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; Ramírez-Solís, A.; Mota, CJ A Am. Chem. Soc. 2002, 124 (11), 2672-2677; Superacid Chemistry, 2nd Edition, Olah G. A., Prakash GKS, Molnar A., ​​Sommer J., published by John Wiley & Sons, Inc., Hoboken, New Jersey, 2009).

[0151] The superacid reagent may in particular be a Lewis superacid (e.g. SbF 5 , AsF 5 PF 5 、TaF 5 ), proton or Bronsted superacids (e.g. HF, CF 3 SO 3 H、(CF 3 SO 2 ) 2 NH, HSO 3 F), or a combination thereof (e.g. HF / SbF 5 , HSO 3 F / AsF 5 , H 2 SO 4 / SO 3 、HCl / AlCl 3 ).

[0152] Examples of super acids and their acidity constants are provided below:

[0153] -Fluorosulfate HSO 3 F, H 0 =-15.1;

[0154] -Trifluoromethanesulfonic acid CF 3 SO 3 H,H 0 =-14.1;

[0155] -Hydrofluoric acid HF, H 0=-15.2;

[0156] -HF / SbF 5 Mixture, H 0 =-23 / -24.

[0157] According to a specific embodiment, the superacid reagent is selected from:

[0158] -Selected from HF, CF 3 SO 3 H and HSO 3 The proton of F is super acidic.

[0159] -Form MF 5 Lewis superacids, wherein M is Sb, As, P, Ta or Nb, and

[0160] - a combination of one of the proton super acids and one of the Lewis super acids.

[0161] In a particular mode, the superacid reagent is HF or HSO 3 F.

[0162] In another specific mode, the superacid reagent is selected from:

[0163] -HF / MF 5 , wherein M is Sb, As, P, Ta or Nb; and

[0164] -HSO 3 F / MF 5 , wherein M is Sb, As, P, Ta or Nb.

[0165] Preferably, the superacid reagent is HSO 3 F / Sb 5 or HF / SbF 5 More preferably, the superacid reagent is HF / SbF 5 .

[0166] When the superacid reagent is HF / SbF 5 or HSO 3 F / Sb 5 When SbF 5 The molar percentages are advantageously 5 or HSO 3 F+Sb 5 The molar amount of the mixture is less than or equal to 50%, preferably between 2% and 22%. Needless to say, the value 0% is excluded from the range of "less than or equal to 50%".

[0167] The first phase in step (a) is preferably a liquid. The first phase may in particular consist of the aminoalkene or alkyne, undiluted or in 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 such as methanol, ethanol or isopropanol, a fluorinated alcoholic solvent such as hexafluoropropane-2-ol (HFIP) and its derivatives, or a polyfluorinated or perfluorinated aromatic solvent such as pentafluorobenzene or 1,2,3,4-tetrafluorobenzene.

[0168] Preferably, the solvent is HF. The concentration of the aminoalkene or alkyne 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.

[0169] The first phase may be stored in a storage unit such as a tank.

[0170] In a particular mode, 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, better still between -50°C and -20°C.

[0171] The second phase in step (a) is preferably a liquid. The second phase advantageously consists of undiluted super acid reagent. The second phase may be stored in a storage unit such as a tank.

[0172] In a specific embodiment, the second phase is kept in the storage unit at a temperature between -70°C and 25°C, preferably between -50°C and 5°C, better still between -50°C and -20°C.

[0173] Step (b) of the process according to the invention comprises placing said first phase and said second phase in contact in a continuous flow microreactor.

[0174] The term "continuous flow microreactor" means a reactor of micrometer or millimeter size that allows continuous flow of one or more fluid phases, preferably liquids. A continuous flow microreactor typically comprises a tubular tube comprising an inlet and an outlet, the internal diameter of which is of micrometer or millimeter size. Obviously, for those skilled in the art of microfluidics, the term "microreactor" means a reactor of micrometer size (more specifically, the size of its internal diameter), but may also be a millimeter size reactor, as long as the millimeter size does not affect the microfluidic properties of the microreactor, in particular with respect to the behavior of the fluid flowing through the microreactor.

[0175] The length of the tubular tube may be in the order of a few cm to several meters.

[0176] The term “micrometer-sized” means sizes between 1 μm and 1000 μm, preferably between 100 μm and 1000 μm, better still between 300 μm and 1000 μm (excluding the value of 1000 μm).

[0177] The term "millimeter size" means a size between 1 mm and 10 mm, preferably between 1 mm and 5 mm.

[0178] In one embodiment, the tubular tube of the continuous flow microreactor has the following dimensions:

[0179] - 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

[0180] An internal diameter of between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm and better still between 0.7 mm and 1.2 mm.

[0181] The outer diameter of the tubular tube 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.

[0182] In a specific embodiment, the tubular tube of the continuous flow microreactor has:

[0183] - an internal diameter between 0.5 mm and 1.5 mm, and

[0184] - preferably an external diameter between 1.0 and 2.0 mm.

[0185] The tubular tube is typically arranged as a serpentine or coil along all or part of its length. However, other arrangements are also contemplated.

[0186] Advantageously, the continuous flow microreactor also includes a micro mixer. The term "micro mixer" means a micrometer or millimeter mixer. The micro mixer advantageously includes two inlets and one outlet, typically making it have a T or Y shape. The internal diameter of the micro mixer has a micrometer or millimeter size, and is advantageously between 0.5mm and 2.5mm, preferably between 0.5mm and 1.5mm, and better between 0.7mm and 1.2mm. In a specific embodiment, the continuous flow microreactor comprises:

[0187] - a micromixer comprising two inlets and one outlet, and

[0188] - a tubular tube comprising an inlet and an outlet,

[0189] wherein the inlet of the tubular tube is connected to the outlet of the micromixer.In such a mode, means for continuously feeding the first phase are connected to the first inlet of the micromixer and means for continuously feeding the second phase are connected to the second inlet of the micromixer.

[0190] The continuous feeding means denotes any element or set of elements allowing the continuous transfer of the first and second phases into the continuous flow microreactor, such as a pump or a syringe possibly associated with a syringe pump.

[0191] Elements are referred to as "connected" when they are connected together directly or possibly by tubular tubes or other equivalent elements, the characteristics (e.g., materials, dimensions such as length and diameter) of which may be judiciously selected by one skilled in the art. For example, the micromixer and tubular tube of the continuous flow microreactor are preferably directly connected.

[0192] The contacting step (b) may comprise transferring the first phase contained in the first phase storage unit to the continuous flow microreactor and in particular to the micromixer of the continuous flow microreactor (even more specifically, to the first inlet of the micromixer) via a device for continuously feeding the first phase, and transferring the second phase contained in the second phase storage unit to the continuous flow microreactor and more specifically to the micromixer of the continuous flow microreactor (even more specifically, to the second inlet of the micromixer) via a device for continuously feeding the second phase.

[0193] The continuous feeding means for the first and second phases may for example be first and second syringes, respectively (possibly associated with a syringe pump), or first and second pumps, respectively.

[0194] In a more specific embodiment, the first phase contained in the first phase storage unit (e.g., tank) is typically sucked by a first syringe or pump, and the second phase contained in the second phase storage unit (e.g., tank) is typically sucked by a second syringe or pump, and the first and second phases are each injected into the continuous flow microreactor and more specifically into the micromixer of the continuous flow microreactor (even more specifically, the first phase is injected into the first inlet of the micromixer and the second phase is injected into the second inlet of the micromixer). A first three-way valve, which is connected to the first phase storage unit, the first syringe or pump and the continuous flow microreactor (particularly, connected to the first inlet of the micromixer of the microreactor), and / or a second three-way valve, which is connected to the second phase storage unit, the second syringe or pump and the continuous flow microreactor (particularly, connected to the second inlet of the micromixer of the microreactor), can be used to facilitate the absorption and injection of the second and second phases. The internal diameter of the three-way valve is micrometer or millimeter size, and can be, for example, between 0.8 mm and 1.6 mm. The first and second phases can be absorbed and injected using a syringe pump or a computer-controlled pump. The temperature of the syringe or pump is generally maintained at a temperature between -70°C and 25°C, preferably between -50°C and 5°C, and more preferably between -50°C and -20°C. The temperature of the storage unit is generally maintained at a temperature between -70°C and 25°C, preferably between -50°C and 5°C, and more preferably between -50°C and -20°C.

[0195] 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. 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.

[0196] The size of the microreactor, particularly the diameter and length of the tubular tube and the flow rate of the first and second phases to the microreactor are regulated to allow control and fixation of the residence time of the first and second phases in the microreactor. In step (b), the residence time of the first and second phases contacted in the microreactor is preferably between 2 seconds and 400 seconds. For example, the residence time can be between 2 seconds and 30 seconds, between 30 seconds and 60 seconds, or between 60 seconds and 400 seconds.

[0197] Placing the first and second phases in contact in the continuous flow microreactor is generally carried out at a temperature between -70°C and 25°C, preferably between -50°C and 5°C, and more preferably between -50°C and -20°C (referred to as the "contact temperature"). When 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 equilibrium step may be performed before placing in contact. The purpose of this equilibrium is to allow the first and / or second phase to reach and stabilize at the contact temperature before placing in contact. Therefore, the first equilibrium tubular tube and / or the second equilibrium tubular tube maintained at the contact temperature can be used for this equilibrium. Preferably, the first equilibrium tube and / or the second equilibrium tube are respectively connected to:

[0198] - between the first phase continuous feeding device and the continuous flow microreactor (more specifically, the micromixer of the continuous flow microreactor, even more specifically the first inlet of the micromixer), and / or

[0199] - between the second phase continuous feeding device and the continuous flow microreactor, more specifically the micromixer of said continuous flow microreactor, even more specifically the second inlet of said micromixer.

[0200] The inner diameter of the balancing tubular tube is in micrometers or millimeters and may be independently between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and more preferably between 0.7 mm and 1.2 mm. The length of the balancing tubular tube may be independently between 25 cm and 100 cm. In particular, this value may be selected to allow effective cooling at a given flow rate. The balancing tubular tube is generally arranged as a serpentine or coil over all or part of its length. However, other arrangements may also be envisioned.

[0201] The first and second phases placed in contact in the microreactor may together form one or more phases, preferably a single substantially liquid phase.

[0202] Step (c) of the process according to the invention comprises collecting (or equivalently, "collecting") the fluorination and / or cyclization product of the aminoolefin or alkyne. The product is collected at the outlet of the continuous flow microreactor (particularly, at the outlet of its tubular tube), which is typically connected to a collection unit, such as a flask. The collected product is generally collected in admixture with reaction byproducts and / or superacid reagent residues. To neutralize the superacid reagent residues, a neutralizing agent may be placed in contact with the mixture collected in the collection unit. The neutralizing agent may be, for example, water, a base such as sodium carbonate, sodium hydroxide, potassium hydroxide or other bases in the form of a resin (e.g., Amberlyst A26 hydroxide form), and optionally a mixture of one or more organic solvents such as acetone, methanol or ammoniacal methanol. The amount of neutralizing agent to be used is adjusted according to the amount of residual superacid reagent.

[0203] Due to the corrosive properties of superacids, the elements used to carry out the process of the invention, such as the continuous flow microreactor (especially the tubular tubes and micromixers it comprises), the balancing tubular tubes, the storage unit, the collecting unit, the syringe and / or the three-way valve, are advantageously made of materials that are resistant to such corrosive properties. Examples of materials that may be mentioned include fluoropolymers such as polytetrafluoroethylene and poly(ethylene-co-butadiene) and some metal alloys such as Nickel alloy. In any case, the skilled person will be able to wisely select the appropriate material for each element of the assembly.

[0204] A further subject matter of the present invention is an apparatus for carrying out the process according to the invention. Figure 1 1 is a diagram illustrating a process according to one embodiment of the present invention and an apparatus that can be used to perform the process.

[0205] The device according to the invention comprises the following elements:

[0206] - a storage unit (1) for a first phase comprising an aminoolefin or an alkyne,

[0207] - a storage unit (1') for a second phase containing a superacid reagent,

[0208] - a continuous flow microreactor (2), preferably comprising a micromixer (21) and a tubular tube (22),

[0209] - means for continuous feeding of the first phase (3),

[0210] - means for continuous feeding of the second phase (3'),

[0211] - a balancing tubular tube (4) for the first phase,

[0212] - a balancing tubular tube (4') for the second phase, and

[0213] - Collection unit (5).

[0214] More specifically, the device according to the present invention comprises:

[0215] - a storage unit (1) for a first phase comprising an aminoolefin or an alkyne,

[0216] - a storage unit (1') for a second phase containing a superacid reagent,

[0217] - a first phase continuous feeding device (3) connected to the first phase storage unit (1) and the first phase balancing tubular pipe (4),

[0218] - a second phase continuous feeding device (3') connected to the second phase storage unit (1') and the second phase balancing tubular pipe (4'),

[0219] - a continuous flow microreactor (2) comprising a micromixer (21) comprising two inlets and one outlet, and a tubular tube (22) comprising one inlet and one outlet, wherein the inlet of the tubular tube (22) is connected to the outlet of the micromixer (21),

[0220] wherein the first phase balancing tubular tube (4) is connected to a first inlet of the micromixer (21), and the second phase balancing tubular tube (4') is connected to a second inlet of the micromixer (21), and

[0221] - A collecting unit (5) connected to the outlet of the tubular tube (22) of the microreactor (2).

[0222] The connection between the first phase continuous feeding device (3), the first phase storage unit (1) and the first phase balancing tubular pipe (4) can be provided by a three-way valve (6). The connection between the second phase continuous feeding device (3'), the second phase storage unit (1') and the second phase balancing tubular pipe (4') can be provided by a three-way valve (6'). Valves (6) and (6') can be computer controlled.

[0223] In a particular embodiment, the apparatus according to the invention further comprises one or more washing units comprising a washing solvent. Figure 2 A diagram showing a process according to an embodiment of the present invention and an apparatus that can be used to carry out the process, the apparatus further comprising a washing unit. A first washing unit (7) and a second washing unit (7') can be connected to a first phase continuous feed device (3) and a second phase continuous feed device (3') respectively, so that a washing solvent can circulate in the continuous flow microreactor. A three-way valve (8, 8') can be used to alternately carry out the injection of the first and second phases and the injection of the washing solvent. Such three-way valves are installed so that they connect:

[0224] - on the one hand, a first phase storage unit (1), a first washing unit (7) and a first phase continuous feeding device (3) (or a three-way valve (6)), and

[0225] - On the other hand, the second phase storage unit (1'), the second washing unit (7') and the second phase continuous feeding device (3') (or the three-way valve (6')).

[0226] A waste collection unit (9) may be used to collect the washing solvent after circulating through the apparatus. A three-way valve (10) may be used to connect the outlet of the tubular tube (22) with the collection unit (5) and the waste collection unit (9).

[0227] The washing solvent may in particular be water, optionally containing a base (e.g. sodium carbonate, sodium hydroxide or potassium hydroxide) and / or one or more suitable organic solvents such as acetone. In a specific embodiment, a plurality of successive washing solvents such as water, followed by an alkaline aqueous solution, and then acetone are used.

[0228] The three-way valves described in this patent application (eg valves (6), (6'), (8) and (8')) may be, for example, manual or automatic switching valves. The automatic switching three-way valves may be computer controlled.

[0229] In a specific embodiment, the tubular tube (22) of the continuous flow microreactor (2) has the following dimensions:

[0230] - 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

[0231] An internal diameter of between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm and better still between 0.7 mm and 1.2 mm.

[0232] The outer diameter of the tubular tube (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.

[0233] In a specific embodiment, the tubular tube (22) of the continuous flow microreactor (2) has:

[0234] - an internal diameter between 0.5 mm and 1.5 mm, and

[0235] - Preferably, an external diameter between 1.0 and 2.0 mm.

[0236] The tubular tube (22) is typically arranged as a serpentine or coil along all or part of its length. However, other arrangements are contemplated.

[0237] The micromixer (21) is typically T-shaped or Y-shaped. The internal diameter of the micromixer (21) is in micrometer or millimeter dimensions and is advantageously between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm and better still between 0.7 mm and 1.2 mm.

[0238] The continuous feeding means (3, 3') represent any element or group of elements allowing the continuous transfer of the first and / or second phase into the continuous flow microreactor (2), preferably a pump or a syringe possibly associated with a syringe pump.

[0239] The inner diameter of the balancing tubular tubes (4, 4') is in micrometer or millimeter dimensions and may independently be between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm, and better still between 0.7 mm and 1.2 mm. The length of the balancing tubular tubes (4, 4') may independently be between 25 cm and 100 cm. The balancing tubular tubes (4, 4') are generally arranged in a serpentine or coiled configuration over all or part of their length. However, other arrangements are conceivable.

[0240] The invention will be better understood from the following examples, which are given by way of illustration only and are not intended to limit the scope of the invention as defined by the appended claims.

[0241] Example

[0242] Example 1: Fluorination and / or cyclization of aminoolefins or alkynes according to the process of the present invention

[0243] The process for fluorination and / or cyclization of aminoalkenes or alkynes proceeds via the general procedure described below:

[0244] This equipment comprises two pumps or syringe pumps, and it is equipped with two high pressure metal syringes that are connected to automatic valve separately.These syringes are connected to fluid tank via metal tube.Syringe cools by the chamber cooling containing dry ice, thereby allows the liquid in syringe to cool by heat conduction.The parts contacting with super acid mixture have been designed and adapted to corrosive media by selecting the material compatible with the medium of this type (i.e. the inside of syringe, the inside of three-way valve, the metal connector pipe (internal diameter 1mm, external diameter 1.6mm) for conveying fluid).

[0245] Fluid 1 (HF / SbF 5 Super acid) and 2 (dissolved substrate) were placed separately in tanks immersed in a cold bath (acetone / water, T = -35 °C) and connected to the system via tubing (inner diameter = 0.8 mm, outer diameter = 1.6 mm).

[0246] The three-way valve module is a motorized ball valve that allows the fluid channel to be opened, closed or switched. Therefore, once the syringe has been filled with fluids 1 and 2, the contact placement of the fluids can be automatically initiated via software, which controls the distribution of small volumes V of each fluid at given rates F1 and F2. Therefore, controlling the pump and valve limits the operator's contact with the super acid during the reaction. The fluid is then transported to a T-shaped mixer (internal diameter 1 mm) via a balancing loop, the length of which is determined to reach the desired reaction temperature (here, L = 50 cm, V = 0.25 mL), which itself is connected to a tube of variable length L (internal diameter 0.8 mm, external diameter 1.6 mm), allowing the residence time (t R ). The collection is manually checked 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 filtered over MgSO 4 The crude residue was purified by silica gel chromatography and then by 1 H. 13 C and 19 F NMR analysis and comparison with results previously obtained in the laboratory. The compounds were characterized by one or more of the following techniques: 1 H. 13 C and 19 F NMR, HSQC, HMBC, HRMS.

[0247] A wash tank (alkali / water, then acetone / water, then acetone) was also connected to a manual valve, allowing washing at the end of the experiment.

[0248]

[0249] 1-(4-(2-Fluoropropyl)piperazin-1-yl)ethanone 1a was prepared by immersing the mixture in a bath maintained at -20°C for a length of L = 47 cm (t R =8.2s) was obtained by following the general flow procedure. Adjust the HF in 1:1 HF / SbF 5 Super acid mixture (F 1 =1 mL / min) and 1-(4-allylpiperazin-1-yl)ethan-1-one substrate 1 (F 2 =1 mL / min, c = 0.5 mol / L), producing 8.3 mol% SbF 5 The final acidity was 1.00477 g. The reaction mixture was collected for 1 minute (0.43 mmol, 73 mg). The residue was purified by silica gel chromatography (98 / 2 CH 2 Cl 2 / MeOH) allowed to obtain 61.2 mg of product 1a (75%).

[0250] 1 H NMR (400 MHz, CDCl 3 ,ppm)δ:1.42(dd,CH 3 ,J=23.8Hz,J=6.3Hz),3.28(m,CH 2 ), 3.98 (bs, NH). 4.89 (dm, CH, J = 49.4Hz), 6.64 (dd, 2CH, J = 8.5Hz, J = 0.9Hz), 6.74 (t, CH, J = 7.3Hz), 7.19 (dd, 2CH, J = 8.4Hz, J = 7.4Hz). 13 C NMR (100 MHz, CDCl 3 ,ppm)δ:18.8(d,CH 3 ,=22Hz),49.6(d,CH 2 ,J=21Hz),89.6(d,CH,J=167Hz),113.1(2CH),118.1(1CH),129.4(2CH),147.9. 19 F{ 1 H}NMR (CDCl 3 ,376MHz,ppm)δ:-180.0.

[0251]

[0252] 4,6-Dimethyl-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide 2a was prepared by immersing the mixture in a bath maintained at -20°C for a length of L = 130 cm (t R =52.3s) was obtained by following the general flow procedure. 5 Super acid mixture (F 1 =0.25 mL / min) and N-allyl-4-methylbenzenesulfonamide substrate 2 in HF (c = 0.5 mol / L) 2 = 0.5 mL, yielding 5.1 mol% SbF 5 The final acidity was 0.887 mmol, 187.8 mg. The reaction mixture was collected for 2 minutes (0.887 mmol, 187.8 mg). The residue was purified by silica gel chromatography (98 / 2 CH 2 Cl 2 / MeOH) allowed to obtain 171.2 mg of product 2a (76%).

[0253] 1 H NMR (400 MHz, CDCl 3,ppm)δ:1.34(d,J=7.2Hz,3H),2.37(s,3H),2.98(m,1H),3.41(m,1H),3.82(m,1H) ,4.89(t,J=7.7Hz,1H),7.09(s,1H),7.14(d,J=8.1Hz,1H),7.62(d,J=8.1Hz,1H). 13 C NMR (100 MHz, CDCl 3 ,ppm)δ:19.5(CH 3 ),21.6(CH 3 ),31.5(CH),48.2(CH 2 ),124.0(CH),128.2(CH),129.0,134.2,140.2,142.7.

[0254]

[0255] N-(2-Fluoropropyl)-4-methylbenzenesulfonamide 2b was prepared by immersing the mixture in a bath maintained at -20°C with a length L = 78.2 cm (t R =9.2s) was obtained according to the general flow procedure. Adjust 1:1v / vHF / SbF 5 Super acid mixture (F 1 =1 mL / min) and N-allyl-4-methylbenzenesulfonamide substrate 2 (F 2 =2mL / min, c=1mol / L) in HF, yielding 1.9mol% SbF 5 The final acidity was 0.852 mmol, 180 mg. The reaction mixture was collected for 30 seconds (0.852 mmol, 180 mg). The residue was purified by silica gel chromatography (98 / 2 CH 2 Cl 2 / MeOH) allowed to obtain 147.7 mg of product 2b (75%).

[0256] 1 H NMR (400 MHz, CDCl 3 ,ppm)δ:1.32(dd,J=23.8,6.3Hz,3H,CH 3 ),2.46(s,3H,CH 3 ),3.03(dddd,J=18.4,13.8,7.6,4.8Hz,1H),3.23(dddd,J=28.4,13.7,8.1,2.9Hz,1H),4.84–4.62(dm,J H-F=45Hz, 1H), 4.84 (s, 1H), 7.35 (d, J = 8Hz, 2H), 7.77 (d, J = 8.3Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ,ppm)δ:143.8(Cq),136.94(Cq),129.9(2CH),127.16(2CH),89.3(d,J=167.6Hz),48.3(CH 2 ,d,J=21.0Hz),21.7(CH 3 ),18.2(CH 3 ,d,J=21.8Hz). 19 F{ 1 H}NMR CDCl 3 ,376MHz,ppm)δ:-180.2.HRMS(ESI):calculated value for C10H14FNO2S:231.0729; found value:232.080241[M+H] + and 254.062169[M+Na] + .

[0257]

[0258] N-(2-Fluoropropyl)-4-nitrobenzenesulfonamide 3b was prepared by immersing the mixture in a bath maintained at -20°C with a length L = 78.2 cm (t R =13.6s) was obtained according to the general flow procedure. Adjust 1:1v / vHF / SbF 5 Super acid mixture (F 1 =1 mL / min) and N-allyl-4-nitrobenzenesulfonamide substrate 3 (F 2 =1 mL / min, c = 1 mol / L) in HF, yielding 8.4 mol% SbF 5 The final acidity was 1.004. The reaction mixture was collected for 1 minute (0.867 mmol, 120 mg). The residue was purified by silica gel chromatography (98 / 2 CH 2 Cl 2 / MeOH) allowed to obtain 190 mg of product 3b (84%).

[0259] 1 H NMR (400 MHz, CDCl 3, 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, CDCl 3 , ppm) δ: 18.0 (d, J = 22 Hz, CH 3 ), 48.2 (d, J = 21 Hz, CH 2 ), 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 (CDCl 3 , 376 MHz, ppm) δ: -180.2.

[0260]

[0261] N-(2-Fluoropropyl)-4-(trifluoromethyl)benzenesulfonamide 4b was obtained according to the general flow procedure using a tubular reactor with a length L = 78.2 cm (t R = 35.7 s) immersed in a bath maintained at -20 °C. The flow rates of the 1:1 v / v HF / SbF 5 superacid mixture (F 1 = 0.25 mL / min) and the N-allyl-4-trifluorobenzenesulfonamide substrate 4 (F 2 = 0.5 mL / min, c = 0.49 mol / L) in HF were adjusted to produce a final acidity of 5.2 mol% SbF 5 . The reaction mixture was collected for 2 minutes (using 0.398 mmol, 105.6 mg). Purification by silica gel chromatography (98 / 2 CH 2 Cl 2 / MeOH) allowed the obtention of 90.8 mg of the product 4b (80%).

[0262] No traces of the cyclized product 4a were observed under the conditions studied.

[0263] 1 H NMR (400 MHz, CDCl 3,ppm)δ:1.29(dt,J=23.8,6.3Hz,3H),3.34–2.97(m,2H),4.71(dm,J=49Hz,1H),5.24(brs,NH),7.78(d,J=8.3Hz,2H),8.00(d,J=8.2Hz,2H). 19 F{ 1 H}NMR (CDCl 3 ,376MHz,ppm)δ:-179.8.

[0264]

[0265] 1-(4-(2-chloro-2-fluoropropyl)piperazin-1-yl)ethan-1-one 5a was prepared by immersing the mixture in a bath maintained at -20°C with a length L = 200 cm (t R =60.3s) was obtained according to the general flow procedure. Adjust 1:1 v / v HF / SbF 5 Super acid mixture (F 1 =0.5 mL / min) and 1-(4-(2-chloroallyl)piperazin-1-yl)ethan-1-one substrate 5 (F 2 =0.5 mL / min, c = 0.5 mol / L) in HF, yielding 6.4 mol% SbF 5 The final acidity was 0.499 mmol, 111.1 mg. The reaction mixture was collected for 2 minutes (0.499 mmol, 111.1 mg). The residue was purified by silica gel chromatography (99 / 1 CH 2 Cl 2 / MeOH) allowed to obtain 77 mg of product 5a (70%).

[0266] 1 H NMR (400 MHz, CDCl 3 ,ppm)δ:1.93(d,J=19.4Hz,3H),2.06(s,3H),2.57(m,4H),2.78(dd,J=24.2Hz,J=14.3Hz,1H),2.94(dd,J=14.3Hz,J=14.3Hz,1H),3.42and 3.57(2m,4H). 13 C NMR (100 MHz, CDCl 3 ,ppm)δ:21.7(s,CH 3 ),28.4(d,J=25Hz,CH 3 ),41.9and 46.8(2s,2CH 2 ),54.4and 54.6(s,CH 2 ),67.8(d,J=22Hz,CH2 ), 114.3 (d, J = 243Hz, 1C), 169.3 (s). 19 F{ 1 H}NMR (CDCl 3 ,376MHz,ppm)δ:-98.9.

[0267]

[0268] Route A (starting from compound 5) : 1-(4-(2,2-difluoropropyl)piperazin-1-yl)ethan-1-one 5b was prepared by immersing the mixture in a bath maintained at 0°C for a length of L = 600 cm (t R =274s) was obtained by following the general flow procedure. Adjust 1:1 v / v HF / SbF 5 Super acid mixture (F 1 =0.5 mL / min) and 1-(4-(2-chloroallyl)piperazin-1-yl)ethan-1-one substrate 5 (F 2 =0.25 mL / min, c = 0.499 mol / L) in HF, yielding 12.1 mol% SbF 5 The final acidity was 0.215 mmol, 44.3 mg. The reaction mixture was collected for 2 minutes (0.215 mmol, 44.3 mg). The product was purified by silica gel chromatography (100% CH 2 Cl 2 To 98 / 2CH 2 Cl 2 / MeOH) allowed to obtain 38 mg of product 5b (74%).

[0269] Route B (starting from compound 9) : 1-(4-(2,2-difluoropropyl)piperazin-1-yl)ethan-1-one 5b can alternatively be prepared by using a length L = 400 cm (t R =136s) was obtained by following the general flow procedure. Adjustment 3:1 v / v HF / SbF 5 Super acid mixture (F 1 =0.5 mL / min) and 1-(4-(prop-2-yn-1-yl)piperazin-1-yl)ethan-1-one substrate 9 (F 2 = 0.5 mL / min, c = 0.5 mol / L) in HF, yielding 2.65 mol% SbF 5 The final acidity was 0.50 mmol, 85.8 mg. The reaction mixture was collected for 30 seconds (0.50 mmol, 85.8 mg). The product was purified by silica gel chromatography (100% CH 2 Cl 2 To 98 / 2CH 2 Cl 2Purification by / MeOH allowed the isolation of 73 mg of product 5b (71%).

[0270] 1 H NMR (400 MHz, CDCl 3 , 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 (CDCl 3 , 376 MHz, ppm) δ: -92.2.

[0271]

[0272] 1-(2,2-Difluoropropyl)-4-phenylpiperidine 6a was obtained according to the general flow procedure using a tubular reactor with length L = 200 cm (t R = 2.7 s) immersed in a bath maintained at -40 °C. The flow rates of the 3:1 v / v HF / SbF 5 superacid mixture (F 1 = 0.5 mL / min) and the 4-phenyl-1-(prop-2-yn-1-yl)piperidine substrate 6 (F 2 = 1 mL / min, c = 0.5 mol / L) in HF were adjusted to give a final acidity of 2.41 mol% SbF 5 . The reaction mixture was collected for 30 s (using 0.232 mmol, 46.25 mg). Purification by silica gel chromatography (100% CH 2 Cl 2 to 98 / 2 CH 2 Cl 2 / MeOH) allowed the isolation of 40.7 mg of product 6a (88%).

[0273] 1 H NMR (400 MHz, CDCl 3 , 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, CDCl 3)δ: 146.3, 128.4, 126.8, 126.1, 124.4 (t, J = 239Hz), 63.0 (t, J = 28Hz), 55.5, 42.2, 33.6, 22.0 (t, J = 27Hz). 19 F{ 1 H}NMR (376MHz, CDCl 3 ,ppm)δppm:-92.3.

[0274]

[0275] 1-(2-Fluoroallyl)-4-phenylpiperidine 6b was prepared by immersing the mixture in a bath maintained at -40°C with a length of L = 30 cm (t R =2.3s) was obtained according to the general flow procedure. Adjust 3:1v / vHF / SbF 5 Super acid mixture (F 1 =1 mL / min) and 4-phenyl-1-(prop-2-yn-1-yl)piperidine substrate 6 (F 2 =2mL / min, c=0.48mol / L) in HF, yielding 2.4mol% SbF 5 The final acidity was 0.494 mmol, 90.2 mg. The reaction mixture was collected for 30 seconds (0.494 mmol, 90.2 mg). The product was purified by silica gel chromatography (100% CH 2 Cl 2 to 98 / 2 DCM / MeOH) allowed to obtain 27.3 mg of product 6a (25%).

[0276] 1 H NMR (400 MHz, CDCl 3 ,ppm)δ:1.93-1.80(m,4H,2CH 2 ),2.24-2.09(m,2H),2.58-2.42(m,1H,CH),3.12-3.04(m,2H),3.15(d,J=16.9Hz, 2H), 4.48 (dd, J=49.0, 2.7Hz, 1H), 4.73 (dd, J=16.8, 2.7Hz, 1H), 7.37-7.16 (m, 5H). 13 C NMR (100 MHz, CDCl 3 ,ppm)δ:162.8(Cq,d,J=260.7Hz),146.3(Cq),128.44(CH),126.9(CH),126.2(CH),93.3(d,J=18.7Hz,CF),59.1(d,J=27.6Hz),54.1(CH 2),42.5(CH),33.4(CH 2 ). 19 F{ 1 H}NMR (CDCl 3 ,376MHz,ppm)δ:-98.2. HRMS(ESI):C14H18NFcalcd:219.1423;Found:220.1496[M+H] + .

[0277]

[0278] 1-(4-(3-chloro-3-fluoropropyl)piperazin-1-yl)ethan-1-one 7a was prepared by immersing the mixture in a bath maintained at -20°C with a length L = 400 cm (t R =120.7s) was obtained by following the general flow procedure. Adjust 1:1 v / v HF / SbF 5 Super acid mixture (F 1 =0.5 mL / min) and (Z / E)-1-(4-(3-chloroallyl)piperazin-1-yl)ethan-1-one substrate 7 (F 2 = 0.5 mL / min, c = 0.5 mol / L) in HF, yielding 8.4 mol% SbF 5 The final acidity was 1.004. The reaction mixture was collected for 1 minute (0.271 mmol, 40.4 mg was used). The product was purified by silica gel chromatography (100% CH 2 Cl 2 To 98 / 2CH 2 Cl 2 / MeOH gradient) allowed to obtain 32.5 mg of product 7a (57%).

[0279] 1 H NMR (400 MHz, CDCl 3 ,ppm)δ:2.07(s,3H,CH 3 ),2.24(m,2H,CH 2 ),2.39(m,4H,2CH 2 ),3.65–3.55(m,2H),3.50–3.39(m,2H),2.54(t,J=6.9Hz,2H),6.29(dt,J=50.9,5.5Hz,1H,CHFCl). 19 F{ 1 H}NMR (CDCl 3 ,376MHz,ppm)δ:-117.08.

[0280]

[0281] 1-(4-(3,3-difluoropropyl)piperazin-1-yl)ethan-1-one 7b was prepared by immersing the mixture in a bath maintained at 0°C for a length of L = 600 cm (t R =241s) was obtained by following the general flow procedure. Adjust 1:1 v / v HF / SbF 5 Super acid mixture (F 1 =0.5 mL / min) and (Z / E)-1-(4-(3-chloroallyl)piperazin-1-yl)ethan-1-one substrate 7 (F 2 = 0.25 mL / min, c = 0.5 mol / L) in HF, yielding 12.1 mol% SbF 5 The final acidity was 0.218 mmol, 44.8 mg. The reaction mixture was collected for 2 minutes (0.218 mmol, 44.8 mg). The product was purified by silica gel chromatography (100% CH 2 Cl 2 To 98 / 2CH 2 Cl 2 / MeOH gradient) allowed to isolate 45 mg of product 7b (85%).

[0282] 1 H NMR (400 MHz, CDCl 3 ,ppm)δ:2.05–1.92(m,2H,CH 2 ),2.06(s,3H,CH 3 ),2.41(dt,J=14.7,5.0Hz,4H),2.51(t,J=7.2Hz,2H),3.44(t,J=5.0Hz,2H,CH 2 ),3.59(t,J=5.1Hz,2H,CH 2 ),5.91(tt,J=56.7,J=4.6Hz,1H,CHF 2 ). 13 C NMR (100 MHz, CDCl 3 ,ppm)δ:168.8(C=O),116.2(t,J=238.6Hz,CH),53.1(CH 2 ),52.5(CH 2 ),51.1(t,J=6.3Hz,CH 2 ),46.1(CH 2 ),41.2(CH 2 ),31.5(t,J=21.1Hz,CH 2 ),21.1(CH 3 ). 19 F{ 1H}NMR (CDCl 3 ,376MHz,ppm)δ:-117.1.

[0283]

[0284] N-(2-Fluoropropyl)aniline 8a was prepared by immersing the mixture in a bath maintained at -50°C with a length L = 50 cm (t R =5.0s) was obtained according to the general flow procedure. Adjust 3:1 v / v HF / SbF 5 Super acid mixture (F 1 =1.5 mL / min) and N-allylaniline substrate 8 (F 2 =1.5 mL / min, c = 0.57 mol / L) in HF, yielding 3.74 mol% SbF 5 The final acidity was 0.429 mmol, 53.6 mg. The reaction mixture was collected for 30 seconds (0.429 mmol, 53.6 mg). The product was purified by silica gel chromatography (100% CH 2 Cl 2 To 98 / 2CH 2 Cl 2 / MeOH gradient) allowed to isolate 43 mg of product 8a (66%).

[0285] 1 H NMR (400 MHz, CDCl 3 ,ppm)δ:1.43(dd,J=23.8,6.3Hz,3H,CH 3 ),3.44-3.17(m,2H),5.01–4.77(dm,J=49.56Hz,1H,CH-F),6.64(m,2H,CH ar ), 6.75(tt,J=7.4,1.0Hz,1H),7.24–7.12(m,2H,CH). 19 F{ 1 H}NMR (CDCl 3 ,376MHz,ppm)δ:-179.9.

[0286]

[0287] 3-Methylindoline 8b and 1,2,3,4-tetrahydroquinoline 8c were prepared by immersing the mixture in a bath maintained at 0°C with a length of L = 200 cm (t R =40s) was obtained by following the general flow procedure. Adjust 1:1 v / v HF / SbF 5 Super acid mixture (F 1 =0.5 mL / min) and N-allylaniline substrate 8 (F2 =1.0 mL / min, c = 0.74 mol / L) in HF, yielding 5.2 mol% SbF 5 The final acidity was 0.429 mmol, 53.6 mg. The reaction mixture was collected for 30 seconds (0.429 mmol, 53.6 mg). The product was purified by silica gel chromatography (CH 2 Cl 2 / MeOH gradient) allowed to isolate 31.3 mg of product 8b (37%) and 35.9 mg of product 8c (42%).

[0288] 3-Methylindoline 8b 1 H NMR (400 MHz, CDCl 3 ,ppm)δ:1.33(d,J=6.8Hz,1H),3.12(t,J=8.6Hz,1H),3.45–3.27(m,1H),3.71(t,J=8.6Hz,1H),6.66 (d,J=7.7Hz,1H),6.75(td,J=7.4,0.9Hz,1H),7.04(ddd,J=8.7,2.0,1.0Hz,1H),7.12–7.08(m,1H),

[0289] 1,2,3,4-Tetrahydroquinoline 8c 1 H NMR (400 MHz, CDCl 3 ,ppm)δ:1.95(dtd,J=8.8,6.4,4.2Hz,1H),2.77(t,J=6.4Hz,1H),3.33–3.28(m,1H) ,6.48(d,J=7.9Hz,1H),3.78(s,1H),6.61(td,J=7.4,1.1Hz,1H),7.00–6.89(m,1H).

[0290]

[0291] N-(2-Fluoropropyl)-4-nitroaniline 12b was prepared by immersing the mixture in a bath maintained at 0°C for a length of L = 200 cm (t R =40s) was obtained by following the general flow procedure. Adjust 1:1 v / v HF / SbF 5 Super acid mixture (F 1 =0.5 mL / min) and N-allyl-4-nitroaniline substrate (F 2 =1 mL / min, c = 0.3 mol / L) in HF, yielding 5.1 mol% SbF 5 The final acidity was 1.0447 mg. The reaction mixture was collected for 1 minute and 21 seconds (0.448 mmol, 79.8 mg). The reaction mixture was purified by silica gel chromatography (CH2 Cl 2 / MeOH gradient) allowed to isolate 65 mg of product 12b (73%).

[0292] In the tubular reactor L = 600 cm (t R =241s), F 1 =0.25mL / min and F 2 =0.5 mL / min, the product 12b was obtained in 92% yield.

[0293] 1 H NMR (400 MHz, CDCl 3 ,ppm)δ:1.44(dd,J=23.8,6.3Hz,3H,CH 3 ),3.40(m,2H,CH 2 ),4.79(bs,1H,NH),4.87(dm,J=49.1, 3 J H-H =6.3Hz, CFH), 6.57 (d, J = 9.3Hz, 2-H, CH), 8.09 (d, J = 9.3Hz, 2H, CH). 19 F{ 1 H}NMR (CDCl 3 ,376MHz,ppm)δ:-179.9.

[0294]

[0295] 1-(4-(2-Fluoroallyl)piperazin-1-yl)ethan-1-one 9b was prepared by immersing the mixture in a bath maintained at -40°C with a length L = 30 cm (t R =2s) was obtained according to the general flow procedure. Adjust 5:1v / vHF / SbF 5 Super acid mixture (F 1 =1.5 mL / min) and 1-(4-(prop-2-yn-1-yl)piperazin-1-yl)ethan-1-one substrate 9 (F 2 =3 mL / min, c = 0.5 mol / L) in HF, yielding 1.57 mol% SbF 5 The final acidity was 0.748 mmol, 154.3 mg. The reaction mixture was collected for 30 seconds (0.748 mmol, 154.3 mg). The product was purified by silica gel chromatography (100% CH 2 Cl 2 To 98 / 2CH 2 Cl 2 / MeOH) allowed to isolate 97.9 mg of the product 9b (70%).

[0296] 1 H NMR (400 MHz, CDCl 3 ,ppm)δ:2.09(s,3H,CH 3 ),2.50(m,4H,2CH 2 ),3.11(dd,J=16.5Hz,J=2.7Hz,CH 2 ),3.51(m,2H,CH 2 ),3.65(m,2H,CH 2 ), 4.47 (dt, J = 48.8Hz, J = 2.8Hz, CH), 4.74 (dt, J = 16.6Hz, J = 2.8Hz, CH). 13 C NMR (100 MHz, CDCl 3 ,ppm)δ:41.2(CH 2 ),46.1(CH 2 ),58.4(d,J=Hz,CH 2 ),93.8(CH 2 ), 19 F{ 1 H}NMR (CDCl 3 ,376MHz,ppm)δ:-98.7.HRMS(ESI):C 9 H 15 FN 2 Calculated value for O: 186.1168; Found: 187.1241 [M+H] + .

[0297]

[0298] (4-Fluoro-4-methylpiperidin-1-yl)(4-nitrophenyl)methanone 10a was prepared by immersing the mixture in a bath maintained at 0°C for a length of L = 600 cm (t R =104s) was obtained by following the general flow procedure. Adjust 1:1 v / v HF / SbF 5 Super acid mixture (F 1 =1 mL / min) and N,N-diallyl-4-nitrobenzamide substrate 10 (F 2 =1 mL / min, c = 0.23 mol / L) in HF, yielding 8.4 mol% SbF 5 The reaction mixture was collected for 1 min 53 s (0.353 mmol, 75.7 mg used). Purification by silica gel chromatography (70 / 30 petroleum ether / EtOAc) allowed the isolation of 43.1 mg of the product 10a (46%).

[0299] 1 H NMR (400 MHz, CDCl 3 ,ppm)δ:1.41(d,J=21.4Hz,3H,CH 3 ),1.71(m,4H,2CH 2 ),3.17(m,1H),4.53(m,1H),3.41(m,2H,CH 2 ), 7.56 (d, J = 8.8Hz, 2H, 2CH), 8.27 (d, J = 8.8Hz, 2H, 2CH). 19 F{ 1 H}NMR (CDCl 3 ,376MHz,ppm)δ:-151.7.

[0300]

[0301] 4-Fluoro-4-methyl-1-(4-nitrobenzyl)piperidine 16a was prepared by immersing the mixture in a bath maintained at 0°C for a length of L = 600 cm (t R =104s) was obtained by following the general flow procedure. Adjust 1:1 v / v HF / SbF 5 Super acid mixture (F 1 =1 mL / min) and N-allyl-N-(4-nitrobenzyl)prop-2-en-1-amine substrate 16 (F 2 =1 mL / min, c = 0.34 mol / L) in HF, yielding 8.4 mol% SbF 5 The final acidity was 1.004. The reaction mixture was collected for 1 minute (0.341 mmol, 88.4 mg). The residue was purified by silica gel chromatography (99 / 1 CH 2 Cl 2 / MeOH) allowed to isolate 37 mg of product 16a (47%).

[0302] 1 H NMR (400 MHz, CDCl 3 ,ppm)δ:1.35(d,J=21.6Hz,CH 3 ),1.66and1.85(m,2CH),2.26(m,2CH),2.60(m,2CH),3.62(s,CH 2 ),7.52(d,J=8.8Hz,2CH ar ),8.17(d,J=8.8,2CH ar ). 13 C NMR (100 MHz, CDCl 3 ,ppm)δ:26.9(d,J=24Hz,CH3 ), 36.6 (d, J = 22 Hz, 2CH 2 ), 49.5 (d, J = 1.1 Hz, 2CH 2 ), 62.1 (CH 2 ), 91.9 (d, J = 167 Hz, C-F), 123.5 (2CH), 129.4 (2CH), 146.8 (Cq), 147.1 (Cq). 19 F{ 1 H} NMR (CDCl 3 , 376 MHz, ppm) δ: -151.55. HRMS (ESI): Calculated for C 13 H 18 FN 2 O 2 : 252.1274; found: 253.1346 [M + H] + .

[0303]

[0304] 3-Fluoro-3-methyl-1-(4-nitrobenzyl)piperidine 16b was obtained by following the general flow procedure using a tubular reactor with a length L = 600 cm (t R = 104 s) immersed in a bath maintained at -40 °C. The flow rates of the 1:1 v / v HF / SbF 5 superacid mixture (F 1 = 1 mL / min) and the N-allyl-N-(4-nitrobenzyl)prop-2-en-1-amine substrate 16 (F 2 = 1 mL / min, c = 0.34 mol / L) in HF were adjusted to produce a final acidity of 8.4 mol% SbF 5 . The reaction mixture was collected for 1 minute (using 0.341 mmol, 88.4 mg). It was purified by silica gel chromatography (99 / 1 CH 2 Cl 2 / MeOH), allowing the isolation of 12 mg of 3-fluoro-3-methyl-1-(4-nitrobenzyl)piperidine 16b (35%).

[0305] 1 1H NMR (400 MHz, CDCl 3 , ppm) δ: 1.34 (d, J = 21.6 Hz, CH 3 ), 1.53 (m, 2CH), 1.83 (m, 2CH), 2.22 (m, 2CH), 2.55 (m, 2CH), 3.61 (s, CH 2 ), 7.51 (d, J = 8.8 Hz, 2CHar ),8.16(d,J=8.7Hz,2CH ar ). 13 C NMR (100 MHz, CDCl 3 ,ppm)δ:22.0(d,J=4Hz,CH 2 ),25.0(d,J=24Hz,CH 3 ),35.0(d,J=22.1Hz,CH 2 ),53.1(CH 2 ),61.8(CH 2 ),62.1(d,J=23Hz,CH 2 ), 92.2 (d, J = 170Hz, Cq), 123.5 (2CH), 129.3 (CH), 146.4 (Cq), 147.1 (Cq). 19 F{ 1 H}NMR (CDCl 3 ,376MHz,ppm)δ:-146.8.HRMS(ESI):C 13 H 18 FN 2 O 2 Calculated value: 252.1274; Found: 253.1346 [M+H] + .

[0306]

[0307] Vinflunine 18a was prepared by immersing the sample in a bath maintained at -40°C for a length of L = 600 cm (t R =603s) of the tubular reactor was obtained according to the general flow procedure. The flow rate F 1 = 0.2 or 0.3 mL / min of 2:1 v / v HF / SbF 5 Mixture and F 2 =0.2 or 0.3mL / min of norvinblastine tartrate 18 dissolved in anhydrous chloroform (c=0.03mol / L). The reaction mixture was collected for 10 minutes, allowing the collection of 23mg of a crude residue. NMR and HPLC analysis of the crude mixture allowed the identification of the main amount of vinflunine in a yield of about 3-15% (NMR yield) relative to a standard reference. The crude mixture was purified using C18 reverse phase (ACN / TFA aqueous solution, separating the peak of interest at a 0.2% gradient at 30% ACN), allowing the separation of an enriched fraction (HPLC).

[0308]

[0309] N-(2-fluoropropyl)-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide 19a was prepared by using a dry ice bath with a length of L = 78 cm (t R =7.8s) was obtained according to the general flow procedure. Adjust HF / SbF 5 The flow rate of the superacid mixture and N-allyl-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide 19 (c=0.16 mol / L). The reaction mixture was collected for 30 seconds (0.156 mmol, 65.6 mg was used). Purification by silica gel chromatography (PE / EtOAc gradient from 5% to 30% EtOAc) allowed to obtain 50.2 mg of product 19a (72%).

[0310] 1 H NMR (400 MHz, CDCl 3 ,ppm)δ:1.29(dd,J=23.8,6.3Hz,3H),2.38(s,3H),3.02(m,1H),3.21(m,1H),4.69(dm,J=49.2Hz,1H),5.0 7(bm,1H),6.75(s,1H),7.10(d,J=8.2Hz,1H),7.17(d,J=7.9Hz,1H),7.54–7.43(m,1H),7.91–7.79(m,1H). 13 C NMR (100 MHz, CDCl 3 ,ppm)δ:145.4,144.2(q,J=38.5Hz,CF 3 ),142.7,139.9,139.4,129.87(s),128.8(s),128.1(s),125.7,121.1(q,J=2 69.2Hz, CF), 106.4, 89.8 (s), 88.5, 48.2 (d, J = 21.1Hz, CF), 21.4, 18.2, 18.1. 19 F NMR (CDCl 3 ,376MHz,ppm)δ:-62.42(CF 3 ),-179.9(CF).HRMS(ESI):C 20 H 19 F 4 N 3 O 2 Calculated value of S: 441.1134; Measured value C 20 H 19 F 4 N 3 O 2S442.1206[M+H] + .

[0311]

[0312] 4-Fluoro-4-methyl-1-((4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)sulfonyl)piperidine 20a was prepared by immersing the mixture in an acetone / dry ice bath with a length of L = 400 cm (t R =4.1s) was obtained by following the general flow procedure. Adjustment of HF / SbF 5 The flow rate of the superacid mixture and N-diallyl-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide 20 (c=0.11 mol / L). The reaction mixture was collected for 2 minutes (0.076 mmol, 37 mg were used). Purification by silica gel chromatography (PE / EtOAc gradient from 5% to 30% EtOAc) allowed to obtain 7.2 mg of product 20a (20%).

[0313] 1 H NMR (400 MHz, CDCl 3 ,ppm)δ:7.77(d,J=8.7Hz,1H),7.48(d,J=8.7Hz,1H),7.17(d,J=7.9Hz,1H),7.09(d,J=8.2Hz,1H),6.75(s,1H),3.58–3.2 8(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=21.0Hz,1H). 13 C NMR (100 MHz, CDCl 3 ,ppm)δ:145.4,144.2(q,J=38.5Hz),142.6,139.9,136.7,129.8,128.8,128.7,125.71,122.2,120.1,106.3,90 .5(d,J=175.4Hz), 53.9(d,J=25.7Hz), 45.5, 34.5(d,J=22.6Hz), 24.5(d,J=23.4Hz), 21.4, 21.11(d,J=3.6Hz). 19 F{ 1 H}NMR (CDCl 3 ,376MHz,ppm)δ:-62.44,-150.01.HRMS(ESI):C 23 H24 F 4 N 3 O 2 S[M+H]calcd.: [M+H] 482.151987; found: 482.154140.

[0314]

[0315] N-(2-Fluoroallyl)-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide 21a was immersed in an acetone / dry ice bath with a length of L = 25 cm (t R =4.2s) was obtained according to the general flow procedure. Adjust HF / SbF 5 The flow rate of the superacid mixture and N-(prop-2-yn-1-yl)-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide 21 (c=0.11 mol / L). The reaction mixture was collected for 30 seconds (0.07 mmol, 31 mg was used). Purification by silica gel chromatography (PE / EtOAc-0% to 10% EtOAc) allowed the fluorovinyl compound 21a to be obtained in 29% yield.

[0316] 1 H NMR (400 MHz, CDCl 3 ,ppm)δ:7.85(d,J=8.7Hz,1H),7.47(d,J=8.7Hz,1H),7.17(d,J=8.0Hz,1H),7.10(d,J=8.1Hz,1H),6.74(s,1H),4.77( t, J=6.4Hz, 1H), 4.61 (dd, J=16.2, 3.5Hz, 1H), 4.44 (dd, J=47.9, 3.5Hz, 1H), 3.76 (dd, J=13.1, 6.3Hz, 1H), 2.38 (s, 2H). 13 C NMR (100 MHz, CDCl 3 ,ppm)δ:161.12,159.07,145.26,144.13(q,J=39.0Hz),142.69,139.83,139.36,129.77,128.73, 128.14, 125.67, 125.64, 125.55, 106.38, 93.36 (d, J = 17.4Hz), 43.45 (d, J = 32.6Hz), 29.73, 21.37. 19 F{ 1 H}NMR (CDCl 3,376MHz,ppm)δ:-62.44(s),-104.12–-104.45(m).HRMS(ESI):C 20 H 18 F 4 N 3 O 2 S[M+H] calculated: 440.105037; found: 440.106449.

[0317]

[0318] N-(2,2-difluoropropyl)-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide 21b was prepared by using a length L = 39 cm (t R =2s) in a tubular reactor at low temperature according to the general flow procedure. 5 Flow rate of superacid mixture and N-(prop-2-yn-1-yl)-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide 21. The reaction mixture was collected for 15 seconds (0.118 mmol, 49.5 mg used). Purification by silica gel chromatography (PE / EtOAc gradient) allowed to obtain 47.2 mg of product 21b (86%).

[0319] 1 H NMR (500 MHz, CDCl 3 ,ppm)δ:1.65(t,J=18.6,3H),2.40(s,3H),3.35(td,J=13.0,6.8Hz,2H),5.08(bs,1H) ,6.77(s,1H),7.12(d,J=8.1Hz,2H),7.20(d,J=7.9Hz,2H),7.51(m,2H),7.86(m,2H). 13 C NMR (126 MHz, CDCl 3 ,ppm)δ:145.3,144.1(q,J=38.6Hz,CF 3 ),142.7,139.8,139.2,129.7,128.7,127.9,125.6,125.6,123.3,121.4,121.0(q,J=269.2Hz,CF 2 ), 119.5, 106.4, 106.34 (s, J = 1.4Hz), 48.15 (t, J = 30.9Hz), 29.7, 21.4, 21.3, 21.2, 21.0. 19 F NMR (CDCl 3,376MHz,ppm)δ:-62.4(s),-96.6(m).HRMS(ESI):C 20 H 18 F 5 N 3 O 2 Calculated value of S: 459.1040; C 20 H 19 F 5 N 3 O 2 Measured value of S: 460.1112 [M+H] + .

[0320] Example 2: Comparative Study

[0321] 1) productivity

[0322] The productivity of each reaction is calculated to give the amount of product formed in a given time. The productivity is given relative to the volume of the reactor so that reactors of different sizes or configurations can be compared to each other. Similarly, the productivity of a static reaction volume can be calculated and compared to the reactor volume in flow chemistry at a given time. This is called the productivity expressed in kg.m -3 .h -1 The space-time yield (STY) is calculated.

[0323]

[0324] For example, in the case of compound 1, it can be noted that the mass productivity of the fluorination reaction increased by a factor of 34 from a static method to the process described in the present invention, which is a flow process.

[0325] Table 1

[0326] Static The present invention (flow) Yield (%) 69 75 <![CDATA[Reaction time t in min R > 10 0.14 Reaction volume (mL) 6 0.24 Product m(g) 0.13 0.062 Product n(mmol) 0.689 0.325 Productivity (mmol / min) 0.0698 2.32 Productivity (g / h) 0.78 26.6 <![CDATA[STY(kg.m -3 .h -1 )]]> 130 110714

[0327] The productivity of the static process and the process of the invention for each reaction product was calculated from the data summarized in the following table (Table 2). In general, the process according to the invention is more efficient, especially for reactors with very short residence times (t R <1 min), allowing the mass productivity to be multiplied by a factor of up to 34 relative to a static process.

[0328] As mentioned before, the acidity of the medium is an important parameter. The use of changes in acidity during the flow process has also been investigated, and for several syntheses, SbF 5 The amount of is greatly reduced, while the efficiency of the reaction is improved, and a higher productivity is achieved compared to the static process.

[0329] Table 2

[0330]

[0331]

[0332] i Sébastien Thibaudeau,Agnès Martin-Mingot,Marie-Paule Jouannetaud,Omar Karam,Fabien Zunino Chem.Commun 2007,3198-3200.

[0333] ii Fei Liu,Agnès Martin-Mingot,Marie-Paule Jouannetaud,Fabien Zunino,Sébastien Thibaudeau Org.Lett.2010,12(4),868-871.

[0334] iii Fei Liu,Agnès Martin-Mingot,Marie-Paule Jouannetaud,ChristianBachmann,Gilles Frapper,Fabien Zunino,Sébastien Thibaudeau J.Org.Chem.2011,76,1460-1463.

[0335] iv Cantet,Anne-Céline;Carreyre,Helene;Gesson,Jean-Pierre;Jouannetaud,Marie-Paule;Renoux,Brigitte J.Org.Chem.2008,73(7),2875-2878.

[0336] va) Guillaume Compain, Agnès Martin-Mingot, Gilles Frapper, Christian Bachmann, Marie-Paule Jouannetaud, Sébastien Thibaudeau Chem. Commun., 2012, 48, 5877–5879. b) Guillaume Compain, Céline Bonneau, Agnès Martin-Mingot, Sébastien Thibaudeau J.Org.Chem.2013,78,4463-4472.

[0337] 2) Selectivity

[0338] While applying a super acid reagent to compound 2 in static mode systematically produces only compound 2a, the process of the present invention allows for selectively obtaining compound 2a or 2b by adjusting the residence time and concentration of the super acid reagent.

[0339]

[0340] Additionally, application of a superacid reagent to compound 9 in static mode systematically produces only difluoro compound 5b, whereas the process of the present invention allows selective access to compound 9b or 5b by adjusting the conditions.

[0341]

[0342] In this example, production of the fluorovinyl product 21a of propargylated celecoxib 21 is possible only under the conditions of the present invention, which allows the capture of reaction intermediates that are not accessible under batch conditions, as in the case of 9b.

[0343]

[0344] Application of a superacid reagent to compound 5 in a static mode produces difluoro compound 5b and very difficultly produces compound 5a, whereas use of the process of the present invention allows selectively obtaining compound 5a or 5b by adjusting the conditions.

[0345]

[0346] Finally, the apparatus described in the present invention allows super-electrophilic activation of celecoxib diallyl derivative 20 and allows a tandem cyclization / fluorination reaction to selectively produce compound 20a, which is a pharmaceutically interesting unit, where the process of the present invention requires analysis of such acidity (which cannot be achieved under static conditions). Product 20a cannot be obtained with similar reactions under batch conditions.

[0347]

Claims

1. A process for fluorinating and / or cyclizing aminoolefins or alkynes, include: a) providing a first phase comprising an amino olefin or an alkyne and a second phase comprising a super acid reagent, b) placing the first phase and the second phase in contact in a continuous flow microreactor, and c) recovering the fluorination and / or cyclization product of the aminoalkene or alkyne.

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

3. The process according to claim 1 or 2, It is characterized in that The continuous flow microreactor comprises a micromixer and a tubular tube, wherein the tubular tube preferably has: - a length between 20 cm and 800 cm, and An internal diameter of between 0.5 mm and 2.5 mm, preferably between 0.5 mm and 1.5 mm and better still between 0.7 mm and 1.2 mm.

4. The process according to any one of claims 1 to 3, It is characterized in that The process is carried out in an apparatus comprising: - a storage unit (1) for a first phase comprising an aminoolefin or an alkyne, - a storage unit (1') for a second phase containing a superacid reagent, - a first phase continuous feeding device (3) connected to the first phase storage unit (1) and the first phase balancing tubular pipe (4), - a second phase continuous feeding device (3') connected to the second phase storage unit (1') and the second phase balancing tubular pipe (4'), - a continuous flow microreactor (2) comprising a micromixer (21) comprising two inlets and one outlet, and a tubular tube (22) comprising one inlet and one outlet, wherein the inlet of the tubular tube (22) is connected to the outlet of the micromixer (21), wherein the first phase balancing tubular tube (4) is connected to a first inlet of the micromixer (21), and the second phase balancing tubular tube (4') is connected to a second inlet of the micromixer (21), and - A collecting unit (5) connected to the outlet of the tubular tube (22) of the microreactor (2).

5. The process according to any one of claims 1 to 4, It is characterized in that The superacid reagent is selected from HF / MF 5 and HSO 3 F / MF 5 , wherein M is Sb, As, P, Ta or Nb; preferably, the superacid reagent is HF / SbF 5 .

6. The process according to any one of claims 1 to 5, It is characterized in that The amino alkene or alkyne is allylamine or propargylamine.

7. The process according to claim 6, It is characterized in that The aminoalkene or alkyne is an aminoalkene of formula (Ia): in: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, halogen, C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, C 1 -C 12 Heteroalkyl, C 3 -C 12 Cycloalkyl, C 2 -C 12 Heterocycloalkyl, aryl, heteroaryl, group -S(O) 2 -R 8 and the group -C(O)-R 9 , where R 8 and R 9 Independently selected from C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, C 1 -C 12 Heteroalkyl, C 3 -C 12 Cycloalkyl, C 2 -C 12 Heterocycloalkyl, aryl and heteroaryl, The alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted, or Each selected from R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 The two groups of may alternatively be taken together with the atoms to which they are attached to form an optionally substituted 3 to 12-membered ring.

8. The process according to claim 7, Features: -R 1 and R 2 are independently selected from hydrogen, C 2 -C 12 -alkenyl, aryl [optionally substituted by C 1 -C 6 -alkyl, nitro, or a fluorine-containing group selected from -CF 3 , -OCF 3 , -SCF 3 , -OCF 2 R’, -OCF(R’) 2 , -SCF 2 R’ and -SCF(R’) 2 , where each R’ independently represents hydrogen, halogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl or C 3 -C 6 -cycloalkyl], -S(O) 2 -R 8 and -C(O)-R 9 , where R 8 and R 9 are independently aryl optionally substituted by C 1 -C 6 -alkyl, nitro, or a fluorine-containing group selected from -CF 3 , -OCF 3 , -SCF 3 , -OCF 2 R’, -OCF(R’) 2 , -SCF 2 R’ and -SCF(R’) 2 , where each R’ independently represents 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 a piperidine or piperazine optionally substituted with an aryl or acetyl group, -R 3 and R 4 is hydrogen, and -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.

9. The process according to claim 6, It is characterized in that The aminoalkene or alkyne is an aminoalkyne of formula (Ib): in: R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen, halogen, C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, C 1 -C 12 Heteroalkyl, C 3 -C 12 Cycloalkyl, C 2 -C 12 Heterocycloalkyl, aryl, heteroaryl, group -S(O) 2 -R 8 and the group -C(O)-R 9 , where R 8 and R 9 Independently selected from C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, C 1 -C 12 Heteroalkyl, C 3 -C 12 Cycloalkyl, C 2 -C 12 Heterocycloalkyl, aryl and heteroaryl, The alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted, or Each selected from R 1 , R 2 , R 3 , R 4 and R 5 The two groups of may alternatively be taken together with the atoms to which they are attached to form an optionally substituted 3 to 12-membered ring.

10. The process according to claim 9, Features: -R 1 and R 2 are independently selected from hydrogen, C 2 -C 12 Alkenyl, aryl [optionally C 1 -C 6 Alkyl, nitro or selected from -CF 3 、-OCF 3 、-SCF 3 、-OCF 2 R', -OCF(R') 2 、-SCF 2 R' and -SCF(R') 2 substituted with a fluorinated group, wherein each R' independently represents hydrogen, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl or C 3 -C 6 Cycloalkyl], -S(O) 2 -R 8 and -C(O)-R 9 , where R 8 and R 9 independently is optionally C 1 -C 6 Alkyl, nitro or selected from -CF 3 、-OCF 3 、-SCF 3 、-OCF 2 R', -OCF(R') 2 、-SCF 2 R' and -SCF(R') 2 A fluorinated aromatic group substituted with a fluorinated group, wherein each R' independently represents 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 piperidine or piperazine optionally substituted with aryl or acetyl, and -R 3 , R 4 and R 5 For hydrogen.

11. The process according to claim 6, It is characterized in that The amino olefin or alkyne is selected from:

12. Apparatus for carrying out a process according to any one of claims 1 to 11, It is characterized in that The device comprises: - a storage unit (1) for a first phase comprising an aminoolefin or an alkyne, - a storage unit (1') for a second phase containing a superacid reagent, - a first phase continuous feeding device (3) connected to the first phase storage unit (1) and the first phase balancing tubular pipe (4), - a second phase continuous feeding device (3') connected to the second phase storage unit (1') and the second phase balancing tubular pipe (4'), - a continuous flow microreactor (2) comprising a micromixer (21) comprising two inlets and one outlet, and a tubular tube (22) comprising one inlet and one outlet, wherein the inlet of the tubular tube (22) is connected to the outlet of the micromixer (21), wherein the first phase balancing tubular tube (4) is connected to a first inlet of the micromixer (21), and the second phase balancing tubular tube (4') is connected to a second inlet of the micromixer (21), and - a collecting unit (5) connected to the outlet of the tubular tube (22) of the microreactor (2), The tubular tube (22) of the continuous flow microreactor (2) preferably has: - a length between 20 cm and 800 cm, and - An internal diameter between 0.5 and 2.5 mm and preferably between 0.7 and 1.2 mm.

13. The device according to claim 12, It is characterized in that The device also includes: - a three-way valve (6) providing a connection between the first phase continuous feeding device (3), the first phase storage unit (1) and the first phase balancing tubular pipe (4), and / or - A three-way valve (6') providing connection between the second phase continuous feeding device (3'), the second phase storage unit (1') and the second phase balancing tubular pipe (4').

Images